Defining clinically meaningful thresholds for forced vital capacity in patients with neuromuscular disorders: Lessons learned from the COMET study in Pompe disease

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Background Respiratory impairment in neuromuscular disorders (NMDs) is generally assessed using forced vital capacity (FVC). Any improvement in FVC trajectory will delay ventilatory support; however, the change required for patients to perceive a noticeable clinical benefit, the clinically meaningful threshold (CMT), has not been defined in NMDs. Objective To derive the within-person and between-group CMTs for FVC (% predicted) in patients with late-onset Pompe disease (LOPD). Methods This analysis leverages data from the Phase 3 COMET trial (NCT02782741, registered 25 May 2016), which assessed the efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on upright FVC (% predicted) in LOPD. Anchor- and distribution-based methods were used to estimate the within-person and between-group CMTs for FVC at Weeks 49 and 97. Results COMET enrolled 99 participants aged ≥18 years (52% male; mean age 48.0 years). The within-person CMT for absolute change in FVC expressed as % predicted was estimated as 3.0% [95% confidence interval (CI) 2.3, 3.8]. The proportion of patients with a meaningful increase in FVC was higher in the AVA versus ALG group across the CI of the estimated CMT (odds ratios: 2.3–2.6; nominal p-values: 0.026–0.058). The between-group CMT, needed to evaluate differences between treatment groups, was estimated as 2.1% predicted [95% CI 1.1, 3.1]. Conclusions We identified a narrow range of within-person and between-group CMTs for upright FVC (% predicted) in LOPD. Post hoc application of these thresholds to COMET showed that a greater proportion of patients in the AVA group had clinically meaningful improvement in FVC versus ALG. These findings may aid in interpretation of data from studies in other NMDs.