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PLEO-CMT

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

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Year of Publication: 2021

Authors: Shahram Attarian, Peter Young, Thomas H. Brannagan, ..., Kevin Felice

Journal: Orphanet Journal of Rare Diseases

Citation: Orphanet J Rare Dis 2021;16:433

Link: https://doi.org/10.1186/s13023-021-02040-8

Clinical Question

Does PXT3003 (a combination of baclofen, naltrexone, and D-sorbitol) improve disability in patients with mild to moderate Charcot-Marie-Tooth disease type 1A compared to placebo?

Bottom Line

High-dose PXT3003 significantly improved disability (ONLS score) and mobility (10MWT) in CMT1A patients with a good safety profile, demonstrating a dose-dependent treatment effect that suggests promise as a disease-modifying therapy

Major Points

  • High-dose PXT3003 improved ONLS score by -0.37 points vs placebo (p=0.008)
  • Low-dose PXT3003 did not achieve statistical significance vs placebo (p=0.287)
  • Significant dose-effect relationship: -0.17 points per unit dose increase (p=0.013)
  • High-dose improved 10-meter walk test significantly (p=0.016)
  • Odds ratio for non-deterioration was 3.39 (p=0.026) for high-dose vs placebo
  • Both doses were safe with no treatment-related serious adverse events
  • Study affected by intercurrent event (crystal formation in high-dose formulation) requiring early discontinuation of high-dose arm
  • Treatment compliance was >90% across all groups

Design

Study Type: Phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind; treatments were liquid formulations indistinguishable by look or taste in identical kits; randomization code created by independent statistician

Enrollment Period: December 2015 to March 2018

Follow-up Duration: Up to 15 months

Centers: 30

Countries: Belgium, Canada, France, Germany, Netherlands, Spain, United Kingdom, USA

Sample Size: 323

Analysis: Linear mixed model ANCOVA on mFAS with multiple imputation; modified intention-to-treat using modified full analysis set (mFAS); Bonferroni correction for multiple comparisons

Inclusion Criteria

  • Age 16-65 years
  • Genetically proven diagnosis of CMT1A
  • Mild to moderate severity (CMTNS-v2 score 2-18)
  • Clinically confirmed muscle weakness in at least foot dorsiflexors
  • Motor nerve conduction velocity ≥15 m/s in ulnar nerve

Exclusion Criteria

  • Any other type of concomitant peripheral neuropathy (e.g., diabetic neuropathy)
  • Another significant neurological disease
  • Major systemic disease

Arms

FieldControlLow-dose PXT3003High-dose PXT3003
InterventionPlacebo liquid formulation, 5 mL orally twice daily (2.5 mL BID for first 2 weeks, then escalated to 5 mL BID)Baclofen 3 mg, naltrexone 0.35 mg, D-sorbitol 105 mg per 5 mL dose, orally twice dailyBaclofen 6 mg, naltrexone 0.70 mg, D-sorbitol 210 mg per 5 mL dose, orally twice daily
DurationUp to 15 monthsUp to 15 monthsUp to 15 months (discontinued early due to crystal formation)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change in Overall Neuropathy Limitations Scale (ONLS) total score from baseline to months 12 and 15 (mean)PrimaryIncreased (worsened)High-dose: Decreased (improved); Low-dose: Decreased (improved)High-dose vs placebo: 0.008; Low-dose vs placebo: 0.287
10-meter walk test (time in seconds)SecondaryWorsenedHigh-dose: ImprovedHigh-dose vs placebo: 0.016
CMTNS-v2 Sensory scoreSecondaryBaseline referenceHigh-dose: Improved (not significant)Not significant
CMTNS-v2 Examination scoreSecondaryBaseline referenceHigh-dose: Improved (not significant)Not significant
Nine-hole peg testSecondaryBaseline referenceHigh-dose: Improved (not significant)Not significant
Any TEAEAdverse83 (82.2%)High-dose: 87 (77.0%); Low-dose: 89 (81.7%)0.581
Treatment-related TEAEsAdverse34 (33.7%)High-dose: 38 (33.6%); Low-dose: 39 (35.8%)0.935
Serious TEAEsAdverse5 (5.0%)High-dose: 3 (2.7%); Low-dose: 10 (9.2%)0.108
NauseaAdverse3 (3.0%)High-dose: 6 (5.3%); Low-dose: 7 (6.4%)0.502
DiarrheaAdverse5 (5.0%)High-dose: 6 (5.3%); Low-dose: 3 (2.8%)0.620
HeadacheAdverse3 (3.0%)High-dose: 6 (5.3%); Low-dose: 6 (5.5%)0.639
DizzinessAdverse1 (1.0%)High-dose: 3 (2.7%); Low-dose: 4 (3.7%)0.496

Subgroup Analysis

Responder analysis showed odds ratio of 3.39 (p=0.026, 97.5% CI [0.99, 11.62]) for non-deterioration in high-dose vs placebo. Sensitivity analyses using FAS, completers, and per protocol populations showed consistent treatment effects. Longitudinal model estimated -0.31 points/year improvement with high-dose (p=0.013). Dose-effect analysis showed -0.17 points per unit dose increase (p=0.013).

Criticisms

  • Intercurrent event (crystal formation in high-dose formulation) led to early discontinuation of high-dose arm and reduced statistical power from 90% to 75%
  • High dropout rate (33.7% overall) due to stability issues with high-dose formulation
  • Modified full analysis set (mFAS) used instead of original FAS, though sensitivity analyses supported validity
  • Short treatment duration (15 months) relative to slow disease progression of CMT1A
  • Predominantly White population (>97%) limits generalizability
  • Physiological parameters (CMAP, SNAP, nerve conduction velocity) did not show significant improvement
  • Low-dose arm did not achieve statistical significance, leaving only single effective dose level
  • Potential partial unblinding of placebo group due to high-dose discontinuation

Funding

Pharnext (owns patent rights to PXT3003); clinical research organizations assisted with data management and statistical analyses

Based on: PLEO-CMT (Orphanet Journal of Rare Diseases, 2021)

Authors: Shahram Attarian, Peter Young, Thomas H. Brannagan, ..., Kevin Felice

Citation: Orphanet J Rare Dis 2021;16:433

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