Amyotrophic Lateral Sclerosis
Conditions
Keywords
Amyotrophic lateral sclerosis, ALS, Lou Gehrig's disease, riluzole, lithium, neurodegeneration
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.
Interventions
DRUGLithium 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.
DRUGRiluzole
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.
DRUGplacebo
an inactive substance
Sponsors
ALS Association
ALS Society of Canada
National Institute of Neurological Disorders and Stroke (NINDS)
University of Toronto
State University of New York - Upstate Medical University
Columbia University
University of Kentucky
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire (ALSFRS-R) | 9 months: Baseline to study termination (January 2009 - October 2009) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire(ALSFRS-R) | 9 months: Baseline to study termination (January 2009 - October 2009) | 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. |
| Vital Capacity (VC) (Percent of Predicted Normal) | 9 months: Baseline to study termination (January 2009- October 2009) | Secondary efficacy was measured by comparing the rate of decline of mean VC by treatment group. |
Countries
Canada, United States
Participant flow
Recruitment details
Between January 2009 to June 2009, 97 patients were screened and 84 subjects were randomized at 21 clinical sites; 11 in the United States and 10 in Canada. All sites were members of the Northeast ALS Consortium (NEALS) and/or the Canadian ALS Consortium (CALS).
Pre-assignment details
All patients were required to be on a stable dose of riluzole for at least 30 days prior to screening. 13 subjects failed screening: 3 due to low lung function test results, 3 due to prohibited medications,3 due to study closure, 2 due to abnormal lab test results and 1 due to death unrelated to the study.
Participants by arm
| Arm | Count |
|---|---|
| Lithium + Riluzole Subjects randomized to lithium + riluzole were required to be taking riluzole 50 milligrams (mg) twice per day at least 30 days prior to the screening visit and during the trial. Lithium carbonate and matching placebo were supplied in 150 mg capsules. Dosing started at 450 mg/day (1 capsule taken in the a.m. and 2 capsules taken in the p.m.), titrated to maintain plasma lithium levels of 0.4 - 0.8 milliequivalent per liter (mEq/L). The number of capsules taken per day was titrated individually for each patient based on blood testing to maintain plasma levels of lithium = 04. - 0.8 milliequivalent per liter (mEq/L). | 40 |
| Placebo + Riluzole Participants randomized to placebo + riluzole were required to be taking riluzole 50 milligrams (mg) twice per day at least 30 days prior to the screening visit and during the trial. Matching placebo was supplied in 150 mg capsules. Dosing started at 450 mg/day (1 capsule in the a.m. and 2 capsules in the p.m). Paired sham dosage modifications were made for placebo subjects, i.e. all subjects randomized to placebo were 'paired' with a lithium subject and underwent identical dosage changes to maintain blinding. | 44 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | ALS Disease Progression | 1 | 0 |
| Overall Study | Death | 1 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Total | Lithium + Riluzole | Placebo + Riluzole |
|---|---|---|---|
| Age Continuous | 56.24 Years STANDARD_DEVIATION 11.16 | 58.3 Years STANDARD_DEVIATION 10.2 | 55.5 Years STANDARD_DEVIATION 11.9 |
| ALS Functional Rating Scale-Revised (ALSFRS-R) | 37.43 Scores on a scale STANDARD_DEVIATION 5.24 | 38.4 Scores on a scale STANDARD_DEVIATION 4.6 | 36.5 Scores on a scale STANDARD_DEVIATION 5.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 82 Participants | 40 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 81 Participants | 39 Participants | 42 Participants |
| Sex: Female, Male Female | 30 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Male | 54 Participants | 30 Participants | 24 Participants |
| Vital Capacity | 90.18 Percent of predicted normal STANDARD_DEVIATION 18.2 | 94.0 Percent of predicted normal STANDARD_DEVIATION 18.1 | 86.9 Percent of predicted normal STANDARD_DEVIATION 16.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 39 / 40 | 43 / 44 |
| serious Total, serious adverse events | 10 / 40 | 8 / 44 |
Outcome results
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.
Time frame: 9 months: Baseline to study termination (January 2009 - October 2009)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lithium + Riluzole | Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire (ALSFRS-R) | 18 Participants |
| Placebo + Riluzole | Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire (ALSFRS-R) | 14 Participants |
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.
Time frame: 9 months: Baseline to study termination (January 2009 - October 2009)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lithium + Riluzole | Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire(ALSFRS-R) | -1.24 Scores on a scale | Standard Error 0.21 |
| Placebo + Riluzole | Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire(ALSFRS-R) | -1.09 Scores on a scale | Standard Error 0.2 |
Secondary
Vital Capacity (VC) (Percent of Predicted Normal)
Secondary efficacy was measured by comparing the rate of decline of mean VC by treatment group.
Time frame: 9 months: Baseline to study termination (January 2009- October 2009)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lithium + Riluzole | Vital Capacity (VC) (Percent of Predicted Normal) | -1.89 Percent of predicted normal | Standard Error 0.45 |
| Placebo + Riluzole | Vital Capacity (VC) (Percent of Predicted Normal) | -3.12 Percent of predicted normal | Standard Error 0.47 |