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

Sponsor
Oliver Blanchard
Study ID
NCT06249867
Phase
PHASE2
Status
Recruiting
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Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - 85 Years
Healthy Volunteers
Not accepted

Interventions

  • Darifenacin 7.5 MG Extended Release Oral Tablet — DRUG
    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.
  • Placebo — DRUG
    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.

Study Details

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.

Key Dates

First listed
Feb 8, 2024
Start date
Nov 8, 2024
Status verified
Nov 2024
Primary completion
Aug 31, 2027
Completion
Sep 30, 2027

Study Design

Enrollment
30 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Experimental: Darifenacin Treatment
    Patients in the Treatment arm will receive a daily dose of 1 or 2 darifenacin extended-release tablets.
  • Placebo Comparator: Placebo
    Patients in the Placebo arm will receive a daily dose of 1 or 2 placebo tablets.

Primary Outcome Measure

Safety and tolerability of oral doses of 15 mg darifenacin [ Time Frame: 24 weeks ]

Central Contacts

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