A Registry-Based Clinical Trial of Pimozide in Patients With Neuromuscular Junction Transmission Dysfunction Due to ALS
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.
|Amyotrophic Lateral Sclerosis (ALS)||Drug: Pimozide 2 mg per day Drug: Pimozide 4 mg per day Drug: Placebo (Lactose tablet)||Phase 2|
|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|
- 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.
- 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.
|Study Start Date:||April 2015|
|Estimated Study Completion Date:||December 2021|
|Primary Completion Date:||August 2016 (Final data collection date for primary outcome measure)|
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)|
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02463825
|South Health Campus|
|Calgary, Alberta, Canada, T3M 1M4|
|Principal Investigator:||Lawrence Korngut, MD, FRCPC||University of Calgary and Alberta Health Services|