Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis,JAMA

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Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis
JAMA ( IF 63.1 ) Pub Date : 2019-10-08 , DOI: 10.1001/jama.2019.14735
Marc C. Hochberg ₁ , Ali Guermazi _{2,

3} , Hans Guehring ₄ , Aida Aydemir ₅ , Stephen Wax ₅ , Patricia Fleuranceau-Morel ₅ , Asger Reinstrup Bihlet ₆ , Inger Byrjalsen ₆ , Jeppe Ragnar Andersen ₆ , Felix Eckstein _{7,

8}

Affiliation

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.

中文翻译：

关节内注射 Sprofermin 与安慰剂对骨关节炎患者股胫关节软骨厚度的影响

重要性 Sprifermin 作为一种改善疾病的骨关节炎药物正在接受研究。目的评价sprifermin对骨关节炎患者症状较多的膝关节总股胫关节软骨厚度变化的影响。设计、设置和参与者 FORWARD（FGF-18 重复给药的骨关节炎随机试验）是一项在 10 个地点进行的为期 5 年的剂量探索、多中心随机临床试验。符合条件的参与者年龄在 40 至 85 岁之间，患有有症状的放射学膝关节骨关节炎和 Kellgren-Lawrence 2 级或 3 级。2013 年 7 月开始招募，2014 年 5 月结束；最后一次参与者访问发生在 2017 年 5 月 8 日。报告了 2 年的主要结果和 3 年的随访分析。干预参与者被随机分为 5 组中的 1 组：每 6 个月（n = 110）或每 12 个月（n = 110）关节内注射 100 μg sprifermin，每 6 个月（n = 111）或每 12 个月（n = 110）注射 30 μg sprifermin，或安慰剂每 6 个月（n = 108）。每次治疗由超过 3 周的每周注射组成。主要结果和测量主要终点是2年时通过定量磁共振成像测量的股胫关节软骨总厚度的变化。次要终点（共 15 个）包括西安大略总分和麦克马斯特大学骨关节炎指数 (WOMAC) 总分自基线的 2 年变化。主要结果的最小临床重要差异 (MCID) 未知；对于髋关节和膝关节骨关节炎患者的 WOMAC 总评分，绝对 MCID 为 7 U（95% CI，4 至 10 U），MCID 百分比为 14%（95% CI，9% 至 18%）。结果在 549 名参与者（中位年龄，65.0 岁；379 名女性 [69.0%]）中，474 名（86.3%）完成了 2 年的随访。与安慰剂相比，每 6 个月给药 100 μg sprifermin，股胫关节软骨总厚度从基线到 2 年的变化为 0.05 mm（95% CI，0.03 至 0.07 mm）；每 12 个月 100 μg sprifermin 0.04 mm（95% CI，0.02 至 0.06 mm）；每 6 个月 30 μg sprifermin 0.02 mm（95% CI，-0.01 至 0.04 mm）；每 12 个月 30 μg sprifermin 为 0.01 mm（95% CI，-0.01 至 0.03 mm）。与安慰剂相比，每 6 个月或每 12 个月给予 100 μg sprifermin 的总 WOMAC 评分相对于基线的平均绝对变化没有统计学显着差异，或每 6 个月或每 12 个月服用 30 μg sprifermin。最常报告的治疗出现的不良事件是关节痛（安慰剂：n = 46 [43.0%]；每 6 个月给予 100 μg sprifermin：n = 45 [41.3%]；每 12 个月给予 100 μg sprifermin：n = 50 [45.0%]；每 6 个月服用 30 μg sprifermin：n = 40 [36.0%]；每 12 个月服用 30 μg sprifermin：n = 48 [44.0%]）。结论和相关性在有症状的放射学膝关节骨关节炎参与者中，与安慰剂相比，每 6 或 12 个月关节内注射 100 μg sprifermin 导致 2 年后股胫关节软骨总厚度的改善具有统计学意义，但临床表现不确定重要性; 每 6 或 12 个月服用 30 μg sprifermin 与安慰剂没有显着差异。反应的持久性也不确定。试验注册 ClinicalTrials.gov 标识符：NCT01919164。

更新日期：2019-10-08

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