HK1115295B - Methods for treating adhesive capsulitis - Google Patents

Description

Method for treating adhesive capsulitis

RELATED APPLICATIONS

The advantages of U.S. provisional application No.60/645,772, filed on 21/2005, U.S. provisional application No.60/677,440, filed on 3/5/2005, and U.S. provisional application No.60/719,470, filed on 22/9/2005, as claimed in claim 2005. The entire teachings of the above application are incorporated herein by reference.

Government support

The invention is supported by the national institutes of health, Grant MO1RR 10710. The government has certain rights in this invention.

Background

Adhesive capsulitis (fifty shoulders) is a severely painful clinical syndrome and significantly reduces shoulder movement, which may occur congenital, after injury or in patients with diabetes and/or thyroid disease. The duration of the condition can range from months to years and seriously affects quality of life. Longer physical treatments, sometimes including cortisone injections and/or manual treatments under anesthesia and/or arthroscopic shoulder surgery, are currently the standard for orthopedic treatment. However, more effective treatments are needed.

Disclosure of Invention

The present invention relates to the discovery that collagenase injections are effective in dissolving collagen adhesions in the shoulder capsule and treating the condition, adhesive capsulitis. As such, the present invention relates to a method of treating or preventing adhesive capsulitis, or fifty shoulders, in a patient in need of such treatment comprising injecting or otherwise delivering an effective dose of collagenase to the collagen adhesions in the shoulders. The invention also relates to the use of collagenase in a pharmaceutical product for the treatment of adhesive capsulitis.

Brief Description of Drawings

Fig. 1 is a bar graph reporting improved mobility, or voluntary elevation, in 12 patients receiving 1/3 collagenase injection therapy.

Figure 2 is a graph of normal shoulder movement pattern vs. collagenase dose group.

FIG. 3 is a graph of shoulder motion pattern after a 0.58mg injection of open collagenase.

FIGS. 4A-4EE are graphs and histograms depicting data obtained in the clinical trials described herein.

Detailed Description

The present invention relates to the discovery that collagenase injections into the shoulder capsule are effective in dissolving the collagen adhesions and treating the condition, adhesive capsulitis. As such, the present invention relates to a method of treating or preventing adhesive capsulitis, or frozen shoulder, in a patient in need of such treatment comprising injecting or otherwise delivering an effective amount of collagenase to the collagen adhesions in the shoulder capsule. The invention also relates to the use of collagenase in a pharmaceutical product for the treatment of adhesive capsulitis.

Collagenase injections have been proposed for the treatment of diseases, such as Duptyren's disease and Peyronie's disease. Two diseases are associated with collagen plaques or spinal cord. Wegman, Thomas L, 1996, 31/12, U.S. Pat. No.5,589,171, 11/7/2000, U.S. Pat. No.6,086,872, 8/2/2000, U.S. Pat. No.6,022,539, incorporated herein by reference.

Collagenase is an enzyme with a particular ability to degrade collagen. One preferred form of collagenase is derived from the fermentation of Clostridium histolyticum and is purified by chromatographic techniques.

Sterile lyophilized collagenase powders with a minimum test of 50ABC unit/mg are commercially available. The test may suitably vary from batch to batch, but contemplates determining the weight of the powder to be used with a pharmaceutically acceptable carrier, such as physiological saline, to prepare the desired effect concentration for treatment.

Preferably, the collagenase composition comprises a mixture of collagenase I and collagenase II in a mass ratio of about 1:1 and has a specific activity of at least about 700SRC units/mg, such as at least about 1000SRCunit/mg, more preferably at least about 1500SRC units/mg. At 25 ℃, pH 7.4, one SRC u dissolved rat tail collagen in ninhydrin reactant equivalent to 1 nanomole leucine per minute. Collagenase is also described in ABC u. Collagenase efficacy testing was based on degradation of undenatured collagen (from bovine tendon) at pH 7.2 at 37 ℃ for 20-24 hours. The number of peptide bonds cleaved was measured by reaction with ninhydrin. The amino groups released by insulin degradation control were subtracted. A neat ABC u collagenase will dissolve the ninhydrin reactant equivalent to 1.09 nmol leucine/min. 1SRCu corresponds to about 6.3ABC u or 18.5GPA u.

The collagenase is preferably administered by injection in a pharmaceutically acceptable liquid carrier. The carrier preferably does not react with or inactivate collagenase. Examples are physiological saline, aqueous NaCl/CaCl2 buffered solutions (e.g., containing 0.9% NaCl and 2mM CaCl2), aqueous dextran solutions, and aqueous hydroxyethyl starch solutions. For example, a lyophilized formulation may contain 0.1mg lactose monohydrate/1,000 ABC u. Each vial used below contained 5,150ABCu enzyme.

According to the present invention, collagenase in a liquid carrier is injected into the collagen adhesions in the shoulder capsule. The dose and concentration of collagenase used is effective to soften and loosen or rupture adhesions.

The total volume of injected fluid preferably does not exceed about 0.50 ml. Smaller amounts down to about 0.25ml to about 0.1ml are generally more preferred.

Preferably, the injection is a sterile injection within the deltoid and pectoral spaces. For pain relief in the patient, a 5-10ml anesthetic injection of sterile 1% lidocaine is preferably performed prior to the collagenase injection.

The entire dose is preferably injected in one portion, although injection in two or more portions into the shoulder capsule at the same site or at different sites is possible, preferably intratumoral injection, or intraadhesion injection. The goal of these methods is to ensure a better distribution of the collagenase within the small amount of adhesions. Preferably, after injection, the patient wears the sling to secure the shoulder girdle for 5-6 hours. The patient is physically treated at home for about at least 1 month to help restore the normal range of shoulder motion.

In other embodiments, the collagenase may be administered topically and topically (e.g., via a transdermal patch or cream or salve), preferably at a location proximal to the affected shoulder joint or may be administered via infusion (e.g., microcapsules or microspheres that release collagenase over time).

The subject may be any animal, preferably a mammal or a human patient. Examples of animals to be treated in accordance with the present invention include livestock (e.g., cats, dogs, etc.), farm animals (e.g., horses, cows, pigs, etc.), and foreign animals (e.g., monkeys, apes, etc.). Preferably, the human patients are those with congenital, trauma followed by reduced shoulder joint movement or patients with diabetes and/or thyroid disease.

In one embodiment, the patient is characterized by extreme reduction in all azimuth shoulder joint motion, including active elevation, active internal rotation (the level of the spine reached at the back by the thumb), active external rotation, passive elevation, lateral passive external rotation, 90 ° external rotation, functional scoring. Pain rises to a level that interferes with daily living and reduces the quality of life. The present invention also improves or reduces pain or alleviates another symptom of the condition in all aspects of shoulder joint movement.

The same method, total amount and concentration of collagenase may be repeated even if the outcome of a single treatment is not considered sufficient. Successful clinical results were achieved with repeated injections at 4 to 6 week intervals.

Examples

Example 1

Method of producing a composite material

40 patients entered the study protocol, 11 males and 29 females, with a mean age of 52 ± 8.9 years. The average length of time for all patients with adhesive capsulitis was 16 months (varying between 2-144 months) at the time of initial description. 18 patients were congenital, 2 patients were type 1 diabetes and 6 patients were type 2 diabetes, 5 patients had hypothyroidism, 3 patients had hypothyroidism and diabetes, and two patients had post-traumatic adhesive capsulitis. After local anesthesia with 10ml of 2% lidocaine injection, all patients received a first randomized placebo-controlled double-blind injection of clostridial collagenase or placebo (0.9% saline with 2mM calcium) into the anterior capsule at a total volume of 0.5ml, 0.145mg, 0.29mg, or 0.58 mg. Patients were subjected to a one month continuous assessment based on the american society shoulder and elbow surgeon shoulder assessment chart assessing pain, shoulder motion, strength, stability and function. The degree of shoulder joint motion is assessed and measured by active/passive elevation, active/passive external rotation, 90 passive external rotation and active internal rotation (the level of the spine reached by the thumb). If the shoulder joint movement score or pain score is not statistically significant to the baseline value, the patient has the option to enter an additional open 0.58mg collagenase injection administration at 4-6 week intervals. Only 1 (randomized placebo double-blind) injection was obtained in 9 patients, and a second open 0.58mg collagenase injection was obtained in 30 patients. The control treatment protocol (dose response) for the first randomized placebo double-blind injection cannot be disclosed until all 60 patients have been enrolled. However, the results of open collagenase injections have shown clear and significant advantages. All patients were performed at 2 months, 3 months, 6 months, 9 months, 12 months and 24 months after the last injection, using the shoulder joint assessment format. The average time of follow-up survey was 10.8 ± 8.2 months. Statistical analysis consisted of testing student shoulder joint evaluation baseline mean changes.

Results

After the first randomized, placebo, double-blind injection, 30 of 40 patients required a short series of repeat open 0.58mg collagenase injections. Table 1 shows the mean increase in range of motion, function and pain of the affected shoulder joints relative to baseline parameters one month after the subsequent second and third injection follow-up investigations. All improvements were statistically significant, with p < 0.0001. Diabetic patients (n ═ 15) showed minor increases in active and passive external rotation, internal rotation (vertebral levels) and passive elevated baseline when compared to the naive patient (n-18). For example, for active external rotation at one month after the second injection, the average improvement in the innate patient is 31.4 ° ± 14.1 °, but only 20.5 ° ± 15.5 ° (p ═ 0.02) in diabetic patients. Patients with hypothyroidism and patients after injury show the same rate of recovery of shoulder joint movement relative to the innate patient. The improvement in shoulder motion, pain and function lasted longer with an average length of 10.8 ± 8.2 months.

Adverse reactions to injections included tenderness at the injection site in all patients and biceps ecchymosis in patients with approximately 2/3. These were not even alleviated within 7-14 days.

TABLE 1 treated shoulder and contralateral shoulder Baseline

Second injection (n ═ 30) third injection (n ═ 12)

Active elevation

Passively raised

Active external rotation

Passive external rotation

90 degree passive external rotation

Internal rotation (vertebral level) +5 level ± 3.8 level +6 level ± 4.8 level

Function +20 percentage points plus 8 percentage points plus 23.5 percentage points plus 11 percentage points

Division point

Pain 4 (mild)

Conclusion

Most patients (30 out of 40) required a short series of open (0.58mg) collagenase injections before significant improvement in shoulder joint movement, pain and function was observed following the first randomized, placebo, double-blind injection. Thus, regardless of the dose-response protocol of the first injection treatment that has not been observed, it is clear that collagenase injections of adhesive capsulitis have shown significant advantages. Open collagenase treatment results in a significant reduction in the time to return to painless function when compared to standard orthopedic treatment, which can last for months or even years. Phase 2 studies have shown that collagenase injection of the shoulder capsule is a safe and effective therapeutic approach to the treatment of adhesive capsulitis, ensuring that the study is continued within the FDA regulatory process.

Example 2

The FDA regulated, prospective, phase II, randomized, placebo controlled, double-blind, dose-response study was designed to create a non-surgical treatment for adhesive capsulitis (fifty shoulder) with collagenase injection therapy.

60 patients entered the study protocol, 47 women and 13 men, mean age 52 years, mean duration of adhesive capsulitis, 17 months. All patients received a first, randomized, placebo-controlled, double-blind, total extra-articular injection of 0.5ml of total volume of the anterior shoulder capsule, or saline (n-15), or 0.145mg (n-16), 0.29mg (n-15), or 0.58mg (n-14) collagenase. The patient underwent a one month continuous assessment of shoulder joint range, pain, and function for all azimuthal movements. At 1 month, if the motor, pain and functional scores were not significantly different from those before treatment, the patient had the option of receiving four additional 0.58mg collagenase injections at 4-6 week intervals.

In the part of the open study, for the first open procedure, except when 5,000u group, n is 9, active and passive elevation, for placebo, 2,500u, 5,000u, and 10,000u treatment groups, n is 13, 12, 9, and 10, respectively. For subjects tested for contralateral shoulder joints, in the first open course, for placebo, 2,500u, 5,000u, and 10,000u treatment groups, n is 10, 8, and 8, respectively. For the second open course, for subjects tested for contralateral shoulder joints, for placebo, 2,500u, 5,000u, and 10,000u treatment groups, n is 4, 5, 3, and 5, respectively. The three objects in the resulting data are 1/3 for the data.

The results of the randomized placebo-controlled, dose-response study showed that there was a statistically significant difference in drug treatment vs. placebo in the restoration of normal shoulder joint movement and function. Most patients required a second (n ═ 19) and third (n ═ 19), open 0.58mg collagenase injections and continued to show significant improvement in movement, function and pain. This study has shown that a short series of collagenase injections into the shoulder capsule is a safe and effective therapeutic approach to the treatment of adhesive capsulitis, ensuring continued research within the FDA regulatory process.

60 patients completed all 30-day visits during the double-blind period and provided data for statistical analysis. The placebo, 2,500u, 5,000u, and 10,000u treatment sample sizes were 15, 16, 15, and 14, respectively. Of those 60 subjects, 46 subjects had contralateral shoulder baseline data: there were 12, 10, 12, and 12 subjects in the placebo, 2,500u, 5,000u, and 10,000u treatment groups, respectively.

TABLE 1 treated shoulder and contralateral shoulder Baseline

Second injection third injection

(n＝46) (n＝60)

Active elevation (degree) 166.9 + -12.4112.1 + -19.6

Positive external rotation (degree) 77.1 + -14.026.6 + -16.7

Active internal rotation (vertebral level) 14.4 + -3.65.3 + -2.34

Passive elevation (deg.) 175.3 + -8.1130.4 + -17.2

Passive external rotation (degree) 86.1 + -10.028.0 + -18.0

Passive external rotation (degree) of 90 deg. 103.8 + -11.169.4 + -15.3

Function (0-60 grade) 60.0 + -032.0 + -7.6

Pain (0-5 grade) 5.0 + -02.0 + -0.9

For the protocol definition success criteria, no outcome measure approaches the statistical significance of any effective treatment relative to placebo. One may want to know if the success criteria are too stringent for this study from the protocol definition proposed in the published standards. Contralateral shoulder joints appear to not support that standard in contrast to published standards. For example, the protocols for active elevation and active rotation (spinal level) define standards of 160 ° and 10 °, respectively, but from table 1, the subject in this study has two results measuring better functionality for the contralateral shoulder joint than is prescribed by the published standards.

TABLE 2 mean of 30-day double-blind follow-up to adjust treated shoulder Baseline

Placebo 2,500u 5,000u 10,000u

(n＝15) (n＝16) (n＝15) (n＝14)

Active elevation (degree) 124.5131.9130.2139.7

Active external rotation (deg.) 42.442.352.6 x 48.6

Active internal rotation (vertebral level) 8.08.48.47.9

Passive elevation (degree) 145.5145.2148.6145.9

Passive external rotation (deg.) 44.549.355.659.5

Passive external 90 deg. (deg.) rotation of 83.881.789.487.9

Function (0-60 rating) 43.044.248.649.8

Pain (0-5 scale) 3.33.43.93.4

*P≤0.05

Covariance analysis adjusts the different baseline values of the double-blind stage treatment method so that, in fact, each treatment has the same pattern for the shoulder joint being treated. Adjusted accordingly, 4 of the 8 assayed items analyzed showed a therapeutic activity of 5,000u or 10,000u (table 2). The 10,000u dose showed activity on active elevation, passive elevation, and functional scores relative to placebo. 5,000u treatment showed activity on active external rotation. It is noteworthy that for each of those four assays, subjects in the placebo group had the most adverse or nearly the most adverse results on average compared to any of the positively treated groups.

The exploratory analyzed open data supports double-blind data of covariance analysis results.

After one open course of treatment, subjects received a total of 10,000u, 12,500u, 15,000u, or 20,000u of collagenase, depending on their treatment group in the double-blind stage. For active elevation, the change in the baseline of the shoulder joint or the baseline of the contralateral shoulder joint being treated is consistent with active collagenase treatment. For example, relative to the treated shoulder baseline, active elevation increased by 43.6 ° for the 10,000u group and only 28.3 ° for the placebo group. For the functional score, the 10,000u group increased 21.6 percentage points on a 60 percentage point scale relative to 20.6 percentage points for the improvement in placebo group. Some measurements showed more improvement in the placebo group than the collagenase treated group. For example, for active external rotation, the group in the double-blind phase (n-15) receiving placebo treatment had a 35.2 ° change after one course of open treatment (n-13 subjects continuing from the double-blind phase) over pre-treatment, but the group in the double-blind phase (n-14) receiving 10,000u treatment changed only 27 ° after an additional 10,000u treatment over pre-treatment (n-10 subjects continuing from the double-blind phase).

Discussion of the related Art

This study demonstrated that a single collagenase injection of 2,500, 5,000, or 10,000u was more effective in treating adhesive capsulitis than the placebo injection. The protocol established two "success" criteria for 11 measurements, which were clearly not met. The protocol also enacted a more sensitive analysis of the data using covariance analysis and that method provided evidence that collagenase was active in this study.

Eight of the measurement items were analyzed using covariance analysis and four of the eight provided evidence of collagenase activity. Placebo had an active elevation, passive elevation, and functional score of p <0.05 compared to 10,000u treatment. Active external rotation, 5,000u treatment had p <0.05, although 10,000u dosing was not achieved. For passive 90 ° external rotation, while the p-value for this difference was ≧ 0.05, placebo had an adjusted mean of 83.8 ° as compared to an adjusted mean of 87.9 ° for 10,000u treatment. Three other test items: active internal rotation (spinal level), passive elevation, and pain scores are not at all sensitive to some collagenase effects, and placebo and collagenase effects are very similar.

The gold standard in the clinical trial was a protocol specific analysis of data collected in randomized, placebo-controlled, double-blind studies, with evidence that collagenase is active in adhesive capsulitis, as discussed above.

In addition to evidence collected from gold standards, supportive or exploratory analysis may provide important corroboration. The open part of the study, especially scoring for active elevation and function, corroborates the double blind part. The open part of the study suggests that additional injections may be beneficial.

Conclusion

Analysis of test items of active elevation, active external rotation, passive elevation and functional scoring, such as covariance analysis of double-blind data, showed evidence of activity in shoulder adhesive capsulitis. The three collagenase doses administered in this study did not meet the criteria for a successful protocol definition, so it could not be concluded that a single injection of collagenase was effective, even at the highest dose of 10,000 u.

Example 3

Shoulder joint motion was improved but not normalized at one month after the first randomized, placebo-controlled, double-blind injection in all 60 patients. The highest collagenase dose (0.58mg) tended to be the most effective (figure 2). Placebo function score reached 70% of normal, collagenase function score reached 73%, 0.29mg dose function score reached 81% and 0.58mg dose function score reached 83%. The placebo pain score and 0.145mg dose pain score reached 66% of normal, and the 0.29mg and 0.58mg dose standard pain scores were both 74%. The posterior spinal level achieved with placebo treatment (active internal rotation) was L3 and all collagenase dose treatments were L2. The normal spinal level reached is T8. Only 14 patients were given the first injection because they returned to normal after one month.

23 patients underwent a second open injection consisting of 0.58mg collagenase. Active elevation, active external rotation, active internal rotation, passive elevation, lateral passive elevation, 90 ° passive elevation, the improvement in function and pain scores was significant (p <0.01) and evident, with follow-up after the start of open injection (figure 3). In fig. 3, the 0-antenna baseline value is indicated. The Y-axis is the normal value. At one month post-injection, all parameters reached normal values based on the unaffected contralateral mode. Minor changes in all parameters were followed for several months throughout the disease observation. The 20 patients continued with a third open, 0.58mg collagenase injection. After one year, all parametric results were similar to those described in figure 2 for the second injection. These patients were followed up for 12 months.

Adverse reactions consisting of tenderness in the injection area and ecchymosis in the biceps were local and minimal. These were reduced within 7-14 days. There was no adverse immune response.

Conclusion

This study has shown that collagenase injection for the treatment of adhesive capsulitis is a novel method of early recovery of shoulder joint movement, function and pain relief. The highest dose (0.58mg) used tends to be the most effective in the control study. However, it is clear that short term injections with a dose of 0.58mg are more effective in open studies.

Additional results

It should be noted that the purpose of using the separation example is not to suggest that separate and distinct studies are preferable to separate analysis of the results. Of course, the present invention also relates to the results described in these results obtained using the collagenase preparations of the present invention. The results of these studies also included the data provided in the table below.

While the present invention has been particularly shown and described with reference to the preferred embodiments thereof, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined by the following claims.

Claims (9)

1. Use of collagenase in the manufacture of a medicament for the treatment or prevention of adhesive capsulitis in a subject in need of such treatment, wherein said collagenase is delivered to the adhesive joint capsule in the shoulder joint.

2. Use according to claim 1, wherein the collagenase is derived from Clostridium histolyticum.

3. The use according to claim 2, wherein the collagenase is injected in a dose of at least about 700SRC units.

4. Use according to claim 3, wherein collagenase in a volume of less than 0.5ml is injected.

5. Use according to claim 3, wherein the collagenase comprises collagenase I and collagenase II.

6. Use according to claim 4, wherein the injection is injected in the form of a single dose into the interval between the deltoid and pectoral muscles.

7. The use according to claim 1, wherein the subject is a human patient.

8. Use according to claim 7, wherein the patient is characterized by an active forward elevation of only 90 ° and an active external rotation of less than 50 °.

9. The use according to claim 1, wherein the patient achieves an active external rotation of greater than 15 ° after one month of receiving at least one collagenase administration as compared to before treatment.