富拉鲁单抗单药治疗中度至重度原发性骨关节炎慢性膝关节疼痛患者的疗效和安全性：一项随机、安慰剂对照和活性对照试验。
Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomised, placebo- and active-controlled trial.
作者信息
Mayorga A J, Wang S, Kelly K M, Thipphawong J
机构信息
Janssen Research & Development, LLC, Titusville, NJ, USA.
Janssen Research & Development, LLC, Fremont, CA, USA.
出版信息
Int J Clin Pract. 2016 Jun;70(6):493-505. doi: 10.1111/ijcp.12807.
AIMS
The efficacy and safety of monotherapy with fulranumab, a monoclonal antibody that neutralises human nerve growth factor (NGF), was evaluated compared with placebo and an active comparator, controlled-release (CR) oxycodone, in patients with moderate to severe chronic knee pain of primary osteoarthritis (OA).
METHODS
In this phase-2, double-blind (DB), double-dummy, placebo- and active-controlled study, patients (40-80 years) were randomised (1:1:1:1) to placebo, fulranumab 3 or 9mg every 4 weeks (Q4 wk), or oxycodone CR twice-daily. Primary efficacy end-point: responder rates based on percent improvement in average osteoarthritis-related pain intensity (OAPI) scores from baseline to week-12 or when Food and Drug Administration (FDA) put a clinical hold on all anti-NGF trials, whichever was earlier. Secondary efficacy end-points: average OAPI score (week-16), Western Ontario and McMaster Osteoarthritis Index Global Score and subscales (pain, physical function, stiffness), and Patient Global Assessment.
RESULTS
As of an FDA clinical hold on all anti-NGF trials, only 196/300 patients were randomised and 33% (65/196) had completed 12 weeks of the 16-week DB phase. Responders were patients who did not withdraw and whose pain improved. Responder rates were not significantly different between fulranumab treatment groups (3mgQ4wk: 71%, p = 0.739; 9mgQ4wk: 80%, p = 0.843) and placebo (77%), whereas, oxycodone CR (56%) had significantly lower responder rates in comparison to both fulranumab (3mgQ4wk: p = 0.008; 9mgQ4wk: p = 0.012) and placebo (p = 0.0021). Secondary efficacy results were consistent with primary. None of the joint replacements (four in three patients) were adjudicated as rapidly progressing OA/osteonecrosis.
CONCLUSION
Low sample size because of early termination make interpretation of this study difficult, but fulranumab monotherapy resulted in significantly better pain relief and function compared with oxycodone CR (but not against placebo) and was generally well-tolerated.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT01094262.
目的
在原发性骨关节炎（OA）所致中重度慢性膝关节疼痛患者中，评估人神经生长因子（NGF）中和性单克隆抗体fulranumab单药治疗与安慰剂及活性对照药控释（CR）羟考酮相比的疗效和安全性。
方法
在这项2期双盲（DB）、双模拟、安慰剂和活性药物对照研究中，将40 - 80岁患者按1:1:1:1随机分组，分别接受安慰剂、fulranumab每4周3或9mg（Q4 wk），或每日2次的羟考酮CR治疗。主要疗效终点：基于从基线到第12周或美国食品药品监督管理局（FDA）对所有抗NGF试验实施临床暂停（以较早者为准）时，平均骨关节炎相关疼痛强度（OAPI）评分改善百分比的缓解率。次要疗效终点：平均OAPI评分（第16周）、西安大略和麦克马斯特大学骨关节炎指数总体评分及各子量表（疼痛、身体功能、僵硬），以及患者总体评估。
结果
截至FDA对所有抗NGF试验实施临床暂停时，仅196/300例患者被随机分组，且33%（65/196）完成了16周DB期的12周治疗。缓解者为未退出且疼痛改善的患者。fulranumab治疗组（3mg Q4wk：71%，p = 0.739；9mg Q4wk：80%，p = 0.843）与安慰剂组（77%）的缓解率无显著差异，而羟考酮CR（56%）与fulranumab（3mg Q4wk：p = 0.008；9mg Q4wk：p = 0.012）和安慰剂（p = 0.0021）相比，缓解率显著更低。次要疗效结果与主要结果一致。在所有关节置换病例（3例患者中的4例）中，均未判定为快速进展性OA/骨坏死。
结论
由于早期终止导致样本量小，使得本研究的解读存在困难，但与羟考酮CR相比（而非与安慰剂相比），fulranumab单药治疗在疼痛缓解和功能改善方面效果显著更好，且总体耐受性良好。
试验注册
ClinicalTrials.gov：NCT01094262。
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