Clinical Trial Simulations Based on Genetic Stratification and the Natural History of a Functional Outcome Measure in Creutzfeldt-Jakob Disease
Clinical Trial Simulations Based on Genetic Stratification and the Natural History of a Functional Outcome Measure in Creutzfeldt-Jakob Disease
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DOI：
10.1001/jamaneurol.2015.4885
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发表时间：
2016-04-01
期刊：
影响因子：
29
通讯作者：
Collinge, John
中科院分区：
文献类型：
--
作者：
Mead, Simon;Burnell, Matthew;Collinge, John
神经退行性疾病药物开发的一个主要挑战是，具有有意义终点的充分功效研究通常需要数百名参与者和长时间。朊病毒疾病代表了由蛋白质错误折叠引起的脑疾病的原型，最常见的亚型是散发性克雅氏病（sCJD），一种快速进行性痴呆。有没有完善的试验方法在朊病毒diseases.Objective建立一个更强大的和有意义的临床试验方法在sCJD.DESIGN，SETTING，和PARTICIPANTS分层医学和模拟方法的基础上进行的前瞻性间隔队列研究从2008年10月至2014年6月。这项研究涉及598名可能或明确的sCJD参与者，在英国的一个国家专家转诊服务中心随访了470多个患者年，包括住院、护理之家和医院患者访视。我们将线性混合模型拟合到结果测量，以及涉及10至120名患者的模拟临床试验（无脱落）与早期至中度晚期朊病毒疾病使用模型参数比较的权力各种designs.Main结局和措施共2681评估进行了功能导向的复合终点（医学研究理事会量表）和临床研究相关（脑磁共振成像、脑电图和脑脊液分析）和分子数据（朊病毒蛋白[PrP]基因测序，PrPSc型）。PrP基因序列与相对于任何其他人口统计学或调查因素的下降显著相关。sCJD和多态性密码子129基因型MM、VV和MV患者分别在5.3（95%CI，4.2-6.9）、13.2（95%CI，10.9-16.6）和27.8（95%CI，21.9-37.8）天丧失10%的功能（P <0.001）。模拟表明，使用医学研究理事会量表下降50%作为主要结局的充分把握度（80%;双侧α = 0.05）开放标签随机试验，每10天仅评估120例受试者，每天仅评估90例受试者，比使用生存率作为主要结局提供了更大的把握度。限制VV或MV密码子129基因型甚至进一步增加功率。或者，单臂干预研究（总样本量的一半）可以提供类似的权力相比，自然历史cohol.CONCLUSIONS和相关性功能终点神经退行性变不需要长期和非常大的临床研究，以充分的权力的疗效。sCJD患者可能是一个有效的和具有成本效益的测试疾病修饰疗法组。分层医学和自然史队列方法可能会改变孤儿疾病临床试验的可行性。
IMPORTANCE A major challenge for drug development in neurodegenerative diseases is that adequately powered efficacy studies with meaningful end points typically require several hundred participants and long durations. Prion diseases represent the archetype of brain diseases caused by protein misfolding, the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. There is no well-established trial method in prion disease.OBJECTIVE To establish a more powerful and meaningful clinical trial method in sCJD.DESIGN, SETTING, AND PARTICIPANTS A stratified medicine and simulation approach based on a prospective interval-cohort study conducted from October 2008 to June 2014. This study involved 598 participants with probable or definite sCJD followed up over 470 patient-years at a specialist national referral service in the United Kingdom with domiciliary, care home, and hospital patient visits. We fitted linear mixed models to the outcome measurements, and simulated clinical trials involving 10 to 120 patients (no dropouts) with early to moderately advanced prion disease using model parameters to compare the power of various designs.MAIN OUTCOMES AND MEASURES A total of 2681 assessments were done using a functionally orientated composite end point (Medical Research Council Scale) and associated with clinical investigations (brain magnetic resonance imaging, electroencephalography, and cerebrospinal fluid analysis) and molecular data (prion protein [PrP] gene sequencing, PrPSc type).RESULTS Of the 598 participants, 273 were men. The PrP gene sequence was significantly associated with decline relative to any other demographic or investigation factors. Patients with sCJD and polymorphic codon 129 genotypes MM, VV, and MV lost 10% of their function in 5.3 (95% CI, 4.2-6.9), 13.2 (95% CI, 10.9-16.6), and 27.8 (95% CI, 21.9-37.8) days, respectively (P < .001). Simulations indicate that an adequately powered (80%; 2-sided alpha = .05) open-label randomized trial using 50% reduction in Medical Research Council Scale decline as the primary outcome could be conducted with only 120 participants assessed every 10 days and only 90 participants assessed daily, providing considerably more power than using survival as the primary outcome. Restricting to VV or MV codon 129 genotypes increased power even further. Alternatively, single-arm intervention studies (half the total sample size) could provide similar power in comparison to the natural history cohort.CONCLUSIONS AND RELEVANCE Functional end points in neurodegeneration need not require long and very large clinical studies to be adequately powered for efficacy. Patients with sCJD may be an efficient and cost-effective group for testing disease-modifying therapeutics. Stratified medicine and natural history cohort approaches may transform the feasibility of clinical trials in orphan diseases.