Safety and Efficacy of EN3835 in Participants With Frozen Shoulder

A Phase 2, Randomized, Double Blind, Placebo Controlled Study of the Safety and Efficacy of EN3835 for the Treatment of Adhesive Capsulitis of the Shoulder

This study will evaluate the safety and efficacy of EN3835 for the treatment of adhesive capsulitis of the shoulder (frozen shoulder).

Inclusion Criteria:

1. Have idiopathic unilateral adhesive capsulitis (also known as frozen shoulder).
2. Have unaffected range of motion in the contralateral shoulder as determined by the investigator.
3. Be willing to undergo x-ray and magnetic resonance imaging (MRI) of both affected and unaffected shoulder.
4. Agree to participate in supervised, in-office physical therapy sessions and to complete home exercises at designated time points during the study.
5. Agree to avoid general lifting and carrying during the study as instructed.
6. Be able to read, understand, and independently complete participant reported outcome instruments in English.
7. If female, be of non-childbearing potential (history of hysterectomy, bilateraloophorectomy, bilateral tubal ligation, or postmenopausal with no history of menstrual flow in the 12 months prior to the Screening Visit); or, if of childbearing potential, be non-pregnant, non-lactating and agree to use effective contraception when with a male partner for the duration of the study (and for 28 days after any active treatment period for participant who early terminate). Acceptable forms of contraception include hormonal measures (oral contraceptive pills, contraceptive patch, contraceptive ring, and injections), intrauterine devices, double barrier method (condom plus diaphragm, condom or diaphragm plus spermicidal gel or foam), surgical sterilization of the male partner, and abstinence.
8. If male with reproductive potential, agree to use effective contraception (abstinence, surgical sterilization [vasectomy], or condom with spermicide) with a female partner of child-bearing potential for the duration of the study (and for 28 days after any active treatment period for participant who early terminate).
9. Be willing and able to cooperate with the requirements of the study.
10. Be adequately informed and understand the nature and risks of the study and be able to provide consent .

Exclusion Criteria:

1. Has a known allergy to collagenase or any other excipient of EN3835 or any other procedural medication (including local anesthetics).

2. Has received treatment for adhesive capsulitis (in the timeframes outlined below) or is planning to receive any treatment (other than study treatment) for adhesive capsulitis at any time during the study in the affected shoulder, including but not limited to:

   • Physical therapy or acupuncture within 2 weeks before the first injection of study treatment.
   • Intra-articular or intrabursal injection(s) of lidocaine, suprascapular nerve blocks, or electroanalgesic and/or thermoanalgesic modalities within 1 month before the Screening Visit.
   • Intra-articular or intrabursal injection(s) of corticosteroids within 8 weeks before the Screening Visit.
   • Intra-articular or intrabursal injection(s) of sodium hyaluronate and/or glenohumeral distension arthrography within 3 months before the Screening Visit.
   • Manipulation under anaesthesia at any time prior to the study.
   • Surgery (including arthroscopic or open capsular release, capsulectomy, or capsulotomy) at any time prior to the study.

3. Has any abnormalities/conditions in the affected shoulder that would be potentially confounding as determined by the central MRI review committee grading criteria.

4. Has a prosthesis or replacement of right or left shoulder, elbow, wrist, and/or hand.

5. Has systemic conditions (malignancy, hypertension, diabetes, thyroid disease, thrombosis, physical impairment, infection, significant medical condition) that restricts study participation.

6. Has any contraindications for MRI (implant containing metal, internal metallic object, permanent cosmetics/make-up/tattoos, claustrophobia, anemia, uncontrolled hypertension, epilepsy, asthma, sickle cell disease) as determined by the technologist, the radiologist, and/or investigator performing the imaging, with exemption of the area to be treated/reviewed.

7. Has a known coagulation disorder or is taking any medications that would increase the risk of bleeding (except <150 milligrams of aspirin daily), 7 days prior to first injection and for the duration of the study.

8. Has received oral or parenteral steroids for any reason within 3 weeks before the Screening Visit.

9. Has, at any time, received collagenase for the treatment of adhesive capsulitis (including participant who received treatment in Study AUX-CC-870 or AUX-CC-871).

10. Has received treatment with an investigational product within 30 days (or 5 half lives, whichever is longer) of the screening visit.

11. Has received collagenase treatments (for example, Santyl® ointment and/or XIAFLEX/XIAPEX®) for any other indication within 30 days prior to study treatment administration, or is planning to be treated with collagenase (other than study treatment) at any time during the study.

12. Has donated blood within 30 days prior to the Screening Visit or has plans to donate blood during the study.

13. Has a corrected QT interval (QTc) of ≥ 450 milliseconds (ms) for male participant or ≥470 ms for female participant on the screening electrocardiogram (ECG).

14. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) Title 45, Part 46, Section 46.111(b) and other local and national regulations, including but not limited to, employees (temporary, part-time, full-time, etc) or a family member of the research staff conducting the study, or of the sponsor, or of the contract research organization, or of the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).

15. Has concurrent diseases that might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the participant's well-being, (for example, evidence of any significant hematological, endocrine, cardiovascular, respiratory, neurological, renal, hepatic, or gastrointestinal disease). If there is a history of such disease but the condition has been stable for more than 5 year(s) and is judged by the investigator not to interfere with the participant's participation in the study, the participant may be included, with the documented approval of the Medical Monitor.

16. Has any other condition(s) that, in the investigator's opinion, might indicate the participant to be unsuitable for the study.