Clinical trial NCT00561366: A Multicenter, Double-Blind Study to Investigate the Safety and Efficacy of Arimoclomol in Volunteers With ALS
Official title: A Multicenter, Double-Blind, Placebo-Controlled, Phase 2b Study to Investigate the Safety and Efficacy of Arimoclomol in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS
Lou Gehrig's disease
Lead sponsor: CytRx
Sponsor class: INDUSTRY
First posted: 2007-11-20
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: ALSFRS-R
timeFrame: 9 months
Secondary outcomes:
measure: ALSFRS-R
timeFrame: 18 months
measure: Survival
timeFrame: 18 months
measure: Muscle strength
timeFrame: 9 and 18 months
measure: Pulmonary function
timeFrame: 9 and 18 months
measure: MUNE
timeFrame: 9 and 18 months
measure: Quality of Life
timeFrame: 9 and 18 months
Other outcomes:
Locations:
city: Pacific Palisades
country: United States
facility: University of California Los Angeles - Tier 2 Site
state: California
city: San Francisco
country: United States
facility: University of California - San Francisco - Tier 2 Site
state: California
city: Denver
country: United States
facility: University of Colorado Health Sciences Center - Tier 2 Site
state: Colorado
city: Miami
country: United States
facility: University of Miami - Tier 2 Site
state: Florida
city: Atlanta
country: United States
facility: Emory University - Tier 2 site
state: Georgia
city: Chicago
country: United States
facility: Northwestern University, Dept. of Neurology - Tier 2 Site
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center - Tier 2 site
state: Kansas
city: Baltimore
country: United States
facility: John Hopkins University - Tier 2 Site
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital - Tier 1 Site
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center - Tier 2 Site
state: Massachusetts
city: Saint Louis
country: United States
facility: Saint Louis University, Neuromuscular Div. - Tier 2 Site
state: Missouri
city: St. Louis
country: United States
facility: Washington University - Tier 2 Site
state: Missouri
city: Lincoln
country: United States
facility: BryanLGH Medical Center - Tier 2 Site
state: Nebraska
city: Albany
country: United States
facility: Upstate Clinical Research, LLC - Tier 2 Site
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine - Tier 2 Site
state: New York
city: New York
country: United States
facility: Columbia University Medical Center - Tier 2 site
state: New York
city: Syracuse
country: United States
facility: SUNY Downstate Medical Center - Tier 1 Site
state: New York
city: Durham
country: United States
facility: Duke University Medical Center - Tier 1 Site
state: North Carolina
city: Winston Salem
country: United States
facility: Wake Forest University School of Medicine -Tier 2 Site
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation -Tier 2 site
state: Ohio
city: Portland
country: United States
facility: Providence ALS Center - Tier 2 Site
state: Oregon
city: Hershey
country: United States
facility: Pennsylvania State University School of Medicine - Tier 2 Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University College of Medicine - Tier 1 Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Tier 2 Site
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center - Tier 2
state: Tennessee
city: Dallas
country: United States
facility: Texas Neurology, PA - Tier 2 Site
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center - Tier 2 Site
state: Texas
city: Burlington
country: United States
facility: University of Vermont, College of Medicine - Tier 2
state: Vermont
city: Charlottesville
country: United States
facility: University of Virginia - Tier 2 Sites
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Clinic - Tier 2 Site
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin - Tier 2 Site
state: Wisconsin
city: Vancouver
country: Canada
facility: University of British Columbia, Gordon and Leslie Diamond Health Care Centre - Tier 2 Site
state: British Columbia
city: London
country: Canada
facility: London Health Science Center - Tier 2 Site
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto, Sunnybrook Health Sciences Centre - Tier 2 Site
state: Ontario
city: Montreal
country: Canada
facility: Montreal Neurological Institute - Tier 2
state: Quebec
Study officials:
affiliation: Massachusetts General Hospital
name: Merit Cudkowicz, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: State University of New York - Upstate Medical University
name: Jeremy Shefner, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: