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Background <p>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.</p> Methods <p>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.</p> Results <p>We found strong association between the RCGI-S scores with gray matter volume (r(14) = −0.81; 95% CI [−0.93, −0.51], <i>p</i> &lt; 0.001), and RCGI-C scores significantly correlated with increases in ventricular volume (χ<sup>2</sup>(1) = 18.6, <i>p</i> &lt; 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], <i>p</i> = 0.02).</p> Conclusion <p>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.</p>

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Retrospective assessment of clinical global impression of severity and change in GM1 gangliosidosis: a tool to score natural history data in rare disease cohorts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月14日

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  • Connor J. Lewis,
  • Jean M. Johnston,
  • Silvia Zaragoza Domingo,
  • Gilbert Vezina,
  • Precilla D’Souza,
  • William A. Gahl,
  • David A. Adams,
  • Cynthia J. Tifft,
  • Maria T. Acosta

摘要

Background

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.

Methods

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.

Results

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 (χ2(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).

Conclusion

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.