Phase I/II study to evaluate the efficacy and safety of bacterial collagenase administered in patients with Dupuytren's contracture.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fidia Farmaceutici S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

18 Dec 2024 → ongoing

Decision date (initial)

2024-10-20

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Fidia Farmaceutici S.p.A.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Dose response, Safety, Pharmacokinetic

Primary objective in the Phase I part:
-To evaluate the safety and tolerability profile of each tested escalating dose of V. alginolyticus collagenase
following one injection into the affected cord in the primary joint (MP or PIP) in order to identify the
maximum tolerated dose in the absence of limiting toxicity as defined for the dose escalating process and that
will be tested in the Phase II part

Primary objective in the Phase II part:
-To evaluate the efficacy of the dose identified in Phase I part, following up to three injections of V.
alginolyticus collagenase into the affected cord in terms of clinical success (expanded cohort) as compared to
matching placebo

Secondary objectives 13

1. Secondary objectives in the Phase I part: - To evaluate the efficacy of each escalating dose of V. alginolyticus collagenase following one single injection into the affected cord in terms of clinical success and clinical improvement
2. Secondary objectives in the Phase II part: -To evaluate the efficacy of up to 3 injections of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) in terms of clinical improvement of the Dupuytren contracture as compared to matching placebo
3. To evaluate the mean number of injections of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) necessary to achieve clinical success as compared to matching placebo
4. To evaluate the median time (in days) to achieve and maintain clinical success after the last injection of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) as compared to matching placebo. Clinical success can be achieved on Days 3, 7±1 and 30±3 after each injection (approximately Days 3, 7±1, 30±3, 32±3, 36±3, 60±3, 62±3, 66±3 and 90±3 if up to 3 injections are performed)
5. To determine the reduction from baseline in contracture degree after the last injection of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) as compared to matching placebo
6. To evaluate the efficacy of each injection (up to 3 injections) of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) in terms of clinical success in the treatment of the Dupuytren contracture as compared to matching placebo
7. To evaluate the efficacy of each injection (up to 3 injections) of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) in terms of clinical improvement of the Dupuytren contracture as compared to the matching placebo
8. To evaluate the safety and tolerability profile of up to 3 injections of V. alginolyticus collagenase or matching placebo into the affected cord
9. Follow-up objectives in the Phase II part:  To evaluate the efficacy of up to 3 injections of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) in terms of change from baseline in contracture degree at 6 months from the last injection as compared to matching placebo
10. To evaluate the efficacy of up to 3 injections of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) in terms of maintenance of clinical success at 6 months from the last injection as compared to matching placebo
11. To evaluate the safety and tolerability profile of up to 3 injections of V. alginolyticus collagenase or matching placebo into the affected cord at 6 months from the last injection
12. Secondary objectives in both study parts: - To evaluate the serum pharmacokinetic profile of each escalating dose of V. alginolyticus collagenase following the first and each additional injection.
13. To evaluate the immunogenic profile of V. alginolyticus collagenase following the first and each additional injection

Conditions and MedDRA coding

Dupuytren contracture

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Informed consent: signed written informed consent before inclusion in the study
2. Sex and Age: men/women, ≥18 year old inclusive
3. Dupuytren contracture: diagnosis of Dupuytren contracture with a fixed flexion deformity ≥20° and ≤100°, if in a MP joint, or ≥20° and ≤80°, if in a PIP joint, of at least one finger, other than the thumb, caused by a palpable cord that, according to the investigator’s judgement, could benefit from treatment with collagenase
4. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study
5. Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception: a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit b. A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit c. A male sexual partner who agrees to use a male condom with spermicide d. A sterile sexual partner e. Sexual abstinence Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all women of child-bearing potential, pregnancy test result must be negative at screening and Day 1 predose.

Exclusion criteria 9

1. Previous Dupuytren contracture treatments: a. surgical treatments: patients who underwent fasciectomy or surgical fasciotomy in the selected primary hand, and patients treated with needle aponeurotomy (percutaneous needle fasciotomy) in the selected joint; b. pharmacological treatments: patients previously treated with any pharmacological treatment of Dupuytren’s contracture in the selected primary hand within 90 days prior to screening. Additionally, patients previously treated with C. histolyticum in the same finger of the selected joint, or with V. alginolyticus collagenase, regardless of the hand or joint treated. However, patients enrolled in a placebo study arm in previous clinical trials of V. alginolyticus collagenase may be included
2. Hand disorders: chronic muscular, neurological or neuromuscular disorders affecting hands which may interfere with the clinical assessment
3. Bleeding and anticoagulants: history of bleeding, coagulopathies including any disorder that could increase the patient’s tendency to bruising or haematoma or bleeding, anticoagulant or antiaggregant therapy within 7 days of the screening with the exception of daily intake of ≤150 mg of acetylsalicylic acid
4. Allergy: ascertained or presumptive hypersensitivity to collagenase; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study
5. Diseases: significant history of cardiovascular, skin, endocrine or neurological diseases that affected the hands or of any other medical condition which may interfere with the aim of the study (including clinically significant abnormal ECG)
6. Medications: intake of tetracycline derivatives within 14 days before the screening
7. Investigative drug studies: previous participation in any clinical studies within 30 days before the screening visit
8. Blood donation: blood donations for 3 months before this study
9. Pregnancy (women of child-bearing potential only): positive or missing pregnancy test at screening or Day 1, pregnant or lactating women

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Primary endpoint in the Phase I part: Overall safety profile of each escalating dose of V. alginolyticus collagenase in order to identify the maximum tolerated dose in the absence of limiting toxicity as defined for the dose escalating process.
2. Primary endpoint in the Phase II part: -Proportion of patients who achieve clinical success defined as a reduction in contracture to ≤5° in 30±3 days after the last injection of V. alginolyticus collagenase into the cord in the affected primary joint as measured by passive angle of finger extension as compared to matching placebo In the evaluation of each endpoint, MP and PIP joints will be evaluated cumulatively and separated.

Secondary endpoints 22

1. Secondary endpoints in the Phase I part: - Proportion of patients who achieve a reduction in contracture to ≤5° (clinical success) as measured by passive finger goniometry 30±3 days after one injection of each tested ascending dose
2. Proportion of patients who have ≥50% reduction from baseline in contracture (clinical improvement) as measured by passive finger goniometry 30±3 days after one injection of each tested ascending dose
3. Percentage change from baseline in contracture degree as measured by passive finger goniometry 30±3 days after one injection of each tested single ascending dose
4. Percentage change from baseline in passive finger flexion 30±3 days after one injection of each tested dose
5. Change from baseline in the range of motion after injection of each tested single ascending dose
6. Secondary endpoints in the Phase II part:  Proportion of patients who achieve a clinical improvement defined as a reduction from baseline in contracture by ≥50% in 30±3 days after the last injection of V. alginolyticus collagenase into the cord in the affected primary joint as measured by passive angle of finger extension as compared to matching placebo
7. Mean number of injections of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) necessary to achieve clinical success as compared to matching placebo
8. Median time (in days) to achieve and maintain clinical success after the last injection of V. alginolyticus collagenase into the affected cord in the primary joint (MP or PIP) as compared to matching placebo
9. Percentage change from baseline in contracture degree as measured by passive finger extension in 30±3 days after the last injection of V. alginolyticus collagenase into the cord in the affected primary joint as compared to matching placebo
10. Percentage change from baseline in passive finger flexion in 30±3 days after the last injection of V. alginolyticus collagenase into the cord in the affected primary joint as compared to matching placebo
11. Change from baseline in the range of motion in 30±3 days after the last injection of V. alginolyticus collagenase into the cord in the affected primary joint as compared to matching placebo
12. Proportion of patients who achieve clinical success defined as a reduction in contracture to ≤5° in 30±3 days after each received injection of V. alginolyticus collagenase into the cord in the affected primary joint as measured by passive angle of finger extension as compared to matching placebo
13. Proportion of patients who achieve a clinical improvement defined as a reduction from baseline in contracture by ≥50% in 30±3 days after each received injection of V. alginolyticus collagenase into the cord in the affected primary joint as measured by passive angle of finger extension as compared to matching placebo
14. Secondary endpoints in both study parts: - Blood exposure after each injection of V. alginolyticus collagenase evaluated as serum levels of V. alginolyticus collagenase at pre-dose and 10 min, 0.5, 1, and 2 h post-dose
15. Immunogenicity of V. alginolyticus collagenase evaluated through assay of serum anti-drug antibodies in all subjects at pre-dose and 30±3 days post-dose
16. Overall safety profile of injection of V. alginolyticus collagenase or matching placebo
17. Follow-up endpoints: Percentage change from baseline in contracture degree as measured by passive finger extension 6 months after the last injection of V. alginolyticus collagenase into the cord in the affected primary joint as compared to matching placebo
18. Proportion of patients who have an increase in joint contracture to ≥20° in the presence of a palpable cord (recurrence) as measured by passive finger extension 6 months after the last injection of V. alginolyticus collagenase into the cord in the affected primary joint as compared to matching placebo
19. Percentage change from baseline in passive finger flexion 6 months after the last injection of V. alginolyticus collagenase into the cord in the affected primary joint as compared to matching placebo
20. Change from baseline to Month 6 in the range of motion after the last injection of V. alginolyticus collagenase into the cord in the affected primary joint as compared to matching placebo
21. Safety profile of injection of V. alginolyticus collagenase or matching placebo after 6 months
22. Immunogenicity of V. alginolyticus collagenase evaluated through assay of serum anti-drug antibodies in all subjects at Month 6 after the last injection

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fidia Farmaceutici S.p.A.

Sponsor organisation

Fidia Farmaceutici S.p.A.

Address

Via Ponte Della Fabbrica 3 A

City

Abano Terme

Postcode

35031

Country

Italy

Scientific contact point

Organisation

Fidia Farmaceutici S.p.A.

Contact name

Nicola Giordan

Public contact point

Organisation

Fidia Farmaceutici S.p.A.

Contact name

Nicola Giordan

Third parties 1

Locations

4 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 51 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications