Study of Efficacy, Safety and Tolerability of DFV890 in Patients With Knee Osteoarthritis

Study Overview
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Brief Summary
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This is a double-blinded, two-arm, phase II study to assess efficacy, safety and tolerability of DFV890 in participants with symptomatic knee osteoarthritis. The study includes a screening period, a treatment period and a follow-up period. At most, the study duration is 21 weeks.

Detailed Description
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The purpose of the Phase 2a proof of concept study is to evaluate the safety and tolerability of DFV890 in participants with symptomatic knee OA, and to determine the efficacy of DFV890 in reducing knee pain as evidenced by change in KOOS (knee injury and osteoarthritis outcome score).

Official Title
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A Randomized, Two-arm, Placebo-controlled, Participant and Investigator-blinded Study Investigating the Efficacy, Safety and Tolerability of DFV890 in Patients With Symptomatic Knee Osteoarthritis

Conditions
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Symptomatic Knee Osteoarthritis

Intervention / Treatment
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* Drug: DFV890
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female participants >= 50 and <= 80 years old on the day of Informed Consent signature. Participants must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 - 35 kg/m2 at screening. BMI = Body weight (kg) / [Height (m)]2 High sensitivity C-reactive protein (hsCRP) >=1.8 mg/L at screening Symptomatic OA with pain (corresponding to Numeric Rating Scale [NRS] 5-9, inclusive) in the target knee for the majority of days in the last 3 months prior to screening KOOS pain sub-scale score <= 60 in index knee at screening and baseline Radiographic disease: K&L grade 2 or 3 knee osteoarthritis in the target knee, confirmed by X-ray at screening. Active synovial inflammation at screening, defined as either moderate (score 9-12) or severe (score >=13) based on contrast enhanced MRI (CE-MRI) of the whole knee for synovitis detection from 11 sites Key Exclusion Criteria: Total WBC count < 3,000/µL, absolute peripheral blood neutrophil count (ANC) < 1,000/µL, hemoglobin < 8.5 g/dL (85 g/L) or platelet count < 100,000/µL at Screening Known autoimmune disease with inflammatory arthritis (including but not limited to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus), crystal-induced arthritis (gout, pseudogout associated arthritis), active acute or chronic infection or past infection of the knee joint, Lyme disease involving the knee, reactive arthritis, systemic cartilage disorders, moderate to severe fibromyalgia (widespread pain index, WPI, >4 out of 19), or a known systemic connective tissue disease Any known active infections, including skin or knee infections or infections that may compromise the immune system, such as HIV or chronic hepatitis B or C infection. COVID-19 specific: PCR or antigen test against COVID-19 is mandatory where required by the local Health Authority and/or by local regulation, e.g. in Germany. Use of prohibited medications: any local i.e. treatment into the knee, including but not restricted to viscosupplementation and corticosteroids within 12 weeks prior to Day 1; long-term treatment (>14 days) with oral corticosteroids >5 mg/day within 4 weeks prior to Day 1; oral glucosamine, chondroitin sulfate, or any nutraceutical with potential activity on cartilage repair within 2 weeks prior to Day 1; systemic Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or selective COX-2 inhibitors within 5 half-lives from PRO assessments; any other immunomodulatory drugs or treatment which cannot be discontinued or switched to a different medication within 28 days or 5 half-lives of screening (whichever is longer if required by local regulations), or until the expected PD effect has returned to baseline. Moderate to severe pain in the contralateral knee for the majority of days in the last 3 months prior to Screening, as per patient judgment. Participants with the CYP2C9 *3/*3 genotype defined as homozygous carriers of the CYP2C9*3 allele. Severe malalignment greater than 7.5 degrees in the target knee (either varus or valgus), measured using x-ray at Screening

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DFV890<br>DFV890 | Drug: DFV890<br>* DFV890<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Knee injury and Osteoarthritis Outcome Score (KOOS) pain sub-scale at week 12 | To determine the efficacy of oral DFV890 vs. placebo in participants with knee OA for relieving OA pain | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in synovitis activity level measured from Ktrans by DCE-MRI at week 12 | To assess the efficacy of DFV890 vs. placebo in participants with knee OA on inflammatory joint structure features | Baseline to Week 12 | 
| Number of adverse events and serious adverse events | To assess the safety and tolerability of DFV890 vs. placebo | Up to Week 19 (end of study) | 
| Change from baseline in serum high sensitivity C-reactive protein level and absolute neutrophil counts at week 2,4,8 and 12 | To assess the effect of DFV890 compared to placebo on systemic inflammatory status | Baseline to Week 12 | 
| Change from baseline in KOOS sub-scales (other symptoms, function in daily living, function in sport and recreation, knee-related quality of life) at weeks 2, 4, 8 and 12 | To assess the efficacy of DFV890 vs. placebo in improving participants' report of knee symptoms and associated problems over time | Week 2, 4, 8 and 12 | 
| Change in KOOS pain subscale and NRS for pain from baseline to weeks 2, 4, 8 and 12 | To assess the efficacy of DFV890 vs. placebo in relieving OA pain over time | Baseline to Week 2, 4, 8 and 12 | 
| Pharmacokinetics of DFV890: Cmax | To assess pharmacokinetics of DFV890 in plasma | Week 2 and Week 12 | 
| Pharmacokinetics of DFV890: AUC last | To assess pharmacokinetics of DFV890 in plasma | Week 2 and Week 12 | 
| Pharmacokinetics of DFV890: AUC0-12h | To assess pharmacokinetics of DFV890 in plasma | Week 2 and Week 12 | 
| Pharmacokinetics of DFV890: Ctrough | To assess pharmacokinetics of DFV890 in plasma | Week 2 and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoarthritis, Knee osteoarthritis, DFV890, Adult, NLRP3 inhibitor, Inflammasome inhibition