A Study to Investigate the Safety and Effectiveness of Different Doses of Sprifermin in Participants With Osteoarthritis of the Knee

Study Overview
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Brief Summary
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This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2 trial of Sprifermin administered intra-articularly in participants with primary osteoarthritis of the knee and Kellgren-Lawrence Grade 2 or 3. The trial was intended to investigate the efficacy and safety of different intra articular dosages of Sprifermin in these individuals.

Detailed Description
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Participants were equally randomized to either one of 4 treatment arms or a placebo arm. The trial consists of a Screening period lasting up to 42 days, a two-year double-blind placebo-controlled (DBPC) treatment phase, which begins at randomization (Week 0) and ends at Year 2, and a 3-year extended follow-up phase.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo Controlled, Parallel-group Trial to Investigate the Efficacy and Safety of Different Intra Articular (i.a.) Dosages of Sprifermin in Subjects With Primary Osteoarthritis of the Knee

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Drug: Sprifermin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age from 40 to 85 years; of either sex Primary femorotibial osteoarthritis according to American College of Rheumatology (ACR) clinical and radiographic criteria , and meeting protocol-specified X-ray criteria in the target knee at screening Pain score in the target knee and/or the need for regular symptomatic treatment of knee pain with paracetamol (acetaminophen), systemic non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase (COX)-2 selective inhibitors (coxibs), or tramadol on most days in the previous month (that is, more than half of the days in the previous month) A history of pain due to Osteoarthritis in the target knee for at least 6 months A protocol-specified pain score for the target knee in response to Question 1 of the WOMAC pain index (how much pain have you had [in the target knee, over the past 48 hours] when walking on a flat surface?) after washout of at least 5 half-lives of analgesic medication(s): acetaminophen, topical or oral NSAIDS, coxibs, opioids, and/or tramadol Women of childbearing potential must use a form of contraception with a failure rate of less than 1 percent per year throughout the trial Exclusion Criteria: Malalignment of greater than 5 degrees in the femorotibial axis of the target knee Clinical signs of inflammation (redness) in the target knee Intra-articular administration of corticosteroids or hyaluronic acid into either knee within 6 months before Screening Planned knee surgery (affecting either the target or the contralateral knee) within the next two years Concomitant conditions or treatments deemed to be incompatible with trial participation Any contraindication to MRI according to MRI guidelines, including the inability to undergo a knee MRI exam because of inability to fit in the scanner or knee coil Pregnancy or breastfeeding Participation in another clinical trial within the 30 days (or 5 half-lives of the investigated compound, whichever is longer) before screening Legal incapacity or limited legal capacity

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received Placebo matched to Sprifermin as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months. | Drug: Placebo<br>* Participants received Placebo matched to sprifermin as intra-articular injection.<br>|
| Experimental: Sprifermin (AS902330) 30 mcg/placebo - 2 Cycles<br>Participants received Sprifermin 30 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months. | Drug: Sprifermin<br>* Participants received Sprifermin as intra-articular injection.<br>* Other names: Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18);Drug: Placebo<br>* Participants received Placebo matched to sprifermin as intra-articular injection.<br>|
| Experimental: Sprifermin (AS902330) 30 mcg- 4 Cycles<br>Participants received Sprifermin 30 micrograms (mcg) as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months. | Drug: Sprifermin<br>* Participants received Sprifermin as intra-articular injection.<br>* Other names: Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18);|
| Experimental: Sprifermin (AS902330) 100 mcg/Placebo (2 cycles)<br>Participants received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 0, 1, 2 in Cycle 1 and at week 52, 53, 54 in Cycle 3; and received placebo matched to Sprifermin once every week for 3 consecutive weeks for 2 alternative cycles, that is at week 26, 27, 28 in Cycle 2 and at week 78, 79, 80 in Cycle 4 at interval of 6 months. | Drug: Sprifermin<br>* Participants received Sprifermin as intra-articular injection.<br>* Other names: Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18);Drug: Placebo<br>* Participants received Placebo matched to sprifermin as intra-articular injection.<br>|
| Placebo Comparator: Sprifermin (AS902330) 100 mcg- 4 Cycles<br>Participants received Sprifermin 100 mcg as intra-articular injection once every week for 3 consecutive weeks for 4 cycles, that is at week 0, 1, 2 in Cycle 1; at week 26, 27, 28 in Cycle 2; at week 52, 53, 54 in Cycle 3 and at week 78, 79, 80 in Cycle 4 at interval of 6 months. | Drug: Sprifermin<br>* Participants received Sprifermin as intra-articular injection.<br>* Other names: Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Cartilage Thickness in the Total Femorotibial Joint as Evaluated by Quantitative Magnetic Resonance Imaging (qMRI) at Year 2 | The change in cartilage thickness at 2 years was calculated based on quantitative magnetic resonance imaging (qMRI). | Baseline, Year 2 (Week 104) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale, Stiffness Subscale, Physical Function Subscale and Total Score at Week 52, Week 78 and Week 104 | WOMAC pain subscale consists of 5 questions (Likert Scale) relating to pain. Sum of items of pain subscale ranges from 0-11. Higher scores=worse pain. Stiffness subscale consists of 2 questions relating articular function. Sum of items of stiffness subscale ranges from 0-8. Higher scores=worse function. Physical function subscale consists of 17 question relating to physical activities. Sum of items of physical function subscale ranges from 0-68. Higher scores= worse functional limitations. Each sub-scale is directly transformed into a 0-100 scale, where higher score indicates worse condition. WOMAC total score(24questions) is sum of total subscales which was directly transformed into score range from 0-100. Higher scores=worse condition. Negative value in change is indicative of improvement. | Baseline, Week 52, Week 78 and Week 104 | 
| Change From Baseline in the 20-meter Walk Test at Week 12, 26, 38, 52, 64, 78, 90 and 104 | The 20-meter walk test is an objective test of physical function which consists of measuring the time needed for the participant to walk 20 meters at a normal pace. A stopwatch was used for time measurement. | Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104 | 
| Change From Baseline in the Patient's Global Assessment (PGA) at Week 12, 26, 38, 52, 64, 78, 90 and 104 | The Patient Global Assessment is based on participant's answer to the question Considering all the ways your osteoarthritis of the knee has affected you during the last 48 Hours, select the number that best describes the impact of your knee osteoarthritis on your daily life, and can take on values between 0-10 (0=None, 10=Extreme), for summaries the values are rescaled to 0-100 by multiplication with 10. Higher scores indicated worsening of condition. A negative value in change in Patient's Global Assessment is indicative of an improvement. | Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104 | 
| Change From Baseline in Minimal Joint Space Width (mJSW) in the Medial and Lateral Compartments as Evaluated by X-ray at Week 52 and 104 | Change in joint space narrowing was visualized with the fixed flexion knee radiograph. Determination of joint space narrowing by X-ray is considered to be a semi-quantitative method for assessment of progression of knee Osteoarthritis (OA). X-rays of both the target knee and the contralateral knee were performed. X-rays were read centrally. X-ray images were used to measure mJSW in the medial femorotibial and lateral femorotibial compartments and to determine the participant's baseline Kellgren-Lawrence grades (KLG). | Baseline, Week 52 and 104 | 
| Change From Baseline in Cartilage Thickness in the Medial and Lateral Compartments as Well as in the Total Femorotibial Joint | The change in cartilage thickness was calculated based on quantitative magnetic resonance imaging (qMRI). | Medial and Lateral: Baseline, Week 26, 52, 78 and 104; Total: Baseline, Week 26, 52 and 78 | 
| Change From Baseline in Cartilage-Volume in the Medial and Lateral Compartments as Well as in the Total Femorotibial Joint at Week 26, 52, 78 and 104 | The change in cartilage volume in the medial and lateral compartments as well as in the total femorotibial joint at Week 26, 52, 78 and 104 was calculated based on qMRI. | Baseline, Week 26, 52, 78 and 104 | 
| Synovial Fluid Levels of Sprifermin/FGF-18 | Levels of sprifermin/FGF-18 in synovial fluid were measured to provide a first estimate of the residence time of sprifermin in the synovial fluid. | Pre-dose at Week 0, 2 hours post-dose at Week 1 and 2 of Cycle 1, 2, 3 and 4 (each cycle is of 28 days) | 
| Serum Levels of Sprifermin/FGF-18 |  | Pre-dose at Week 0, 2 hours post-dose at Week 1 and 2 of Cycle 1, 2, 3 and 4 (each cycle is of 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoarthritis of knee, Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18), Sprifermin, Placebo