美国马里兰大学Marc C. Hochberg研究组的一项最新研究探讨了关节内注射新药Sprifermin与安慰剂对骨关节炎患者股骨胫骨关节软骨厚度的影响。该研究发表在2019年10月8日出版的《美国医学会杂志》上。

FORWARD是一项为期5年、剂量发现、在10个地点进行的多中心随机临床试验。2013年7月至2014年5月，研究组招募了549例年龄在40到85岁之间，患有症状性膝关节骨性关节炎，Kellgren-Lawrence 2或3级的参与者。将这些参与者随机分为5组，其中110名每6个月关节内注射100μg Sprifermin，110名每12个月注射100μg Sprifermin，111名每6个月注射30μg Sprifermin，110名每12个月注射30μg Sprifermin，108名每6个月注射一次安慰剂。

共有474名（86.3%）参与者完成了2年的随访。治疗两年后，与安慰剂组相比，每6个月注射100μg Sprifermin组的股骨-胫骨关节软骨总厚度比基线增长了0.05mm，每12个月注射100μg Sprifermin组增长了0.04mm，每6个月注射30μg Sprifermin组增长了0.02mm，每12个月注射30μg Sprifermin组增长了0.01mm。4个Sprifermin治疗组的总体WOMAC评分较安慰剂组均无显著改善。最常见的不良反应是关节痛，但各组间的发生率并无显著差异。

综上，对于膝关节骨性关节炎患者，每6个月或12个月注射100μg Sprifermin与安慰剂相比，可显著改善2年后的股骨-胫骨关节软骨总厚度，但其临床意义和缓解的持久性尚不确定。

附：英文原文

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

Author: Marc C. Hochberg, Ali Guermazi, Hans Guehring, Aida Aydemir, Stephen Wax, Patricia Fleuranceau-Morel, Asger Reinstrup Bihlet, Inger Byrjalsen, Jeppe Ragnar Andersen, Felix Eckstein

Issue&Volume: Vol 322 No 14

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.

DOI: 10.1001/jama.2019.14735

Source: https://jamanetwork.com/journals/jama/article-abstract/2752470