A Study to Assess the Safety, Tolerability, and Pharmacology of Darifenacin in Patients With ALS

Summary

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder characterized by selective death of upper and lower motor neurons, which leads to severe disability and fatal outcomes. One of the major hallmarks of ALS is the denervation of neuromuscular junctions (NMJs), which is one of the earliest events seen in ALS patients and mouse models of ALS. Under healthy conditions, glial cells called Perisynaptic Schwann Cells (PSCs) have a key role in regulating the stability and maintenance of NMJs, but they only participate in NMJ repair once denervation occurs. Denervation and the subsequent decline in synaptic activity triggers a loss of muscarinic acetylcholine receptors (mAChRs) in the PSC, and the resulting decrease in mAChR-mediated gene expression drives the "repair mode" of the PSC. In assessing the NMJ under conditions of ALS, a scarcity of process extensions in PSCs was observed for months prior to disease onset in the superoxide dismutase 1 (SOD1) mouse model of ALS, indicating inadequate glial repair. Collectively, these preclinical findings support the hypothesis that dampening glial mAChRs will restore the anticipated "repair" response of PSCs in the NMJ. Hence, the use of a selective M3 muscarinic receptor antagonist, Darifenacin, as a disease-modifying therapeutic in familial and sporadic ALS could improve NMJ function, resulting in a beneficial impact on the autonomy and quality of life of ALS patients.

The purpose of the current Phase 2 trial is therefore to test the safety, tolerability, and pharmacology of Darifenacin in patients with ALS. Specifically, 30 eligible subjects between 18 and 85 years of age will take 7.5 mg of darifenacin or placebo daily (by mouth) for two weeks followed by an increased dose of 15 mg for the next 22 weeks. The trial will evaluate the effects of this medication on several outcome measures including patient safety, physical and neurological function, muscle strength, depression levels, and NMJ innervation of patients with ALS. Detailed clinical assessments will be conducted at regular intervals throughout the study in order to achieve these objectives.

Conditions

• Amyotrophic Lateral Sclerosis

Interventions

DRUG

Darifenacin 7.5 MG Extended Release Oral Tablet

During the first two weeks (titration period), patients in the treatment arm will receive a daily dose of 7.5 mg darifenacin extended-release tablet. After the titration period, the dose will be increased to 15 mg once daily, which consists of two 7.5 mg tablets together for a period of 22 weeks.

DRUG

Placebo

During the first two weeks (titration period), patients in the placebo arm will receive a daily dose of 1 placebo tablet. After the titration period, the dose will be increased to two placebo tablets taken together, for a period of 22 weeks.

Sponsors & Collaborators

• Université de Montréal

  collaborator OTHER

• Oliver Blanchard

  lead OTHER

Principal Investigators

• Oliver Blanchard, MD · McGill University - Montreal Neurological Institute

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

85 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2024-11-08

Primary Completion

2027-08-31

Completion

2027-09-30

Countries

• Canada

Study Locations