Defining Clinically Meaningful Thresholds (CMT) for Forced Vital Capacity (FVC) and Six-Minute Walk Test (6MWT) in Patients with Late-Onset Pompe Disease (LOPD)
Author(s)
Berger K1, Ivanescu C2, Msihid J3, Periquet M4, Hamed A5, An Haack K6, Zhou T5, Boentert M7, Kruijshaar ME8, van der Beek NAME9, Pollissard L10
1Sanofi, New Rochelle, NY, USA, 2IQVIA, Amsterdam, NH, Netherlands, 3Sanofi, Chilly Mazarin, 91, France, 4Sanofi, Berlin, Germany, 5Sanofi, Cambridge, MA, USA, 6Sanofi, Chilly-Mazarin, France, 7Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany, 8Department of Pediatrics/Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center, Rotterdam, Netherlands, 9Department of Neurology/Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center, Rotterdam, Netherlands, 10Sanofi, Chilly-Mazarin, 75, France
Presentation Documents
OBJECTIVES: Interpretation of clinical trial results is limited without a defined CMT for within-patient change or between-group differences of study endpoints. Pooled data (n=100) from COMET trial (NCT02782741) comparing avalglucosidase alfa (AVA) vs. alglucosidase alfa (ALG) in LOPD was used to estimate within-patient and between-group CMTs for FVC (%predicted) and 6MWT.
METHODS: Distribution and anchor-based methods, supplemented with empirical cumulative distribution function curves, were used. Anchor appropriateness was assessed using Spearman correlations, with values >0.30 preferable. Data from multiple anchors (Patient Global Impression of Change, Pompe Disease Impact Scale, SF-12, and EQ-5D-5L) and timepoints (W49 and W97) were triangulated into a single value using a weighted average and 95% confidence interval (CI). The derived within-patient CMTs were applied post-hoc to COMET data to compare the proportion of responders in AVA vs. ALG using a logistic regression.
RESULTS: Correlations between anchors and absolute change from baseline in FVC and 6MWT were <0.30 at W49, with some anchors exceeding 0.30 at W97. The weighted average [95%CI] at W49 for within-patient and between-group CMTs for improvement in FVC (%predicted) was 3.0%[2.2;3.9] and 2.1%[1.1;3.1], respectively. For 6MWT, estimates were 45.0m[28.4;61.6] and 33.1m[16.6;49.6], respectively. Similar results were obtained at W97. Responder analysis results showed that irrespective of the CMT threshold used, the proportion of patients with an increase in FVC and 6MWT at W49 was higher in AVA vs. ALG. Group mean differences in FVC and 6MWT between AVA and ALG in COMET were within the estimated range of between-group thresholds (difference in least square means [95%CI], FVC: 2.43% [–0.13;4.99]; 6MWT: 30.01 m [1.33;58.69]).
CONCLUSIONS: This study successfully derived within-patient and between-group CMTs for FVC and 6MWT in LOPD to facilitate interpretation of functional data in clinical trials and routine care. CMT-based responder analyses confirm presence of a clinically meaningful benefit for AVA vs ALG therapy.
Conference/Value in Health Info
Value in Health, Volume 26, Issue 6, S2 (June 2023)
Code
CO168
Topic
Clinical Outcomes
Topic Subcategory
Clinical Outcomes Assessment
Disease
Diabetes/Endocrine/Metabolic Disorders (including obesity), Respiratory-Related Disorders (Allergy, Asthma, Smoking, Other Respiratory)