A Study Evaluating the Safety, Tolerability, and Range of Biologically Active Doses of ICM-203 in Mild to Moderate Knee Osteoarthritis

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability, and activity of ICM-203, a recombinant adeno-associated viral (AAV) vector that expresses a therapeutic gene that promotes cartilage formation, reduces joint inflammation and pain, as well as improves joint physical function, by injecting escalating doses of ICM-203 or matching placebo into the knee of subjects with mild to moderate knee osteoarthritis (OA).

Official Title
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A Phase 1/2a, Double-Blind, Placebo-Controlled Single Dose Escalation Study of Intra-Articular ICM 203 in Subjects With Kellgren-Lawrence Grade 2 or Grade 3 Osteoarthritis of the Knee

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Genetic: ICM-203
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body Mass Index (BMI) of 18.0 to 40.0 kg/m2, inclusive, at the time of screening. Kellgren-Lawrence grade 2 or grade 3 OA of target knee. Target knee pain between 4 and 9, inclusive, on an NRS ranging from 0 (no pain) to 10 (worst pain imaginable). KOOS function in daily living score >25, a measure of knee function ranging from 0 (extreme problems) to 100 (no problems). A stable treatment regimen for symptomatic relief of OA, including NSAIDs, for 4 weeks prior to screening. Exclusion Criteria: History of rheumatoid arthritis, psoriatic arthritis, gout, pseudogout, autoimmune OA, chondrocalcinosis, hemochromatosis, villonodular synovitis, and synovial chondromatosis or other disorder that in the opinion of the Investigator could cause inflammation of the knee. Injection of steroid, hyaluronate or other agent, into the target knee less than 90 days prior to day 1. Major injury to the target knee, such as torn ligament or severe sprain, within 12 months of screening. Disability so severe that the subject cannot comply with the study requirements, including knee symptoms that result in significant difficulty or inability to walk. Surgery on the target knee within 180 days prior to day 1 Total knee arthroplasty or other knee surgery planned in the next 12 months. Active joint infection or other concurrent medical (diabetes, uncontrolled hypertension, severe osteoporosis, glaucoma) or psychiatric condition that, in the opinion of the Investigator, would make the subject unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 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: Sequential Assignment
Interventional Model Description: Group 1: ICM-203 6x10e12 vg or Placebo Group 2: ICM-203 2x10e13 vg or Placebo Group 3: ICM-203 6x10e13 vg or Placebo (Optional)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: ICM-203 (Low dose) vs Placebo<br>8 subjects will be randomized to receive a single intra-articular injection of ICM-203 at 6x10e12 vg (n=6) or placebo (n=2) into the target knee at Day 1 | Genetic: ICM-203<br>* Intra-articular injection<br>Drug: Placebo<br>* Intra-articular injection<br>|
| Experimental: Group 2: ICM-203 (Medium dose) vs Placebo<br>4 subjects will be randomized to receive a single intra-articular injection of ICM-203 at 2x10e13 vg (n=3) or placebo (n=1) into the target knee at Day 1 | Genetic: ICM-203<br>* Intra-articular injection<br>Drug: Placebo<br>* Intra-articular injection<br>|
| Experimental: Group 3: ICM-203 (High dose) vs Placebo (Optional)<br>4 subjects will be randomized to receive a single intra-articular injection of ICM-203 at 6x10e13 vg (n=3) or placebo (n=1) into the target knee at Day 1 | Genetic: ICM-203<br>* Intra-articular injection<br>Drug: Placebo<br>* Intra-articular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-Emergent Adverse Events (TEAEs) | Incidence of Treatment-Emergent Adverse Events following administration of study drug | Up to Week 52 | 
| Severity of Treatment-Emergent Adverse Events (TEAEs) | Severity of Treatment-Emergent Adverse Events graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0, following administration of study drug | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Knee pain | Evaluation of change from baseline in knee pain as measured using a Numerical Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable) | Up to Week 52 | 
| Knee function | Evaluation of change from baseline in knee function as measured using the Function in Daily Living subscore of the Knee Injury and Osteoarthritis Outcome Score (KOOS) | Up to Week 52 | 
| Analgesic use | Evaluation of change from baseline in in use of analgesics, such as acetaminophen and NSAIDs | Up to Week 52 | 
| Magnetic Resonance Imaging Osteoarthritis Knee Score (MOAKS) | Evaluation of change from baseline in MOAKS, focusing on articular cartilage and effusion-synovitis | Up to Week 52 | 
| Joint space width | Evaluation of change from baseline in Joint space width in mm as measured on knee radiograph | Up to Week 52 | 
| Humoral response to AAV5.2 capsid | Evaluation of change from baseline in neutralizing antibody titers against AAV5.2 in serum | Up to Week 52 | 
| Cellular immune response to AAV5.2 capsid | Evaluation of change from baseline in T-cell responses to AAV5.2 capsid | Up to Week 52 | 
| Systemic biodistribution of ICM-203 | Evaluation of presence of ICM-203 in peripheral blood after administration of study drug | Up to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adeno-associated virus, gene therapy, ICM-203, osteoarthritis