Study to Investigate the Safety and Efficacy of Lithium in Volunteers With Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis Clinical Trial

Official title:

A Multicenter, Double-Blind, Placebo-Controlled, Study to Investigate the Safety and Efficacy of Lithium in Combination With Riluzole in Volunteers With Amyotrophic Lateral Sclerosis (ALS)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00818389
• Other study ID #: U01NS049640
• Secondary ID: 3U01NS049640-04S
• Status: Terminated
• Phase: Phase 2/Phase 3
• First received: January 6, 2009
• Last updated: March 18, 2011
• Start date: January 2009
• Est. completion date: October 2009

Study information

• Verified date: March 2011
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentCanada: Health Canada
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the effectiveness of lithium combined with riluzole to riluzole combined with placebo in people with amyotrophic lateral sclerosis.

Description:

Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative disorder that results in progressive wasting and paralysis of voluntary muscles.

In this double blind, randomized, placebo-controlled clinical trial, researchers will evaluate the safety and effectiveness of the drug lithium given in combination with riluzole, a drug commonly used to treat ALS, compared to a placebo given in combination with riluzole.

Approximately 250 participants will be recruited from multiple centers, in the US and Canada, that belong to the Northeast ALS Consortium (NEALS) and the Canadian ALS Clinical Trials and Research Network (CALS). Enrollment will occur in stages. Initially 84 participants will be enrolled in the trial. An interim analysis using available data will occur after the 84th participant is enrolled. During this time, the Data and Safety Monitoring Board (DSMB) appointed by the National Institutes of Health (NIH) may decide to stop the trial for efficacy or futility reasons or to stop enrollment and request that follow-up continue with the 84 participants already enrolled in the trial, or the DSMB may decide to continue enrollment.

Participants will be randomized to one of two arms of the study. Arm one will receive lithium and riluzole. Arm two will receive riluzole and placebo (an inactive substance). All participants will be receiving riluzole. After screening and randomization, participants will be followed every 4 weeks for the first 12 weeks. Subsequent in-person visits will occur every 8 weeks with a final visit at week 52. Between in-person visits, telephone interviews will take place every 4 weeks to administer the Amyotropic Lateral Sclerosis Functional Rating Scale—Revised (ALSFRS-R) questionnaire. A follow-up telephone interview will occur at week 56 (off study medication) to review adverse events. The primary outcome measure is disease progression as measured by the ALSFRS-R questionnaire. Participants randomized to placebo whose disease progresses will be crossed over to lithium for the remaining period of the study (up to 52 weeks total).

Duration of the study for participants is 56 weeks which includes 52 weeks of treatment and a followup telephone interview at week 56.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 84
• Est. completion date: October 2009
• Est. primary completion date: October 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Familial or sporadic ALS

• Participants diagnosed with laboratory supported probable, clinically possible, probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria

• Disease duration from symptom onset no greater than 36 months at the Screening Visit

• Age 18 years or older

• Capable of providing informed consent and complying with trial procedures

• On a stable dose of riluzole 50 milligrams (mg) twice per day(bid) for at least 30 days prior to screening

• Vital capacity (VC) equal to or more than 60% predicted normal value for gender, height and age at the Screening Visit

• Creatinine <1.5 milligrams per deciliter (mg/dl) [133 micromoles per liter (umol/L]

• Participants maintained on thyroid medication must be euthyroid for at least 3 months before the Screening Visit.

• Participants with psoriasis must have inactive disease for at least 30 days before the Screening Visit.

• Women must not be able to become pregnant (e.g., post menopausal for at least one year, surgically sterile, or practicing adequate birth control methods) for the duration of the study. Women of childbearing potential must have a negative serum pregnancy test at the Screening Visit and be non-lactating.

• Geographic accessibility to the study site

Exclusion Criteria:

• History of known sensitivity or intolerability to lithium or to any other related compound

• Prior exposure to lithium within 90 days of the Screening Visit

• Exposure to any investigational agent within 30 days of the Screening Visit

• Participants who are malnourished, dehydrated or on a sodium-free diet will be excluded due to the potential side effects of lithium carbonate

• Use of digoxin or iodide salts [e.g. calcium iodide, hydrogen iodide (hydriodic acid), iodide, iodinated glycerol (Organidin), iodine, potassium iodide (SSKI), and sodium iodide supplementation beyond table salt]

• Presence of any of the following clinical conditions: Substance abuse within the past year; Unstable cardiac, pulmonary, renal, hepatic, endocrine, hematologic, or active malignancy or infectious disease; autoimmune deficiency syndrome (AIDS) or AIDS-related complex; Clinically active psoriasis within 30 days of the Screening Visit; Unstable psychiatric illness defined as psychosis (hallucinations or delusions) or untreated major depression within 90 days of the Screening Visit; Screening serum creatinine greater than or equal to 1.5 mg/dL (133 umol/L), thyroid stimulating hormone (TSH) > 20% above the upper limit; Presence of any clinically significant conduction abnormalities on electrocardiogram (ECG); or Lactating or have a positive serum pregnancy test at the Screening Visit.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

Drug:
• Lithium Carbonate
Participants will receive capsules that contain 150 milligrams (mg) lithium carbonate. Participants will be randomized to lithium/riluzole or placebo/riluzole and treated for 52 weeks. Participants originally randomized to placebo who fail (progress) will crossover to lithium for the remainder of the trial.
• Riluzole
All participants enrolled in this study will be taking a stable dose of riluzole 50 milligrams (mg) by mouth (PO) twice per day (BID) for at least 30 days prior to screening.
• placebo
an inactive substance

Locations

Country	Name	City	State
Canada	University of Calgary, Area 3, University of Calgary Medical Clinic, 3350 Hospital Drive NW Foothills Hosp. Grounds	Calgary	Alberta
Canada	University of Alberta, Division of Neurology, Dept of Medicine, 2E3.17 Walter C. MacKenzie Health Sciences Center	Edmonton	Alberta
Canada	University of New Brunswick, The Stan Cassidy Centre for Rehabilitation, 800 Priestman St.	Fredericton	New Brunswick
Canada	Dalhousie University, Capital District Health Authority, Queen Elizabeth II Health Sciences Centre, P.O. Box 9000, Summer Street	Halifax	Nova Scotia
Canada	McMaster University, McMaster University Medical Centre, Hamilton Health Sciences, 1200 Main Street West, Room 4U7, Box 2000	Hamilton	Ontario
Canada	Queen's University, The Adult Neuromuscular Clinic, PCCC, St. Mary's of the Lake Hospital Site, Department of Physical Medicine and Rehabilitation, 340 Union Street, Postal Bldg 3600	Kingston	Ontario
Canada	University of Western Ontario, Department of Clinical Neurological Sciences, Motor Neuron Disease Clinic, 339 Windermere Road, Box 5339	London	Ontario
Canada	McGill University, Montreal Neurological Hospital, 3801 University, Room 205	Montreal	Quebec
Canada	University of Montreal, CHUM (Centre Hospitalier de l'Université de Montréal) Notre-Dame Hospital 1560,Sherbrooke east street	Montreal	Quebec
Canada	University of Ottawa, The Rehabilitation Centre, 505 Smyth Road	Ottawa	Ontario
Canada	Laval University, CHA-Enfant-Jesus Hospital, 1401, 18th Street	Quebec City	Quebec
Canada	University of Saskatchewan, Saskatoon City Hospital, 701 Queen Street, Room 7717 - 7th Floor	Saskatoon	Saskatchewan
Canada	University of Toronto, Sunnybrook Health Sciences Centre, ALS/Neuromuscular Clinic - SCIL, Room UG-35, 2075 Bayview Ave	Toronto	Ontario
Canada	University of British Columbia, GF Strong Rehab Centre, 4255 Laurel Street	Vancouver	British Columbia
Canada	University of Manitoba	Winnipeg	Manitoba
United States	Johns Hopkins University, Department of Neurology, 600 N. Wolfe St, Meyer 6-181	Baltimore	Maryland
United States	University of Vermont, Department of Neurology, 89 Beaumont Drive, Given Bldg, Room C-225	Burlington	Vermont
United States	Massachusetts General Hospital, 149 13th St, Room 2266	Charlestown	Massachusetts
United States	University of Virginia, Department of Neurology, 3100 Hospital Drive	Charlottesville	Virginia
United States	Ohio State University, Neuromuscular Division, 1654 Uphan Drive, 417 Means Hall	Columbus	Ohio
United States	Texas Neurology, PA, 6301 Gaston Ave, Suite 400 West Tower	Dallas	Texas
United States	Wayne State University, Department of Neurology, 4201 St. Antoine, 8C UHC	Detroit	Michigan
United States	Duke University Medical Center, Box 3333	Durham	North Carolina
United States	Penn State Hershey Medical Center, Department of Neurology, H037, Pennsylvania State Hershey Medical Center	Hershey	Pennsylvania
United States	Indiana University, Department of Neurology, 1050 Wishard Blvd, RG 6	Indianapolis	Indiana
United States	Mayo Clinic-Jacksonville, Neurology Department, 4500 San Pablo Road	Jacksonville	Florida
United States	University of Kentucky Medical Center, BAMC, Department of Neurology, Room A307, 1101 Veteran's Drive	Lexington	Kentucky
United States	Cedars-Sinai ALS Center, Neurology Specialty Clinic, 8730 Alden Drive, Thalians, E 245	Los Angeles	California
United States	University of Miami, Miller School of Medicine, 1150 NW 14th Street, Suite 609 (SCs are suite 701)	Miami	Florida
United States	Hennepin County Medical Center, Dept of Neurology, 701 Part Ave S, P5-200	Minneapolis	Minnesota
United States	Columbia Univ Med Ctr, Eleanor and Lou Gehrig ALS/MDA Center, 710 West 168th St, 9th Floor	New York	New York
United States	Drexel University College of Medicine, 245 North 15th Street	Philadelphia	Pennsylvania
United States	Phoenix Neurological Assoc., 1331 N. 7th Street, Suite 350	Phoenix	Arizona
United States	UCSF ALS Center, University of California San Francisco, Neurology, Box 0114, UCSF	San Francisco	California
United States	Washington University, 660 S. Euclid Ave., Box 8111 Neurology	St. Louis	Missouri
United States	SUNY Upstate Medical University, 750 E Adams St, 6610UH	Syracuse	New York
United States	Wake Forest University, ALS Center, Paul Sticht Center, Ground Floor, Medical Center Blvd	Winston-Salem	North Carolina

Sponsors (8)

Lead Sponsor	Collaborator
Massachusetts General Hospital	ALS Association, ALS Society of Canada, Columbia University, National Institute of Neurological Disorders and Stroke (NINDS), State University of New York - Upstate Medical University, University of Kentucky, University of Toronto

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S, Paparelli A. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2052-7. doi: 10.1073/pnas.0708022105. Epub 2008 Feb 4. Erratum in: Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16404-7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire (ALSFRS-R)	ALSFRS-R is a self-administered ordinal rating scale questionnaire (rating 0-4 for each question,4 is most functional,0-48 total)of 12 functional activities. The most functional total score is 48. ALSFRS-R done at baseline and weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 & 52, dependent on enrollment duration. Number of subjects who failed by treatment group was evaluated. Failure was defined as 6-point drop in ALSFRS-R or death from baseline.	9 months: Baseline to study termination (January 2009 - October 2009)	No
Secondary	Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire(ALSFRS-R)	ALSFRS-R is a self-administered ordinal rating scale questionnaire (rating 0-4 for each question,4 is most functional,0-48 total)of 12 functional activities. The most functional total score is 48. ALSFRS-R done at baseline and weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 & 52, dependent on enrollment duration. Secondary efficacy was evaluated by comparing the mean rate of decline of ALSFRS-R score by treatment group.	9 months: Baseline to study termination (January 2009 - October 2009)	No
Secondary	Vital Capacity (VC) (Percent of Predicted Normal)	Secondary efficacy was measured by comparing the rate of decline of mean VC by treatment group.	9 months: Baseline to study termination (January 2009- October 2009)	No