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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Lithium Carbonate
* Drug: Riluzole
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>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<br>* 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.<br>Drug: Riluzole<br>* 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.<br>|
| Placebo Comparator: 2<br>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: Riluzole<br>* 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.<br>Drug: placebo<br>* an inactive substance<br>|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyotrophic lateral sclerosis, ALS, Lou Gehrig's disease, riluzole, lithium, neurodegeneration