Back to results

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

Primary Purpose

Amyotrophic Lateral Sclerosis (ALS)

Status

Unknown status

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

Pimozide 2 mg per day

Pimozide 4 mg per day

Placebo (Lactose tablet)

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis (ALS)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

Diagnosis of clinically possible or clinically suspected ALS as defined by the El-Escorial diagnostic criteria for ALS
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.
History of Parkinson's disease
History of traumatic brain injury
History of neuroleptic malignant syndrome
History of hypersensitivity or serious adverse reaction(s) to a neuroleptic medication
History of prolonged QTc interval > 500 ms
History of hyponatremia < 130 mmol/L
History of current heparin or warfarin use
History of hepatic and/or renal impairment that may affect pimozide metabolism
History of current pregnancy or breastfeeding
Current antipsychotic use
Presence of central nervous system depression, comatose states, liver disorders, renal insufficiency, and blood dyscrasias
Presence of depressive disorders or Parkinson's syndrome
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
Presence of acquired long QT interval, such as associated with concomitant use of drugs known to prolong the QT interval
Presence of hypokalemia or hypomagnesemia
Presence of clinically significant bradycardia (heart rate < 50 beats per minute)
The concomitant use of CYP 3A4-inhibiting drugs such as azole antimycotics, antiviral protease inhibitors, macrolide antibiotics and nefazodone
The concomitant use of CYP 2D6-inhibiting drugs such as quinidine is also contraindicated
Concomitant use of serotonin reuptake inhibitors, such as, sertraline, paroxetine, citalopram and escitalopram
Severe dysphagia with risk of aspiration
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

Sites / Locations

South Health Campus

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

Group 1 Pimozide (2mg per day)

Group 2 Pimozide (4mg per day)

Group 3 Placebo (Lactose tablet)

Arm Description

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.

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).

Placebo tablets will be utilized and administered in an identical manner for subjects in Group 3

Outcomes

Primary Outcome Measures

ALS Functional Rating Scale-Revised (ALSFRS-R)

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)

SVC will be measured using a spirometer.

Decremental responses on repetitive nerve stimulation (DRRNS)

Using Caldwell Electromyographic System, perform repetitive nerve stimulation studies and estimates of amplitude of decremental responses.

Secondary Outcome Measures

Adverse Effects

Adverse event review will be conducted at study visits. Adverse events will be reported to the un-blinded study observer.

Full Information

NCT ID

NCT02463825

First Posted

April 21, 2015

Last Updated

October 24, 2016

Sponsor

University of Calgary

Collaborators

Hotchkiss Brain Institute, University of Calgary

1. Study Identification

Unique Protocol Identification Number

NCT02463825

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2016

Overall Recruitment Status

Unknown status

Study Start Date

April 2015 (undefined)

Primary Completion Date

August 2016 (Actual)

Study Completion Date

December 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Calgary

Collaborators

Hotchkiss Brain Institute, University of Calgary

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Amyotrophic Lateral Sclerosis (ALS)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

25 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Group 1 Pimozide (2mg per day)

Arm Type

Experimental

Arm Description

Arm Title

Group 2 Pimozide (4mg per day)

Arm Type

Experimental

Arm Description

Arm Title

Group 3 Placebo (Lactose tablet)

Arm Type

Placebo Comparator

Arm Description

Placebo tablets will be utilized and administered in an identical manner for subjects in Group 3

Intervention Type

Drug

Intervention Name(s)

Pimozide 2 mg per day

Intervention Type

Drug

Intervention Name(s)

Pimozide 4 mg per day

Intervention Type

Drug

Intervention Name(s)

Placebo (Lactose tablet)

Primary Outcome Measure Information:

Title

ALS Functional Rating Scale-Revised (ALSFRS-R)

Description

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

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)

Title

Slow Vital Capacity (SVC)

Description

SVC will be measured using a spirometer.

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)

Title

Decremental responses on repetitive nerve stimulation (DRRNS)

Description

Using Caldwell Electromyographic System, perform repetitive nerve stimulation studies and estimates of amplitude of decremental responses.

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)

Secondary Outcome Measure Information:

Title

Adverse Effects

Description

Adverse event review will be conducted at study visits. Adverse events will be reported to the un-blinded study observer.

Time Frame

Day 12, visit 3 (day 23), visit 4 (day 36), visit 5 (day 51), and visit 6 (day 65).

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients classified as having clinically definite, clinically probable, or clinically probable (laboratory-supported) ALS according to the El-Escorial diagnostic criteria for ALS Evidence of decremental response greater or equal to 5.0% in at least one nerve-muscle pair at the initial screening visit Age 18 years or greater Consent to participate in the Canadian Neuromuscular Disease Registry (CNDR) (follow-up study component only). Exclusion Criteria: Diagnosis of clinically possible or clinically suspected ALS as defined by the El-Escorial diagnostic criteria for ALS 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. History of Parkinson's disease History of traumatic brain injury History of neuroleptic malignant syndrome History of hypersensitivity or serious adverse reaction(s) to a neuroleptic medication History of prolonged QTc interval > 500 ms History of hyponatremia < 130 mmol/L History of current heparin or warfarin use History of hepatic and/or renal impairment that may affect pimozide metabolism History of current pregnancy or breastfeeding Current antipsychotic use Presence of central nervous system depression, comatose states, liver disorders, renal insufficiency, and blood dyscrasias Presence of depressive disorders or Parkinson's syndrome 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 Presence of acquired long QT interval, such as associated with concomitant use of drugs known to prolong the QT interval Presence of hypokalemia or hypomagnesemia Presence of clinically significant bradycardia (heart rate < 50 beats per minute) The concomitant use of CYP 3A4-inhibiting drugs such as azole antimycotics, antiviral protease inhibitors, macrolide antibiotics and nefazodone The concomitant use of CYP 2D6-inhibiting drugs such as quinidine is also contraindicated Concomitant use of serotonin reuptake inhibitors, such as, sertraline, paroxetine, citalopram and escitalopram Severe dysphagia with risk of aspiration 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Lawrence Korngut, MD, FRCPC

Organizational Affiliation

University of Calgary and Alberta Health Services

Official's Role

Principal Investigator

Facility Information:

Facility Name

South Health Campus

City

Calgary

State/Province

Alberta

ZIP/Postal Code

T3M 1M4

Country

Canada

12. IPD Sharing Statement

Learn more about this trial

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

We'll reach out to this number within 24 hrs