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Does intra-articular administration of sprifermin structurally modify cartilage, as measured by cartilage thickness on quantitative magnetic resonance imaging, in patients with knee osteoarthritis?
In this dose-finding trial including 549 participants randomized to 30 μg or 100 μg of sprifermin every 6 or 12 months vs placebo, there was a significant increase after 2 years in total femorotibial cartilage thickness for 100 μg of sprifermin every 6 months (0.05 mm) and every 12 months (0.04 mm).
Compared with placebo, intra-articular administration of 100 μg of sprifermin every 6 or 12 months resulted in improvement in femorotibial joint cartilage thickness after 2 years that was statistically significant, but of uncertain clinical importance; the durability of response also was uncertain.
Sprifermin is under investigation as a disease-modifying osteoarthritis drug.
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.
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%).
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.
ClinicalTrials.gov Identifier: NCT01919164
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Corresponding Author: Marc C. Hochberg, MD, MPH, School of Medicine, University of Maryland, 10 South Pine St, MSTF 8-34, Baltimore, MD 21201 (firstname.lastname@example.org).
Accepted for Publication: August 26, 2019.
Author Contributions: Dr Hochberg had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Hochberg, Guehring, Aydemir, Reinstrup Bihlet, Ragnar Andersen, Eckstein.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Hochberg, Aydemir, Wax, Byrjalsen, Eckstein.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Aydemir, Byrjalsen, Eckstein.
Administrative, technical, or material support: Wax, Reinstrup Bihlet, Byrjalsen, Ragnar Andersen, Eckstein.
Supervision: Guermazi, Guehring, Reinstrup Bihlet, Byrjalsen, Ragnar Andersen, Eckstein.
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.
Funding/Support: The study was funded by Merck KGaA and EMD Serono Research Institute Inc (a business of Merck KGaA).
Role of the Funder/Sponsor: The study sponsors were involved in the decision to submit for publication, but did not have the right to veto the publication or to control the decision regarding to which journal the manuscript was submitted. The study sponsor was involved in the design and conduct of the study; the collection, management, analysis, and interpretation of data; the preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We thank the participants who participated in the FORWARD study and their families, the FORWARD investigators and research staff, Nordic Bioscience, and readers and research staff from BioClinica, Boston Imaging Core Lab LLC, and Chondrometrics GmbH. Medical writing and editorial support were provided by Muchaala Yeboah, PhD, and Emily Heath, PhD (both with Bioscript Science), who received payment from Merck KGaA for their work. The manuscript was written in accordance with Good Publication Practice guidelines.
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