A Multicenter, Double-Blind Study to Investigate the Safety and Efficacy of Arimoclomol in Volunteers With ALS

A Multicenter, Double-Blind, Placebo-Controlled, Phase 2b Study to Investigate the Safety and Efficacy of Arimoclomol in Volunteers With Amyotrophic Lateral Sclerosis (ALS)

Arimoclomol is a small molecule that upregulates "molecular chaperones" in cells under stress. Arimoclomol extends survival by five weeks when given both pre-symptomatically and at disease onset in a mutant superoxide dismutase (SOD1) transgenic mouse model of ALS. Furthermore, it has been demonstrated to have neuroprotective and neuroregenerative effects in other rat models of nerve damage. Molecular chaperone proteins are critical in the cellular response to stress and protein misfolding. Recent data suggest that the SOD1 mutation responsible for ALS in some patients with familial disease reduces the availability of a variety of molecular chaperones, and thus weakens their ability to respond to cellular stress. Protein misfolding and consequent aggregation may play a role in the pathogenesis of both the familial and sporadic forms of ALS. Therapeutic agents such as arimoclomol that improve cellular chaperone response to protein misfolding may be helpful in ALS.

Study Overview

• Status: Withdrawn
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Arimoclomol

Detailed Description

This is a Phase 2b double-blind, randomized, placebo-controlled parallel-group study evaluating the safety and efficacy of arimoclomol (400 mg t.i.d.) compared to placebo. A safety lead-in phase will be employed to ensure the safety of all study volunteers.

Tier I (Safety Lead-in): During the enrollment period for the safety lead-in phase, 24 volunteers meeting inclusion/exclusion criteria will be randomized at 4 investigative sites. These volunteers will have weekly visits during the first 4 weeks after starting treatment. Pharmacokinetics (PK) will be performed at various timepoints throughout these 4 weeks. After the initial 4 weeks of treatment, visits will continue at 4-week intervals up to Week 36, subsequently visits will occur every 8 weeks up to Week 68. A final visit will occur at Week 72. There will be a 28-day post study medication Follow-Up Telephone Call to assess medical status and adverse events.

Tier II: After the Tier I volunteers finish 4 weeks of treatment, their data will be reviewed by the IDMC and, if no serious safety issues are identified, the recommendation will be made to start the second enrollment period (Tier II). During Tier II enrollment, volunteers recruited from approximately 30 to 40 centers in the US and Canada will be randomized. After screening and randomization, volunteers will be followed every 4 weeks for 9 months. Subsequently visits will occur every 8 weeks up to Week 68, with interim Follow-Up Telephone Calls at Weeks 16, 24, and 32 and a final visit at Week 72. A Week 76 Follow-Up Telephone Call to assess medical status and adverse events will occur at 28 days post last dose of study medication.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 2G9
      • University of British Columbia, Gordon and Leslie Diamond Health Care Centre - Tier 2 Site
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Science Center - Tier 2 Site
    • Toronto, Ontario, Canada, M4N 3M5
      • University of Toronto, Sunnybrook Health Sciences Centre - Tier 2 Site
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute - Tier 2
• United States
  • California
    • Pacific Palisades, California, United States, 90272
      • University of California Los Angeles - Tier 2 Site
    • San Francisco, California, United States, 94117
      • University of California - San Francisco - Tier 2 Site
  • Colorado
    • Denver, Colorado, United States, 80262
      • University of Colorado Health Sciences Center - Tier 2 Site
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami - Tier 2 Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University - Tier 2 site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University, Dept. of Neurology - Tier 2 Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center - Tier 2 site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins University - Tier 2 Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital - Tier 1 Site
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center - Tier 2 Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University, Neuromuscular Div. - Tier 2 Site
    • St. Louis, Missouri, United States, 63110
      • Washington University - Tier 2 Site
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • BryanLGH Medical Center - Tier 2 Site
  • New York
    • Albany, New York, United States, 12205
      • Upstate Clinical Research, LLC - Tier 2 Site
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine - Tier 2 Site
    • New York, New York, United States, 10032
      • Columbia University Medical Center - Tier 2 site
    • Syracuse, New York, United States, 13210
      • SUNY Downstate Medical Center - Tier 1 Site
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center - Tier 1 Site
    • Winston Salem, North Carolina, United States, 27157
      • Wake Forest University School of Medicine -Tier 2 Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation -Tier 2 site
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence ALS Center - Tier 2 Site
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Pennsylvania State University School of Medicine - Tier 2 Site
    • Philadelphia, Pennsylvania, United States, 19107
      • Drexel University College of Medicine - Tier 1 Site
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center - Tier 2 Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232-2551
      • Vanderbilt University Medical Center - Tier 2
  • Texas
    • Dallas, Texas, United States, 75214
      • Texas Neurology, PA - Tier 2 Site
    • San Antonio, Texas, United States, 78229-3900
      • University of Texas Health Science Center - Tier 2 Site
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont, College of Medicine - Tier 2
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia - Tier 2 Sites
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Clinic - Tier 2 Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin - Tier 2 Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Familial or sporadic ALS.
• Diagnosed with laboratory-supported probable, probable or definite ALS according to the World Federation of Neurology El Escorial criteria for less than or equal to 36 months' duration prior to the Screening Visit.
• Vital capacity (VC) equal to or greater than 70% predicted value for gender, height and age at the Screening Visit.
• Geographic accessibility to the study site.
• Ability to take oral medication at the Screening Visit, based on verbal report.
• Fluency in English, Spanish or Canadian French.

Exclusion Criteria:

• History of known sensitivity or intolerability to arimoclomol or to any other related compound.
• Prior exposure to arimoclomol through a clinical trial or physician-sponsored IND.
• Exposure to any investigational agent within 30 days of the Screening Visit.

• Presence of any of the following clinical conditions:

  1. Substance abuse within the past year
  2. Unstable cardiac, pulmonary, renal, hepatic, endocrine, hematologic, or active malignancy or infectious disease
  3. AIDS or AIDS-related complex
  4. Unstable psychiatric illness defined as psychosis (hallucinations or delusions), untreated major depression within 90 days of the Screening Visit.
• Laboratory values: Screening serum creatinine greater than or equal to 1.5 mg/dL, creatinine clearance less than 70 cc/min, alanine aminotransferase (ALT) greater than 3.0 times the upper limit of normal, total bilirubin greater than 1.5 times the upper limit of normal, white blood cell (WBC) count less than 3,500/mm3, platelet concentration of <100,000/ul, hematocrit level of less than 33 % for female or less than 35 % for male, or coagulation tests (PT, PTT) greater than or equal to 1.5 times upper limit of normal.
• Female volunteers who are breast-feeding.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 2	Drug: Arimoclomol; capsule, 400 mg t.i.d.
Placebo Comparator: 1	Drug: Placebo; Placebo t.i.d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
ALSFRS-R	9 months

Secondary Outcome Measures

Outcome Measure	Time Frame
ALSFRS-R	18 months
Survival	18 months
Muscle strength	9 and 18 months
Pulmonary function	9 and 18 months
MUNE	9 and 18 months
Quality of Life	9 and 18 months

Collaborators and Investigators

• Sponsor: CytRx
• Investigators: Principal Investigator: Jeremy Shefner, MD, PhD, State University of New York - Upstate Medical University

Study record dates

Study Registration Dates

• First Submitted: November 16, 2007
• First Submitted That Met QC Criteria: November 16, 2007
• First Posted (Estimate): November 20, 2007

Study Record Updates

• Last Update Posted (Estimate): February 9, 2012
• Last Update Submitted That Met QC Criteria: February 8, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: ALS; Lou Gehrig's disease
• 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
• Other Study ID Numbers: AALS-003