Koch Marcus W, Kaur Sharanjit, Sage Kayla, Kim Janet, Levesque-Roy Myriam, Cerchiaro Graziela, Yong Voon Wee, Cutter Gary R, Metz Luanne M
Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
Department of Community Health Sciences, University of Calgary, Calgary, Canada.
Ann Neurol. 2021 Dec;90(6):940-948. doi: 10.1002/ana.26239. Epub 2021 Oct 15.
Primary progressive multiple sclerosis (PPMS) does not respond well to immunomodulatory or immunosuppressive treatment. Chronic activation of microglia has been implicated in the pathophysiology of PPMS. The antimalarial drug hydroxychloroquine (HCQ) reduces the activity of human microglia and has neuroprotective effects in vitro.
We conducted a single-arm, phase II futility trial of 200 mg oral HCQ twice daily for 18 months. In an effort to investigate disability worsening in the absence of overt focal inflammation, we excluded participants with contrast enhancing lesions on a screening magnetic resonance imaging (MRI). The primary end point was ≥20% worsening on the timed 25-foot walk measured between 6 and 18 months of follow-up.
Based on original trial data, 40% of the cohort were expected to worsen. We used a Simon 2-stage design to compare a null hypothesis of 40% of the cohort worsening against the one-sided alternative of 20%. Using a 5% type 1 error rate and 80% power, HCQ treatment would be deemed successful if fewer than 10 of 35 participants experienced clinically significant worsening. The study met its primary end point, as only 8 of 35 participants worsened between 6 and 18 months. HCQ was overall well-tolerated, with adverse events in 82% and serious adverse events in 12% of participants. All serious adverse events were unlikely related to HCQ use.
HCQ treatment was associated with reduced disability worsening in people with PPMS. HCQ is a promising treatment candidate in PPMS and should be investigated further in randomized controlled clinical trials. ANN NEUROL 2021;90:940-948.
原发性进行性多发性硬化症（PPMS）对免疫调节或免疫抑制治疗反应不佳。小胶质细胞的慢性激活与PPMS的病理生理学有关。抗疟药物羟氯喹（HCQ）可降低人小胶质细胞的活性，并在体外具有神经保护作用。
我们进行了一项单臂II期无效试验，每天两次口服200mg HCQ，持续18个月。为了研究在无明显局灶性炎症情况下的残疾恶化情况，我们排除了在筛查磁共振成像（MRI）上有对比增强病变的参与者。主要终点是在随访6至18个月期间，25英尺定时步行测试中恶化≥20%。
根据原始试验数据，预计该队列中有40%的人会恶化。我们采用Simon两阶段设计，将该队列中40%的人恶化的零假设与20%的单侧备择假设进行比较。使用5%的I型错误率和80%的检验效能，如果35名参与者中少于10人出现临床显著恶化，则HCQ治疗将被视为成功。该研究达到了主要终点，因为在6至18个月期间，35名参与者中只有8人恶化。HCQ总体耐受性良好，82%的参与者出现不良事件，12%的参与者出现严重不良事件。所有严重不良事件不太可能与使用HCQ有关。
HCQ治疗与PPMS患者残疾恶化减少有关。HCQ在PPMS中是一种有前景的治疗候选药物，应在随机对照临床试验中进一步研究。《神经病学纪事》2021年；90：940 - 948。
