A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A

Abstract

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A.

Methods: In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set.

Results: High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: - 0.37 points; 97.5% CI [- 0.68 to - 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated.

Conclusion: The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot-Marie-Tooth disease type 1A.

Keywords: CMT1A; Charcot–Marie–Tooth; Neuromuscular disorder; Overall Neuropathy Limitations Scale; PMP22; PXT3003; Randomized controlled trial.

Fig. 1

Subject disposition. The full analysis set (FAS) consisted of all randomized subjects. The modified FAS (mFAS) consisted of all randomized subjects except those who dropped out for reasons unrelated to outcome as judged by an independent adjudication committee. The completers population included all subjects who had at least a 12-month visit. The per protocol population consisted of all subjects who had no major protocol violation between randomization and at least the 12-month visit. N is the number of subjects in each group

Fig. 2

Primary efficacy endpoint results. Mean change in Overall Neuropathy Limitations Scale (ONLS) total score in the modified full analysis set (mFAS, no imputation) high-dose PXT3003 (dark grey), low-dose PXT3003 (medium grey) and placebo (light grey) groups over the course of the study (panel A, error bars are standard error of the mean). The treatment effect vs placebo as measured by baseline-adjusted change with multiple imputation in ONLS score is shown in panel B for the primary analysis and the first sensitivity analysis (FAS: full analysis set). Panel C shows the second sensitivity analysis (LG: longitudinal model). The error bars in B and C are 97.5% confidence intervals. Axes are reversed to emphasize that lower ONLS scores indicate improvement

Fig. 3

Secondary efficacy endpoints results. Baseline-adjusted mean change in time to walk 10 m in the modified full analysis set (no imputation) for the high-dose, low-dose and placebo groups over the course of the study is shown in panel A (error bars are standard errors of the mean). Treatment effect vs placebo as measured by baseline-adjusted change with multiple imputation for all secondary endpoints are shown in panel B (error bars are 97.5% confidence intervals). The vertical axis is reversed to show that negative numbers indicate improvement. 10MWT: 10 m walk test (time to walk 10 m), CMTNSv2-S and E: Charcot–Marie–Tooth Neuropathy Scale version 2 Sensory and Examination scores, 9HPT: nine-hole peg test

Fig. 4

Study design. Subjects were randomized to one of three treatment arms after a screening period of maximum four weeks. During the treatment period, subjects attended six visits, two of which (dashed line) could be done by telephone