Darifenacin for ALS
Trial Summary
What is the purpose of this trial?
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.
Will I have to stop taking my current medications?
If you are taking standard ALS medications like Riluzole, Edaravone, or Albrioza, you must be on a stable dose before starting the trial and continue that dose during the study. If you are taking certain other medications, like strong CYP3A4 inducers or inhibitors, or antimuscarinic medications, you may need to stop them before joining the trial.
Research Team
Oliver Blanchard, MD
Principal Investigator
McGill University - Montreal Neurological Institute
Eligibility Criteria
This trial is for people aged 18-85 with ALS, a progressive neurological disorder. Participants will be taking Darifenacin or a placebo to see if it can help maintain nerve and muscle connections by influencing certain cells at the neuromuscular junction.Inclusion Criteria
Exclusion Criteria
Timeline
Screening
Participants are screened for eligibility to participate in the trial
Titration
Participants receive a daily dose of either a placebo or 7.5 mg darifenacin for two weeks
Treatment
Participants receive a daily dose of 15 mg darifenacin or placebo for 22 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
Treatment Details
Interventions
- Darifenacin
Darifenacin is already approved in United States, European Union for the following indications:
- Overactive bladder with symptoms of urge urinary incontinence, urgency and frequency
- Overactive bladder with symptoms of urge urinary incontinence, urgency and frequency
Find a Clinic Near You
Who Is Running the Clinical Trial?
McGill University
Lead Sponsor
Université de Montréal
Collaborator