Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial

Abstract

Importance: Sprifermin is under investigation as a disease-modifying osteoarthritis drug.

Objective: To evaluate the effects of sprifermin on changes in total femorotibial joint cartilage thickness in the more symptomatic knee of patients with osteoarthritis.

Design, setting, and participants: FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) was a 5-year, dose-finding, multicenter randomized clinical trial conducted at 10 sites. Eligible participants were aged 40 to 85 years with symptomatic, radiographic knee osteoarthritis and Kellgren-Lawrence grade 2 or 3. Enrollment began in July 2013 and ended in May 2014; the last participant visit occurred on May 8, 2017. The primary outcome at 2 years and a follow-up analysis at 3 years are reported.

Interventions: Participants were randomized to 1 of 5 groups: intra-articular injections of 100 μg of sprifermin administered every 6 months (n = 110) or every 12 months (n = 110), 30 μg of sprifermin every 6 months (n = 111) or every 12 months (n = 110), or placebo every 6 months (n = 108). Each treatment consisted of weekly injections over 3 weeks.

Main outcomes and measures: The primary end point was change in total femorotibial joint cartilage thickness measured by quantitative magnetic resonance imaging at 2 years. The secondary end points (of 15 total) included 2-year change from baseline in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. The minimal clinically important difference (MCID) is unknown for the primary outcome; for total WOMAC score in patients with hip and knee osteoarthritis, the absolute MCID is 7 U (95% CI, 4 to 10 U) and the percentage MCID is 14% (95% CI, 9% to 18%).

Results: Among 549 participants (median age, 65.0 years; 379 female [69.0%]), 474 (86.3%) completed 2-year follow-up. Compared with placebo, the changes from baseline to 2 years in total femorotibial joint cartilage thickness were 0.05 mm (95% CI, 0.03 to 0.07 mm) for 100 μg of sprifermin administered every 6 months; 0.04 mm (95% CI, 0.02 to 0.06 mm) for 100 μg of sprifermin every 12 months; 0.02 mm (95% CI, -0.01 to 0.04 mm) for 30 μg of sprifermin every 6 months; and 0.01 mm (95% CI, -0.01 to 0.03 mm) for 30 μg of sprifermin every 12 months. Compared with placebo, there were no statistically significant differences in mean absolute change from baseline in total WOMAC scores for 100 μg of sprifermin administered every 6 months or every 12 months, or for 30 μg of sprifermin every 6 months or every 12 months. The most frequently reported treatment-emergent adverse event was arthralgia (placebo: n = 46 [43.0%]; 100 μg of sprifermin administered every 6 months: n = 45 [41.3%]; 100 μg of sprifermin every 12 months: n = 50 [45.0%]; 30 μg of sprifermin every 6 months: n = 40 [36.0%]; and 30 μg of sprifermin every 12 months: n = 48 [44.0%]).

Conclusions and relevance: Among participants with symptomatic radiographic knee osteoarthritis, the intra-articular administration of 100 μg of sprifermin every 6 or 12 months vs placebo resulted in an improvement in total femorotibial joint cartilage thickness after 2 years that was statistically significant, but of uncertain clinical importance; there was no significant difference for 30 μg of sprifermin every 6 or 12 months vs placebo. Durability of response also was uncertain.

Trial registration: ClinicalTrials.gov Identifier: NCT01919164.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Hochberg reported being the president of Rheumcon Inc; and receiving consulting fees from Bioiberica SA, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. Dr Guermazi reported being the president of Boston Imaging Core Lab LLC; and receiving consulting fees from OrthoTrophix, GE Healthcare, EMD Serono, Merck Serono, AstraZeneca, Sanofi, TissueGene, Galapagos, Roche, and Pfizer. Dr Guehring is an employee of Merck KGaA. Ms Aydemir and Drs Wax and Fleuranceau-Morel are employees of EMD Serono (a business of Merck KGaA). Dr Wax also reported receiving consulting fees from Merck Serono; and holding a patent with EMD Serono. Drs Reinstrup Bihlet, Byrjalsen, and Ragnar Andersen are employees and shareholders in Nordic Bioscience. Dr Eckstein is an employee and shareholder of Chondrometrics GmbH; and reported receiving grants and consulting fees from Merck KGaA, Kolon TissueGene, Samumed LLC, AbbVie, Bioclinica, TissueGene, Servier Roche, Medtronic, Ampio, Orthotrophix, Medivir, FNIH, and Galapagos.

Figures

Figure 1.. Study Disposition at Year 2

aParticipant was not included in any adverse event analyses. bParticipant was randomized to 30 μg of sprifermin every 12 months, but received 100 μg of sprifermin at visit 3. Actual treatment is set as 100 μg of sprifermin every 12 months for the adverse event analyses and as 30 μg of sprifermin every 12 months for the other analyses. cParticipant was randomized to placebo, but received 30 μg of sprifermin at visit 7. Actual treatment was set as 30 μg of sprifermin every 12 months for the adverse event analyses and as placebo for the other analyses. dNonadherence refers to protocol nonadherence. eParticipants may not be included in the primary analysis population (due lack of quantitative magnetic resonance imaging measurement), but may still be included in the year 3 analysis (in the other efficacy and adverse event analyses). fParticipants may be included in the primary analysis population even if they discontinued treatment. gThere were no quantitative magnetic resonance imaging measurements up to year 2.

Figure 2.. Change From Baseline in Total Femorotibial Joint Cartilage Thickness Over 2 Years in the Primary Analysis Population

Each cycle consists of 3 once-weekly intra-articular injections of the specified dose over 3 consecutive weeks. Total femorotibial joint cartilage thickness was calculated as the total volume divided by the total surface area (ie, average cartilage thickness). The box plot inner horizontal lines indicate median; boxes, interquartile range (25th and 75th percentiles); vertical whiskers, 1.5 interquartile range beyond the 25th and 75th percentiles; and dots, more extreme values.

Figure 3.. Change From Baseline in Medial and Lateral Femorotibial Joint Cartilage Thickness Over 2 Years in the Primary Analysis Population

Medial femorotibial compartment quantitative MRI cartilage thickness was calculated as the medial cartilage volume divided by medial surface area. Lateral femorotibial compartment quantitative MRI cartilage thickness was calculated as the lateral cartilage volume divided by lateral surface area. The box plot inner horizontal lines indicate median; boxes, interquartile range (25th and 75th percentiles); vertical whiskers, 1.5 interquartile range beyond the 25th and 75th percentiles; and dots, more extreme values.

Figure 4.. Change From Baseline in Total WOMAC Score and in the WOMAC Subscale Scores Over 2 Years in the Intent-to-Treat Population

The box plot inner horizontal lines indicate median; boxes, interquartile range (25th and 75th percentiles); vertical whiskers, 1.5 interquartile range beyond the 25th and 75th percentiles; and dots, more extreme values. WOMAC indicates Western Ontario and McMaster Universities Osteoarthritis Index.