Lewis Connor J, Johnston Jean M, Zaragoza Domingo Silvia, Vezina Gilbert, D'Souza Precilla, Gahl William A, Adams David A, Tifft Cynthia J, Acosta Maria T
Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD, USA.
Neuropsynchro, Barcelona, Spain.
Orphanet J Rare Dis. 2025 Mar 14;20(1):125. doi: 10.1186/s13023-025-03614-6.
Clinical trials for rare diseases pose unique challenges warranting alternative approaches in demonstrating treatment efficacy. Such trials face challenges including small patient populations, variable onset of symptoms and rate of disease progression, and ethical considerations, particularly in neurodegenerative diseases. In this study, we present the retrospective clinical global impression (RCGI) severity and change (RCGI-S/C) scale on 27 patients with GM1 gangliosidosis, a post hoc clinician-rated outcome measure to evaluate natural history study participants as historical controls for comparisons with treated patients in a clinical trial.
We conducted a systematic chart review of 27 GM1 gangliosidosis natural history participants across 95 total visits. RCGI-S was assessed at the first visit and rated 1 (normal) to 7 (among the most extremely ill). Each subsequent follow-up was rated on the RCGI-C scale from 1 (very much improved) to 7 (very much worse). We demonstrate scoring guidelines of both scales with examples and justifications for this pilot in GM1 gangliosidosis natural history participants. The convergent validity of the RCGI scales was explored through correlations with magnetic resonance imaging (MRI) and the Vineland Adaptive Behavioral Scales.
We found strong association between the RCGI-S scores with gray matter volume (r(14) = -0.81; 95% CI [-0.93, -0.51], p < 0.001), and RCGI-C scores significantly correlated with increases in ventricular volume (χ(1) = 18.6, p < 0.001). Baseline RCGI-S scores also strongly correlated with Vineland adaptive behavioral composite scores taken at the same visit (r(14) = -0.72; 95% CI [-0.93, -0.17], p = 0.02).
RCGI-S/C scales, which use the clinical evaluation to assess the severity of disease of each patient visit over time, were consolidated into a single quantitative metric in this study. Longitudinal RCGI-C scores allowed us to quantify disease progression in our late-infantile and juvenile GM1 patients. We suggest that the retrospective CGI may be an important tool in evaluating historical data for comparison with changes in disease progression/mitigation following therapeutic interventions.
罕见病的临床试验面临独特挑战，需要采用替代方法来证明治疗效果。此类试验面临诸多挑战，包括患者群体规模小、症状发作和疾病进展速度不一，以及伦理考量，尤其是在神经退行性疾病方面。在本研究中，我们介绍了针对27例GM1神经节苷脂病患者的回顾性临床整体印象（RCGI）严重程度和变化（RCGI-S/C）量表，这是一种事后临床医生评定的结局指标，用于评估自然史研究参与者，作为临床试验中与接受治疗患者进行比较的历史对照。
我们对27例GM1神经节苷脂病自然史研究参与者进行了系统的病历审查，共涉及95次就诊。首次就诊时评估RCGI-S，评分为1（正常）至7（病情极其严重）。随后的每次随访根据RCGI-C量表进行评分，从1（显著改善）至7（显著恶化）。我们通过与磁共振成像（MRI）和文兰适应性行为量表的相关性，展示了这两个量表在GM1神经节苷脂病自然史研究参与者中的评分指南及该试点的理由。
我们发现RCGI-S评分与灰质体积之间存在强关联（r(14) = -0.81；95% CI [-0.93, -0.51]，p < 0.001），并且RCGI-C评分与脑室体积增加显著相关（χ(1) = 18.6，p < 0.001）。基线RCGI-S评分也与同一就诊时的文兰适应性行为综合评分密切相关（r(14) = -0.72；95% CI [-0.93, -0.17]，p = 0.02）。
RCGI-S/C量表通过临床评估来评估每位患者随时间推移就诊时的疾病严重程度，在本研究中被整合为一个单一的定量指标。纵向RCGI-C评分使我们能够量化晚期婴儿型和青少年型GM1患者的疾病进展。我们认为，回顾性临床整体印象量表可能是评估历史数据的重要工具，可用于与治疗干预后疾病进展/缓解的变化进行比较。
