Assessing the safety and effects of Darifenacin in ALS patients

A Randomized, Double-blind, Single Center, Phase 2 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 15 mg of Darifenacin Daily in Patients With Amyotrophic Lateral Sclerosis

This study is testing whether the medication Darifenacin is safe and can help people with ALS by looking at its effects on muscle function.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years to 85 Years
• Sex: All
• Sponsor: McGill University (Academic / other)
• Locations: 2 sites (Ottawa, Ontario and 1 other locations)
• Trial ID: NCT06249867 on ClinicalTrials.gov

What this trial studies

This study evaluates the safety, tolerability, and pharmacological effects of Darifenacin in patients diagnosed with Amyotrophic Lateral Sclerosis (ALS). It focuses on the role of Perisynaptic Schwann Cells in neuromuscular junctions, which are critical for muscle function and are affected early in ALS. Participants will receive either Darifenacin or a placebo to determine its impact on the progression of ALS symptoms and the health of neuromuscular junctions. The study aims to provide insights into a novel therapeutic approach for managing ALS.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 to 85 with a confirmed diagnosis of familial or sporadic ALS and a disease duration of less than 36 months.

Not a fit: Patients with advanced ALS or those who do not meet the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved treatment options for patients with ALS, potentially slowing disease progression.

How similar studies have performed: While there have been limited studies on similar approaches, this specific investigation into Darifenacin's effects on ALS is novel and untested.

Eligibility criteria

Inclusion Criteria:

1. Able to comprehend and willing to sign an Informed Consent Form (ICF).
2. Male or female, ≥ 18 years old and ≤85 years old, at the time of signing the ICF.
3. 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).
4. ALS duration of less than 36 months from the symptom onset.
5. FVC of ≥ 50 %.
6. Able to swallow tablets without crushing.
7. 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.
8. 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.
9. 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.
10. 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.

Exclusion Criteria:

1. Patients with, or at risk for, the following conditions:

   * Untreated or uncontrolled narrow-angle glaucoma;
   * Gastric retention
   * Urinary retention
   * Liver disease
2. Patients with a known history of severe allergic or anaphylactic reactions to antimuscarinic medications
3. If diagnosed with another neurodegenerative disease (e.g. Multiple Sclerosis, Parkinson, Myasthenia Gravis, and Alzheimer's disease).
4. Subjects with severe hepatic impairment or abnormal liver enzymes, as defined as Child-Pugh B and C scores.
5. Subject has a history of, or positive test result at Screening, for hepatitis C virus antibody.
6. Subjects with acute or prolonged hepatitis B \& C.
7. 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.
8. Subjects with any uncontrolled (unresolved) medical condition other than ALS, as determined by the Investigator.
9. 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).
10. 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.
11. Patients with prior darifenacin treatment.
12. History of drug and/or alcohol abuse (according to Diagnostic and Statistical Manual of Mental Disorders) prior to the screening as determined by the Investigator.
13. If female, subjects who are pregnant, breastfeeding, or intending to conceive during the course of the study.
14. Subjects with an abnormal electrocardiogram (ECG) at screening (any abnormality that the PI believes that entering the study place the participant at risk).
15. Subjects who are receiving strong CYP3A4 inducers such as carbamazepine (anticonvulsant), phenytoin (anticonvulsant), rifampin (antibiotic), and modafinil (wakefulness-promoting agent).
16. Subjects who are receiving potent CYP3A4 inhibitors such as clarithromycin (macrolide antibiotic), ketoconazole and itraconazole (antifungal medications), nefazadone (antidepressant), nelfinavir and ritonavir (protease inhibitors).
17. Subjects who are receiving or received within 30 days prior to the starting of the trial CYP2D6 substrates with a narrow therapeutic window such as include flecainide (Class IC anti-arrhythmic), thioridazine (antipsychotic) and tricyclic antidepressants.
18. Subjects who are receiving or received botulinum injections in the past 6 months.
19. Subjects who are receiving or received within 30 days prior to the starting of the trial antimuscarinic medications for the treatment of overactive bladder such as fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium.
20. Only for patients that consented to the Optional Needle Muscle Biopsy procedures.
21. Subject is taking an anticoagulant (with the exception of aspirin at the investigator's discretion) or is at risk of increased or uncontrolled muscle biopsy-related bleeding.
22. Subjects with bleeding risk factors which include, but are not limited to, anatomical factors at or near the muscle biopsy site (e.g., vascular abnormalities, neoplasms, or other abnormalities) or abnormal platelet or coagulation test values at visit 1.

Where this trial is running

Ottawa, Ontario and 1 other locations

• Ottawa Hospital Research Institute — Ottawa, Ontario, Canada (Recruiting)
• Montreal Neurological Institute — Montreal, Quebec, Canada (Recruiting)

Study contacts

• Principal investigator: Oliver Blanchard, MD — McGill University - Montreal Neurological Institute
• Study coordinator: Nisha Pulimood, PhD

Conditions Amyotrophic Lateral Sclerosis; Amyotrophic lateral sclerosis; Darifenacin; Neuromuscular junction