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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: placebo; Drug: Lithium Carbonate; Drug: Riluzole

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • University of Calgary, Area 3, University of Calgary Medical Clinic, 3350 Hospital Drive NW Foothills Hosp. Grounds
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta, Division of Neurology, Dept of Medicine, 2E3.17 Walter C. MacKenzie Health Sciences Center
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 2G9
      • University of British Columbia, GF Strong Rehab Centre, 4255 Laurel Street
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3T 2N2
      • University of Manitoba
  • New Brunswick
    • Fredericton, New Brunswick, Canada, E3B 4R3
      • University of New Brunswick, The Stan Cassidy Centre for Rehabilitation, 800 Priestman St.
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6A5
      • Dalhousie University, Capital District Health Authority, Queen Elizabeth II Health Sciences Centre, P.O. Box 9000, Summer Street
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University, McMaster University Medical Centre, Hamilton Health Sciences, 1200 Main Street West, Room 4U7, Box 2000
    • Kingston, Ontario, Canada, K7L 5A2
      • 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
    • London, Ontario, Canada, N6A 5A5
      • University of Western Ontario, Department of Clinical Neurological Sciences, Motor Neuron Disease Clinic, 339 Windermere Road, Box 5339
    • Ottawa, Ontario, Canada, K1H 8M2
      • University of Ottawa, The Rehabilitation Centre, 505 Smyth Road
    • Toronto, Ontario, Canada, M4N 3M5
      • University of Toronto, Sunnybrook Health Sciences Centre, ALS/Neuromuscular Clinic - SCIL, Room UG-35, 2075 Bayview Ave
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • University of Montreal, CHUM (Centre Hospitalier de l'Université de Montréal) Notre-Dame Hospital 1560,Sherbrooke east street
    • Montreal, Quebec, Canada, H3A 2B4
      • McGill University, Montreal Neurological Hospital, 3801 University, Room 205
    • Quebec City, Quebec, Canada, G1J 1Z4
      • Laval University, CHA-Enfant-Jesus Hospital, 1401, 18th Street
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7K 0M7
      • University of Saskatchewan, Saskatoon City Hospital, 701 Queen Street, Room 7717 - 7th Floor
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Phoenix Neurological Assoc., 1331 N. 7th Street, Suite 350
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai ALS Center, Neurology Specialty Clinic, 8730 Alden Drive, Thalians, E 245
    • San Francisco, California, United States, 94143
      • UCSF ALS Center, University of California San Francisco, Neurology, Box 0114, UCSF
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic-Jacksonville, Neurology Department, 4500 San Pablo Road
    • Miami, Florida, United States, 33136
      • University of Miami, Miller School of Medicine, 1150 NW 14th Street, Suite 609 (SCs are suite 701)
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University, Department of Neurology, 1050 Wishard Blvd, RG 6
  • Kentucky
    • Lexington, Kentucky, United States, 40502'
      • University of Kentucky Medical Center, BAMC, Department of Neurology, Room A307, 1101 Veteran's Drive
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University, Department of Neurology, 600 N. Wolfe St, Meyer 6-181
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Massachusetts General Hospital, 149 13th St, Room 2266
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University, Department of Neurology, 4201 St. Antoine, 8C UHC
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center, Dept of Neurology, 701 Part Ave S, P5-200
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University, 660 S. Euclid Ave., Box 8111 Neurology
  • New York
    • New York, New York, United States, 10032
      • Columbia Univ Med Ctr, Eleanor and Lou Gehrig ALS/MDA Center, 710 West 168th St, 9th Floor
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University, 750 E Adams St, 6610UH
  • North Carolina
    • Durham, North Carolina, United States, 27707
      • Duke University Medical Center, Box 3333
    • Winston-Salem, North Carolina, United States, 27157-1078
      • Wake Forest University, ALS Center, Paul Sticht Center, Ground Floor, Medical Center Blvd
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University, Neuromuscular Division, 1654 Uphan Drive, 417 Means Hall
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center, Department of Neurology, H037, Pennsylvania State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19103
      • Drexel University College of Medicine, 245 North 15th Street
  • Texas
    • Dallas, Texas, United States, 75214
      • Texas Neurology, PA, 6301 Gaston Ave, Suite 400 West Tower
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont, Department of Neurology, 89 Beaumont Drive, Given Bldg, Room C-225
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia, Department of Neurology, 3100 Hospital Drive

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Participants randomized to lithium/riluzole (randomization is 1:1 lithium/riluzole to placebo/riluzole, i.e., participants have an equal chance of getting randomized to lithium vs. placebo).	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.; Drug: 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 Comparator: 2; Participants randomized to placebo/riluzole (randomization is 1:1 lithium/riluzole to placebo/riluzole, i.e., participants have an equal chance of getting randomized to lithium vs. placebo).	Drug: placebo; an inactive substance; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Columbia University; National Institute of Neurological Disorders and Stroke (NINDS); University of Toronto; State University of New York - Upstate Medical University; University of Kentucky; ALS Association; ALS Society of Canada
• Investigators: Principal Investigator: Swati Aggarwal, MD, Massachusetts General Hospital; Principal Investigator: Lorne Zinman, MD, MSc, FRCPC, Sunnybrook Health Sciences Center, Univ. of Toronto, Toronto, CA; Principal Investigator: Jinsy Andrews, MD, Columbia University, New York, NY

Publications and helpful links

General Publications

• 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.
• Aggarwal SP, Zinman L, Simpson E, McKinley J, Jackson KE, Pinto H, Kaufman P, Conwit RA, Schoenfeld D, Shefner J, Cudkowicz M; Northeast and Canadian Amyotrophic Lateral Sclerosis consortia. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010 May;9(5):481-8. doi: 10.1016/S1474-4422(10)70068-5. Epub 2010 Apr 1.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: January 6, 2009
• First Submitted That Met QC Criteria: January 6, 2009
• First Posted (Estimate): January 7, 2009

Study Record Updates

• Last Update Posted (Estimate): April 19, 2011
• Last Update Submitted That Met QC Criteria: March 18, 2011
• Last Verified: March 1, 2011

More Information

Terms related to this study

• Keywords: ALS; lithium; neurodegeneration; Amyotrophic lateral sclerosis; Lou Gehrig's disease; riluzole
• 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; Central Nervous System Depressants; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neuroprotective Agents; Protective Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Anticonvulsants; Antimanic Agents; Lithium Carbonate; Riluzole
• Other Study ID Numbers: U01NS049640 (U.S. NIH Grant/Contract); 3U01NS049640-04S1 (U.S. NIH Grant/Contract)