A Phase 1/2 Trial of PTR-01 in Adult Patients With Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Study Overview
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Brief Summary
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Protocol PTR-01-001 is a Phase 1/2 study of PTR-01. The study is divided into an up to 4-week Screening Period, a 10-week Treatment Period and an 8-week Follow-up Period. Cohorts 1, 2, 3 and 4 will consist of 2, 4, 3 and 3 patients respectively. Each cohort will consist of patients divided into two groups (Group 1 and Group 2) randomized in a 1:1 ratio. Patients in Group 1 will receive three doses of active drug followed by 3 doses of saline control. Patients in Group 2 will receive three doses of saline control followed by 3 doses of active drug. Cohort 1 patients randomized to Group 1 will receive 3 doses of active treatment (PTR-01) at a dose of 0.1 mg/kg followed by 3 doses of saline control for a total of 6 doses. Cohort 1 patients randomized to Group 2 will receive 3 doses of saline control followed by 3 doses of active treatment (PTR-01) at a dose of 0.1 mg/kg for a total of 6 doses.

Detailed Description
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Protocol PTR-01-001 is a saline-controlled, single and repeat dose, dose-escalation, crossover study designed to determine the safety, tolerability, tissue kinetics, pharmacodynamics and preliminary efficacy of PTR 01. The study is divided into three periods: an up to 4-week Screening Period, a 10-week Treatment Period and an 8-week Follow-up Period. During the Screening Period and Follow-up Period there will be no study drug treatment. During the Treatment Period a total of 3 doses of PTR-01 and 3 doses of saline control will be administered to patients for a total of 6 doses over a 10-week period in three cohorts dosed at 0.1, 0.3, 1.0 and 3.0 mg/kg (active drug). Twelve patients with a diagnosis of RDEB and a history of at least one chronic wound will be enrolled. Those patients who do not have documentation of genetic analysis and IF staining will have blood for genetic analysis and a biopsy for IF staining prior to enrollment (both required). Cohorts 1, 2, 3 and 4 will consist of 2, 4, 3 and 3 patients respectively. Each cohort will consist of patients divided into two groups (Group 1 and Group 2) randomized in a 1:1 ratio. Patients will receive doses 2 weeks apart. Patients in Group 1 will receive three doses of active drug followed by 3 doses of saline control. Patients in Group 2 will receive three doses of saline control followed by 3 doses of active drug. This cross-over design will yield a total of 14 patients all of whom will receive active drug and saline control. Prior to randomization, patients will complete a Screening Period to assess the extent and impact of skin disease involvement and the chronicity of at least one wound. Only patients who meet all of the eligibility criteria will be randomized for treatment. Cohort 1 patients randomized to Group 1 will receive 3 doses of active treatment (PTR-01) at a dose of 0.1 mg/kg followed by 3 doses of saline control for a total of 6 doses. Cohort 1 patients randomized to Group 2 will receive 3 doses of saline control followed by 3 doses of active treatment (PTR-01) at a dose of 0.1 mg/kg for a total of 6 doses. After the last patient in Cohort 1 has received their third dose and safety labs for all patients have been reviewed by the Data Safety Monitoring Board (DSMB), the next cohort may be enrolled. This same schedule and safety review process will be followed for all subsequent dosing cohorts, with Cohort 2, Cohort 3 and Cohort 4 receiving 0.3, 1.0 and 3.0 mg/kg respectively. Efficacy assessments will be performed prior to first dose of therapy (at the end of the Screening Period), after the last dose of study drug in Period 1, after the last dose of study drug in Period 2 of the Treatment Period and 2 weeks (Day 85) after the last dose of study drug (at the end of the Follow-up Period).

Official Title
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A Phase 1/2 Randomized, Saline-Controlled, Single-Blind, Multiple Ascending Dose, Dose-Escalation, Multi-Center Trial of PTR-01 in Adult Patients With Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Conditions
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Recessive Dystrophic Epidermolysis Bullosa

Intervention / Treatment
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* Drug: PTR-01
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be at least 16 years of age. Has signed the current approved informed consent form. Has a diagnosis of RDEB based on genetic analysis and consistent with a recessive inheritance pattern. Has deficient C7 staining at the dermal-epidermal junction (DEJ) by IF. Has at least 1 unhealed wound 10-200 cm2 for at least 6 weeks at the Screening Visit. Agrees to use contraception as follows: For women of childbearing potential (WOCBP) agrees to use highly effective contraceptive (including abstinence) methods from Screening, through the study, and for at least 10 weeks after the last dose of study drug. Non-childbearing potential is defined as a female who meets either of the following criteria: age ≥50 years and no menses for at least 1 year or documented hysterectomy, bilateral tubal ligation, or bilateral oophorectomy (see Section 7.4.1.2 for details on the definition of non-childbearing potential). For males, agrees to use a condom with any WOCBP sexual partner from Day 1 of study treatment, through the study, and at least 10 weeks after the last dose of study drug. Be willing and able to comply with this protocol. Exclusion Criteria: Has known systemic hypersensitivity to any of the inactive ingredients in PTR-01. Is pregnant or nursing. Has received in the last six months any investigational gene therapy product or in the last three months any non-gene therapy investigational products. Is anticipated to receive new regimens of antibiotics or other anti-infectives during the trial. Has any other medical or personal condition that, in the opinion of the Investigator, may potentially compromise the safety or compliance of the patient, or may preclude the patient's successful completion of the clinical study.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, Saline-Controlled, Single-Blind, Multiple Ascending Dose, Dose-Escalation, Multi-Center
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTR-01 0.1 mg/kg<br>Three intravenous infusions of PTR-01 at 0.1 mg/kg with doses 2 weeks apart. | Drug: PTR-01<br>* Recombinant human collagen 7 (rC7)<br>* Other names: Recombinant human collagen 7 (rC7);|
| Experimental: PTR-01 0.3 mg/kg<br>Three intravenous infusions of PTR-01 at 0.3 mg/kg with doses 2 weeks apart. | Drug: PTR-01<br>* Recombinant human collagen 7 (rC7)<br>* Other names: Recombinant human collagen 7 (rC7);|
| Experimental: PTR-01 1.0 mg/kg<br>Three intravenous infusions of PTR-01 at 1.0 mg/kg with doses 2 weeks apart. | Drug: PTR-01<br>* Recombinant human collagen 7 (rC7)<br>* Other names: Recombinant human collagen 7 (rC7);|
| Placebo Comparator: Normal Saline<br>Saline control to mimic PTR-01. | Drug: Normal saline<br>* Saline control<br>|
| Experimental: PTR-01 3.0 mg/kg<br>Three intravenous infusions of PTR-01 at 3.0 mg/kg with doses 2 weeks apart. | Drug: PTR-01<br>* Recombinant human collagen 7 (rC7)<br>* Other names: Recombinant human collagen 7 (rC7);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events | The primary endpoint of this study is safety and tolerability, as assessed by treatment-emergent adverse events, infusion-associated reactions (IAR) and immunogenicity | Up to Day 127 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To measure the peak serum concentration (Cmax) of PTR-01 | Pharmacokinetic parameter estimates of Cmax | Pre-dose, 15 minutes, 60 minutes, 2 hours, 4 hours, 8 hours and 24 hours post-dose | 
| To measure the time to peak concentration (Tmax) of PTR-01 | Pharmacokinetic parameter estimates of Tmax | Pre-dose, 15 minutes, 60 minutes, 2 hours, 4 hours, 8 hours and 24 hours post-dose | 
| To measure the area under the curve (AUC) of PTR-01 | Pharmacokinetic parameter estimates of AUC | Pre-dose, 15 minutes, 60 minutes, 2 hours, 4 hours, 8 hours and 24 hours post-dose | 
| To measure the clearance of PTR-01 | Pharmacokinetic parameter estimates of clearance | Pre-dose, 15 minutes, 60 minutes, 2 hours, 4 hours, 8 hours and 24 hours post-dose | 
| To measure the half-life (t1/2) of PTR-01 | Pharmacokinetic parameter estimates of t1/2 | Pre-dose, 15 minutes, 60 minutes, 2 hours, 4 hours, 8 hours and 24 hours post-dose | 
| Change from Baseline in rC7 | Change in rC7 on skin biopsy by immunofluorescence (IF) | Screening and Day 127 | 
| Change from Baseline in anchoring fibrils | Change in anchoring fibrils on skin biopsy by electron microscopy (EM) | Screening and Day 127 | 
| Duration of rC7 residence in tissue | Duration of rC7 residence in tissue by skin biopsy | Screening and Day 127 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RDEB