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A Registry-Based Clinical Trial of Pimozide in Patients With Neuromuscular Junction Transmission Dysfunction Due to ALS

This study is ongoing, but not recruiting participants.
Hotchkiss Brain Institute, University of Calgary
Information provided by (Responsible Party):
DR. LAWRENCE KORNGUT, University of Calgary Identifier:
First received: April 21, 2015
Last updated: October 24, 2016
Last verified: October 2016

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease that results in rapid decline in normal muscle function and tone leading to difficulties with mobility, eating, drinking, breathing, sleeping, and communicating. The disease is progressive and no cure currently exists. Most people diagnosed with ALS succumb within 3 to 5 years. The only approved treatment to slow the progression of ALS is called Rilutek® (riluzole) which has only a modest effect and has been shown to increase survival by a few months.

Muscular dysfunction present in people with ALS is caused by nerve breakdown and a dysfunction in the communication between the muscles and the nerves. The area where these communications occur is called the neuromuscular junction. Some recent studies have focused on using different medications to enhance communication at the neuromuscular junction with the goal of improving muscle function as a result. This approach is unproven but may help to slow the progression of the disease.

Pimozide is a medication that has been demonstrated to enhance communication at the neuromuscular junction in fish and mice. This study will look at whether Pimozide may help to slow the progression of ALS and how much medication needs to be taken to have an effect.

Condition Intervention Phase
Amyotrophic Lateral Sclerosis (ALS)
Drug: Pimozide 2 mg per day
Drug: Pimozide 4 mg per day
Drug: Placebo (Lactose tablet)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Registry-Based Randomized-Controlled, Double-Blinded Clinical Trial of Pimozide in Patients With Neuromuscular Junction Transmission Dysfunction Due to Amyotrophic Lateral Sclerosis

Resource links provided by NLM:

Further study details as provided by University of Calgary:

Primary Outcome Measures:
  • ALS Functional Rating Scale-Revised (ALSFRS-R) [ Time Frame: Change from randomization in ALSRSR-R at visit 5(day 51) and change from randomization in ALSFRS-R at visit 6 (day 65) ]
    A questionnaire based rating scale that assesses the functioning of ALS subjects across 4 domains: gross motor activity, fine motor activity, bulbar, and respiratory function

  • Slow Vital Capacity (SVC) [ Time Frame: Change from screen (day -14) and randomization (day 1) in SVC at visit 5 (day 51), and Change from screen (day -14) and randomization (day 1) in SVC at visit 6 (day 65) ]
    SVC will be measured using a spirometer.

  • Decremental responses on repetitive nerve stimulation (DRRNS) [ Time Frame: Change from screen (day -14) and randomization (day 1) in DRRNS at visit 5 (day 51), and Change from screen (day -14) and randomization (day 1) in DRRNS at visit 6 (day 65) ]
    Using Caldwell Electromyographic System, perform repetitive nerve stimulation studies and estimates of amplitude of decremental responses.

Secondary Outcome Measures:
  • Adverse Effects [ Time Frame: Day 12, visit 3 (day 23), visit 4 (day 36), visit 5 (day 51), and visit 6 (day 65). ]
    Adverse event review will be conducted at study visits. Adverse events will be reported to the un-blinded study observer.

Estimated Enrollment: 25
Study Start Date: April 2015
Estimated Study Completion Date: December 2021
Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1 Pimozide (2mg per day)
Pimozide will be initiated at 1 mg twice daily and maintained on 2mg/day for 50 days. End of study dose reduction will begin following the Final Outcome Measure Visit (Day 65). Pimozide will then be stopped.
Drug: Pimozide 2 mg per day
Experimental: Group 2 Pimozide (4mg per day)
Pimozide will be initiated at 1 mg twice daily then increased by 1mg twice daily every five days to 4 mg/day) for 45 days. End of study dose reduction will begin following the Final Outcome Measure Visit (Day 65). Pimozide will be titrated by reducing the dose by 1 mg twice daily every day to full discontinuation (over 2 days).
Drug: Pimozide 4 mg per day
Placebo Comparator: Group 3 Placebo (Lactose tablet)
Placebo tablets will be utilized and administered in an identical manner for subjects in Group 3
Drug: Placebo (Lactose tablet)

Detailed Description:

This clinical trial has two components: an acute therapy component consisting of a Phase II placebo-controlled, double-blinded, randomized-controlled pilot study of pimozide for the treatment of ALS; and a second component featuring a longitudinal follow-up study on ALS progression and outcomes. This clinical trial is registry-based including subject recruitment facilitated by the Canadian Neuromuscular Disease Registry (CNDR; National Principal Investigator: L. Korngut), and longitudinal follow-up data collection will occur during the second component of this clinical trial through the CNDR.

The acute therapy study duration for each subject is around 11 weeks. The follow up study duration through the CNDR is up to 5 years.

Number of study participants:25

Randomization: Subjects will be block randomized with a block size of five subjects. Within each block one subject will be randomly assigned to placebo with the remaining four subjects randomized to the treatment groups. Study physicians will be blinded to patient randomization status. Randomization will occur with a 4:1 ratio of study drug (20 subjects) to placebo (5 subjects). After administration of maximum dose for 45-50 days, subjects will taper the allocated treatment or placebo. Randomization will occur via permuted block randomization and study personnel will be blinded to the randomization at all times allowing full concealment.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients classified as having clinically definite, clinically probable, or clinically probable (laboratory-supported) ALS according to the El-Escorial diagnostic criteria for ALS
  2. Evidence of decremental response greater or equal to 5.0% in at least one nerve-muscle pair at the initial screening visit
  3. Age 18 years or greater
  4. Consent to participate in the Canadian Neuromuscular Disease Registry (CNDR) (follow-up study component only).

Exclusion Criteria:

  1. Diagnosis of clinically possible or clinically suspected ALS as defined by the El-Escorial diagnostic criteria for ALS
  2. If the subject is taking riluzole the dose must be stable for 30 days prior to randomization visit. Riluzole cannot be initiated during the study.
  3. History of Parkinson's disease
  4. History of traumatic brain injury
  5. History of neuroleptic malignant syndrome
  6. History of hypersensitivity or serious adverse reaction(s) to a neuroleptic medication
  7. History of prolonged QTc interval > 500 ms
  8. History of hyponatremia < 130 mmol/L
  9. History of current heparin or warfarin use
  10. History of hepatic and/or renal impairment that may affect pimozide metabolism
  11. History of current pregnancy or breastfeeding
  12. Current antipsychotic use
  13. Presence of central nervous system depression, comatose states, liver disorders, renal insufficiency, and blood dyscrasias
  14. Presence of depressive disorders or Parkinson's syndrome
  15. History of congenital long QT syndrome or with a family history of this syndrome and in patients with a history of cardiac arrhythmias or Torsade de Pointes
  16. Presence of acquired long QT interval, such as associated with concomitant use of drugs known to prolong the QT interval
  17. Presence of hypokalemia or hypomagnesemia
  18. Presence of clinically significant bradycardia (heart rate < 50 beats per minute)
  19. The concomitant use of CYP 3A4-inhibiting drugs such as azole antimycotics, antiviral protease inhibitors, macrolide antibiotics and nefazodone
  20. The concomitant use of CYP 2D6-inhibiting drugs such as quinidine is also contraindicated
  21. Concomitant use of serotonin reuptake inhibitors, such as, sertraline, paroxetine, citalopram and escitalopram
  22. Severe dysphagia with risk of aspiration
  23. Has taken any compound under current or known future study as a potential therapy for ALS less than 30 days prior to dosing OR history of exposure to stem cell therapy for treatment of ALS at any time
  Contacts and Locations
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Please refer to this study by its identifier: NCT02463825

Canada, Alberta
South Health Campus
Calgary, Alberta, Canada, T3M 1M4
Sponsors and Collaborators
University of Calgary
Hotchkiss Brain Institute, University of Calgary
Principal Investigator: Lawrence Korngut, MD, FRCPC University of Calgary and Alberta Health Services
  More Information

Responsible Party: DR. LAWRENCE KORNGUT, Director, Calgary ALS and Motor Neuron Disease Clinic, University of Calgary Identifier: NCT02463825     History of Changes
Other Study ID Numbers: REB14-0617
Study First Received: April 21, 2015
Last Updated: October 24, 2016

Additional relevant MeSH terms:
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Dyskinesia Agents processed this record on May 25, 2017