Phase I/II Evaluation of Vibrio alginolyticus Collagenase for Safety and Efficacy in Dupuytren's Contracture Patients

The primary objective of this Phase I/II study is to evaluate the **safety** and tolerability profile of each tested escalating dose of Vibrio alginolyticus collagenase following one injection into the affected cord in the primary joint (MP or PIP) to identify the maximum tolerated dose in the absence of limiting toxicity. This dose will be tested in the Phase II part to evaluate its efficacy following up to three injections in terms of clinical success in patients with Dupuytren contracture, as compared to matching placebo. This is clinically relevant as it aims to establish a safe and effective treatment regimen for Dupuytren contracture, a condition characterized by progressive hand deformity.

Secondary objectives include: - Evaluating the efficacy of each escalating dose in Phase I in terms of clinical success and improvement. - Assessing the efficacy of up to three injections in Phase II in terms of clinical improvement and success compared to placebo. - Determining the mean number of injections required for clinical success and the median time to achieve and maintain clinical success. - Evaluating the reduction in contracture degree from baseline and the efficacy of each injection in terms of clinical improvement. - Assessing the safety and tolerability profile of up to three injections. - Evaluating the serum pharmacokinetic and immunogenic profiles following each injection.

The clinical trial focuses on evaluating the safety, tolerability, and efficacy of V. alginolyticus collagenase in individuals diagnosed with **Dupuytren contracture**. The study population includes both male and female participants aged 18 years and older. Participants must have a fixed flexion deformity of 20° to 100° in a metacarpophalangeal (MP) joint or 20° to 80° in a proximal interphalangeal (PIP) joint, caused by a palpable cord. The trial does not involve a vulnerable population. Participants are required to provide informed consent and demonstrate full comprehension of the study's nature and purpose. Women of child-bearing potential must adhere to reliable contraception methods, and a negative pregnancy test is mandatory at screening and on Day 1 predose. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the trial details.

The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of **Vibrio alginolyticus collagenase** in patients diagnosed with **Dupuytren contracture**. This study is structured as a Phase I/II trial, incorporating a single ascending dose in Phase I followed by an expansion in Phase II. The trial employs a **randomized**, double-blind, placebo-controlled design to ensure the reliability and validity of the results. The estimated duration of the trial extends from September 2024 to July 2026, with participant involvement expected to last up to six months post-treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, diagnosis, and ability to comprehend the study's nature. Following successful screening, participants will be randomized to receive either the investigational product or a matching placebo. The trial will include multiple follow-up visits to monitor safety and efficacy outcomes, with assessments conducted at specified intervals, including 30±3 days and six months after the last injection. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any adverse events are addressed.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with study procedures, or withdraw consent. The primary endpoints focus on identifying the maximum tolerated dose in Phase I and achieving clinical success in Phase II, defined as a reduction in contracture to ≤5° within 30±3 days post-injection. Secondary endpoints include the proportion of patients achieving clinical improvement, changes in contracture degree, and the immunogenicity of the investigational product. The trial's rigorous design and comprehensive endpoint evaluation aim to provide valuable insights into the treatment of Dupuytren contracture with **Vibrio alginolyticus collagenase**.

The clinical trial involves the administration of **Vibrio alginolyticus collagenase**, an experimental medication formulated as a **solution for injection**. This investigational product is designed for **intralesional use** and is administered directly into the affected cord of patients with Dupuytren contracture. The primary objective in the Phase I part of the study is to evaluate the safety and tolerability profile of escalating doses of Vibrio alginolyticus collagenase, with the aim of identifying the maximum tolerated dose. In the Phase II part, the efficacy of the identified dose will be assessed following up to three injections. The active substance, Vibrio alginolyticus collagenase, is a protein derived from the bacterium Vibrio alginolyticus, and it functions as a proteolytic enzyme. The product is manufactured by FIDIA FARMACEUTICI S.P.A.

The study also includes a **placebo** control, which is a sterile lyophilised powder for injection that matches the experimental medication. The placebo is used to provide a comparator for evaluating the clinical success of the Vibrio alginolyticus collagenase treatment. The placebo is administered in the same manner as the experimental drug, ensuring that the study maintains a double-blind design. This allows for an unbiased assessment of the treatment's efficacy and safety. The placebo does not contain any active substance and serves as a control to help determine the true effects of the investigational product.

The efficacy of **Vibrio alginolyticus collagenase** in the treatment of Dupuytren contracture will be assessed through a series of primary and secondary endpoints in a Phase I/II clinical trial. In the Phase II part, the primary endpoint is the proportion of patients achieving clinical success, defined as a reduction in contracture to ≤5° within 30±3 days after the last injection, as measured by passive angle of finger extension, compared to a matching placebo. Secondary endpoints include the proportion of patients achieving a clinical improvement, defined as a reduction from baseline in contracture by ≥50% within 30±3 days after the last injection, and the mean number of injections required to achieve clinical success. Additionally, the median time to achieve and maintain clinical success, percentage change from baseline in contracture degree, and changes in the range of motion will be evaluated.

In both study parts, the blood exposure to **Vibrio alginolyticus collagenase** will be assessed by measuring serum levels at pre-dose and at several time points post-dose. Immunogenicity will be evaluated through the assay of serum anti-drug antibodies at pre-dose and 30±3 days post-dose. Follow-up endpoints include the percentage change from baseline in contracture degree and passive finger flexion six months after the last injection, as well as the safety profile and immunogenicity of the treatment. These assessments will provide comprehensive data on the efficacy and safety of the treatment regimen.