Clinical trial NCT01919164: A Study to Investigate the Safety and Effectiveness of Different Doses of Sprifermin in Participants With Osteoarthritis of the Knee
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Osteoarthritis, Knee
Keywords: Osteoarthritis of knee
Recombinant Human Fibroblast Growth Factor-18 (rhFGF-18)
Sprifermin
Placebo
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Nordic Bioscience A/S
First posted: 2013-08-08
Enrollment: 549
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Cartilage Thickness in the Total Femorotibial Joint as Evaluated by Quantitative Magnetic Resonance Imaging (qMRI) at Year 2
timeFrame: Baseline, Year 2 (Week 104)
Secondary outcomes:
measure: 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
timeFrame: Baseline, Week 52, Week 78 and Week 104
measure: Change From Baseline in the 20-meter Walk Test at Week 12, 26, 38, 52, 64, 78, 90 and 104
timeFrame: Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
measure: Change From Baseline in the Patient's Global Assessment (PGA) at Week 12, 26, 38, 52, 64, 78, 90 and 104
timeFrame: Baseline, Week 12, 26, 38, 52, 64, 78, 90 and 104
measure: 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
timeFrame: Baseline, Week 52 and 104
measure: Change From Baseline in Cartilage Thickness in the Medial and Lateral Compartments as Well as in the Total Femorotibial Joint
timeFrame: Medial and Lateral: Baseline, Week 26, 52, 78 and 104; Total: Baseline, Week 26, 52 and 78
measure: 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
timeFrame: Baseline, Week 26, 52, 78 and 104
measure: Synovial Fluid Levels of Sprifermin/FGF-18
timeFrame: 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)
measure: Serum Levels of Sprifermin/FGF-18
timeFrame: 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)
Other outcomes:
Locations:
city: Lakewood
country: United States
facility: Research site
state: Colorado
city: Baltimore
country: United States
facility: Research site
state: Maryland
city: Buenos Aires
country: Argentina
facility: Research site
city: Brno
country: Czechia
facility: Research site
city: Pardubice
country: Czechia
facility: Research site
city: Prague
country: Czechia
facility: Research site
city: Aalborg
country: Denmark
facility: Research site
city: Ballerup
country: Denmark
facility: Research site
city: Vejle
country: Denmark
facility: Research site
city: Tallinn
country: Estonia
facility: Research site
city: Hong Kong
country: Hong Kong
facility: Research Site
city: Lodz
country: Poland
facility: Research site
city: Bucharest
country: Romania
facility: Research site
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible, MD
role: STUDY_DIRECTOR
References:
citation: Eckstein F, Hochberg MC, Guehring H, Moreau F, Ona V, Bihlet AR, Byrjalsen I, Andersen JR, Daelken B, Guenther O, Ladel C, Michaelis M, Conaghan PG. Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study. Ann Rheum Dis. 2021 Aug;80(8):1062-1069. doi: 10.1136/annrheumdis-2020-219181. Epub 2021 May 7.
citation: Guehring H, Moreau F, Daelken B, Ladel C, Guenther O, Bihlet AR, Wirth W, Eckstein F, Hochberg M, Conaghan PG. The effects of sprifermin on symptoms and structure in a subgroup at risk of progression in the FORWARD knee osteoarthritis trial. Semin Arthritis Rheum. 2021 Apr;51(2):450-456. doi: 10.1016/j.semarthrit.2021.03.005. Epub 2021 Mar 11.
citation: Eckstein F, Kraines JL, Aydemir A, Wirth W, Maschek S, Hochberg MC. Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of location in the femorotibial joint: post-hoc analysis of a randomised, placebo-controlled phase II clinical trial. Ann Rheum Dis. 2020 Apr;79(4):525-528. doi: 10.1136/annrheumdis-2019-216453. Epub 2020 Feb 25.
citation: Hochberg MC, Guermazi A, Guehring H, Aydemir A, Wax S, Fleuranceau-Morel P, Reinstrup Bihlet A, Byrjalsen I, Ragnar Andersen J, Eckstein F. Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial. JAMA. 2019 Oct 8;322(14):1360-1370. doi: 10.1001/jama.2019.14735.