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

NCT06249867 | Recruiting Phase 2 DMC

• 1 other identifier: ALS-DARI-1
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief 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

Keywords

Amyotrophic lateral sclerosis; Darifenacin; Neuromuscular junction

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability of oral doses of 15 mg darifenacin

  The incidence of adverse events and any abnormal clinical assessments will be monitored.

  24 weeks

Secondary Outcomes (7)

• Pharmacokinetics of oral doses of darifenacin

  4 weeks

• Electrical Impedance Myography (EIM)

  24 weeks

• Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score

  24 weeks

• Forced Vital Capacity (FVC)

  24 weeks

• King's College (KINGS) stage

  24 weeks

Other Outcomes (4)

• Depression and depressive symptoms

  24 weeks

• Physical function and daily activities

  24 weeks

• Neuromuscular junction innervation

  24 weeks

Study Arms (2)

Darifenacin Treatment

EXPERIMENTAL

Patients in the Treatment arm will receive a daily dose of 1 or 2 darifenacin extended-release tablets.

Drug: Darifenacin 7.5 MG Extended Release Oral Tablet

Placebo

PLACEBO COMPARATOR

Patients in the Placebo arm will receive a daily dose of 1 or 2 placebo tablets.

Drug: Placebo

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.

Also known as: Darifenacin

Darifenacin Treatment

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to comprehend and willing to sign an Informed Consent Form (ICF).
• Male or female, ≥ 18 years old and ≤85 years old, at the time of signing the ICF.
• Confirmed diagnosis of familial or sporadic ALS, defined as meeting the probable, laboratory-supported probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology Modified El Escorial criteria (1).
• ALS duration of less than 36 months from the symptom onset.
• FVC of ≥ 50 %.
• Able to swallow tablets without crushing.
• A female patient is eligible to participate if she is not breastfeeding, has negative pregnancy test at screening, has no intention of becoming pregnant during the course of the study, and agrees to use appropriate contraceptive drugs or devices (as defined in section 3.4 of the study protocol) for the duration of the study.
• If male and has a partner who may become pregnant, agrees to ensure that he and/or his partner use a reliable form of birth control (as defined in section 3.4 of the study protocol) for the duration of the study and refrain from donating sperm during this period.
• Participants receiving standard care for ALS prior to entering the trial (i.e. Riluzole, Edaravone, and Albrioza), must be on a stable dosing regimen prior to the randomization and agree to remain on this dosage during the study period:
• In the case of taking Riluzole, the patient must have been on a stable dose at least 30 days prior to start date.
• In the case of taking Edaravone, the patient must have been on a stable dose at least 30 days prior to start date.
• In the case of receiving Albrioza, the patient must have been on a stable dose at least 30 days prior to start date.
• For participants who consent to the optional biopsy:
• Participants with normal platelet or coagulation test values.
• Participants who are receiving anticoagulant medications will need to abstain from using anticoagulants for a specific number of days before and after the biopsy, as decided by the study doctor on a case-by-case basis.

You may not qualify if:

• Patients with, or at risk for, the following conditions:
• Untreated or uncontrolled narrow-angle glaucoma;
• Gastric retention
• Urinary retention
• Liver disease
• Patients with a known history of severe allergic or anaphylactic reactions to antimuscarinic medications
• If diagnosed with another neurodegenerative disease (e.g. Multiple Sclerosis, Parkinson, Myasthenia Gravis, and Alzheimer's disease).
• Subjects with severe hepatic impairment or abnormal liver enzymes, as defined as Child-Pugh B and C scores.
• Subject has a history of, or positive test result at Screening, for hepatitis C virus antibody.
• Subjects with acute or prolonged hepatitis B \& C.
• Any medical condition that might interfere with the patient's participation in the trial, poses any added risk for the patient, or confounds the assessment of the patient according to the Investigator's judgement.
• Subjects with any uncontrolled (unresolved) medical condition other than ALS, as determined by the Investigator.
• Subjects who are currently enrolled in another clinical trial and receiving an Investigational Product (IP) (including but not limited to stem cell therapy or gene therapy).
• Treatment with an investigational drug within 1 month or within a time period equal to 5 half-lives (if known) whichever is longer, of starting study treatment.
• Patients with prior darifenacin treatment.

Sponsors & Collaborators

• Oliver Blanchard: lead
• Université de Montréal: collaborator

Study Sites (2)

Ottawa Hospital Research Institute

Ottawa, Ontario, K1Y 4E9, Canada

RECRUITING

Montreal Neurological Institute

Montreal, Quebec, H3A 2B4, Canada

RECRUITING

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Interventions

darifenacin

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Oliver Blanchard, MD

  McGill University - Montreal Neurological Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nisha Pulimood, PhD

CONTACT

514-396-2401; nisha.pulimood@mcgill.ca

Gabriele Riva, PhD

CONTACT

gabriele.riva@mcgill.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Model Details: Participants are assigned to either a treatment (darifenacin) or placebo group in parallel for the duration of the study. Treatment will include a two-week titration period with a 7.5 mg dose of darifenacin, which will be increased to 15 mg dose for the following 22 weeks. Dosing regimen of the placebo group will be administered to match the treatment dosing regimen.

Study Record Dates

• First Submitted: January 22, 2024
• First Posted: February 8, 2024
• Study Start: November 8, 2024
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): September 1, 2027
• Last Updated: September 5, 2025

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2)