Safety and Tolerability Study of KNS-760704 in Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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This was a 2-part study of dexpramipexole in patients with ALS. Part 1 was a randomized, placebo-controlled, multi-center study to evaluate the safety, tolerability, and clinical effects of oral administration of 3 dosage levels of dexpramipexole vs. placebo for 12 weeks. Part 2 was a randomized, double-blind, 2-arm, parallel group, extension study evaluating the safety, tolerability, and clinical effects of oral administration of 2 dosage levels of dexpramipexole for up to 72 weeks.

Detailed Description
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This study was a two-part, multicenter, double-blind study in subjects with ALS to evaluate the safety and tolerability of dexpramipexole treatment, as well as the preliminary effects on measures of clinical function and mortality of dexpramipexole treatment. In part 1, 102 subjects with ALS were randomized at 20 US sites to receive placebo, dexpramipexole at 50 mg/day; dexpramipexole at 150 mg/day; or dexpramipexole at 300 mg/day for 12 weeks. Participants who completed Part 1 were eligible to enroll into Part 2. Part 2 was a randomized, double-blind, 2-arm, parallel-group, extension study evaluating the longer-term safety, tolerability, and clinical effects of oral administration of 2 dosage levels of dexpramipexole. In part 2, following a 4-week, placebo washout, continuing subjects received dexpramipexole at 50 mg/day or 300 mg/day as double-blind treatment for up to 72 additional weeks (Part 2 duration was up to a total of 76 weeks, including the 4 week placebo portion).

Official Title
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A 2-Part, Randomized, Double-Blind, Safety and Tolerability Study Evaluating KNS-760704 in Patients With Amyotrophic Lateral Sclerosis (ALS)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Placebo
* Drug: Dexpramipexole 50 mg/day
* Drug: Dexpramipexole 150 mg/day
* Drug: Dexpramipexole 300 mg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with diagnosis of familial or sporadic ALS, defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology El Escorial criteria Patients with ALS symptom onset < 24 months from randomization Patients with upright vital capacity (VC) > 65% of predicted for age, height, and gender Exclusion Criteria: Patients in whom causes of neuromuscular weakness other than ALS have not been excluded Patients without clinical evidence of upper motor neuron dysfunction Patients with clinically suspected ALS according to the World Federation of Neurology El Escorial criteria Patients with prior exposure to KNS-760704 or the R(+) enantiomer of pramipexole (i.e., R(+)-pramipexole) Patients taking other investigational agents (including lithium) within 30 days of randomization or during the study

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part 1: Placebo or Dexpramipexole<br>During Part 1, subjects received twice daily doses of dexpramipexole (50 mg/day, 150 mg/day, or 300 mg/day) or matching placebo for approximately 12 weeks. | Drug: Placebo<br>* Placebo: 2 tablets taken orally twice daily<br>Drug: Dexpramipexole 50 mg/day<br>* Dexpramipexole: 2 x 12.5 mg tablets taken orally twice daily<br>* Other names: BIIB050;Drug: Dexpramipexole 150 mg/day<br>* Dexpramipexole: 2 x 37.5 mg tablets taken orally twice daily<br>* Other names: BIIB050;Drug: Dexpramipexole 300 mg/day<br>* Dexpramipexole: 2 x 75 mg tablets taken orally twice daily<br>* Other names: BIIB050;|
| Experimental: Part 2: Placebo washout<br>At the beginning of Part 2, subjects received twice daily doses of placebo for approximately 4 weeks. | Drug: Placebo<br>* Placebo: 2 tablets taken orally twice daily<br>|
| Experimental: Part 2: Dexpramipexole<br>Following the Part 2 placebo washout, subjects received dexpramipexole (50 mg/day or 300 mg/day), subjects received twice daily doses of placebo for up to 18 months. | Drug: Dexpramipexole 50 mg/day<br>* Dexpramipexole: 2 x 12.5 mg tablets taken orally twice daily<br>* Other names: BIIB050;Drug: Dexpramipexole 300 mg/day<br>* Dexpramipexole: 2 x 75 mg tablets taken orally twice daily<br>* Other names: BIIB050;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Potentially Clinically Significant Hematology Results by Treatment Group | Number of Participants with Potentially Clinically Significant Hematology Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test. | 12 weeks | 
| Part 1: Number of Participants With Potentially Clinically Significant Blood Chemistry Results by Treatment Group | Number of Participants with Potentially Clinically Significant Blood Chemistry Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test. | 12 weeks | 
| Part 1: Number of Participants With Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group | Number of Participants with Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group. Percentages are based on the number of patients with at least one non-missing post-baseline value in each treatment group. | 12 weeks | 
| Part 1: Number of Participants With Potentially Clinically Significant Vital Sign Measurements by Treatment Group | Number of Participants with Potentially Clinically Significant Vital Sign Measurements by Treatment Group. Percentages are based on the number of patients with at least one non-missing post-baseline value in each treatment group. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Slope of ALSFRS-R (ALS Functional Rating Scale With Respiratory Component) From Baseline to Week 12 by Treatment Group | The ALSFRS-R (ALS functional rating scale with respiratory component) is a validated scale which measures 4 functional domains, comprising respiratory function, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48, with higher scores representing better function. Slope is calculated using a linear mixed effects model with x-axis time in months and y-axis ALSFRS-R score. Units for slope are change per month in units on the ALSFRS-R scale. | 12 weeks | 
| Part 1: Slope of Upright Vital Capacity From Baseline to Week 12 by Treatment Group | Slope of change in Upright Vital Capacity (percent predicted upright vital capacity) from Baseline to Week 12. A negative change/slope indicates clinical worsening. Slope is calculated using a linear mixed effects model with x-axis time in months and y-axis as percent predicted upright vital capacity. Units for slope are change per month in percent predicted upright vital capacity. | 12 weeks | 
| Part 2 Placebo Washout: Number of Participants With Potentially Clinically Significant Hematology | Number of Participants with Potentially Clinically Significant Hematology Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test. | 4 weeks | 
| Part 2 Placebo Washout: Number of Participants With Potentially Clinically Significant Blood Chemistry Results | Number of Participants with Potentially Clinically Significant Blood Chemistry Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test. | 4 weeks | 
| Part 2 Placebo Washout: Number of Participants With Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings | Number of Participants with Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group. Percentages are based on the number of patients with at least one non-missing post-baseline value in each treatment group. | 4 weeks | 
| Part 2 Placebo Washout: Number of Participants With Potentially Clinically Significant Vital Sign Measurements | Number of Participants with Potentially Clinically Significant Vital Sign Measurements by Treatment Group. Percentages are based on the number of patients with at least one non-missing post-baseline value in each treatment group. | 4 weeks | 
| Part 2 Placebo Washout: Absolute Change in ALSFRS-R Total Score | The ALSFRS-R (ALS functional rating scale with respiratory component) is a validated scale which measures 4 functional domains, comprising respiratory function, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48, with higher scores representing better function. Units are points on the ALSFRS-R score as an absolute change from the baseline of the placebo washout to week 4 of the placebo washout. | 4 weeks | 
| Part 2 Placebo Washout: Absolute Change in Upright Vital Capacity (Percent Predicted) From Baseline to End of Placebo Washout (Week 4) | Absolute change in Upright Vital Capacity From Baseline to Week 4. Units are percent of predicted Upright Vital Capacity. A negative change indicates clinical worsening. | 4 weeks | 
| Part 2 Double-Blind Treatment: Number of Participants With Potentially Clinically Significant Hematology Results by Treatment Group | Number of Participants with Potentially Clinically Significant Hematology Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per parameter. | up to 76 weeks | 
| Part 2 Double-Blind Treatment: Number of Participants With Potentially Clinically Significant Blood Chemistry Results by Treatment Group | Number of Participants with Potentially Clinically Significant Blood Chemistry Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per parameter. | up to 76 weeks | 
| Part 2 Double-Blind Treatment: Number of Participants With Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group | Number of Participants with Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per parameter. | up to 76 weeks | 
| Part 2 Double-Blind Treatment: Number of Participants With Potentially Clinically Significant Vital Sign Measurements by Treatment Group | Number of Participants with Potentially Clinically Significant Vital Sign Measurements by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per parameter. | up to 76 weeks | 
| Part 2 Double-Blind Treatment: Slope of the ALSFRS-R (ALS Functional Rating Scale With Respiratory Component) From Baseline to Week 28 by Treatment Group | The ALSFRS-R (ALS functional rating scale with respiratory component) is a validated scale which measures 4 functional domains, comprising respiratory function, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48, with higher scores representing better function. Slope is calculated using a linear mixed effects model with x-axis time in months and y-axis ALSFRS-R score. Units for slope are change per month n units on the ALSFRS-R scale. | 28 weeks | 
| Part 2 Double-Blind Treatment: Slope of Percent Predicted Upright Vital Capacity From Baseline by Treatment Group | Slope of Upright Vital Capacity (percent predicted) through Week 28. A negative change indicates clinical worsening. Slope is calculated using a linear mixed effects model with x-axis time in months and y-axis percent predicted upright vital capacity. Units for slope are change per month in percent predicted upright vital capacity. | Baseline of randomized phase of Part 2 to week 28 of randomized phase of Part 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALS, Amyotrophic Lateral Sclerosis, Lou Gehrig, Lou Gehrig's, Lou Gehrig's disease, Motor Neuron Disease, Nervous System Diseases, KNS-760704, BIIB050