Safety and Tolerability Study of KNS-760704 in Amyotrophic Lateral Sclerosis (ALS) (CL201)

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

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.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Dexpramipexole 50 mg/day; Drug: Dexpramipexole 150 mg/day; Drug: Dexpramipexole 300 mg/day

Detailed Description

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
• Enrollment (Actual): 194
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Los Angeles, California, United States, 90095
      • UCLA, Dept. of Neurology - Neuromuscular/ALS Research Center
    • San Francisco, California, United States, 94115
      • The Forbes Norris MDA/ALS Research Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Health Sciences Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21228
      • Johns Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02129
      • Massachusettes General Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Bryan LGH Medical Center East
  • New York
    • New York, New York, United States, 10032
      • Columbia University, Lou Gehrig MDA/ALS Research Center
    • Syracuse, New York, United States, 13210
      • Suny Upstate Medical University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh School of Medicine
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Sciences Center of San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Part 1: Placebo or Dexpramipexole; 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; Placebo: 2 tablets taken orally twice daily; Drug: Dexpramipexole 50 mg/day; Dexpramipexole: 2 x 12.5 mg tablets taken orally twice daily; Other Names: KNS-760704; BIIB050; Drug: Dexpramipexole 150 mg/day; Dexpramipexole: 2 x 37.5 mg tablets taken orally twice daily; Other Names: KNS-760704; BIIB050; Drug: Dexpramipexole 300 mg/day; Dexpramipexole: 2 x 75 mg tablets taken orally twice daily; Other Names: KNS-760704; BIIB050
Experimental: Part 2: Placebo washout; At the beginning of Part 2, subjects received twice daily doses of placebo for approximately 4 weeks.	Drug: Placebo; Placebo: 2 tablets taken orally twice daily
Experimental: Part 2: Dexpramipexole; 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; Dexpramipexole: 2 x 12.5 mg tablets taken orally twice daily; Other Names: KNS-760704; BIIB050; Drug: Dexpramipexole 300 mg/day; Dexpramipexole: 2 x 75 mg tablets taken orally twice daily; Other Names: KNS-760704; BIIB050

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Knopp Biosciences

Publications and helpful links

General Publications

• Cudkowicz M, Bozik ME, Ingersoll EW, Miller R, Mitsumoto H, Shefner J, Moore DH, Schoenfeld D, Mather JL, Archibald D, Sullivan M, Amburgey C, Moritz J, Gribkoff VK. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med. 2011 Nov 20;17(12):1652-6. doi: 10.1038/nm.2579.

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2008
• Primary Completion (Actual): July 31, 2009
• Study Completion (Actual): September 4, 2009

Study Registration Dates

• First Submitted: March 26, 2008
• First Submitted That Met QC Criteria: March 28, 2008
• First Posted (Estimate): March 31, 2008

Study Record Updates

• Last Update Posted (Actual): July 8, 2021
• Last Update Submitted That Met QC Criteria: June 16, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; ALS; Motor Neuron Disease; Nervous System Diseases; Lou Gehrig's disease; Lou Gehrig; Lou Gehrig's; KNS-760704; BIIB050
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Protective Agents; Dopamine Agonists; Dopamine Agents; Antioxidants; Antiparkinson Agents; Anti-Dyskinesia Agents; Pramipexole
• Other Study ID Numbers: KNS-760704-CL201