HK1133190A - Bifeprunox doses for treating schizophrenia - Google Patents

Description

Bifeprunox dosage for treating schizophrenia

The present invention relates to a daily dosage of bifeprunox for treating patients with schizophrenia, to the treatment of patients with stable schizophrenia and patients with acute worsening schizophrenia with bifeprunox, and to pharmaceutical compositions comprising dosages of at least one bifeprunox compound.

Schizophrenia is a life-long disabling psychiatric disorder characterized by severe and variable symptoms, including positive and negative symptoms, cognitive deficits, and depression. The course of the disease can be divided into 4 major stages: pre-, acute, stable/sustained and late course. The pre-morbid stage refers to symptoms that appear before the onset of positive symptoms. During the acute phase, the patient experiences significant positive symptoms such as delusions and hallucinations. The stabilization/maintenance phase can be divided into 2 sub-phases. The first 5-10 years of illness is often characterized by multiple exacerbations of positive symptoms, with more stable periods interspersed between episodes. This sub-phase is followed by a plateau phase characterized by a stabilization of symptoms and a reduction in the number of exacerbations. The key therapeutic goals during the maintenance phase are to promote patient return to society and to establish a long-term maintenance program. In the advanced stages of the disease, positive symptoms tend to diminish with age and many patients with long-term impairment regain some degree of social and occupational competence, however, the age effects of dysfunction are rarely overcome.

In the maintenance and late stages of the course of schizophrenia, most patients continue to face a number of problems, such as the need for further symptomatic improvement and long-term control of psychotic symptoms, including prevention of relapse; maintaining cognitive function; preventing weight gain, hyperglycemia, and dyslipidemia; and improving the quality of life. In addition, positive symptoms may become more resistant to treatment with each subsequent episode. Consistent with this concept, 85% -90% of schizophrenic patients experience clinical exacerbations. Furthermore, at least half of the patients who are administered antipsychotic agents do not follow the prescribed treatment regimen and are therefore at risk for relapse. Thus, despite intense efforts directed to improved treatments, most schizophrenic patients are severely disabled; they frequently relapse and may require hospitalization.

The compounds currently used for the treatment of schizophrenia have been associated with several undesirable side effects. These side effects include weight gain, hyperprolactinemia, elevated triglyceride levels, metabolic syndrome (markers: diabetes, hyperlipidemia, hypertension, and obesity), QTc interval prolongation, glucose abnormalities, and the display of extrapyramidal symptoms. For example, prolonged QTc intervals, i.e. corrected QT intervals in an electrocardiogram, may lead to problematic cardiac rhythms or arrhythmias. Similarly, the weight gain observed with conventional atypical antipsychotics such as risperidone and olanzapine has been accompanied by an increased risk of cardiovascular disease and diabetes.

Furthermore, treatment of schizophrenia with drugs may be over an extended period of time. As such, these undesirable side effects affect patients on a daily basis and in a manner that plays a role in their long-term health. These side effects may also lead to patient non-compliance with the treatment regimen. Even when treatment continues for a limited and/or short duration, side effects can affect the patient's willingness to follow the treatment regimen.

Thus, there is a need for methods for avoiding and/or reducing these undesirable side effects as well as maintaining, reducing and/or improving baseline conditions in patients undergoing treatment for schizophrenia.

The present inventors have found that treatment of schizophrenic patients with a (pharmaceutical composition) dose comprising at least one bifeprunox compound, in particular a daily dose of 20-30mg, enables one or more of these side effects and one or more symptoms of schizophrenia to be reduced and/or avoided. In one embodiment of the invention, the dose is administered once daily. Embodiments of specific doses are 20mg doses and 30mg doses. A daily dose of 20mg is particularly preferred.

Beneficial effects of such treatment include, but are not limited to, a reduction in the patient's total positive and negative symptom scale (PANSS) score, maintenance of body weight, maintenance and/or improvement of triglyceride levels and/or total cholesterol levels, particularly maintenance of clinical stability of schizophrenia in patients with chronic stable schizophrenia (therapeutic effects are e.g. increased time to deterioration), improvement of one or more psychotic symptoms or maintenance and/or reduction of the extrapyramidal signs and symptoms (EPS) profile (profile) similar to baseline measurements prior to administration. A further beneficial effect is a reduced incidence of hyperglycemia and/or one or more diabetes-related adverse events.

In one embodiment of the invention bifeprunox is used for long term treatment of patients with schizophrenia, particularly in daily doses of 20-30 mg. The term "long-term treatment" refers to treatment for at least 3 months or at least 6 months, for example.

The embodiments disclosed herein, while providing some general summaries of the various embodiments of the disclosure, are not intended to limit the scope of the disclosure in any way.

Bifeprunox compounds are described in U.S. Pat. No. 6,225,312 and U.S. Pat. No. 7,030,241, the contents of which are incorporated herein by reference. The hydrochloride salt of this compound (7- [4- ([1, 1' -biphenyl ] -3-ylmethyl) -1-piperazinyl ] -2(3H) -benzoxazolone (bifeprunox)) is described and claimed in WO97/36893, and the monomethanesulfonate salt is described and claimed in WO 02/066449. In the second of these patent publications, the direct formation of monomethanesulfonate salts by reaction between a reactive mesylate of N, N-bis (2-ethanol) -m-phenylbenzylamine and 7-amino-2 (3H) -benzoxazolone is disclosed. Stable polymorphs of bifeprunox monomethanesulfonate are disclosed and claimed in WO 2005/016898. The term "bifeprunox compound" also includes bifeprunox N-oxide. Bifeprunox N-oxide is disclosed and claimed in WO 2007/023141.

Bifeprunox compounds are indicated for the treatment of CNS (central nervous system) disorders including schizophrenia, other psychiatric disorders (in particular psychosis) and parkinson's disease. Within the scope of the present invention, the dosage strength (or dosage) is expressed in an amount equivalent to bifeprunox base. As used herein, the term "bifeprunox base" refers to the compound 7- [4- ([1, 1' -biphenyl ] -3-ylmethyl) -1-pyrazinyl ] -2(3H) -benzoxazolone (INN bifeprunox) having the formula:

as used herein, the term "bifeprunox compound" refers to the active compound 7- [4- ([1, 1' -biphenyl ] -3-ylmethyl) -1-pyrazinyl ] -2(3H) -benzoxazolone, the N-oxides and pharmaceutically acceptable salts thereof, the solvates and hydrates thereof. When an N-oxide is used as the bifeprunox compound, the amount in milligrams is the same amount as that selected by one of skill in the art for a bifeprunox compound that does not contain the oxide. In addition, pharmaceutically acceptable salts of bifeprunox or an N-oxide thereof can be obtained using standard procedures well known in the art, for example, by mixing a compound of the present invention with a suitable acid, such as an inorganic or organic acid.

The present disclosure is directed to the use of bifeprunox in the treatment of schizophrenia by administering to a patient in need thereof a pharmaceutical composition comprising a dose of at least one bifeprunox compound for maintaining, reducing and/or improving a condition associated with the treatment of schizophrenia. For example, the pharmaceutical composition comprises at least one bifeprunox compound in an amount of 5mg to 40mg, such as 10mg to 40mg, or further such as 20mg to 30 mg. In one embodiment, bifeprunox is used to treat a patient with schizophrenia that has weight problems or is prone to weight problems.

One embodiment of the present invention relates to a daily dosage of bifeprunox for treating a patient with schizophrenia, wherein said dosage is 20-30mg of at least one bifeprunox compound. In particular, the doses may be used to maintain clinical stability in patients with stable schizophrenia (more particularly, chronic, stable schizophrenia). The embodiments are a 20mg dose and a 30mg dose, respectively.

In a further embodiment, the present invention relates to a daily dose of bifeprunox for treating a patient having acute worsening schizophrenia, wherein said dose is 20-30mg of at least one bifeprunox compound. The embodiment is to use a dose of 20mg and a dose of 30mg, respectively, in said treatment with advantageous side effects.

One embodiment of the present invention relates to bifeprunox, wherein bifeprunox (i.e. at least one bifeprunox compound) is administered in combination with a lithium mood stabilizer, for the treatment of patients with psychiatric and mood disorders, in particular with schizophrenia, and to kits for said use.

A further embodiment of the present invention relates to bifeprunox for use in the treatment of a patient having a CNS disorder, in particular having schizophrenia, wherein at least one bifeprunox compound is administered in combination with an antidepressant, in particular an SSRI, in particular paroxetine, and to a kit for said use.

Further embodiments of the present invention relate to co-administration of bifeprunox with CYP2C9 inhibitors (e.g., fluconazole), with CYP3a4 inhibitors (e.g., ketoconazole and carbamazepine), with CYP2D6 inhibitors (e.g., paroxetine) and with H2-antagonists (e.g., famotidine), respectively (methods therefor), and to kits for use in such treatment.

In one embodiment of the present disclosure, the at least one bifeprunox compound comprises bifeprunox mesylate. Preferably, the at least one bifeprunox compound is bifeprunox mesylate. The bifeprunox mesylate may be selected from the group consisting of alpha, gamma or delta crystalline polymorphic forms, and mixtures thereof. For example, the at least one bifeprunox compound comprises at least one polymorphic form selected from the group consisting of alpha and gamma polymorphic forms.

The crystalline polymorphic forms of bifeprunox alpha mesylate according to the present disclosure are defined by at least those physicochemical parameters disclosed in WO 2005/016898.

In another embodiment, the present disclosure provides bifeprunox mesylate, wherein at least about 50 weight percent (wt.%), at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 90 wt.%, or at least about 95 wt.% of bifeprunox mesylate is in the polymorphic alpha form. In another embodiment, the pharmaceutical composition is substantially free of any gamma or delta polymorphic forms of bifeprunox mesylate. In another embodiment, bifeprunox mesylate provided by the present disclosure comprises less than 10 wt.%, less than 5 wt.%, or less than 2.5 wt.% of bifeprunox mesylate in its gamma or delta polymorphic form. In another embodiment, at least about 99 wt.% of the bifeprunox mesylate is in the polymorphic alpha form.

The preparation of polymorphic form a can be carried out according to the procedure described in WO 2005/016898.

The at least one bifeprunox compound according to the present disclosure may be formulated by methods known in the art into dosage forms wherein the active substance is present in solid form. Examples of such dosage forms are (optionally coated) tablets, capsules, granulated aerosols (granulaerosols), suppositories and suspensions. Such dosage forms may be prepared by mixing the at least one bifeprunox compound with inert pharmaceutically acceptable excipients and carriers.

The pharmaceutical compositions of the present disclosure may include at least one pharmaceutical excipient. Non-limiting examples of suitable excipients include suspending agents (e.g., gums, xanthan gum, cellulose, and sugar), humectants (e.g., sorbitol), solubilizing agents (e.g., ethanol, water, PEG, and propylene glycol), surfactants (e.g., sodium lauryl sulfate, span, tween, and cetyl pyridine), preservatives, antioxidants (e.g., parabens and vitamins E and C), anti-caking agents, coating agents, chelating agents (e.g., EDTA), stabilizers, antimicrobials, antifungal or antibacterial agents (e.g., parabens, chlorobutanol, phenol, sorbic acid), isotonic agents (e.g., sugar, sodium chloride), thickening agents (e.g., methyl cellulose), flavoring agents (e.g., chocolate, thaltin, aspartame, mannitol, root beer (rober), or watermelon or other flavorings stable at pH 7-9), Antifoams (e.g. simethicone, and the like),) Disintegrating agent, flow assistant, lubricant, adjuvant, pigmentColorants, diluents, wetting agents, preservatives, carriers, binders (e.g., hydroxypropylmethyl cellulose, polyvinylpyrrolidone, other cellulosic materials, and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate, and cellulosic materials), disintegrants (e.g., starch polymers and cellulosic materials), glidants, and water-insoluble or water-soluble lubricants or lubricating agents.

In addition to the milled and sieved active (as described herein for bifeprunox) dose, one illustrative dosage form comprises lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (e.g., type a), sodium stearyl fumarate, and optionally anhydrous colloidal silicon dioxide. In one embodiment, the lactose is present in an amount of about 20% to about 90% by weight, about 70% to about 90% by weight, or about 75% to about 85% by weight, based on the total weight of the tablet core. The microcrystalline cellulose is present in an amount of about 5 wt% to about 90 wt%, about 10 wt% to about 15 wt%, or about 11 wt% to about 12 wt%, based on the total weight of the tablet core. Sodium starch glycolate (e.g., type a) is present in an amount of about 0.1% to about 2.5% by weight, about 0.3% to about 0.7% by weight, or about 0.5% by weight, based on the total weight of the tablet core. Sodium stearyl fumarate is present in an amount of about 0.1 wt% to about 1.5 wt%, about 0.6 wt% to about 1.3 wt%, or about 1.0 wt%, based on the total weight of the tablet core. Anhydrous colloidal silica is optionally added to the formulation in order to improve the flow characteristics of the powder. If desired, the anhydrous colloidal silica is typically present in an amount of about 0.05% to about 0.5% by weight, or about 0.4% by weight, based on the total weight of the tablet core. The amount of the optional coating is from about 2.0 wt% to about 5.0 wt%, from about 3.0 wt% to about 4.0 wt%, or about 3.5 wt%, based on the total weight of the tablet core.

In at least one embodiment, a pharmaceutical composition comprising at least one bifeprunox compound according to the present disclosure can be administered to a subject in need thereof, e.g., a human subject.

The present disclosure also aims, but is not limited to, reducing the patient's PANSS total score, maintaining body weight, maintaining and/or improving triglyceride levels and/or total cholesterol levels, maintaining clinical stability of schizophrenia, improving one or more psychotic symptoms or maintaining an EPS profile similar to baseline measurements prior to administration. The present disclosure is also directed to methods for reducing the incidence of hyperglycemia and/or diabetes-related adverse events. These methods are exemplified in the following clinical examples provided below.

U.S. patent application nos. 10/920,361, 10/920,386, and 11/354,652 are hereby incorporated by reference in their entirety. All data herein should be understood as approximate and subject to normal measurement errors depending on e.g. the device used and other parameters affecting the peak position and peak intensity. The phrase "about," as used herein, unless otherwise specifically limited or unless the context requires otherwise, generally refers to a mean plus or minus 5% of the stated value.

Brief Description of Drawings

Figure 1 shows PANSS positive scores (FAS, LOCF) for group 34.

Figure 2 shows the PANSS negative score (FAS, LOCF) for group 35.

Figure 3 shows PANSS general psychopathology scores (FAS, LOCF) for group 36.

Figure 4 shows the proportion of patients (FAS, LOCF) in group 42 with a reduction in total PANSS score of at least 25%.

FIG. 5 shows the proportion of patients (FAS, LOCF) in group 43 having a CGI-I score of 2 or less.

Examples

The following examples are intended only to further illustrate the present disclosure in more detail and therefore are not to be construed as limiting the scope of the present disclosure in any way. Example 1 efficacy of bifeprunox in the treatment of schizophrenia

A 6-week, randomized, double-blind, placebo-controlled, and risperidone-referenced study was used to evaluate the efficacy and safety of fixed-dose bifeprunox in treating schizophrenia. A total of 599 subjects were randomly picked.

Treatment began with a single-blind placebo run-in period of at least 3 days, followed by a dose escalation of bifeprunox from 0.25mg up to 30 mg/day or 40 mg/day for bifeprunox-treated subjects. Risperidone treated subjects were titrated up daily from 2mg to 6mg over a period of 3 days and maintained at 6 mg/day for the remainder of the treatment period.

Except for week 5, a rating scale assessment was performed once per week to measure the change in PANSS total score from baseline to endpoint. Other evaluations include: a PANSS positive symptom subtotal score, a PANSS negative symptom subtotal score, a PANSS general psychopathology subtotal score, a BPRS total score, a BPRS psychosis score, a CGI-S score, a CGI-I score, a responder ratio based on a PANSS total score, and the Calgary Depression Scale for Schizophrenia, CDSS.

Safety and tolerability measurements include physical examination, body weight, waist circumference, vital signs, 12-lead Electrocardiogram (ECG), clinical laboratory assessments (hematology, biochemistry, urinalysis, special laboratory assessments on prolactin, IGF-1, IGFBP-3, thyroid function), need for anticholinergic medication during double-blind treatment sessions, concomitant drug use, monitoring of adverse events, and assessment of normal movements.

For the primary endpoint change from baseline to endpoint in PANSS total score, the 20mg bifeprunox treated group showed statistically significant differences from placebo. The mean change (standard deviation) from baseline to endpoint for the PANSS total score was-13.5 (20.1) for the 30mg bifeprunox group, -10.3(20.5) for the 40mg bifeprunox group, -7.7(19.2) for the placebo group, and-19.7 (19.3) for the risperidone group.

The 30mg bifeprunox group showed significant differences from placebo for CGI-S score, PANSS negative symptom subtotal score, and PANSS positive symptom subtotal score. Significant differences were also observed between the 30mg bifeprunox group and placebo for PANSS general psychopathology subscale scores, BPRS total scores, BPRS psychotic group (psychicalsuster) scores, PANSS responder rates and CGI-I responder rates changes from baseline to endpoint. In this study, PANSS responders refer to subjects whose PANSS total score decreases by 20% or more from baseline to endpoint. CGI-I responders refer to subjects who were classified as "having very much improvement" or "having much improvement" on the CGI global improvement scale at the end point.

The 40mg bifeprunox group showed significant differences from placebo for changes in the PANSS positive symptom subtotal score and the BPRS psychiatric population score.

Weight loss was seen in the bifeprunox-treated group as opposed to the increase in the placebo and risperidone-treated groups.

The bifeprunox group had a lower incidence in N-to-H conversion of triglycerides, VLDL and LDL and a higher incidence in N-to-L conversion of total cholesterol and VLDL compared to the placebo and risperidone groups.

Example 2 clinical study of bifeprunox aimed at treatment of schizophrenia

Example 2a clinical study 1

Purpose(s) to: the primary objective of this clinical study was to study whether treatment with 5mg, 10mg or 20mg bifeprunox for 6 weeks in adult subjects with schizophrenia was superior to treatment with placebo by using the change in total score from baseline to endpoint of the Positive and Negative Symptom Scale (PANSS) as a primary outcome measure. Secondary objectives are to use the positive symptom subtotal score of PANSS, the negative symptom subtotal score of PANSS, the general psychopathological subtotal score of PANSS, the concise one derived from PANSSThe efficacy of bifeprunox in the treatment of schizophrenia was evaluated by the gross Psychiatric Rating Scale (BPRS) score, the BPRS psychosis derived from PANSS, the Clinical Global impression Severity score of the disease (CGI-S), the Clinical Global impression improvement score (CGI-I), and the responder rate and CGI-I responder rate based on the total PANSS score. Another objective of this study was to evaluate the safety and tolerability of bifeprunox using physical examination, body weight, vital signs (including pulse rate and systolic/diastolic Blood Pressure (BP) -both lying for 5 minutes and standing for 2 minutes, and oral temperature), 12-lead Electrocardiogram (ECG), safety laboratory assessments (including hematology, biochemistry and urinalysis), need for anticholinergic treatment during the double-blind treatment period, concomitant drug use, monitoring of adverse events and assessment of abnormal movements (including Simpson-Angus Scale, SAS), Barnes Akathisia Scale (BAS) and Abnormal Involuntary Movement Scale (AIMS)).

Method: this is a randomized, double-blind, fixed dose, placebo-controlled, risperidone-referenced, parallel-group, multicenter study in adult subjects with schizophrenia. There were 5 treatment groups in this study. The treatment groups were as follows: bifeprunox 5

mg, bifeprunox 10mg, bifeprunox 20mg, risperidone 6mg, and placebo. Study drug was administered once daily. After baseline measurements were taken, an up-dosing phase was initiated. Bifeprunox-treated subjects were titrated up to 5mg, 10mg, or 20mg according to a standardized titration schedule (day 1: 0.125mg, day 2: 0.25mg, day 3: 0.5mg, day 4: 1.0mg, day 5: 2.0mg, day 6: 5.0mg, day 7: 10.0mg, day 8: 20 mg). When the indicated dose was reached, the subject remained at that dose for the remainder of the 6-week treatment period. Using a once daily schedule, risperidone treated subjects were titrated up to 6mg over 3 days (day 1: 2mg, day 2: 4mg, day 3: 6 mg).

Number of subjects (planned, screened, randomized and analyzed): a total of 575 schizophrenic patients were included in the study. A total of 836 subjects were screened at 40 centers, and a total of 589 subjects (5mg bifeprunox: 115 subjects; 10mg bifeprunox: 120 subjects; 20mg bifeprunox: 115 subjects; placebo: 119 subjects; risperidone: 120 subjects) were randomized at 37 centers.

Test product, dosage and mode of administration: bifeprunox tablets, with a total daily dose of 0.125mg-20mg, are administered orally using a once-a-day dosing regimen.

Reference therapy, dosage and mode of administration: placebo and risperidone, 2mg-6mg, were administered orally using a once-a-day dosing schedule.

Efficacy results: as shown by statistically significant comparisons from PANSS sum sub-scale score analysis, the 20mg bifeprunox dose was effective in reducing the positive and negative symptoms of schizophrenia as well as alleviating general psychopathology compared to placebo. The total PANSS score in the 20mg bifeprunox group was a greater 5.8 point improvement from baseline than in placebo subjects. Bifeprunox at lower doses was not effective. Bifeprunox at the 10mg dose did not show statistically significant improvement for any efficacy endpoint. The 5mg dose showed greater improvement in some secondary efficacy measures compared to placebo, but did not show an improvement over placebo for the primary efficacy endpoint (PANSS total score). Risperidone 6mg was used as an activity reference in this study and was shown to be clearly separated from the placebo group. In general, the degree of improvement seen in the 20mg bifeprunox group is less than those seen in the risperidone group for most of the efficacy endpoints.

Safety results: has the following advantagesThe percentage of subjects with a prominent adverse event (TEAE) in the least one treatment was similar between treatment groups: 89% (102 subjects) in the 5mg bifeprunox group, 87% (104 subjects) in the 10mg bifeprunox group, 83% (95 subjects) in the 20mg bifeprunox group, 85% (101 subjects) in the placebo group, and 89% (107 subjects) in the risperidone group. Overall, of 349 subjects treated with bifeprunox, the most frequently reported TEAEs were headache, dyspepsia, insomnia, nausea, vomiting NOS, constipation and agitation. TEAEs with higher incidence (difference of > 5%) in the 20mg bifeprunox group (114 subjects) compared to the placebo group (119 subjects) included constipation, dyspepsia and vomiting NOS. The associated TEAEs with higher incidence (difference of > 5%) in the 20mg bifeprunox group compared to placebo were constipation, vomiting NOS and headache NOS. The percentage of subjects with at least one severe TEAE was lowest in the 20mg bifeprunox group (11 subjects, 10%), followed by the placebo group (15 subjects, 13%). For the remaining groups, the percentage of subjects with at least one severe TEAE was 16% -18%. For all TEAEs, the incidence of TEAEs considered severe was similar between the 20mg bifeprunox group and the placebo group (< 5% difference). There was no dose-related trend in the bifeprunox group in the overall incidence of TEAEs, incidence of related TEAEs, or incidence of severe TEAEs observed for any event.

The total number of subjects with at least one SAE was higher in the active treatment group compared to the placebo group (9%) (bifeprunox group: 12-15%, risperidone group: 16%). The most commonly reported SAEs (> 5% in any treatment group) are the aggravated psychosis and the aggravated schizophrenia NOS. The incidence of exacerbated schizophrenia NOS was slightly higher in the 20mg bifeprunox group (8 subjects, 7%) compared to placebo and risperidone (5 subjects each, 4%). There were 1 subject (< 1%) in the 10mg bifeprunox group, 2 subjects (2%) in the 20mg bifeprunox group, no subjects in the placebo group, and no subjects in the risperidone group reported suicide attempts. Severe adverse events of suicidal ideation were reported in 1 subject (< 1%) each in the 10mg bifeprunox and risperidone groups (1 additional subject experienced a non-severe adverse event of suicidal ideation in the 20mg bifeprunox group). No dose-related increase trend in the incidence of any SAE was observed for the bifeprunox group. Bifeprunox is safe and well tolerated at all dosage levels. The total number of subjects with at least one AE leading to cessation was similar in the treatment group (5mg bifeprunox: 13 subjects, 11%; 10mg bifeprunox: 17 subjects, 14%; 20mg bifeprunox: 11 subjects, 10%; placebo: 15 subjects, 13%; risperidone: 17 subjects, 14%). The most common (reported by > 2% of subjects in any treatment group) AEs that lead to discontinuation are agonism, exacerbated psychosis, and exacerbated schizophrenia NOS. There were no treatment group differences between the 20mg bifeprunox group and the placebo group in the incidence of AE s that led to discontinuation of study drug therapy. There was no trend of dose-related increases in the incidence of AEs leading to discontinuation in the bifeprunox group. Laboratory assessments, vital signs, ECG and physical examination results did not raise any unexpected safety concerns. Bifeprunox subjects showed a decrease in prolactin compared to the placebo group. Slight weight loss was observed in the bifeprunox group but not in the placebo or risperidone group.

There were no significant differences between treatment groups in the change from baseline to endpoint in BAS, SAS or AIMS scores. The use of anticholinergic drugs for patients treated with bifeprunox was similar to patients with placebo and less than for patients with risperidone.

Conclusion: the conclusion of this study is that bifeprunox administered once daily at a dose of 20mg over 6 weeks is effective in reducing both positive and negative symptoms of schizophrenia. Overall, bifeprunox at all doses was safe and well tolerated by schizophrenic subjects. No dose-response relationship was seen for safety/tolerability.

Example 2b clinical study 2

Primary purpose: to investigate whether treatment with a fixed dose of bifeprunox (30 mg/day or 40 mg/day) for 6 weeks could show better efficacy compared to placebo in adult schizophrenic subjects by using as primary result the change from baseline to endpoint of the total score of the positive and negative symptoms scale (PANSS).

Secondary purpose: in order to evaluate the efficacy of bifeprunox in treating schizophrenia using a positive symptom scale score of PANSS, a negative symptom scale score of PANSS, a general psychopathology sub-scale of PANSS, a concise psychosis rating scale (BPRS) overall score derived from PANSS, a BPRS psychosis score derived from PANSS, a clinical global impression severity score of the disease (CGI-S), a clinical global impression improvement score (CGI-I), a responder rate based on the PANSS overall score, a kalgarian depression scale (CDSS), and a subject satisfaction rating. Bifeprunox Pharmacokinetic (PK) data in schizophrenic subjects was also evaluated and presented in a separate report (combined with data from study S1543003). To use physical examination, body weight, waist circumference, vital signs (pulse rate and systolic/diastolic blood pressure [ BP ]]Both lying for 5 minutes and standing for 2 minutes, and oral temperature), 12-lead Electrocardiogram (ECG), clinical laboratory assessments (hematology, biochemistry, urinalysis, specific laboratory assessments on prolactin, IGF-1, IGFBP-3 and thyroid function), need for anticholinergic treatment during double-blind treatment period, concomitant drug use, monitoring of Adverse Events (AE) and assessment of abnormal movements including simpson-angus scale (SAS), barnst akathist disability scale (BAS) and Abnormal Involuntary Movement Scale (AIMS), to assess the safety and tolerability of bifeprunox.

Method: this is phase III, 6-week randomized, double-blind, placebo-controlled, risperidone-referenced, parallel-group, multi-media in adult subjects with schizophreniaStudy of efficacy, tolerability and safety of cardiac bifeprunox. The subjects who completed this study had long-lasting options. The treatment groups were: bifeprunox 30 mg/day, bifeprunox 40 mg/day, risperidone 6 mg/day, and placebo. Following completion of the single-blind placebo run-in period of at least 3 days, bifeprunox-treated subjects were titrated from 0.25mg up to 30 mg/day or 40 mg/day over a period of 8 days according to a standardized titration schedule. When the indicated dose was reached, the subject remained at that dose for the remainder of the 6-week treatment period. Risperidone treated subjects were titrated up from 2mg to 6mg daily over a period of 3 days and then maintained at 6 mg/day for the remainder of the treatment period. Rating scale assessments for efficacy and abnormal movement disorders were performed once a week except week 5. Safety assessments were performed at screening, during treatment, and at the end of the study. Subject satisfaction with study drug therapy was assessed at week 6. Blood samples were obtained at weeks 2, 4 and 6 for determination of bifeprunox in plasma. Blood samples were also obtained at screening/baseline, week 3 and week 6 for clinical laboratory evaluation.

Number of subjects (planned, consented, randomized and analyzed): a total of 576 subjects with schizophrenia were planned to be included in this study. Of the 783 screened subjects, a total of 599 subjects were randomized (30mg bifeprunox: 148 subjects; 40mg bifeprunox: 148 subjects; placebo: 149 subjects; risperidone: 154 subjects).

Diagnosis and Primary inclusion criteria: male or female subjects 18-75 years old with schizophrenia (according to DSM-IV-TR criteria). The subject must have a PANSS total score of 70-120; at least 2 of the 4 PANSS projects (concept disorder), hallucinations behavior, suspiciousness, unusual thought content) must have a score ≧ 4; and the CGI-S score must be at least 4.

Reference therapy, dosage and mode of administration: placebo and risperidone, 6mg,administered orally once daily.

Efficacy results: based on Hochberg adjusted p-value (adjusted p ═ 0.020), the 30mg bifeprunox treated group showed statistically significant differences compared to placebo for primary end point change from baseline to end point in the PANS total score (LOCF). For the primary efficacy endpoint, the 40mg bifeprunox treated group did not differ significantly from the placebo group (adjusted p 0.156). The mean change (standard deviation) from baseline to endpoint for the PANSS total score was-13.5 (20.1) for the 30mg bifeprunox group, -10.3(20.5) for the 40mg bifeprunox group, -7.7(19.2) for the placebo group, and-19.7 (19.3) for the risperidone group. Treatment effect values corresponding to differences between bifeprunox and placebo (for mean change from baseline to endpoint [ LOCF)]): -5.9 for the 30mg bifeprunox group and-3.2 for the 40mg bifeprunox group. Compared to placebo, no statistically significant difference in the program-based degradation program was seen in CGI-S change from baseline to endpoint for the 30mg bifeprunox treated group. Thus, using a statistically significant degradation program for comparison with placebo, no difference between placebo and the 30mg bifeprunox group was evaluated for changes in the PANSS negative and PANSS positive subscale scores from baseline to endpoint. The 30mg bifeprunox group showed significant differences from placebo for CGI-S score (nominal p 0.028), PANSS negative symptom subtotal score (nominal p 0.027) and PANSS positive symptom subtotal score (nominal p 0.010).

Significant differences were observed between the 30mg bifeprunox group and placebo for changes from baseline to endpoint in the PANSS general psychopathology sub-scale score (p 0.025), the BPRS total score (p 0.019), the BPRS psychosis group score (p 0.002), the PANSS (30%) responder ratio (p 0.019), and the CGI-I responder ratio (p 0.039). No significant difference at the end point was observed between the 30mg bifeprunox group and placebo for subject satisfaction (p ═ 0.051), CGI improvement score, or CDSS score. For the 40mg bifeprunox group, no statistically significant difference from placebo was seen for the primary efficacy parameters. For any of the secondary efficacy parameters, no significant difference from placebo was noted for the 40mg bifeprunox group, except for the PANSS positive symptom subtotal score (p 0.020) and the BPRS psychosis group score (p 0.031).

Safety results: the percentage of subjects with at least one TEAE was comparable in the bifeprunox dose group (74% -76%) and higher than the placebo group (64%) but slightly lower than the risperidone group (78%). Treatment with higher incidence of AEs in the bifeprunox group compared to the placebo group (> 5% difference) included nausea, vomiting, constipation, dyspepsia, diarrhea, and dizziness. No differences between the bifeprunox-treated groups were generally observed in the incidence of individual TEAEs in the bifeprunox group. Of the TEAE s occurring in at least 5% of subjects in any treatment group, those TEAE s with a higher incidence (difference of ≧ 2%) in the 40mg bifeprunox group compared to the 30mg bifeprunox group included nausea, vomiting, dental pain, anorexia, akathisia, dizziness, headache, and insomnia. In contrast, dry mouth, hypersalivation, anorexia, sedation, somnolence, anxiety and vaginitis appeared with a higher incidence (≧ 2% difference) in the 30mg bifeprunox group compared to the 40mg bifeprunox group. The incidence of severe TEAEs was generally very low (< 1%) with the exception of TEAEs for psychiatric disorders (< 6%) and schizophrenia (3% in bifeprunox and placebo groups, respectively, and 2% in risperidone groups). The incidence of severe TEAEs was generally comparable between treatment groups, and there was no difference between bifeprunox treatment groups in the incidence of severe TEAEs for any event. TEAEs of particular interest were defined prior to database lock-in and included events associated with suicide, suicide attempts, sexual dysfunction, syncope, vasovagal attacks, and postural hypotension. Overall, a total of 76 subjects (13%) reported at least one TEAE of particular interest during the course of the study. The percentage of subjects with at least one TEAE of particular interest was higher in the bifeprunox and risperidone treated groups (12% -16%) compared to the placebo group (6%). Most of the TEAEs of particular interest are inLess than 1% of subjects in which treatment group appeared. Vertigo was most commonly reported and occurred at a slightly higher incidence in the bifeprunox-treated group than in the other two groups.

In total, a total of 60 subjects (10%) experienced 81 SAEs (including deaths). Most SAEs occur in ≦ 1% of subjects. The exceptions are psychiatric disorders (< 5%) and schizophrenia (3% in each of the 4 treatment groups). The incidence of SAEs was comparable in the bifeprunox group and placebo. There were no significant differences between treatment groups with respect to the measurement of abnormal movement (BAS, SAS or AIMS score). The use of anticholinergic medication for subjects treated with bifeprunox is similar to subjects treated with placebo. Overall, there were no clinically meaningful changes in clinical laboratory parameters, physical examination results, or ECG readings for bifeprunox. The bifeprunox group had a lower incidence in N-to-H conversion of triglycerides, VLDL and LDL and a higher incidence in N-to-L conversion of total cholesterol and VLDL compared to the placebo and risperidone groups. The incidence of apparently abnormal total cholesterol values was similar (1% -2%) between treatment groups. Subjects reporting significantly abnormal triglyceride values in the 40mg bifeprunox group were slightly less compared to the other groups. The incidence of N-to-H conversion of triiodothyronine was slightly greater in the 30mg bifeprunox and risperidone groups (6% each) compared to the placebo (4%) and 40mg bifeprunox (5%) groups, and the incidence of N-to-L conversion of TSH was slightly greater in the 30mg bifeprunox (4%) and 40mg bifeprunox (5%) groups compared to the placebo (2%) and risperidone (< 1%) groups. In contrast to the increase in the placebo and risperidone treated groups, a small and comparable weight loss was seen in the bifeprunox treated group. The incidence of significantly abnormal weight loss was slightly higher in the 2 bifeprunox-treated groups relative to the placebo and risperidone groups, and slightly higher in the risperidone-treated groups relative to the bifeprunox and placebo groups.

Conclusion: one conclusion of this study is, e.g., fromStatistically significant comparisons of the PANSS total score analysis showed that bifeprunox administered once daily at a dose of 30mg over 6 weeks was effective in reducing the symptoms of schizophrenia. Based on LOCF data, subjects in the 30mg bifeprunox group had a 5.9 point greater improvement in PANSS overall score from baseline to endpoint compared to placebo subjects. This was confirmed by the statistically significant differences noted between active control risperidone and placebo treatment for the primary and secondary efficacy parameters.

For 3 key secondary efficacy endpoints, i.e., change from baseline to endpoint in CGI-S, PANSS negative and positive symptom subscale scores, the 30mg bifeprunox treated group showed significant differences from placebo (based on nominal p-value); no statistical significance was achieved based on the descending program for these 3 key secondary efficacy endpoints. For most other secondary efficacy parameters (PANSS general psychopathology subscale score, BPRS total score, and BPRS psychotic population score changes from baseline to endpoint), a significant difference was observed at endpoint between the 30mg bifeprunox treated group and placebo. Significant differences were also demonstrated at the end point between the 30mg bifeprunox dose and placebo for PANSS and CGI-I responder rates. The 40mg bifeprunox treated group showed no statistically significant difference from placebo for the primary efficacy parameter. For any of the secondary efficacy parameters, there was no significant difference between the 40mg bifeprunox and placebo groups, except for the PANSS positive symptom sub-dose table and the BPRS cluster (cluster) score. Overall, bifeprunox at both the 30mg and 40mg doses was safe and well tolerated by subjects with schizophrenia.

Example 2 c: clinical study 3

Primary purpose: to investigate whether treatment with a fixed dose of bifeprunox (20 mg/day or 30 mg/day) for 6 weeks could show better efficacy compared to placebo in adult schizophrenic subjects by using as primary result the change from baseline to endpoint of the total score of the positive and negative symptoms scale (PANSS).

Secondary purpose: the efficacy of bifeprunox in treating schizophrenia is evaluated for use of a positive symptom subtotal score for PANSS, a negative symptom subtotal score for PANSS, a general psychopathology subtotal for PANSS, a concise psychosis rating scale (BPRS) overall score derived from PANSS, a BPRS psychosis score derived from PANSS, a clinical global impression severity score for disease (CGI-S), a clinical global impression improvement score (CGI-I), a CGI-I responder rate, a PANSS responder rate based on a PANSS overall score, a catarrhal schizophrenia depression scale (CDSS), and a subject satisfaction rating. To use physical examination, body weight, waist circumference, vital signs (pulse rate and systolic/diastolic blood pressure [ BP ]]And oral temperature), 12-lead Electrocardiogram (ECG), clinical laboratory assessments (hematology, biochemistry (including fasting insulin levels, fasting glucose, fasting lipid profile), urinalysis, specific laboratory assessments regarding prolactin, IGF-1, IGFBP-3, and thyroid function), need for anticholinergic therapy during double-blind treatment sessions, concomitant drug use, monitoring of Adverse Events (AE), and assessment of abnormal movement (including simpson-angs scale (SAS), barth sedentary disability scale (BAS), and Abnormal Involuntary Movement Scale (AIMS)), to assess the safety and tolerability of bifeprunox.

Method: this is a phase III, 6-week randomized, double-blind, placebo-controlled, olanzapine-referenced, parallel group, multicenter bifeprunox efficacy, tolerability and safety study in adult subjects with schizophrenia. There were 4 treatment fractions in this study, approximately 144 subjects/fraction. The treatment groups were: bifeprunox 20 mg/day, bifeprunox 30 mg/day, olanzapine 15 mg/day and placebo. After completion of the single-blind placebo run-in period of at least 3 days, bifeprunox-treated subjects were titrated from 0.25mg up to 20 mg/day or 30 mg/day over a period of 7 or 8 days, respectively, according to a standardized titration schedule. When the indicated dose was reached, the subject remained at that dose for the remainder of the 6-week treatment period. OlanzapineThe treated subjects began dosing at 10 mg/day for the initial 7 day period and were then maintained at 15 mg/day for the remainder of the treatment period. Subjects were hospitalized (if not already hospitalized) after qualifying for study entry, starting from the screening visit until at least 10 days after baseline. The subject may be hospitalized for more than 10 days if the investigator deems medically necessary. Rating scale assessments for efficacy and abnormal movement disorders were performed once a week except week 5. Safety assessments were performed at screening, during treatment, and at the end of the study. Subject satisfaction with study drug therapy was assessed at week 6. Whole blood samples were obtained at weeks 2, 4 and 6 for determination of bifeprunox in plasma.

Number of subjects (planned, consented, randomized and analyzed): a total of 576 schizophrenic subjects were planned to be included in the study. A total of 814 subjects were screened at 32 centers, and a total of 604 subjects (20mg bifeprunox: 154 subjects; 30mg bifeprunox: 150 subjects; placebo: 150 subjects; olanzapine: 150 subjects) were randomized at 32 centers.

Diagnosis and Primary inclusion criteria: male or female subjects 18-75 years old with schizophrenia (according to DSM-IV-TR criteria). The subject must have a PANSS total score of 70-120; at least 2 of the 4 PANSS projects (concept disorder, hallucinations behavior, suspicion, unusual thought content) must have a score of ≧ 4; and the CGI-S score must be at least 4.

Test product, dosage and mode of administration: bifeprunox tablets, total daily dose 20mg or 30mg (1 tablet of 20mg tablets and 1 tablet of 10mg tablets), are administered orally using a once-daily dosing regimen.

Reference therapy, dosage and mode of administration: placebo and olanzapine, 5mg and 15mg, were administered orally using a once daily dosing schedule.

Efficacy results: then is turned onFor both primary and key secondary efficacy parameters, both the 20mg and 30mg treatment groups showed an improvement over baseline at the end point, but did not demonstrate efficacy compared to the placebo group. However, in the secondary efficacy parameter CGI improvement score, the 20mg bifeprunox group showed significant improvement over the placebo group with respect to change from baseline to endpoint (nominal p 0.027). In addition, in one other secondary efficacy parameter, the difference between the 20mg bifeprunox group and the placebo group was nearly significant with respect to the PANSS-20% -responder ratio (p ═ 0.061). However, these significant and nearly significant differences in secondary efficacy parameters did not appear to exceed the expected incidental differences, i.e., in the 5% treatment comparison. None of the bifeprunox-treated groups showed significant improvement over the placebo group for any end point of efficacy in all other secondary and key secondary parameters. Olanzapine at a dose of 15mg was used as an activity reference in this study. The PANSS total score difference between olanzapine and placebo was analyzed according to a sensitivity analysis. These results show that olanzapine is significantly different from placebo (p < 0.001). Generally, for most end points of efficacy, the degree of improvement seen in the bifeprunox dose group was higher than those seen in the placebo group, but lower than those seen in the olanzapine group.

Safety results: the percentage of subjects with at least one Treatment Emergent Adverse Event (TEAE) was highest in the 20mg bifeprunox group (126 subjects, 82%), followed by 30mg bifeprunox (115 subjects, 77%), olanzapine (110 subjects, 73%) and placebo (107 subjects, 72%). Overall, of the 304 subjects treated with bifeprunox, the most frequently reported TEAEs were headache, nausea, vomiting, dyspepsia and insomnia. TEAEs with higher incidence (difference of ≧ 5%) in the bifeprunox group compared to the placebo group included nausea, vomiting, and constipation. In general, no significant dose-related increase in the incidence of individual TEAEs was observed in the bifeprunox group. TEAEs with slightly higher incidence (≧ 2% difference) in the 30mg bifeprunox group compared to the 20mg bifeprunox group included fatigueDizziness, and sedation. The percentage of subjects with at least one severe TEAE was comparable in the bifeprunox-treated group and the placebo group (9% -12%) and slightly lower in the olanzapine-treated group (6%). There was no clear indication of a dose-related increase in the incidence of severe TEAEs in the bifeprunox group for any event. TEAEs of particular interest are defined prior to database locking and include the following events: suicide, suicide attempts, events associated with sexual dysfunction, syncope, vagal vascular attacks, and postural hypotension. In total, a total of 58 subjects (10%) reported at least one TEAE of particular interest during the course of the study. The total number of subjects with at least one TEAE of particular interest was higher in the bifeprunox-treated group (30mg bifeprunox: 20 subjects, 13%; 20mg bifeprunox: 17 subjects, 11%) compared to the placebo (11 subjects, 7%) or olanzapine (10 subjects, 7%) groups. Most of the TEAEs of particular interest appeared in ≦ 1% of subjects in any treatment group. The most commonly reported TEAE of particular interest was vertigo, which had a slightly higher incidence in the bifeprunox-treated group than in the other two groups (30mg bifeprunox: 15 subjects, 10%; 20mg bifeprunox: 13 subjects, 8%; placebo: 9 subjects, 6%; olanzapine: 8 subjects, 5%). Other TEAEs of particular interest that appeared in at least 2 subjects within the treatment group included vasovagal syncope (30mg bifeprunox: 2 subjects) and orthostatic hypotension (30mg bifeprunox: 3 subjects).

The percentage of subjects with at least one SAE was lowest in the olanzapine treated group (6 subjects, 4%), followed by the bifeprunox group (20 mg: 15 subjects, 10%; 30 mg: 12 subjects, 8%), while the highest incidence of SAE was noted in the placebo group (20 subjects, 13%). The most commonly reported SAEs are psychiatric disorders (4% of subjects in total) and schizophrenia (2% in total). The incidence of these SAEs was similar or lower in the bifeprunox group compared to the placebo group. The 2 subjects in the 30mg bifeprunox group had SAEs for vasovagal syncope compared to no subjects in the other treatment groups. With this possible exception, there were no other significant indications of dose-related increases in the incidence of any other SAEs observed for the bifeprunox group. The percentage of subjects who discontinued study drug therapy due to AE was greatest in the placebo group (11%), followed by the bifeprunox group (8% each) and the olanzapine treated group (6%). The percentage of subjects with at least one AE leading to study termination was greatest in the placebo group (12%), while the percentage of subjects with at least one AE leading to study termination was comparable in the 20mg bifeprunox (8%), 30mg bifeprunox (7%) and olanzapine (6%) treatment groups. The most common (reported by > 2% of subjects in any treatment group) AEs that lead to discontinuation of study drug therapy are psychiatric disorders and schizophrenia. In the bifeprunox group, there was no clear dose-related increasing trend in the incidence of AE s that led to discontinuation of study drug therapy. Laboratory assessments, vital signs, and ECG results did not raise any unexpected safety concerns. The subjects in the bifeprunox group showed a reduction in prolactin compared to subjects in the placebo and olanzapine groups. The incidence of markedly abnormal weight loss was comparable in the bifeprunox-treated and placebo groups (5% -6%) and lower in the olanzapine-treated group (< 1%). The incidence of significant abnormal weight gain was comparable in the bifeprunox and placebo groups (1% -3%) and much higher in the olanzapine group (19%). There were no significant differences between treatment groups in the change in BAS, SAS or AIMS scores from baseline to endpoint. The use of anticholinergic drugs for subjects treated with bifeprunox was similar to subjects using placebo.

Discussion and conclusions: this was a 6-week, randomized, double-blind, fixed-dose, placebo-controlled, parallel-group, multicenter study on bifeprunox efficacy, tolerability, and safety in the treatment of 604 subjects with schizophrenia using olanzapine as the active reference. The study was performed in 32 centers in the united states (26), colombia (3) and india (5).

The results showing statistically significant differences between active control olanzapine and placebo treatment for the primary efficacy parameter demonstrate that this is an effective study.

Both the 20mg and 30mg treatment groups showed an improvement over baseline at the end point in terms of primary and key secondary efficacy parameters, but did not demonstrate efficacy compared to the placebo group. However, in the secondary efficacy parameter CG I improvement score, the 20mg bifeprunox group showed significant improvement over the placebo group with respect to change from baseline to endpoint (nominal p ═ 0.027). In addition, in one other secondary efficacy parameter, the difference between the 20mg bifeprunox group and the placebo group was nearly significant with respect to the PANSS-20% -responder ratio (p ═ 0.061). However, these significant and nearly significant differences in secondary efficacy parameters did not appear to exceed the expected incidental differences, i.e., in the 5% treatment comparison. None of the bifeprunox-treated groups showed significant improvement over the placebo group for any end point of efficacy in all other secondary and key secondary parameters.

Olanzapine at a dose of 15mg was used as an activity reference in this study. Generally, for most end points of efficacy, the degree of improvement seen in the bifeprunox dose group was higher than those seen in the placebo group, but lower than those seen in the olanzapine group.

In contrast, in the large study of clinical study 1, the 20mg bifeprunox dose was effective in reducing the positive and negative symptoms of schizophrenia and alleviating general psychopathology compared to placebo, as shown by statistically significant comparisons from analysis of PANSS total and sub-scale scores.

In this study, the results were more similar between the 20mg bifeprunox (-24.42[15.6]), 30mg bifeprunox (-24.56[17.02]) and olanzapine (-29.11[16.88]) groups using the analysis of the values observed in the change from baseline to week 6 for the total PANSS score, however, the placebo group also showed similar results (-22.29[19.14 ]). This indicates that subjects staying in the study for 6 weeks responded well to their treatment regimen.

Bifeprunox is well tolerated at both dosage levels. The rate of withdrawal due to adverse events was lower in the bifeprunox group compared to the placebo group. Adverse events that appear to be more frequent in bifeprunox-treated subjects than in placebo subjects are actually predominantly gastrointestinal and range in severity from mild to moderate. Only 2 subjects (in the 20mg bifeprunox group) stopped study drug therapy due to gastrointestinal AEs (1 subject stopped due to nausea, 1 subject stopped due to nausea and vomiting). The percentage of subjects with at least one SAE in the bifeprunox group was lower (7% -8%) compared to the placebo group (13%). The most commonly reported SAEs are psychiatric disorders (4% in total) and schizophrenia (1% in total). The incidence of these SAEs was similar or lower in the bifeprunox group compared to the placebo group. The 2 subjects in the 30mg bifeprunox group had SAEs for vasovagal syncope compared to no subjects in the other treatment groups. With this possible exception, there were no other significant indications of dose-related increases in the incidence of any other SAEs for the bifeprunox group.

Laboratory assessments, vital signs, and ECG results did not raise any unexpected safety concerns. Bifeprunox is associated with a reduction in prolactin, and not with any AEs, consistent with what has been seen in previous studies and expected from the drug-based partial dopamine agonist profile. In contrast, an increase in prolactin was observed in the placebo and olanzapine groups.

A small decrease in mean body weight was noted in the bifeprunox group, while an increase in body weight was noted for the olanzapine group. The incidence of markedly abnormal weight loss was comparable (5% -6%) in the bifeprunox-treated group and placebo group and lower (< 1%) in the olanzapine-treated group. The incidence of significant abnormal weight gain was comparable in the bifeprunox and placebo groups (1% -3%) and much higher in the olanzapine group (19%). These findings are consistent with and significant from those observed in other bifeprunox studies, assuming that weight gain is problematic for atypical antipsychotics and is associated with increased risk of cardiovascular disease and diabetes.

There were no significant differences between treatment groups with respect to the measurement of abnormal movement (BAS, SAS or a IMS score). The use of anticholinergic medication for subjects treated with bifeprunox is similar to subjects using placebo. The incidence of extrapyramidal disorders was low in all groups (bifeprunox group: < 1% -3%; olanzapine: 1%; placebo: 3%). For most of the efficacy endpoints, the 20mg and 30mg doses of bifeprunox did not show statistically significant greater improvement compared to placebo. Better CGI improvement scores were seen in the 20mg (rather than 30mg) bifeprunox group compared to the placebo group.

Nausea, vomiting and constipation were more significant AEs relative to placebo. Overall, bifeprunox at the 20mg and 30mg doses was safe and well tolerated by schizophrenic subjects.

Example 2d clinical study 4

Primary purpose: to investigate whether treatment with bifeprunox for 6 months in chronic schizophrenia patients outperformed treatment with placebo by using the time required for exacerbations from randomization as a primary measure.

Secondary purpose: to investigate whether the acute effect after 6 weeks of treatment with bifeprunox is superior to treatment with placebo by using as a measure the change from baseline in the total score of the positive and negative symptom scale (PANSS).

Other subsidiary objects: to evaluate the long-term safety and tolerability of bifeprunox compared to placebo.

Method: the study was a multinational, multicenter, randomized, double-blind, parallel groupPlacebo-controlled, fixed dose study. The study consisted of a 3-6 day trial run period without anti-psychotic drug, after which patients were randomized to 6 month double-blind treatment with fixed doses of bifeprunox (20 mg/day (BX20) or 30 mg/day (BX 30)) or Placebo (PBO). Patients assigned to the BX group were titrated up from 0.25 mg/day over 7 days (BX20) or 8 days (BX30) and then continued on these doses for the remainder of the study period. Efficacy assessments were performed at baseline (except CGI-I), as well as at weeks 1, 2, 4,6, and 9, and at months 3, 4, 5, and 6. Safety assessments were performed at screening, during treatment and at the end of the study. At predetermined time points, blood samples were obtained for drug concentration analysis of BX and its major metabolites (3 '-and 4' -sulfate conjugates of BX) and for pharmacoeconomical evaluation.

Number of patients planned and analyzed: there were a total of 495 patient plans to participate: 165 in each treatment group.

Diagnosis and Primary inclusion criteria: patients with schizophrenia for more than 2 years were preliminarily diagnosed according to the DSM-IV-TR criteria: have a PANSS total score of ≧ 60 and a CGI-S score of ≧ 4 at screening and baseline (moderate disease); PANSS program P7 (hostile) and G8 (uncooperative) scores at screening and baseline of ≦ 4 (moderate); 18-65 years old (inclusive); is an inpatient, a partially hospitalized or an outpatient followed up in a day care procedure over a 90 day period; and no change in antipsychotic therapy was made within 1 month prior to screening.

Study product, dosage and mode of administration, lot number: bifeprunox-an ascending dose of 7(20mg) or 8 days (30mg) once a day increasing to 20 or 30 mg; encapsulated tablets, for oral administration.

Reference therapy, dosage and mode of administration: placebo-encapsulated tablets, oral.

Efficacy results: the primary efficacy variable is the time required for deterioration, and the analysis is based onFAS. The primary efficacy analysis excluded the assumption that the time required for schizophrenia to worsen was equal in the 3 treatment groups (Cox model, p ═ 0.008). Subsequent pairwise comparisons of each BX and PBO groups showed that patients in the BX group had a statistically significantly longer time to worsening schizophrenia than patients in the PBO group (BX 20: p ═ 0.008, and BX 30: p ═ 0.006). The proportion of patients with exacerbations was 59% in the PBO group, 41% in the BX20 group, and 38% in the BX30 group. The Cox proportional hazards model yields estimated hazard ratios of 0.66(BX20) and 0.65(BX30) relative to PBO; that is, the risk of deterioration is about 1.5 times greater for patients in the PBO group than for patients in the BX20 or BX30 group. Bifeprunox is also statistically significantly superior to PBO in the time-to-deterioration analysis based on PPS. Since most patients in PPS participated in the majority of the study, the results were very close to those of the primary analysis for the estimated risk ratio and the obtained p-value. This illustrates the robustness of the primary efficacy analysis conclusions. The secondary efficacy variable was the PANSS total score at week 6. The change in the PANSS total score (FAS, LOCF) from baseline to week 6 adjusted mean values for each BX group (BX 20: -4.0; BX 30: -2.7) was statistically significantly greater than for PBO group (1.1) (BX 20: p ═ 0.002; BX 30: p ═ 0.017) according to the Hochberg's ascending method.

The same general pattern is seen for progression over time in PANSS total score, PANSS positive and general psychopathology subscale score, BPRS total score, and BPRS psychosis group score (all FAS, LOCF): initially (until week 6 or 9), the mean scores decreased, then they stabilized in the 2 BX groups, while in the PBO group, the mean scores dropped until week 2 or 4, after which the scores steadily increased. For each of these variables, locf (ancova) was used to show that treatment with BX (either dose) was generally statistically significantly superior to treatment with PBO from week 6 or 9 onwards for FAS in pairwise comparisons of each BX group to PBO group.

The mean PANSS negative subscale score (FAS, LOCF) decreased in the 2 BX groups until week 6, after which the score stabilized. In the PBO group, the score decreased until week 4, after which the score tended to increase. In per-visit (per-visit) LOCF analysis (FAS, ANCOVA) of the mean PANSS negative sub-scale score, the treatment with the 2 BX doses was statistically significantly better than the treatment with PBO at all time points except weeks 2 and 4 for the BX30 group.

The mean CDSS total score (FAS, LOCF) initially decreased (baseline to week 2) for all treatment groups, after which the score remained stable (2 BX groups) or increased (PBO group) over time. There were no statistically significant differences between any BX group and PBO group at any time point in each visit LOCF analysis (FAS, ANCOVA) of the mean CDSS total score. This result should be seen where the baseline CDSS score is low, reflecting low levels of depression symptoms.

The mean CGI-S score (FAS, LOCF) decreased in the 2 BX groups until week 6, after which the score stabilized. In the PBO group, the average CGI-S score decreased until week 4, after which the score tended to increase. In the LOCF analysis per visit (FAS, ANCOVA) of the mean CGI-S score, the BX group was statistically significantly better than the PBO group at months 3, 4, 5, and 6 for BX20 and at months 5 and 6 for BX 30.

The mean CGI-I score (FAS, LOCF) decreased in the 2 BX groups until week 6, after which the score stabilized. In the PBO group, the score decreased minimally until week 2, after which the score increased steadily. In each visit LOCF analysis (FAS, ANCOVA) of the mean CGI-I score, the 2 BX doses were statistically significantly better than PBO from week 6 onwards.

For a few patients (PBO: 25 patients; BX 20: 32 patients; BX 30: 36 patients) who met the criteria for primary negative symptoms (predominantly negative symptoms), the mean change from baseline adjusted in the total PANSS score (all groups) and in the PANSS positive sub-scale score (PBO and BX20) generally followed the same pattern and was within the same range as for the total population. Conversely, for patients treated with BX30, the adjusted mean change from baseline in the PANSS positive subscale score followed the same pattern as the total population over time, but the change was greater. The mean change from baseline adjusted in PANSS negative sub-scale score (all groups) followed the same pattern as the total population over time; however, the mean value in this population typically varies by a factor of 2 relative to the total population. There was no statistically significant difference between BX20 and PBO at any time point in each visit LOCF analysis (ANCOVA) of PANSS total score, PANSS positive subtotal score, and PANSS negative subtotal score. BX30 was statistically significantly better than PBO from week 6 onwards in the PANSS total score and 2 onwards in the PANSS positive subscale score, while BX30 was not statistically significantly different from PBO from week 2 onwards in the PANSS negative subscale score.

For a minority of patients who met the criteria for symptoms of major depression (PBO: 18 patients; BX 20: 15 patients; BX 30: 22 patients), the PANSS total score, PANSS positive subtotal score, PANSS negative subtotal score, and CDSS total score generally followed a similar overall pattern as the total population. In the LOCF analysis per visit (ANCOVA) of PANSS total score, PANSS positive subtotal score, PANSS negative subtotal score and CDSS total score, there was no statistically significant difference between any BX group and the PBO group at any time point in this subgroup, probably due to the small number of patients and the low level of depressive symptoms presented at baseline.

From week 9 onwards, the proportion of patients with a reduction in PANSS total score (FAS, LOCF) of at least 25% in the BX20 group was statistically significantly greater than in the PBO group, while the proportion of responders in the BX30 group was statistically significantly greater than in the PBO group only at month 5.

A small proportion (0% -8%) of patients (regardless of treatment) had reductions in PANSS total score of ≥ 35%, ≥ 45%, or ≥ 55%. There was no trend between or among treatment groups with respect to the distribution of patient ratios with a specific reduction.

At week 6 and month 6, the proportion of patients with CGI-I score ≦ 2(FAS, LOCF) was greater in the BX group (week 6: BX 2017%, BX 3019%, month 6: BX 2022%, BX 3020%) than in the PBO group (week 6: 11%, month 6: 9%). The difference between the BX and PBO groups was statistically significant (p < 0.05) from week 9 onwards (BX20) and from week 9 onwards except month 3 (BX 30).

Regardless of treatment and fasting/non-fasting conditions, the calculated mean total cholesterol and mean LDL decreased from baseline to month 6 in all groups (except non-fasting PBO patients). Regardless of treatment and fasting/non-fasting conditions, the calculated mean VLDL and triglycerides decreased from baseline to month 6 in all groups (except non-fasting BX30 patients). Mean HDL increased from baseline to month 6 in all groups regardless of treatment and fasting/non-fasting conditions. The adjusted mean HDL cholesterol values increased from baseline to month 6 in all 3 treatment groups regardless of fasting/non-fasting conditions (PBO: 0.04/0.06 (fasting/non-fasting); BX 20: 0.07/0.08; BX 30: 0.07/0.08 mmol/L). There were no statistically significant differences between any of the BX and PBO groups.

The adjusted mean triglyceride values decreased from baseline to month 6 in all 3 treatment groups regardless of fasting/non-fasting conditions (PBO: -0.06/-0.22 (fasting/non-fasting); BX 20: -0.16/-0.21; BX 30: -0.37/-0.03 mmol/L). There was no statistically significant difference between any of the BX groups (except BX30 (fasted)) and the PBO group.

The adjusted mean fasting glucose values increased from baseline to month 6 in all 3 treatment groups (PBO: 0.10; BX 20: 0.13; BX 30: 0.09 mmol/L). There were no statistically significant differences between any of the BX and PBO groups.

The adjusted mean body weight change from baseline to month 6(APTS, OC, ANCOVA) was-0.8 kg in the PBO group, -0.3kg in the BX20 group, and-0.5 kg in the BX30 group. The adjusted mean body weight loss in the BX20 and BX30 groups was not statistically significantly different from that in the PBO group.

In all treatment groups, patients lost weight regardless of whether they had nausea and/or vomiting, although those who also had nausea and/or vomiting had a greater weight loss (PBO: -0.6 vs. -1.9 kg; BX 20: -1.0 vs. -1.9 kg; BX 30: -1.1 vs. -2.3 kg).

During this study BX (either dose) had no therapeutic effect on the metabolic syndrome status of the patients. Approximately 75% (range: 70% -80%) of the patients had no metabolic syndrome at baseline or at the end of the study. There were no statistically significant treatment differences in the metabolic syndrome status of the patients.

There were no clinically relevant changes within the treatment groups or differences between treatment groups in clinical laboratory assessments, vital signs, metabolic syndrome or ECG parameters.

Conclusion: one conclusion of this study was that the 2 bifeprunox doses (20 mg/day and 30 mg/day) could prevent schizophrenia exacerbation statistically significantly better than placebo. For patients with chronic, stable schizophrenia, baseline conditions were maintained significantly better with BX (both doses) than with PBO after 6 weeks of treatment or after chronic treatment. A comparison of the safety profiles of bifeprunox and placebo shows that the incidence of adverse events related to gastrointestinal system and vertigo is higher in the bifeprunox group relative to the placebo group. The incidence of nausea and vomiting and abnormal movements leading to withdrawal from the study was higher in the BX30 group than in the BX20 group. A favorable metabolic profile (based on body weight changes, blood lipids and presence/absence of metabolic syndrome) was seen for bifeprunox.

Results associated with clinical Studies 1-4

PANSS Total score

Clinical study 1: the mean change in PANSS total score from baseline to endpoint (s.d.) was-9.7 (17.5) for the bifeprunox 5mg group, -5.0(18.3) for the bifeprunox 10mg group, -11.3(17.0) for the bifeprunox 20mg group, -5.3(16.3) for the placebo group, and-15.7 (14.9) for the risperidone group.The therapeutic effect value (LOCF) corresponding to the change between mean bifeprunox and placebo values from baseline to endpoint was-4.1, 0.6 and-5.8 for the bifeprunox 5mg, 10mg and 20mg groups, respectively. According to the pairwise comparison, a statistically significantly greater reduction (LOCF) at the end point was seen for the 20mg bifeprunox group compared to placebo (p-value adjusted for multiple comparisons, 0.031). No significant treatment group differences were seen for the 5mg bifeprunox and 10mg bifeprunox treatment groups compared to placebo, respectively.

Change in PANSS Total score from baseline

Last observation at each visit

(Last Observation Carried Forward)

Intent-to-Treat (Intent-to-Treat) populations

Note: statistically significant after adjustments for multiple comparisons with total type I error of 0.0499 using the descending Dunnett's program. The P-value for the placebo preference was adjusted to 1.000. Confidence intervals were also obtained following the descending Dunnett's program.

Note: pairwise comparisons to placebo were based on the ANCOVA model, using treatment (excluding risperidone) and pooled centers as fixed factors and baseline PANSS total score as co-variable (covariate).

Note: in the bifeprunox 20mg group, no PANSS score was recorded at week 1 or 2 for subject 11259.

Clinical study 2: the mean change (SD) from baseline to endpoint for the PANSS total score was-13.5 (20.1) for the 30mg bifeprunox group, -10.3(20.5) for the 40mg bifeprunox group, -7.7(19.2) for the placebo group, and-19.7 (19.3) for the risperidone group (as illustrated in the table below). Treatment effect values corresponding to differences between bifeprunox and placebo (for mean change from baseline to endpoint [ LOCF)]) -5.9 for the 30mg bifeprunox group and-3.2 for the 40mg bifeprunox group. Based on the Hochberg adjusted p-value (p ═ 0.020), statistically significant treatment group differences were seen at the end point for the 30mg bifeprunox treated group compared to the placebo group. According to the nominal (nominal) p-value (p.ltoreq.0.004 at each of weeks 2 to 4), differences between the 30mg bifeprunox and placebo-treated groups at weeks 2 to 4 were also noted. In addition, the therapeutic effect consistently increased in the 6 week study (range of effect: at week 2-5.6 and at week 4-6.3; Table 3.0.1). Based on Hochberg adjusted p-values, there was clearly no statistically significant difference between the 40mg bifeprunox group and the placebo group at the end point.

Change in PANSS Total score from baseline

Last observation at each visit

Intent-to-treat population

Significant at the 0.050 level according to the Hochberg procedure.

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding risperidone) and pooled centers as fixed factors and baseline PANSS total scores as co-variables.

Note: significance at week 6/end point for multiple comparisons was assessed according to the Hochberg procedure.

Note: the P-values presented for weeks 1 to 4 are for descriptive purposes only.

Trt is therapeutic and Adj is modulated.

The data source is as follows: table 3.0.0, table 3.0.1.

Clinical study 3: the mean change (SD) from baseline to endpoint for the PANSS total score was-13.8 (19.9) for the 20mg bifeprunox group, -13.1(20.2) for the 30mg bifeprunox group, -10.7(19.4) for the placebo group, and-22.0 (18.2) for the olanzapine group (table 15). Treatment effect values corresponding to differences between bifeprunox and placebo (for mean change from baseline to endpoint [ LOCF)]) -3.5 for the 20mg bifeprunox group and-2.2 for the 30mg bifeprunox group. Based on Hochberg adjusted p-values, no statistically significant treatment group differences were seen for the 20mg or 30mg bifeprunox treated groups compared to the placebo group. Similarly, no significant difference was observed between the placebo and any of the 2 bifeprunox dose groups at any other time point during the course of the study (weeks 1 to 4). When analyzing data only for those subjects with the same raters for each visit, the difference in mean change (SD) from baseline to endpoint for PANSS total score (LOCF) was similar to those observed in the primary analysis. The PANSS total score difference between olanzapine and placebo was analyzed according to a sensitivity analysis. These results show that olanzapine is significantly different from placebo (p < 0.001).

Change in PANSS Total score from baseline

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding olanzapine) and pooled centers as fixed factors and baseline PANSS total scores as co-variables.

Note: significance at week 6/end point for multiple comparisons was assessed according to the Hochberg procedure.

Note: the P-values and CIs presented for weeks 1 to 4 and the original P-values at week 6/end point are for descriptive purposes only.

Olanzapine was excluded from the statistical comparison of the treatment groups, as data from this treatment group was only considered in the supportive analysis.

Trt is therapeutic and Adj is modulated.

The data source is as follows: table 3.0.0, table 3.0.1.

Clinical study 4: the adjusted mean change in PANSS overall score from baseline to week 6 was statistically significantly greater for each BX group (BX 20: -4.0, and BX 30: -2.7) than for the PBO (1.1) group (BX 20: p ═ 0.002; BX 30: p ═ 0.017).

PANSS positivity

Clinical study 1: the table below presents the mean PANSS positive subtotal score at baseline and the mean change from baseline obtained by visit and use of LOCF for ITT population. The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-1.1, 0.7 and-1.5 for the bifeprunox 5mg, 10mg and 20mg groups, respectively. A statistically significantly greater reduction at endpoint (LOCF) was seen in the PANSS positive subtotal score for the comparison of the therapeutic effect estimates for the bifeprunox 20mg group and placebo (unadjusted p ═ 0.037).

Change from baseline in PANSS positive subscale score

Last observation at each visit

Intent-to-treat population

Significant at the 0.050 level.

Note: pairwise comparisons to placebo were based on the ANCOVA model using treatment (excluding risperidone) and pooled centers as fixed factors and baseline PANSS positive subscale scores as co-variables.

Note: in the bifeprunox 20mg group, no PANSS score was recorded at week 1 or 2 for subject 11259.

The data source is as follows: table 3.1.0.

For the analysis of the observed values of the change from baseline, a trend similar to PANSS total score was seen in the change from baseline in the PANSS positive subtotal score in the bifeprunox treated group over time. Pairwise comparisons between bifeprunox and placebo groups were not statistically significant.

Clinical study 2: the table below presents the PANSS positive symptom subtotal scores at baseline and the changes from baseline obtained by visit and use of LOCF for the ITT population. The mean change in PANSS positive symptom scale score from baseline to endpoint (SD) was-4.5 for the 30mg bifeprunox group (6.6), 4.2 for the 40mg bifeprunox group (6.9), 2.5 for the placebo group (6.0), and 7.2 for the risperidone group (6.6). The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-1.9 for the 30mg bifeprunox group and-1.7 for the 40mg bifeprunox group. SEP1 produced no significant results, so SEP2 and SEP3 were not evaluated (see section 7.4.1.1). However, a significant difference between bifeprunox 30mg treatment group and placebo was observed at endpoint (nominal p 0.01). Significant differences between the 30mg bifeprunox and placebo treated groups were also observed from week 2 to week 4 (p.ltoreq.0.006).

Similarly, a significant difference between bifeprunox 40mg treated and placebo was observed at endpoint (p 0.020). Differences relative to placebo (p.ltoreq.0.013) were also observed from week 1 to week 3.

Change from baseline in PANSS Positive symptom Scale score

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding risperidone) and center as fixed factors and baseline PANSS positive symptom scale scores as co-variables.

Note: the P-values presented for weeks 1 to 4 are for descriptive purposes only.

Trt ═ treatment.

The data source is as follows: table 3.0.0, table 3.1.0.

Clinical study 3: the table below presents the PANSS positive symptom subtotal scores at baseline and the changes from baseline obtained by visit and use of LOCF for the ITT population. The mean change in passs positive symptom scale score from baseline to endpoint (SD) was-4.3 for the 20mg bifeprunox group (6.1), -4.2 for the 30mg bifeprunox group (6.8), -3.5 for the placebo group (6.2), and-7.0 for the olanzapine group (5.8). The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-1.1 for the 20mg bifeprunox group and-0.7 for the 30mg bifeprunox group. No difference between the placebo and either bifeprunox dose groups was observed at week 6/endpoint or at any other time point during the course of the study (week 1 to week 4), nominal p-value (< 0.05).

Change from baseline in PANSS Positive symptom Scale score

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding olanzapine) and pooled centers as fixed factors and a baseline PANSS positive symptom scale score as a co-variable.

Note: significance at week 6/end point for multiple comparisons was assessed according to the hochberg procedure.

Note: the P-values and CIs presented for weeks 1 to 4 and week 6/end point are for descriptive purposes only.

Trt ═ treatment.

The data source is as follows: table 3.0.0, table 3.1.0.

Clinical study 4: the mean PANSS positive subtotal score (FAS, LOCF) decreased over time in the 2 BX groups until week 9, after which the score increased minimally. In the PBO group, the mean PANSS total score decreased until week 2, after which the score steadily increased (FIG. 1; group 34). Treatment with BX20 or BX30 was statistically significantly better than treatment with PBO from week 6 onwards in each visit LOCF analysis (FAS, ANCOVA) of the PANSS positive subscale score.

PANSS negativity

Clinical study 1: the table below presents the average PANSS negative sub-scale score at baseline and the average change from baseline obtained by visit and use of LOCF for ITT population. Bifeprunox 5mg, bifeprunox 20mg and risperidone 6mThe g group showed the greatest improvement over time. Estimates of therapeutic effect at end-point LOCF (bifeprunox-placebo) were-1.0, -0.3, and-1.4 for the bifeprunox 5mg, 10mg, and 20mg groups, respectively. A statistically significantly greater reduction in the PANSS negative subtotal score was seen at week 3 (unadjusted p 0.013) and point of termination (LOCF) (unadjusted p 0.026) for the bifeprunox 20mg group compared to placebo.

Change from baseline in PANSS negative subtotal score

Last observation at each visit

Intent-to-treat population

Significant at the 0.050 level.

Note: pairwise comparisons to placebo were based on the ANCOVA model using treatment (excluding risperidone) and pooled centers as fixed factors and baseline PANSS negative subscale scores as co-variables.

Note: in the bifeprunox 20mg group, no PANSS score was recorded at week 1 or 2 for subject 11259.

The data source is as follows: table 3.2.0.

For the observed value analysis of the change in the PANSS negative subscale score from baseline, a decrease in score over time in each bifeprunox treated group indicates an improvement. A statistically significant therapeutic effect of bifeprunox was observed at week 2 for the 5mg group of bifeprunox compared to placebo (p ═ 0.032). No other significant differences were noted.

Clinical study 2: the following table presents the PANSS negative symptom subtotal scores at baseline and the changes from baseline obtained by visit and use of LOCF for the ITT population. The mean change in PANSS negative symptom scale score from baseline to endpoint (SD) was-3.1 for the 30mg bifeprunox group (5.6), 2.2 for the 40mg bifeprunox group (5.4), 1.8 for the placebo group (5.6), and 3.8 for the risperidone group (5.5). The therapeutic effect value at end point LOCF (bifeprunox-placebo) was-1.4 for the 30mg bifeprunox group and-0.9 for the 40mg bifeprunox group. SEP1 produced no significant results, so SEP2 and SEP3 were not evaluated.

The 30mg bifeprunox treated group showed significant difference from placebo at the end point (nominal p 0.027). Significant differences between the 30mg bifeprunox and placebo treated groups were also noted from week 2 to week 4 (p ≦ 0.021). No difference between placebo and 40mg bifeprunox dose groups was observed at any time point during the course of the study (week 1 to week 6).

Change from baseline in PANSS negative symptom subscale score

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding risperidone) and pooled centers as fixed factors and baseline PANSS negative symptom scale scores as co-variables.

Note: the P-values presented for weeks 1 to 4 are for descriptive purposes only.

Trt ═ treatment.

The data source is as follows: table 3.0.0, table 3.2.0.

Clinical study 3: the following table presents the PANSS negative symptom subtotal scores at baseline and the changes from baseline obtained by visit and use of LOCF for the ITT population. The mean change in passs negative symptom subscale score from baseline to endpoint (SD) was-3.3 (5.0) for the 20mg bifeprunox group, -3.1(5.2) for the 30mg bifeprunox group, -2.4(5.1) for the placebo group, and-4.6 (5.2) for the olanzapine group. The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-0.9 for the 20mg bifeprunox group and-0.6 for the 30mg bifeprunox group. At week 6/end or at any other time point during the course of the study (weeks 1 to 4), no difference with nominal p-value (< 0.05) was observed between the placebo and either bifeprunox dose groups.

Change from baseline in PANSS negative symptom subscale score

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding olanzapine) and pooled centers as fixed factors and a baseline PANSS negative symptom scale score as a co-variable.

Note: significance at week 6/end point for multiple comparisons was assessed according to the Hochberg procedure.

Note: the P-values and CIs presented for weeks 1 to 4 and week 6/end point are for descriptive purposes only.

Trt ═ treatment.

The data source is as follows: table 3.0.0, table 3.2.0.

Clinical study 4: the mean PANSS negative subscale score (FAS, LOCF) decreased in the 2 BX groups until week 6, after which the score stabilized (FIG. 2; group 35). In the PBO group, the score decreased until week 4, after which the score tended to increase (group 35).

In each visit LOCF analysis (FAS, ANCOVA) of the mean PANSS negative subscale score, treatment with BX20 or BX30 was statistically significantly better than treatment with PBO at all time points except at weeks 2 and 4 for BX 30.

PANSS data for clinical study 4

The mean PANSS total score (FAS, LOCF) decreased over time in the 2 BX groups until week 9, after which the score stabilized (group 28). In the PBO group, the mean PANSS total score decreased until week 2, after which the score steadily increased (group 28).

LOCF analysis of PANSS total scores (group 28) showed that the PANSS total scores in the BX group remained stable when the last observation was made forward. From week 6 onwards, changes in the 2 BX groups were statistically significantly better than changes in the PBO group. In addition, from week 4 onwards BX20 was statistically significantly better than PBO. OC analysis of PANSS total scores showed that patients who continued in this study improved over time (group 29). Changes in the 2 BX groups were statistically significantly better than changes in the PBO group at many time points including week 6 but not month 6.

The difference between the LOCF and POCF analyses indicates that many patients who were withdrawn had a worsening in their PANSS total score and were withdrawn at the first visit where a worsening was seen. This is consistent with the design of this study: patients were asked to withdraw from the study if they were at least minimally deteriorating.

For other efficacy variables, the trend of efficacy scores over time was similar, with the exception of CDSS, where baseline levels indicated that the patients included in the study were not depressed.

Group 27 efficacy Scale score-Baseline and adjusted mean change from Baseline (FAS, LOCF)

a adjusted mean value instead of an adjusted mean change from baseline

Group 31PANSS Total score adjusted mean change from baseline (FAS, LOCF, ANCOVA)

Group 32PANSS Total score adjusted mean change from baseline (FAS, OC, ANCOVA)

Group 33PANSS Total score adjusted mean change from baseline (FAS, POCF, ANCOVA)

General psychopathology score

Clinical study 1: as shown in the table below, general psychopathology scores decreased from baseline to week 6 for each bifeprunox-treated group. Estimates of bifeprunox therapeutic effects using LOCF were-2.2, 0.4 and-2.8 for the 5mg, 10mg and 20mg groups of bifeprunox, respectively. At week 2 (unadjusted p ═ 0.029), week 3 (unadjusted)P of 0.032) and end point (LOCF) (unadjusted p of 0.016), bifeprunox 20mg group had a statistically significantly greater reduction compared to placebo.

Change in PANSS general psychopathological subscale score from baseline

Last observation at each visit

Intent-to-treat population

Significant at the 0.050 level.

Note: pairwise comparisons to placebo were based on the ANCOVA model using treatment (excluding risperidone) and pooled centers as fixed factors and baseline PANSS general psychopathology sub-scale scores as co-variables.

Note: in the bifeprunox 20mg group, no PANSS score was recorded at week 1 or 2 for subject 11259.

The data source is as follows: table 3.3.0.

Analysis of the observed values for the change in PANSS general psychopathological subscale score from baseline, a decrease in score over time in each bifeprunox treated group indicated improvement. Compared to placebo, a statistically significant therapeutic effect of bifeprunox was observed at week 2 (p 0.038) for the 20mg group and at week 6 (p 0.017) for the 5mg group of bifeprunox. No other significant differences were noted.

Clinical study 2: the following table presents the mean PANSS general psychopathology subscale score at baseline and the change from baseline in the PANSS general psychopathology subscale score obtained at each post-baseline visit (LOCF) for the ITT population. The average change in PANSS general psychopathological subscale score from baseline to endpoint (SD) was-6.0 (10.2) for the 30mg bifeprunox group, -3.8(10.1) for the 40mg bifeprunox group, -3.5(9.7) for the placebo group, and-8.6 (9.8) for the risperidone group. The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-2.5 for the 30mg bifeprunox group and-0.7 for the 40mg bifeprunox group. Significant differences were observed between the 30mg bifeprunox group and placebo from week 2 to the end point (p.ltoreq.0.025). There was no significant difference between the 40mg bifeprunox group and placebo at any time point during the course of the study (week 1 to end).

Change in PANSS general psychopathological subscale score from baseline

Last observation at each visit

Intent-to-treat population

Significantly different from placebo, p ≦ 0.050; significantly different from placebo, p ≦ 0.010.

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding risperidone) and pooled centers as fixed factors and baseline PANSS general psychopathology sub-scale scores as co-variables.

Trt ═ treatment.

The data source is as follows: table 3.3.0.

Clinical study 3: the following table presents the mean PANSS general psychopathology subscale score at baseline and the change from baseline in the PANSS general psychopathology subscale score obtained at each post-baseline visit (LOCF) for the ITT population. The average change in PANS S general psychopathological subscale score from baseline to endpoint (SD) was-6.1 for the 20mg bifeprunox group (10.7), -5.8 for the 30mg bifeprunox group (10.3), -4.8 for the placebo group (10.0), and-10.5 for the olanzapine group (9.4). The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-1.5 for the 20mg bifeprunox group and-0.9 for the 30mg bifeprunox group. At the end point or at any other time point during the course of the study (week 1 to week 4), no significant difference was observed between the placebo and any of the 2 bifeprunox dose groups.

Change in PANSS general psychopathological subscale score from baseline

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding olanzapine) and pooled centers as fixed factors and baseline PANSS general psychopathology sub-scale scores as co-variables.

Trt ═ treatment.

The data source is as follows: table 3.3.0.

Clinical study 4: the average PANSS general psychopathology subscale score generally follows the same pattern as the PANSS total score. The mean PANSS general psychopathological subscale score (FAS, LOCF) decreased in the 2 BX groups until week 6, after which the score stabilized (fig. 3; group 36). In the PBO group, the mean PANSS general psychopathology subscale score decreased until week 2, after which the score steadily increased (group 36).

In each visit LOCF analysis (FAS, ANCOVA) scored on the PANSS general psychopathology subscale, both BX20 and BX30 were statistically significantly better than PBO from week 9 onwards. In addition, BX20 was statistically significantly better than PBO at week 6.

BPRS Total score

Clinical study 1: as shown in the table below, the bifeprunox 20mg group showed greater variation than the placebo group in the BPRS total score. At week 2 (unadjusted p ═ 0.042); week 3 (unadjusted p ═ 0.020); week 4 (unadjusted p ═ 0.024); at each time point beginning at end point (LOCF) (unadjusted p ═ 0.012), a statistically significant treatment group difference was seen for bifeprunox 20mg compared to placebo.

Change in BPRS Total score from baseline

Last observation at each visit

Intent-to-treat population

Significant at the 0.050 level.

Note: pairwise comparisons to placebo were based on the ANCOVA model, using treatment (excluding risperidone) and pooled centers as fixed factors and baseline BPRS total scores as co-variables.

Note: in the bifeprunox 20mg group, no PANSS score was recorded at week 1 or 2 for subject 11259.

The data source is as follows: table 3.4.0.

In the BPRS total score analysis performed using the observed values, similar trends observed in the LOCF analysis were noted in the changes from baseline. The bifeprunox treatment effect compared to placebo was statistically significant only for the 5mg group at week 6 (p ═ 0.024). No other significant comparisons were noted.

Clinical study 2: the table below presents the mean BPRS total score at baseline (derived from PANSS) and the variation from baseline in the BPRS total score obtained at each post-baseline visit (LOCF) for the ITT population. The mean change (SD) from baseline to endpoint for the BPRS total score was-8.1 (12.3) for the 30mg bifeprunox group, -6.5(11.7) for the 40mg bifeprunox group, -4.9(11.5) for the placebo group, and-12.2 (11.7) for the risperidone group. The therapeutic effect value at end point LOCF (bifeprunox-placebo) was-3.2 for the 30mg bifeprunox group and-1.9 for the 40mg bifeprunox group. Significant differences were observed between the 30mg bifeprunox group and placebo from week 2 to the end point (p ≦ 0.019). No significant difference was seen between the 40mg bifeprunox group and placebo at any time point during the course of the study (week 1 to end).

Change in BPRS Total score from baseline

Last observation at each visit

Intent-to-treat population

Significantly different from placebo, p ≦ 0.050; significantly different from placebo, p ≦ 0.010.

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (not including risperidone) and center as fixed factors and baseline BPRS total score as co-variables.

Trt ═ treatment.

The data source is as follows: table 3.4.0.

Clinical study 3: the table below presents the mean BPRS total score at baseline (derived from PANSS) and the variation from baseline in the BPRS total score obtained at each post-baseline visit (LOCF) for the ITT population. The mean change (SD) from baseline to endpoint for the BPRS total score was-8.5 (11.9) for the 20mg bifeprunox group, -7.9(12.0) for the 30mg bifeprunox group, -6.7(11.7) for the placebo group, and-13.2 (10.7) for the olanzapine group. The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-2.1 for the 20mg bifeprunox group and-1.1 for the 30mg bifeprunox group. No significant difference between the placebo group and either of the two bifeprunox dose groups was observed at the end point or at any other time point during the study (week 1 to week 4).

Change in BPRS Total score from baseline

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding olanzapine) and pooled centers as fixed factors and baseline BPRS total scores as co-variables.

Trt ═ treatment.

The data source is as follows: table 3.4.0.

BPRS psychotic group score

Clinical study 1: the table below presents the mean BPRS psychosis population score at baseline and the mean change from baseline obtained by visit and LOCF for the ITT population. The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-0.9, 0.4 and-1.1 for the bifeprunox 5mg, 10mg and 20mg groups, respectively. Compared to placebo, for the bifeprunox 20mg group, a statistically significantly greater reduction in the difference between mean change from baseline at endpoint (LOCF) for bifeprunox and placebo was seen in the BPRS psychosis cohort score (unadjusted p 0.044).

Change from baseline in BPRS psychotic population score

Last observation at each visit

Intent-to-treat population

Significant at the 0.050 level.

Note: pairwise comparisons to placebo were based on an ANCOVA model using treatment (excluding risperidone) and pooled centers as fixed factors and baseline BPRS psychosis population scores as co-variables.

Note: in the bifeprunox 20mg group, no PANSS score was recorded at week 1 or 2 for subject 11259.

The data source is as follows: table 3.5.0.

For the observed value analysis of the change in BPRS psychosis population scores from baseline, a greater reduction in score was seen for each of the three bifeprunox treated groups from week 4 compared to placebo. No other statistically significant differences were noted.

Clinical study 2: the table below presents the mean BPRS psychosis population score at baseline and the mean change from baseline obtained by visit and LOCF for the ITT population. The mean change (SD) from baseline to endpoint for the BPRS psychotic group score was-3.2 (4.2) for the 30mg bifeprunox group, -2.6(4.4) for the 40mg bifeprunox group, -1.8(3.5) for the placebo group, and-4.9 (4.0) for the risperidone group. The therapeutic effect value at end point LOCF (bifeprunox-placebo) was-1.4 for the 30mg bifeprunox group and-1.0 for the 40mg bifeprunox group. Significant differences were observed between the 30mg bifeprunox group and placebo from week 2 to the end point (p ≦ 0.002). At the end point (p ═ 0.0)31) And significant differences were seen between the 40mg bifeprunox group and placebo at weeks 2 and 3 (p.ltoreq.0.036).

Change from baseline in BPRS psychotic population score

Last observation at each visit

Intent-to-treat population

Significantly different from placebo, p ≦ 0.050; significantly different from placebo, p ≦ 0.010.

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (not including risperidone) and pooled centers as fixed factors and baseline BPRS psychosis population scores as co-variables.

Trt ═ treatment.

The data source is as follows: table 3.5.0.

Clinical study 3: the table below presents the mean BPRS psychosis population score at baseline and the mean change from baseline obtained by visit and LOCF for the ITT population. The average change in BPRS psychosis population Score (SD) from baseline to endpoint was-3.1 for the 20mg bifeprunox group (3.9), -3.2 for the 30mg bifeprunox group (4.4), 2.6 for the placebo group (4.0), and-4.9 for the olanzapine group (4.0). The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-0.6 for the 20mg bifeprunox group and-0.5 for the 30mg bifeprunox group. At the end point or any other time during the course of the study (weeks 1 to 4)No significant difference was observed between the placebo group and either of the two bifeprunox dose groups at the time point.

Change from baseline in BPRS psychotic population score

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (not olanzapine) and pooled centers as fixed factors and baseline BPRS psychosis population scores as co-variables.

Trt ═ treatment.

The data source is as follows: table 3.5.0.

CGI-S

Clinical study 1: the following table presents the mean CGI disease severity score at baseline and the mean change from baseline obtained by visit and use of LOCF for ITT population. The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-0.31, 0.12 and-0.19 for the bifeprunox 5mg, 10mg and 20mg groups, respectively. The treatment composition pair-wise comparison showed a statistically significantly greater reduction in bifeprunox 20mg at week 2 (p 0.008), week 3 (p 0.020) and week 4 (p 0.032) compared to placebo, but not at end point (LOCF). Treatment group comparisons for bifeprunox 5mg versus placebo at week 3 (p 0.049), week 4 (p 0.033) and end point (LOCF) (p 0.013) wereIs remarkable.

Change in CGI disease severity score from baseline

Last observation at each visit

Intent-to-treat population

Significant at the 0.050 level.

Note: pairwise comparisons were based on the ANCOVA model, using treatment (not including risperidone) and combined

The center was used as a fixed factor and the baseline CGI disease severity score was used as a co-variable. The data source is as follows: table 3.6.0.

Clinical study 2: the following table presents the average CGI-S score at baseline and the mean change from baseline (LOCF) obtained by visit and use of LOCF for ITT population. Mean change in CGI disease severity Score (SD) from baseline to endpoint was-0.69 (1.19) for the 30mg bifeprunox group, -0.54(1.12) for the 40mg bifeprunox group, -0.37(1.07) for the placebo group, and-1.06 (1.20) for the risperidone group. The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-0.28 for the 30mg bifeprunox group and-0.18 for the 40mg bifeprunox group. Based on the descending program, no statistically significant difference in CGI-S change from baseline to endpoint was seen for the 30mg bifeprunox treated group compared to placebo (adjusted p 0.056). At the end point, the 30mg bifeprunox group showed significant differences from placebo (nominal p ═ 0.028). The same remarks apply to weeks 2 to 4Significant differences between the 30mg bifeprunox and placebo treated groups (p ≦ 0.015). No difference was observed between placebo and 40mg bifeprunox dose groups at any time point during the course of the study (week 1 to week 4).

Change in CGI disease severity score from baseline

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding risperidone) and center as fixed factors and baseline CGI disease severity score as co-variables.

Note: the adjusted P-values are based on the Hochberg procedure for multiple comparisons.

Note: the P-values presented for weeks 1 to 4 are for descriptive purposes only.

Trt is therapeutic and Adj is modulated.

The data source is as follows: table 3.0.0, table 3.6.0.

Clinical study 3: the following table presents the average CGI disease severity score at baseline and through visit and use for ITT populationThe mean value from baseline obtained for LOCF varies. Mean change in CGI disease severity Score (SD) from baseline to endpoint was-0.63 (0.98) for the 20mg bifeprunox group, -0.62(1.03) for the 30mg bifeprunox group, -0.49(1.06) for the placebo group, and-1.03 (1.00) for the olanzapine group. The therapeutic effect values at end point LOCF (bifeprunox-placebo) were-0.13 for the 20mg bifeprunox group and-0.09 for the 30mg bifeprunox group. At week 6/end or at any other time point during the course of the study (weeks 1 to 4), there was no significant difference between the placebo and either bifeprunox dose groups, nominal p-value (< 0.05).

Change in CGI disease severity score from baseline

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding olanzapine) and pooled centers as fixed factors and baseline CG I disease severity score as co-variables.

Note: significance at week 6/end point for multiple comparisons was assessed according to the Hochberg procedure.

Note: the P-values and CIs presented for weeks 1 to 4 and week 6/end point are for descriptive purposes only.

Trt ═ treatment.

The data source is as follows: table 3.0.0, table 3.6.0.

CGI-I

Clinical study 1: as shown in table 24, improvement was noted in CGI improvement scores for the 20mg bifeprunox treated group. In the LOCF analysis, the treatment group differences were statistically significant at week 1 (p 0.040) and week 2 (p 0.016) for the bifeprunox 20mg group compared to placebo, but not at the end point. No other significant differences were noted.

Actual value of CGI improvement score

Last observation at each visit

Intent-to-treat population

Significant at the 0.050 level.

Note: pairwise comparisons to placebo were based on the ANCOVA model, using treatment (excluding risperidone) and pooled centers as fixed factors and baseline CGI disease severity score as co-variables.

The data source is as follows: table 3.7.0.

Clinical study 2: the percentage of subjects with much or very much improvement from baseline to end point (LOCF) was reported: 36% in the 30mg bifeprunox group, 28% in the 40mg bifeprunox group, 25% in the placebo group, and 52% in the risperidone group (table below). At the end point, no significant difference was observed between placebo and either of the two bifeprunox dose groups; however, a significant difference was seen between the 30mg bifeprunox group and placebo (p ≦ 0.024) between weeks 2 and 4. No significant difference was seen between the 40mg bifeprunox group and placebo at any time point during the course of the study (week 1 to end). The data from week 2 to the end point are summarized in the table below.

CGI improvement score

Last observation at each visit

Intent-to-treat population

Significantly different from placebo, p ≦ 0.050. Significantly different from placebo, p ≦ 0.010.

Note: the P-values are based on a CMH test that is hierarchical through the centers of the merges.

The data source is as follows: table 3.7.0.

Clinical study 3: the following table presents the frequency of improved assessments for category 7 CGI obtained by visit and use of LOCF for ITT population. Will pass throughAnd the frequency with which the central and hierarchical CMH test was applied to 7 CGI improvement categories with altered ridit scores to assess the statistical differences in treatment groups with respect to the average CGI improvement score. The percentage of subjects with many or very many improvements in combination from baseline to endpoint was reported (obtained by summing the corresponding individual percentages in table 23): 38% in the 20mg bifeprunox group, 34% in the 30mg bifeprunox group, 32% in the placebo group, and 46% in the olanzapine group. Comparison of the 20mg bifeprunox group to the placebo group was found to be significant at the end point (p ═ 0.027). Treatment of the placebo group was less significant with 30mg bifeprunox group (p ═ 0.162). At any other time point during the course of the study (week 1 to week 4), no significant difference was observed between the placebo group and either of the two bifeprunox dose groups.

CGI improvement score

Last observation at each visit

Intent-to-treat population

Significantly different from placebo, p ≦ 0.050.

Note: the P-values are based on a CMH test that is hierarchical through the centers of the merges.

The data source is as follows: table 3.7.0.

PANSS responder rates

Clinical study 1: PANS responder rates for each bifeprunox group compared to placeboHigher in the treatment group. Using the 20% definition from this study protocol, PANSS responder rates were 28%, 24% and 34% for the three dose groups, respectively. Responder ratios for PANSS using all 4 definitions are presented in the table below.

PANSS responder ratio at endpoint

Last observation and advancement method

Intent-to-treat population

Significant at the 0.050 level. Significant at the 0.010 level.

Note: PANSS responders were defined as subjects whose total PANSS score was reduced by a specified percentage.

Significant differences in the rates of PANSS responders using LOCF were seen with the 25% limit for bifeprunox 5mg versus placebo and the 25%, 30% and 35% limits for the bifeprunox 20mg group versus placebo.

Clinical study 2: PANSS responders are defined as subjects whose PANSS total score decreases by 20% or more from baseline to endpoint based on LOCF data. As an exploratory analysis, responder rates were also analyzed using 30%, 35%, 40% and 50% responder limits. A summary of PANSS responder rates at end point (LOCF) is presented in table 25 below.

The PANSS responder rates were slightly higher for the two bifeprunox-treated groups compared to the placebo group. PANSS 20% responder ratio: 36% in the 30mg bifeprunox group, 30% in the 40mg bifeprunox group, 26% in the placebo group, and 54% in the risperidone group. However, the difference between the 30mg bifeprunox group and placebo was not significant (p ═ 0.052). PANSS 30% responder ratio: 24% in the 30mg bifeprunox group, 22% in the 40mg bifeprunox group, 14% in the placebo group, and 31% in the risperidone group. The difference between the 30mg bifeprunox group and placebo was significant (p ═ 0.019). Significant differences between the 30mg bifeprunox group and placebo were also seen for the 35% and 50% responder rates.

PANSS responder ratio at endpoint

Last observation and advancement method

Intent-to-treat population

Significantly different from placebo, p ≦ 0.050.

Note: the P-values are based on a CMH test that is hierarchical through the centers of the merges.

Note: PANSS responders are defined as subjects with a PANSS score reduction of 20% or more (20% limit) or 30% or more (30% limit).

The data source is as follows: table 3.9.0.

Clinical study 3: PANSS responders are defined as subjects whose PANSS total score decreases by 20% or more from baseline to endpoint. As an exploratory analysis, responder rates were also analyzed using 30%, 35%, 40% and 50% responder limits. A summary of PANSS responder rates at end point (LOCF) is presented in the table below. The 20% PANSS responder ratio was slightly higher for the two bifeprunox-treated groups compared to the placebo group: 42% of subjects in the 20mg bifeprunox group, 30mg bifeprunox39% of subjects in the benzonoro group, 32% of subjects in the placebo group, and 54% of subjects in the olanzapine group had an improvement of 20% or more from baseline to endpoint in the PANSS total score. The difference between the 20mg bifeprunox group and the placebo group was significant (p ═ 0.061). However, when using the more stringent criteria defined for responders (30% -50%), the difference between the 20mg or 30mg bifeprunox group and placebo was not significant (all p ≧ 0.118).

PANSS responder ratio at endpoint

Last observation and advancement method

Intent-to-treat population

Note: the P-values are based on a CMH test that is hierarchical through the centers of the merges.

Note: PANSS responders were defined as subjects with a PANSS score that decreased by > 20% from baseline to endpoint.

The data source is as follows: table 3.9.0.

Clinical study 4: the proportion of patients (PANSS responders) with PANSS total score reduction of 25%,. gtoreq.35%,. gtoreq.45%, or. gtoreq.55% relative to baseline at each visit was shown by LOCF (FIG. 4; group 42).

CGI responder ratio

Clinical study 1: CGI responders were defined as subjects classified as "improving very much" or "improving much" on the CGI improvement scale. The rates of CG I responders were higher in the bifeprunox 5mg and 20mg groups than in the placebo group. No statistically significant differences were seen for any of the three bifeprunox dose groups when compared to placebo.

CGI responder ratio at endpoint

Last observation and advancement method

Intent-to-treat population

Note: CGI responders were defined as subjects classified as "improving very much" or "improving much" in the CGI improvement scale.

Note: the P-values are based on the Cochran-Mantel-Haenszel chi-square test, stratified by the center of the merge.

The data source is as follows: table 3.9.0.

Clinical study 2: CGI responders were defined as subjects classified as "improving very much" or "improving much" on the CGI improvement scale. A summary of the CGI-I responder ratio at the end point (LOCF) is presented in the following table. CGI-I responder ratio: 36% in the 30mg bifeprunox group, 28% in the 40mg bifeprunox group, 25% in the placebo group, and 52% in the risperidone group. A significant difference was seen between the 30mg bifeprunox group and placebo (p ═ 0.039).

CGI responder ratio at endpoint

Last observation and advancement method

Intent-to-treat population

Significantly different from placebo, p ≦ 0.050.

Note: the P-values are based on a CMH test that is hierarchical through the centers of the merges.

Note: CGI responders were defined as subjects classified as "improving very much" or "improving much" in the CGI improvement scale.

The data source is as follows: table 3.10.0.

Clinical study 3: CGI responders were defined as subjects classified as "improving very much" or "improving much" on the CGI improvement scale. A summary of the CGI-I responder ratios at the end point (LOCF) is presented in Table 3.10.0(LOCF) and Table 26. CGI-I responder ratio: 38% in the 20mg bifeprunox group, 34% in the 30mg bifeprunox group, 32% in the placebo group, and 46% in the olanzapine group. No significant difference was observed between the placebo group and either of the two bifeprunox dose groups.

CGI responder ratio at endpoint

Last observation and advancement method

Intent-to-treat population

Note: the P-values are based on a CMH test that is hierarchical through the centers of the merges.

Note: CGI responders were defined as subjects classified as "improving very much" or "improving much" in the CGI improvement scale.

The data source is as follows: table 3.10.0.

CDSS

Clinical study 2: the calgari schizophrenia depression scale score is presented in the table below. This table presents the mean CDSS score at baseline and the mean change from baseline obtained by visit and use of LOCF for the ittt population. Mean change in CDSS score (LOCF) from baseline to endpoint (SD) was-0.66 (3.64) for the 30mg bifeprunox group, 0.01(3.66) for the 40mg bifeprunox group, -0.39(3.45) for the placebo group, and-0.89 (3.42) for the risperidone group. The therapeutic effect values at end point LOCF (bifeprunox, placebo) were-0.38 for the 30mg bifeprunox group and 0.29 for the 40mg bifeprunox group. At the end point or at any other time point during the course of the study (week 1 to week 4), no significant difference was observed between placebo and either of the two bifeprunox dose groups.

Change in CDSS Total score from baseline

Last observation at each visit

Intent-to-treat population

Note: treatment comparisons to placebo were based on an ANCOVA model using treatment (excluding risperidone) and pooled centers as fixed factors and baseline CDSS total scores as co-variables.

Trt ═ treatment.

The data source is as follows: table 3.8.0.

Clinical study 3: the following table presentsMean CDSS score at baseline and mean change from baseline obtained by visit and LOCF for the ittt population. Mean change in CDS S score from baseline to endpoint (SD) was-1.30 for the 20mg bifeprunox group (3.85), -0.79 for the 30mg bifeprunox group (3.02), -0.59 for the placebo group (4.20), and-1.47 for the olanzapine group (3.95). The therapeutic effect values at end point LOCF (bifeprunox, placebo) were-0.54 for the 20mg bifeprunox group and-0.34 for the 20mg bifeprunox group. At the end point or at any other time point during the course of the study (week 1 to week 4), no significant difference was observed between the placebo group and either of the two bifeprunox dose groups.

Change in CDSS Total score from baseline

Last observation at each visit

Intent-to-treat population

Note: the treatment comparison and least squares approach was based on an ANCOVA model using treatment (excluding olanzapine) and pooled centers as fixed factors and baseline CDSS total scores as co-variables.

Trt ═ treatment.

The data source is as follows: table 3.8.0.

Clinical study 4: the proportion of patients with a CGI-I score of ≦ 2 at each visit (CGI-responders; FAS, LOCF) is shown in the following table (FIG. 5; group 43).

EPS

EPS is assessed using adverse events emergent in therapy, such as akathisia, dyskinesia, parkinsonism, and the like, and/or formal rating scales such as SAS, BAS, and/or AIMS.

Simpson-Angus scale 16(SAS)

SAS is used to measure parkinson-type symptoms in patients exposed to antipsychotics. This scale consists of 10 items, each rated on a 5 point scale from 0 (the pathology is completely absent) to 4 (the pathology is present in extreme form). The SAS total score is defined as the sum of all the item scores and ranges from 0-40. SAS total scores up to 3 were considered normal.

Baynsi sit-meditation inefficacy scale 17(BAS)

BAS were used to assess drug-induced observable, restless movement of akathisia as well as subjective perception of akathisia and any pain associated with akathisia. The scale consisted of 3 items rated from 0 (no signs of akathisia) to 3 (severe akathisia). The BAS total score is defined as the sum of the scores of the 3 BAS items and ranges from 0 to 9. In addition, the overall clinical assessment of akathisia ranged from 0 (no signs of akathisia) to 5 (severe akathisia).

Abnormal involuntary movement scale 18(AIMS)

An AIMS designed to record the occurrence of dyskinetic movements consists of 12 items. Items 1-7 measure specific involuntary movements on a scale of 0 (none) to 4 (severe). Items 8-10 measure the overall assessment of abnormal movement on a scale of 0 (no sense) to 4 (known, severe affliction). Items 11 and 12 are questions about the dental condition of the patient, with the answer yes/no. The total score is calculated by summing the AIMS items 1 to 10 and ranges from 0-40; the non-total score is calculated by summing items 1 to 7.

Clinical study 1:

note: the percentage of adverse events with respect to gender specificity was based on the number of subjects within the appropriate gender. The percentage for all other adverse events was based on the total number of subjects in the safety population.

Note: each subject was counted up to 1 time in the system organ categories and preferred items. The adverse events were coded to system organ categories and preferred items using the MedDRA dictionary (version 5.0).

Note: an adverse event that emerges from treatment is defined as any adverse event that occurs after the study drug therapy is initiated or any pre-existing medical condition that worsens after randomization. Emergent adverse events in treatment included all adverse events reported in the clinic by study discontinuation of subjects, as well as all SAEs reported within 30 days after a permanent discontinuation of study drug therapy.

The source is as follows: PROTOCOL \ USRTP-NAS01\ VMSDATA \ SAS \ CRK00058100\ ANALYSIS \ TABLELIB \ FINAL \ AE _ OVERALL _ SAFETY. SAS. QUINTILES (US) Run28APR 0412: 26

Overall incidence of adverse events emergent in treatment: safety group

Note: the percentage of adverse events with respect to gender specificity was based on the number of subjects within the appropriate gender. The percentage for all other adverse events was based on the total number of subjects in the safety population.

Note: each subject was counted up to 1 time in the system organ categories and preferred items. The adverse events were coded to system organ categories and preferred items using the MedDRA dictionary (version 5.0).

Note: an adverse event that emerges from treatment is defined as any adverse event that occurs after the study drug therapy is initiated or any pre-existing medical condition that worsens after randomization. Emergent adverse events in treatment included all adverse events reported in the clinic by study discontinuation of subjects, as well as all SAEs reported within 30 days after a permanent discontinuation of study drug therapy.

The source is as follows: PROTOCOL \ USRTP-NAS01\ VMSDATA \ SAS \ CRK00058100\ ANALYSIS \ TABLELIB \ FINAL \ AE _ OVERALL _ SAFETY. SAS. QUINTILES (US) Run28APR 0412: 26

Overall incidence of adverse events emergent in treatment: safety group

Note: the percentage of adverse events with respect to gender specificity was based on the number of subjects within the appropriate gender. The percentage for all other adverse events was based on the total number of subjects in the safety population.

Note: each subject was counted up to 1 time in the system organ categories and preferred items. The adverse events were coded to system organ categories and preferred items using the MedDRA dictionary (version 5.0).

Note: an adverse event that emerges from treatment is defined as any adverse event that occurs after the study drug therapy is initiated or any pre-existing medical condition that worsens after randomization. Emergent adverse events in treatment included all adverse events reported in the clinic by study discontinuation of subjects, as well as all SAEs reported within 30 days after a permanent discontinuation of study drug therapy.

The source is as follows: PROTOCOL \ USRTP-NAS01\ VMSDATA \ SAS \ CRK00058100\ ANALYSIS \ TABLELIB \ FINAL \ AE _ OVERALL _ SAFETY. SAS. QUINTILES (US) Run28APR 0412: 26

Clinical study 2：

Overall incidence of adverse events emergent in treatment: safety group

Operating procedures S1543001

Solvay Pharmaceuticals

Final study report

Indicates gender specific adverse events.

Note: the percentage of adverse events with respect to gender specificity was based on the number of subjects within the appropriate gender. The percentage for all other adverse events was based on the total number of subjects in the safety population.

Note: each subject was counted up to 1 time in the system organ categories and preferred items. The adverse events were coded to system organ categories and preferred items using the MedDRA dictionary (version 6.1).

Note: emergent adverse events in treatment were defined as any adverse event that occurred after the start of study drug therapy or any pre-existing medical condition that worsened in severity after randomization. Emergent adverse events in treatment included all adverse events reported in the clinic by study discontinuation of subjects, as well as all SAEs reported within 30 days after study discontinuation.

Note: adverse events include new or bad physical exam abnormalities.

The data source is as follows: TABLE 4.1.0

Overall incidence of adverse events emergent in treatment: safety group

Operating procedures S1543001

Solvay Pharmaceuticals

Final study report

Indicates gender specific adverse events.

Note: the percentage of adverse events with respect to gender specificity was based on the number of subjects within the appropriate gender. The percentage for all other adverse events was based on the total number of subjects in the safety population.

Note: each subject was counted up to 1 time in the system organ categories and preferred items. The adverse events were coded to system organ categories and preferred items using the MedDRA dictionary (version 6.1).

Note: emergent adverse events in treatment were defined as any adverse event that occurred after the start of study drug therapy or any pre-existing medical condition that worsened in severity after randomization. Emergent adverse events in treatment included all adverse events reported in the clinic by study discontinuation of subjects, as well as all SAEs reported within 30 days after study discontinuation.

Note: adverse events include new or bad physical exam abnormalities.

The data source is as follows: TABLE 4.1.0

Clinical study 3：

Overall incidence of adverse events emergent in treatment: safety group

Indicates gender specific adverse events.

Note: the percentage of adverse events with respect to gender specificity was based on the number of subjects within the appropriate gender. The percentage for all other adverse events was based on the total number of subjects in the safety population.

Note: each subject was counted up to 1 time in the system organ categories and preferred items. The adverse events were coded to system organ categories and preferred items using the MedDRA dictionary (version 6.1).

Note: emergent adverse events in treatment were defined as any adverse event that occurred after the start of study drug therapy or any pre-existing medical condition that worsened in severity after randomization. Emergent adverse events in treatment included all adverse events reported in the clinic by study discontinuation of subjects, as well as all SAEs reported within 30 days after study discontinuation.

The data source is as follows: TABLE 4.1.0

Overall incidence of adverse events emergent in treatment: safety group

Indicates gender specific adverse events.

Note: the percentage of adverse events with respect to gender specificity was based on the number of subjects within the appropriate gender. The percentage for all other adverse events was based on the total number of subjects in the safety population.

Note: each subject was counted up to 1 time in the system organ categories and preferred items. The adverse events were coded to system organ categories and preferred items using the MedDRA dictionary (version 6.1).

Note: emergent adverse events in treatment were defined as any adverse event that occurred after the start of study drug therapy or any pre-existing medical condition that worsened in severity after randomization. Emergent adverse events in treatment included all adverse events reported in the clinic by study discontinuation of subjects, as well as all SAEs reported within 30 days after study discontinuation.

The data source is as follows: TABLE 4.1.0

Overall incidence of adverse events emergent in treatment: safety group

Indicates gender specific adverse events.

Note: the percentage of adverse events with respect to gender specificity was based on the number of subjects within the appropriate gender. The percentage for all other adverse events was based on the total number of subjects in the safety population.

Note: each subject was counted up to 1 time in the system organ categories and preferred items. The adverse events were coded to system organ categories and preferred items using the MedDRA dictionary (version 6.1).

Note: emergent adverse events in treatment were defined as any adverse event that occurred after the start of study drug therapy or any pre-existing medical condition that worsened in severity after randomization. Emergent adverse events in treatment included all adverse events reported in the clinic by study discontinuation of subjects, as well as all SAEs reported within 30 days after study discontinuation.

The data source is as follows: TABLE 4.1.0

Clinical study 4：

The proportion of patients with EPS-related TEAEs was lower in the PBO group (4%) than in either BX group (BX 20: 10%; BX 30: 15%). EPS-associated TEAE s for which there were > 3 patients in any BX group relative to the PBO group included: BX 20-akathisia; BX 30-dyskinesia, akathisia, extrapyramidal disorders. Overall, 15 patients had EPS-related TEAEs leading to withdrawal (2 in PBO group; 4 in BX20 group; 9 in BX30 group).

Group 48 all EPS TEAEs (APTS) by SOC and preference

SAS, BAS and AIMS

Clinical study 1: the simpson-angless scale overall score was rated as normal or abnormal at baseline and end point. Percentage of subjects with normal or abnormal scores at each time point. At baseline, the percentage of subjects with abnormal SAS scores was 8% -12%. At the end point, the percentage of subjects with abnormal SAS scores ranged from 3% to 10%. The percentage of subjects with abnormal SAS scores decreased between baseline and endpoint in all treatment groups. The percentage of subjects that switched between categories from baseline to endpoint did not differ statistically significantly in the treatment group (p 0.800).

The BAS score consisted of an objective score, a restlessness awareness score, a sore associated with restlessness score, a 3 total score, and an overall clinical assessment score. There were no statistically significant differences in treatment groups at baseline or end point for objective scores, restlessness awareness scores, sore scores associated with restlessness, 3 total scores, or overall clinical assessment scores.

The percentage of subjects that transitioned between categories from baseline to endpoint in either BAS overall score or BAS overall clinical assessment score was not statistically significantly different in the treatment groups. There were no statistically significant differences in the treatment groups at baseline or endpoint. There were no statistically significant differences in treatment groups for change values from baseline to endpoint.

Clinical study 2: overall scores on the Simpson-Angus scale at baseline and at terminalThe point is evaluated as normal or abnormal. Percentage of subjects with abnormal SAS scores at baseline: 14% in the 30mg bifeprunox group, 11% in the 40mg bifeprunox group, 7% in the placebo group, and 6% in the risperidone group. The percentage of subjects with abnormal SAS scores between baseline and endpoint decreased in the bifeprunox group, there was no change in the placebo group, and increased in the risperidone group. At the end point, the percentage of subjects with abnormal SAS scores ranged from 7% in the 40mg bifeprunox and placebo group to 14% in the risperidone group.

Compared to the other 3 treatment groups (30mg bifeprunox: 1 subjects, < 1%; 40mg bifeprunox: 5 subjects, 4%; placebo: 6 subjects, 4%), the abnormal transition from normal at baseline to endpoint was highest in the risperidone group (19 subjects, 12%). Statistically significant differences were observed in the treated groups (p < 0.001).

The BAS score consisted of an objective score, a restlessness subjective awareness score, a pain score associated with restlessness, a 3 total score, and an overall clinical assessment score. There were no statistically significant differences between treatment groups at the end point for objective scores (p ═ 0.093), restlessness (p ═ 0.368), restlessness-related affliction scores (p ═ 0.779), 3 total BAS scores (p ═ 0.433), or overall clinical assessment scores of akathisia (p ═ 0.541). There were also no statistically significant differences between treatment groups at baseline (p.gtoreq.0.168) for the above measurements.

The percentage of subjects that switched between categories from baseline to endpoint in either the BAS total score (p 0.482) or BAS overall clinical assessment score (p 0.911) was not statistically significantly different between treatment groups.

There were no statistically significant differences between treatment groups at baseline (mean range 1.0-1.2; p 0.923) or end point (mean range 0.9-1.6; p 0.138). There were no statistically significant differences between treatment groups for the change from baseline to endpoint (mean range-0.3-0.4; p-0.138).

Clinical study 3: the simpson-angless scale overall score was rated as normal or abnormal at baseline and end point. At baseline, the percentage of subjects with abnormal SAS scores was 6% -10%. At the end point, the percentage of subjects with abnormal SAS scores ranged from 3% to 8%. The percentage of subjects with abnormal SAS scores decreased between baseline and endpoint in all treatment groups. The percentage of subjects that switched between categories from baseline to endpoint did not differ statistically significantly in the treatment group (p ═ 0.463). The BAS score consisted of an objective score, a restlessness subjective awareness score, a pain score associated with restlessness, a 3 total score, and an overall clinical assessment score. There were no statistically significant differences in the treatment groups at the end point for objective scores (p ═ 0.421), restlessness perception scores (p ═ 0.584), restlessness-related afflictions scores (p ═ 0.254), 3 total scores (p ═ 0.865), or overall clinical assessment scores (p ═ 0.518). For the subjective affliction score associated with restless (p ═ 0.029), there was a statistically significant difference in the treatment groups at baseline, but not for any other scores.

The percentage of subjects that switched between categories from baseline to endpoint in either the BAS total score (p 0.808) or BAS overall clinical assessment score (p 0.525) was not statistically significantly different in the treatment groups.

There were no statistically significant differences in the treatment groups at baseline (p 0.362) or end point (p 0.187). There were no statistically significant differences in the treatment groups for the change from baseline to endpoint (p 0.187).

Clinical study 4：

SAS

At baseline, the mean SAS overall score ranged from 2.17 to 2.33 in all 3 treatment groups.

There was a small fluctuation in the mean SAS total score among all 3 treatment groups over the course of the study, and the mean SAS total score at month 6 was 0.57-1.16(APTS, OC); thus, the average total score at baseline and month 6 was within the normal range. The adjusted mean maximum change from baseline to month 6 in SAS total scores was < 1 in each treatment group (APTS, OC, ANCOVA). SAS total scores were not clinically relevant differences between any treatment groups.

At baseline, most patients (PBO: 74%; BX 20: 71%; BX 30: 72%) were normal for SAS status, and the proportion of normal patients had increased by month 6 (PBO: 85%; BX 20: 89%; BX 30: 78%). There were no statistically significant differences between any treatment groups in terms of the transition of SAS states (category: no change; abnormal to normal; normal to abnormal).

BAS

At baseline, the average total BAS score ranged from 0.44 to 0.46 in all 3 treatment groups. There was a small fluctuation in the mean total BAS score in all 3 treatment groups over the course of the study, and at month 6 the mean total BAS score was 0.05-0.17(APTS, OC). The adjusted mean maximum change in BAS total score from baseline to month 6 was < 0.6 in each treatment group (APTS, OC, ANCOVA). BAS total scores were not clinically relevant differences between any treatment groups.

For BAS overall assessment scores, the trends were similar: there was a small fluctuation in the mean BAS overall assessment score in all 3 treatment groups over the course of the study; the mean score was 0.22-0.26 at baseline and 0.07-0.14 at month 6(APTS, OC). At month 6 BAS overall assessment scores were not clinically relevant differences (APTS, OC) between any treatment groups. There were no statistically significant differences between any treatment groups in the distribution of BAS items 1, 2 or 3.

AIMS

At baseline, the average AIMS total score was low and was 1.04-1.35 in all 3 treatment groups. For all treatment groups, the adjusted mean score initially increased (largest in the BX30 group), after which the mean score decreased over time; at month 6, scores returned to baseline levels in all 3 treatment groups (PBO: 0.11; BX 20: 1.08; BX 30: 0.86(APTS, OC)). The adjusted mean change in the AIMS total score was not statistically significantly different in the BX20 (all time points) and BX30 (months 5 and 6) groups from the PBO group, while the adjusted mean change was statistically significantly different for the BX30 (week 1 to month 4) group. The adjusted mean maximum change in AIMS overall score from baseline to month 6 was small (PBO: 0.39; BX 20: 1.21; BX 30: 2.45, APTS, OC, ANCOVA). None of the differences were considered clinically significant.

Group 49 sports rating Scale score (APTS)

a PBO-OC: baseline: n 166, week 6: 112, month 6: n-44; LOCF: n 166

b BX 20-OC: baseline: 159, week 6: n 104, month 6: n is 59; LOCF: n is 159

c BX 30-OC: baseline: n-172, week 6: n 106, month 6: n is 57; LOCF: n-172

Body weight

Clinical study 1：

A small reduction in body weight was observed in the bifeprunox-treated group, but not in the placebo-treated group. At the end point, the average weight loss of the subjects in the bifeprunox-treated group was approximately 1lb (5mg bifeprunox, -1.0 lb; 10mg bifeprunox, -1.3 lb; 20mg bifeprunox-0.6 lbs). The placebo treated group had an average weight gain of 1.9 lbs.

Statistical tests of changes in body weight from baseline (ANCOVA model using factors for treatment and body weight at baseline) were performed using a similar method to that used for the secondary efficacy parameters. The pair-wise comparison of bifeprunox treated groups to placebo was statistically significant for both differences between the mean change in body weight from baseline to endpoint for bifeprunox and placebo (5mg [ p ═ 0.025], 10mg [ p ═ 0.009], and 20mg [ p ═ 0.031 ]).

The mean change in body weight of the subjects in the risperidone treated group was an increase of 4.8 lb.

Weight gain: the percentage of subjects whose weight gain was greater than 7% in the bifeprunox-treated group (2-4%) was less than or similar to the percentage observed in the placebo-treated group (5%). In the risperidone treatment group, 13% of subjects gained weight ≧ 7%.

Weight loss: the percentage of subjects whose weight loss was over 7% in the bifeprunox-treated group (5mg, 6%, 10mg, 7%; 20mg, 8%) was high in the placebo-treated group (3%). No subjects in the risperidone treatment group reduced weight by ≧ 7%.

Clinical study 2：

At the end point, a small decrease in mean body weight was observed in the bifeprunox-treated group and the placebo group, while an increase was noted for the risperidone-treated group (table below). At the end point, the average weight change: 2.2lbs in the 30mg bifeprunox group; -1.9lbs in the 40mg bifeprunox group; 0.5lbs in the placebo group; and 3.2lbs in the risperidone group. In the bifeprunox treatment group, the mean change at week 6 was higher than those at the end point.

Body weight change at week 6 and end point: safety group

Note: endpoint was defined as the last scheduled (including early termination), non-missing, post-baseline assessment (excluding follow-up) collected during the study.

The data source is as follows: TABLE 9.4.0

Clinical study 3: a small decrease in mean body weight was observed in the bifeprunox-treated group and the placebo group, while an increase was noted for the olanzapine-treated group. At the end point, the average weight change: -2.3lbs in the 20mg bifeprunox group; 1.1lbs in the 30mg bifeprunox group; 1.3lbs in the placebo group; and 5.2lbs in the olanzapine group. The mean changes at week 6 were comparable to those at the end point (table below).

The incidence of markedly abnormal (7% or more) weight loss was comparable in the bifeprunox-treated and placebo groups (20mg bifeprunox: 6%; 30mg bifeprunox: 5%; placebo: 5%) and lower (< 1%) in the olanzapine-treated group. The opposite phenomenon was seen in the incidence of significantly abnormal (7% or more) weight gain, 19% in the olanzapine treated group compared to 5% in the 30mg bifeprunox group, 1% in the 20mg bifeprunox group and 5% in the placebo group experiencing this.

Body weight change at week 6 and end point: safety group

Note: endpoint was defined as the last scheduled (including early termination), non-missing, post-baseline assessment (excluding follow-up) collected during the study.

The data source is as follows: TABLE 9.4.0

Clinical study 4：

Body weight and BMI and changes therein from baseline are summarized in the table below. In all groups, the adjusted mean body weight and BMI decreased from baseline to month 6. From baseline to month 6, the adjusted mean body weight change (APTS, OC, ANCOVA) was-0.8 kg in the PBO group, -0.3kg in the BX20 group, and-0.5 kg in the BX30 group. The adjusted mean body weight loss in the BX20 and BX30 groups was not statistically significantly different from that in the PBO group.

Weight loss was reported as patient TEAE (PBO: 5%; BX 20: 8%; BX 30: 8%) in all treatment groups (group 45). Weight gain in the PBO group (1.8%) and BX30 group (1.2%) was reported as TEAE for the patients.

The adjusted mean weight change (APTS, LOCF, ANCOVA) from baseline to month 6 in patients with/without nausea and/or vomiting showed that patients in all groups lost weight regardless of their presence or absence of nausea and/or vomiting, although those patients who also had nausea and/or vomiting had greater weight loss (PBO: -0.6 vs. -1.9 kg; BX 20: -1.0 vs. -1.9 kg; BX 30: -1.1 vs. -2.3 kg).

Group 212 body weight, BMI and waist circumference measurements (APTS)

Group 213 body weight, BMI and waist circumference measurements Change from baseline (APTS)

Time required for deterioration

Clinical study 4：

The primary efficacy variable is the time required for deterioration, and the analysis is based on FAS. The primary efficacy analysis excluded the assumption that the time required for schizophrenia to worsen was equal in the 3 treatment groups (p ═ 0.008). The proportion of patients with exacerbations was 59% in the PBO group, 41% in the BX20 group, and 38% in the BX30 group. The Cox proportional hazards model yields estimated hazard ratios of 0.66(BX20) and 0.65(BX30) relative to PBO; that is, the risk of deterioration is about 1.5 times greater for patients in the PBO group than for patients in the BX20 or BX30 group.

Subsequent pairwise comparisons of each BX and PBO groups showed that patients in the BX group had a statistically significantly longer time to worsening schizophrenia than patients in the PBO group (BX 20: p ═ 0.008, and BX 30: p ═ 0.006). Primary efficacy analysis was repeated for PPS. Since most patients in PPS participated in the majority of the study, the results were very close to those of the primary analysis for the estimated risk ratio and the obtained p-value. This illustrates the robustness of the primary efficacy analysis conclusions.

Group 25 time series test for time required to analyze deterioration-Total test (FAS)

Lipid profile

Clinical study 4: the adjusted mean HDL cholesterol values increased from baseline to month 6 in all 3 treatment groups regardless of fasting/non-fasting conditions (PBO: 0.04/0.06 (fasting/non-fasting); BX 20: 0.07/0.08; BX 30: 0.07/0.08 mmol/L). There were no statistically significant differences between any of the BX and PBO groups. The adjusted mean triglyceride values decreased from baseline to month 6 in all 3 treatment groups regardless of fasting/non-fasting conditions (PBO: -0.06/-0.22 (fasting/non-fasting); BX 20: -0.16/-0.21; BX 30: -0.37/-0.03 mmol/L). There was no statistically significant difference between any of the BX groups (except BX30 (fasted)) and the PBO group.

The adjusted mean fasting glucose values increased from baseline to month 6 in all 3 treatment groups (PBO: 0.10; BX 20: 0.13; BX 30: 0.09mmol/L) and there was no statistically significant difference between any of the BX and PBO groups.

The following group 50 summarizes the lipid profiles in fasting and non-fasting patients at baseline (mean) and month 6 (mean change from baseline). Regardless of treatment and fasting/non-fasting conditions, the calculated mean total cholesterol and mean LDL decreased from baseline to month 6 in all groups (except non-fasting PBO patients). Regardless of treatment and fasting/non-fasting conditions, the calculated mean VLDL and mean triglycerides decreased from baseline to month 6 in all groups (except for non-fasting BX30 patients). Mean HDL increased from baseline to month 6 in all groups regardless of treatment and fasting/non-fasting conditions.

Group 50 lipid profile

Mean change from baseline to month 6

b see also Table 197 for direct LDL (measured in 12 patients at baseline (PBO: 2; BX 20: 5; BX: 5) and 1 patient at month 6(BX 20)).

Hyperglycemia and diabetes

Hyperglycemia, which is extreme in some cases and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. In a 6 week placebo-controlled trial, the incidence of hyperglycemia and diabetes-related adverse events (e.g., hyperglycemia, elevated blood glucose, impaired glucose tolerance, diabetes, poorly controlled diabetes) was 0.5% in patients treated with bifeprunox (5/1050) and 0.6% in patients treated with placebo (3/469). In the 26-week, placebo-controlled trial, no patients reported hyperglycemia or diabetes-related adverse events. The assessment of the relationship between the use of atypical antipsychotics and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes in schizophrenic patients and an increased incidence of diabetes in the general population. Due to these confounding factors, the relationship between the use of atypical antipsychotics and the adverse events associated with hyperglycemia is not fully understood. However, epidemiological studies not involving bifeprunox suggest that the risk of hyperglycemia-related adverse events emerging from treatment is increased in patients treated with atypical antipsychotics included in these studies. Since bifeprunox was not marketed when these studies were conducted, it was not known whether bifeprunox was associated with this increased risk. In patients treated with atypical antipsychotics, an accurate risk assessment regarding hyperglycemia-related adverse events is not available.

PR、QT、QTc、QRS

Clinical study 1: changes in PR, QT, QTc, QRS interval and heart rate over time were assessed by evaluating the mean change between baseline and endpoint. In any treatment group, the mean change between baseline and endpoint with respect to PR, QTc or QRS interval was very small. The average change for these intervals is about-2 to 4 milliseconds. There was no trend in the change in mean values by treatment group. The change in mean heart rate between baseline and endpoint was-1.5 bpm to 0.9 bpm. There was no trend in the change in mean values by treatment group.

Clinical study 2: changes in PR, QT, QTc, QRS interval and heart rate over time were assessed by evaluating the mean change between baseline and endpoint. In any treatment group, the mean change between baseline and endpoint with respect to PR, QTc or QRS interval was very small. The range of changes between treatment groups with respect to mean values was: PR ═ 2.5 to 0.2 milliseconds; QT-2.8 ms to 7 ms, QTc-0.4 ms to 3.9 ms; QRS ═ 0.4 ms to 1.4 ms. There was no trend in the change in mean values by treatment group. The mean heart rate varied between the treatment groups from baseline to endpoint by approximately-1.3 bpm to 1.7 bpm. There was no trend in the change in mean values by treatment group.

Clinical study 3: changes in PR, QT, QTc, QRS interval and heart rate over time were assessed by evaluating the mean change between baseline and endpoint. For these summaries, the Baze t corrected QT interval is denoted QTc. In any treatment group, the mean change between baseline and endpoint with respect to PR, QTc or QRS interval was very small. The average change for these intervals is about 3 to 4 milliseconds. There was no trend in the change in mean values by treatment group. The change in mean heart rate between baseline and endpoint was-1 bpm to 1 bpm. There was no trend in the change in mean values by treatment group.

Example 3 a: pharmacokinetics of bifeprunox

The objective of this study was to evaluate the Pharmacokinetics (PK) of bifeprunox. PK of bifeprunox in healthy subjects was studied based on a pooled analysis of PK parameters from 21 clinical pharmacology studies. The pooled analysis included PK profiles following single and multiple dose administration to 132 and 399 subjects, respectively, and the potential impact of age, sex, weight and race was explored. In addition, PK in schizophrenic patients was studied using a population PK approach based on samples from 376 patients in phase II studies and 434 patients in phase III studies.

Bifeprunox is rapidly absorbed after oral administration (at all dose levels, t_{Maximum of}1.5-2 hours). Bifeprunox multidose PK is dose proportional in the range of 20-40 mg/day. The steady state average apparent clearance and apparent volume of the distribution were 62.2L/hr and 1300L, respectively. Bifeprunox was eliminated with a mean plasma steady state half-life of 14.4 hours. 40mg dose was administered with a standard high fat meal with t_{Maximum of}Slight delay of (1.5 hours) and C_{Maximum of}(10%) correlated with a small increase in AUC (29%). Bifeprunox binds to serum proteins at approximately 99%. Bifeprunox is metabolized by CYP2C9, CYP3a4, and to a lesser extent CYP2D 6. Bifeprunox exposure was increased by co-administration with fluconazole (CYP2C9 inhibitor) and to a lesser extent with ketoconazole (CYP 3a4 inhibitor), but not with paroxetine (CYP 2D6 inhibitor) and famotidine (H2-antagonist). Bifeprunox exposure was reduced by co-administration with carbamazepine (CYP 3a4 inducer). Co-administration of warfarin and lithium (see example 3b) compounds with bifeprunox, which are therapeutic index narrowing, did not affect the PK of these compounds to any relevant extent. In slow/intermediate metabolisers (metabolizers) of CYP2C9, higher plasma levels of bifeprunox were observed than in subjects with normal enzymatic activity. At [14C]After a single oral dose of labeled bifeprunox, 13% and 74% of radioactivity was excreted in urine and feces, respectively. No clinical significance was notedAge, sex, weight or ethnicity related effects on bifeprunox PK. PK in schizophrenic patients is similar to that seen in healthy subjects.

One conclusion of this study was that bifeprunox is rapidly absorbed following oral administration; the mean elimination half-life was about 14 hours. Multiple doses of PK were in the range of 20-40mg in proportion to the dose. Bifeprunox has a low interaction potential.

Example 3 b: pharmacokinetic interaction of lithium with bifeprunox in healthy male subjects

The purpose is as follows: bifeprunox, a partial agonist of dopamine D2 and 5-HT1A receptors, is being developed for the treatment of schizophrenia. Since bifeprunox can be used in combination with lithium as a mood stabilizer for the treatment of psychotic and mood disorder patients, the effect of multiple doses of bifeprunox on the Pharmacokinetic (PK) profile of lithium was evaluated. Lithium has a therapeutic index that can complicate treatment of stenosis, and serum levels greater than 1.5mmol/L result in greater lithium toxicity risks than lower levels.

The method comprises the following steps: this was a single-centered, double-blind, randomized, placebo-controlled, parallel-designed study in 48 healthy male subjects. All subjects received labeled published (open-label) lithium (450mg) twice daily on days 1 to 8, provided that serum levels were stable on days 5 to 7, and repeated on days 9 to 20. Subjects whose serum levels were stable on days 5 to 7 were included in those randomized to receive a placebo or an increased dose of bifeprunox (0.025-40mg) once daily on days 9 to 17 in addition to lithium 450mg twice daily and placebo or bifeprunox 40mg on days 18 to 21. A single morning dose of lithium 450mg was administered on day 21 only. Lithium, steady state Cmax, AUC over dosing interval (0-t), and renal clearance (CL-R) values were compared between bifeprunox and placebo groups using ANCOVA with baseline values of lithium measured on day 8 as co-variables.

As a result: there was a small increase in the mean Cmax and AUC (0-t) of lithium in the bifeprunox group, but the ratio of the geometric least squares and 90% Confidence Interval (CI) for the two treatments for AUC, Cmax and CL-R were within a predetermined range of 0.80-1.25. The therapeutic ratios and 90% CI for Cmax, AUC (0-t) and CL-R were 1.11 (90% CI: 1.01-1.20), 1.13 (90% CI: 1.06-1.21), and 0.94 (90% CI: 0.87-1.02), respectively. Bifeprunox and lithium 450mg administered twice daily in combination until 40 mg/day are well tolerated.

And (4) conclusion: co-administration of multiple doses of bifeprunox had no clinically relevant effect on lithium steady state pharmacokinetics. The results suggest that no dose adjustment of lithium is required during concomitant administration with bifeprunox.

Example 4: efficacy and safety of bifeprunox in treating patients with acute worsening schizophrenia

The purpose is as follows: to evaluate the efficacy and safety of bifeprunox in treating patients with acute schizophrenia.

The method comprises the following steps: a dose-finding study of 6 weeks randomized, placebo-controlled, risperidone-referenced included 589 randomized patients with acute exacerbations of schizophrenia (DSM-IV-TR). Patients were randomly assigned to bifeprunox 5mg (n-115), bifeprunox 10mg (n-120), bifeprunox 20mg (n-115), placebo (n-119) or risperidone 6mg (n-120). Treatment with all bifeprunox doses was titrated up to the target dose, first with a dose of 0.125mg on day 1, 0.25mg on day 2, 0.5mg on day 3, 1mg on day 4, 2mg on day 5, and 5mg on day 6, 10mg on day 7, or 20mg on day 8, while treatment with risperidone was titrated over 3 days. The change in the total score of the positive and negative symptom scales (PANSS) from baseline to endpoint is a primary outcome measure. Secondary efficacy measures include: PANSS positive, PANSS negative, PANSS general psychopathology (GPP) score, PANSS derived Brief Psychosis Rating Scale (BPRS) score, clinical global impression-disease severity (CGI-S), CGI-improvement (CGI-I) score, and responder ratio. Safety and tolerability assessments included extrapyramidal symptoms (EPS), weight gain, lipid profile, and serum prolactin. Risperidone was included for determination of sensitivity.

As a result: the reduction in PANSS total score for bifeprunox was statistically significant (P < 0.05) compared to placebo at weeks 3 and 6/end for the 20mg dose. A positive effect of bifeprunox 20mg on secondary efficacy measures PANSS positive, negative, GPP subtotal, BPRS and responder rates was also observed. For all efficacy measures, risperidone 6mg was statistically significant at the endpoint compared to placebo. The most common adverse events (incidence > 5%, and 2 for placebo) included: dyspepsia, nausea, vomiting and constipation. The dose relationship is not obvious for any of the most common adverse events. Bifeprunox is associated with reduced prolactin levels and with EPS rates comparable to placebo. Furthermore, patients receiving bifeprunox experienced a statistically significant (P < 0.05) weight loss compared to placebo and showed statistically significant improvement in non-fasting triglycerides (P < 0.005) and total cholesterol (P < 0.005).

And (4) conclusion: in this study, bifeprunox 20mg was shown to be effective in treating acute schizophrenia. Bifeprunox may have safety advantages resulting from a reduction in body weight and an improvement in lipid profile.

Claims (45)

1. A daily dose of bifeprunox for treating a patient having a CNS disorder, wherein the dose is 20-30mg of at least one bifeprunox compound.

2. The dose of claim 1 for use in treating a schizophrenia patient.

3. The dose of claim 1 or 2, wherein the dose is a once daily dose.

4. The dose according to any one of claims 1 to 3, for the long-term treatment of patients with schizophrenia.

5. The dose of any one of claims 1 to 4 for use in maintaining clinical stability in a schizophrenic patient.

6. The dose of claim 5, wherein said dose is 20mg of at least one bifeprunox compound.

7. The dose of claim 5, wherein said dose is 30mg of at least one bifeprunox compound.

8. The dose according to any one of claims 1 to 3, for use in the treatment of a patient with acute worsening schizophrenia.

9. The dose of claim 8, wherein said dose is 20mg of at least one bifeprunox compound.

10. The dose of any one of claims 1-9, wherein the bifeprunox compound is bifeprunox mesylate.

11. The dose of claim 10, wherein said bifeprunox compound is the alpha polymorph of bifeprunox mesylate.

12. A pharmaceutical composition for use in treating a patient with schizophrenia comprising 30mg of at least one bifeprunox compound and at least one pharmaceutically acceptable carrier.

13. A pharmaceutical composition for use in treating a patient with schizophrenia comprising 20mg of at least one bifeprunox compound and at least one pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 12 or 13 for use in the long-term treatment of patients with schizophrenia.

15. The pharmaceutical composition of any one of claims 12-14 for use in maintaining clinical stability in a schizophrenic patient.

16. The pharmaceutical composition of claim 12 or 13 for use in treating a patient with acute worsening schizophrenia.

17. The pharmaceutical composition of any one of claims 12-16, wherein said bifeprunox compound is bifeprunox mesylate.

18. The pharmaceutical composition of claim 17, wherein said bifeprunox compound is the alpha polymorph of bifeprunox mesylate.

19. Bifeprunox for the long-term treatment of patients with schizophrenia.

20. Bifeprunox for use according to claim 19 in the treatment of patients with stable schizophrenia.

21. Bifeprunox for the treatment of patients with stable schizophrenia.

22. Bifeprunox for use according to any one of claims 19 to 21, wherein at least one bifeprunox compound is administered to said patient in a daily dose of 20 to 30 mg.

23. Bifeprunox for use according to claim 22, wherein said patient is administered a daily dose of 20mg of at least one bifeprunox compound.

24. Bifeprunox for use according to claim 22, wherein said patient is administered a daily dose of 30mg of at least one bifeprunox compound.

25. Bifeprunox for use in the treatment of patients with acute exacerbation of schizophrenia.

26. Bifeprunox for use according to claim 25, wherein said patient is administered a daily dose of 20mg of at least one bifeprunox compound.

27. Bifeprunox for use according to claim 25, wherein said patient is administered a daily dose of 30mg of at least one bifeprunox compound.

28. Bifeprunox for use according to any one of claims 19 to 27, wherein at least one bifeprunox compound is administered in combination with a lithium mood stabilizer.

29. Bifeprunox for use in treating a patient having a psychiatric and mood disorder wherein at least one bifeprunox compound is administered in combination with a lithium mood stabilizer.

30. Bifeprunox for use according to any one of claims 19-27, wherein at least one bifeprunox compound is administered in combination with an antidepressant.

31. Bifeprunox for use according to claim 30 wherein said antidepressant is paroxetine.

32. The bifeprunox of any one of claims 19-31, wherein said bifeprunox compound is bifeprunox mesylate.

33. The bifeprunox of claim 32, wherein said bifeprunox compound is the alpha polymorph of bifeprunox mesylate.

34. A kit for treating a patient having a psychiatric and mood disorder comprising a composition comprising at least one bifeprunox compound and a composition comprising a lithium mood stabilizer.

35. A kit for treating a patient having a CNS disorder comprising a composition comprising at least one bifeprunox compound and a composition comprising an antidepressant.

36. The kit of claim 35, wherein said antidepressant is paroxetine.

37. The kit of any one of claims 34-36 wherein said bifeprunox compound is bifeprunox mesylate.

38. The kit of claim 37 wherein said bifeprunox compound is the alpha polymorph of bifeprunox mesylate.

39. Use of bifeprunox in the manufacture of a medicament for the treatment of a patient with schizophrenia, wherein said patient is administered a daily dose of 20-30mg of at least one bifeprunox compound, and said treatment results in a favorable metabolic profile.

40. The use according to claim 40, wherein the treatment of a schizophrenic patient with bifeprunox avoids and/or reduces side effects selected from the group consisting of weight gain, disturbances in triglyceride levels and/or total cholesterol levels, hyperglycemia and/or the occurrence of one or more diabetes-related adverse events.

41. Use of bifeprunox in the manufacture of a medicament for treating a patient having stable schizophrenia, wherein the patient is administered a daily dose of 20-30mg of at least one bifeprunox compound.

42. Use of bifeprunox in the manufacture of a medicament for treating a patient having acute worsening schizophrenia, wherein the patient is administered a daily dose of 20-30mg of at least one bifeprunox compound.

43. The use of any one of claims 39-42 wherein the bifeprunox compound is bifeprunox mesylate.

44. The use of claim 43, wherein said bifeprunox compound is the alpha polymorph of bifeprunox mesylate.

45. Bifeprunox for the treatment of schizophrenic patients with or prone to weight problems.