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

Knopp Biosciences194 enrolled

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

194

Conditions

Amyotrophic Lateral Sclerosis

Interventions

PlaceboDRUG

Placebo: 2 tablets taken orally twice daily

Dexpramipexole 50 mg/dayDRUG

Dexpramipexole: 2 x 12.5 mg tablets taken orally twice daily

Dexpramipexole 150 mg/dayDRUG

Dexpramipexole: 2 x 37.5 mg tablets taken orally twice daily

Eligibility

Sex: ALLMin age: 21 YearsMax age: 80 Years

Medical Language ↔ Plain English

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

Locations (21)

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 12 weeks

Secondary Outcomes

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.

Data from ClinicalTrials.gov

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Dexpramipexole: 2 x 75 mg tablets taken orally twice daily

UCLA, Dept. of Neurology - Neuromuscular/ALS Research Center

Los Angeles, California, United States

The Forbes Norris MDA/ALS Research Center

San Francisco, California, United States

University of Colorado Health Sciences Center

Aurora, Colorado, United States

University of Miami Miller School of Medicine

Miami, Florida, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States

Massachusettes General Hospital

Boston, Massachusetts, United States

Washington University School of Medicine

St Louis, Missouri, United States

Bryan LGH Medical Center East

Lincoln, Nebraska, United States

...and 11 more locations

Time frame: 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.

Time frame: 12 weeks

Part 2 Placebo Washout: Number of Participants With Potentially Clinically Significant Hematology

Time frame: 4 weeks

Part 2 Placebo Washout: Number of Participants With Potentially Clinically Significant Blood Chemistry Results

Time frame: 4 weeks

Part 2 Placebo Washout: Number of Participants With Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings

Time frame: 4 weeks

Part 2 Placebo Washout: Number of Participants With Potentially Clinically Significant Vital Sign Measurements

Time frame: 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.

Time frame: 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.

Time frame: 4 weeks

Part 2 Double-Blind Treatment: Number of Participants With Potentially Clinically Significant Hematology Results by Treatment Group

Time frame: up to 76 weeks

Part 2 Double-Blind Treatment: Number of Participants With Potentially Clinically Significant Blood Chemistry Results by Treatment Group

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: Baseline of randomized phase of Part 2 to week 28 of randomized phase of Part 2