Clinical trial NCT00818389: Study to Investigate the Safety and Efficacy of Lithium in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Keywords: Amyotrophic lateral sclerosis
ALS
Lou Gehrig's disease
riluzole
lithium
neurodegeneration
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: ALS Association
name: ALS Society of Canada
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: University of Toronto
name: State University of New York - Upstate Medical University
name: Columbia University
name: University of Kentucky
First posted: 2009-01-07
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire (ALSFRS-R)
timeFrame: 9 months: Baseline to study termination (January 2009 - October 2009)
Secondary outcomes:
measure: Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire(ALSFRS-R)
timeFrame: 9 months: Baseline to study termination (January 2009 - October 2009)
measure: Vital Capacity (VC) (Percent of Predicted Normal)
timeFrame: 9 months: Baseline to study termination (January 2009- October 2009)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Neurological Assoc., 1331 N. 7th Street, Suite 350
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai ALS Center, Neurology Specialty Clinic, 8730 Alden Drive, Thalians, E 245
state: California
city: San Francisco
country: United States
facility: UCSF ALS Center, University of California San Francisco, Neurology, Box 0114, UCSF
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic-Jacksonville, Neurology Department, 4500 San Pablo Road
state: Florida
city: Miami
country: United States
facility: University of Miami, Miller School of Medicine, 1150 NW 14th Street, Suite 609 (SCs are suite 701)
state: Florida
city: Indianapolis
country: United States
facility: Indiana University, Department of Neurology, 1050 Wishard Blvd, RG 6
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Medical Center, BAMC, Department of Neurology, Room A307, 1101 Veteran's Drive
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University, Department of Neurology, 600 N. Wolfe St, Meyer 6-181
state: Maryland
city: Charlestown
country: United States
facility: Massachusetts General Hospital, 149 13th St, Room 2266
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University, Department of Neurology, 4201 St. Antoine, 8C UHC
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center, Dept of Neurology, 701 Part Ave S, P5-200
state: Minnesota
city: St. Louis
country: United States
facility: Washington University, 660 S. Euclid Ave., Box 8111 Neurology
state: Missouri
city: New York
country: United States
facility: Columbia Univ Med Ctr, Eleanor and Lou Gehrig ALS/MDA Center, 710 West 168th St, 9th Floor
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University, 750 E Adams St, 6610UH
state: New York
city: Durham
country: United States
facility: Duke University Medical Center, Box 3333
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University, ALS Center, Paul Sticht Center, Ground Floor, Medical Center Blvd
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University, Neuromuscular Division, 1654 Uphan Drive, 417 Means Hall
state: Ohio
city: Hershey
country: United States
facility: Penn State Hershey Medical Center, Department of Neurology, H037, Pennsylvania State Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University College of Medicine, 245 North 15th Street
state: Pennsylvania
city: Dallas
country: United States
facility: Texas Neurology, PA, 6301 Gaston Ave, Suite 400 West Tower
state: Texas
city: Burlington
country: United States
facility: University of Vermont, Department of Neurology, 89 Beaumont Drive, Given Bldg, Room C-225
state: Vermont
city: Charlottesville
country: United States
facility: University of Virginia, Department of Neurology, 3100 Hospital Drive
state: Virginia
city: Calgary
country: Canada
facility: University of Calgary, Area 3, University of Calgary Medical Clinic, 3350 Hospital Drive NW Foothills Hosp. Grounds
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta, Division of Neurology, Dept of Medicine, 2E3.17 Walter C. MacKenzie Health Sciences Center
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia, GF Strong Rehab Centre, 4255 Laurel Street
state: British Columbia
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Fredericton
country: Canada
facility: University of New Brunswick, The Stan Cassidy Centre for Rehabilitation, 800 Priestman St.
state: New Brunswick
city: Halifax
country: Canada
facility: Dalhousie University, Capital District Health Authority, Queen Elizabeth II Health Sciences Centre, P.O. Box 9000, Summer Street
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster University, McMaster University Medical Centre, Hamilton Health Sciences, 1200 Main Street West, Room 4U7, Box 2000
state: Ontario
city: Kingston
country: Canada
facility: 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
state: Ontario
city: London
country: Canada
facility: University of Western Ontario, Department of Clinical Neurological Sciences, Motor Neuron Disease Clinic, 339 Windermere Road, Box 5339
state: Ontario
city: Ottawa
country: Canada
facility: University of Ottawa, The Rehabilitation Centre, 505 Smyth Road
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto, Sunnybrook Health Sciences Centre, ALS/Neuromuscular Clinic - SCIL, Room UG-35, 2075 Bayview Ave
state: Ontario
city: Montreal
country: Canada
facility: University of Montreal, CHUM (Centre Hospitalier de l'Université de Montréal) Notre-Dame Hospital 1560,Sherbrooke east street
state: Quebec
city: Montreal
country: Canada
facility: McGill University, Montreal Neurological Hospital, 3801 University, Room 205
state: Quebec
city: Quebec City
country: Canada
facility: Laval University, CHA-Enfant-Jesus Hospital, 1401, 18th Street
state: Quebec
city: Saskatoon
country: Canada
facility: University of Saskatchewan, Saskatoon City Hospital, 701 Queen Street, Room 7717 - 7th Floor
state: Saskatchewan
Study officials:
affiliation: Massachusetts General Hospital
name: Merit Cudkowicz, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Swati Aggarwal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Health Sciences Center, Univ. of Toronto, Toronto, CA
name: Lorne Zinman, MD, MSc, FRCPC
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University, New York, NY
name: Jinsy Andrews, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.