杜氏肌营养不良症的基因型与运动功能：多机构荟萃分析及其对临床试验的影响。
Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials.
机构信息
From the Dubowitz Neuromuscular Centre (F.M., M.C., A.Y.M.), NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, and Great Ormond Street Hospital Trust, United Kingdom; Analysis Group, Inc. (J.S., G.S., H.L., M.J., I.D.), Boston; The Collaborative Trajectory Analysis Project (J.S., S.J.W.), Cambridge, MA; Department of Physical Medicine and Rehabilitation, and Pediatrics (C.M.), University of California, Davis, Sacramento; Child Neurology (N.G.), University Hospitals Leuven, Belgium; Department of Neurology (E.H.N.), Leiden University Medical Centre, the Netherlands; Department of Pediatrics (B.W.), University of Massachusetts Medical School, Worcester; MDUK Oxford Neuromuscular Center (L.S.), Department of Paediatrics, University of Oxford, United Kingdom and Neuromuscular Center of Liège (L.S.), Division of Paediatrics, CHU and University of Liège, Belgium; John Walton Muscular Dystrophy Research Centre (V.S., M.G.), Newcastle University and Newcastle Hospitals NHS Foundation Trust, United Kingdom; Department of Rehabilitation (I.J.M.d.G.), Donders Centre of Neuroscience, Radboud University Nijmegen Medical Center, the Netherlands; Cincinnati Children's Hospital Medical Center (C.T.), and College of Medicine (C.T.), University of Cincinnati, OH; Department of Pediatric Neurology (E.M.), Fondazione Policlinico Gemelli IRCCS, Catholic University, Rome, Italy; and Department of Human Genetics (A.A.-R.), Leiden University Medical Center, the Netherlands.
出版信息
Neurology. 2023 Apr 11;100(15):e1540-e1554. doi: 10.1212/WNL.0000000000201626. Epub 2023 Feb 1.
BACKGROUND AND OBJECTIVES
Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients with untreated patients with the same genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials.
METHODS
More than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children's Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-m walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors.
RESULTS
The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors.
DISCUSSION
These findings suggest the viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multigenotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in this study.
背景与目的
在杜氏肌营养不良症（DMD）的临床试验中，基因型靶向治疗的传统比较方法是将接受治疗的患者与具有相同基因型类别的未接受治疗的患者进行比较。这种方法避免了基因型效应对药物疗效的混杂影响，但也缩小了合格对照的范围，增加了在这种已经罕见的疾病中进行试验招募的挑战。为了评估基因型不匹配对照在 DMD 中的适用性，我们量化了基因型类别对临床试验中使用的 1 年运动功能终点变化的影响。
方法
从 6 个真实世界/自然史数据来源（鲁汶大学、由 CureDuchenne 共享的 PRO-DMD-01、iMDEX、北星英国、辛辛那提儿童医院医疗中心和 DMD 意大利组）中研究了超过 1600 患者年的随访时间（超过 700 名患者），基因型分为可跳过外显子 44、45、51 或 53 的类型，或其他可跳过、无义突变和其他突变。在每个数据来源中，研究了基因型类别与北星动态评估总分（ΔNSAA）和 10 米步行/跑速度（Δ10MWR）1 年变化之间的关联，并在调整基线预后因素前后进行了研究。
结果
在 12 个月后，研究的基因型类别解释了大约 2%的 ΔNSAA 结局的变异性，而其他预后因素解释了大数据源中>30%的变异性。基于所有数据来源的荟萃分析，研究中跳过适宜突变类别的 pooled 效应估计值的大小都很小（在 1 年随访中，NSAA 总分增加<2 个单位），小于 NSAA 的临床重要差异，并且在调整非基因型预后因素后，标准误差<1 个单位。
讨论
这些发现表明，对于运动功能结局，长达 12 个月的试验设计可以采用基因型混合或不匹配的对照，这将减轻招募挑战并减少分配给安慰剂的患者数量。这种试验设计，包括多基因型平台试验和混合设计，应该确保治疗组和对照组之间对于最重要的预后因素的基线平衡，同时考虑到本研究中量化的剩余小基因型效应。
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