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

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ClinicalTrials.gov Identifier: NCT00818389
Recruitment Status : Terminated (NINDS DSMB recommended trial be terminated for futility after reviewing an interim analysis of 84 subjects.)
First Posted : January 7, 2009
Results First Posted : April 19, 2011
Last Update Posted : April 19, 2011
Sponsor:
Collaborators:
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
Information provided by:
Massachusetts General Hospital

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Amyotrophic Lateral Sclerosis
Interventions Drug: Lithium Carbonate
Drug: Riluzole
Drug: placebo
Enrollment 84
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.
Arm/Group Title Lithium + Riluzole Placebo + Riluzole
Hide Arm/Group Description 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). 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.
Period Title: Overall Study
Started 40 44
Completed 36 [1] 38 [2]
Not Completed 4 6
Reason Not Completed
Death             1             3
ALS Disease Progression             1             0
Withdrawal by Subject             2             2
Adverse Event             0             1
[1]
4 subjects terminated study early before 1st interim analysis. Study terminated early for futility.
[2]
6 subjects terminated study early before 1st interim analysis. Study terminated early for futility.
Arm/Group Title Lithium + Riluzole Placebo + Riluzole Total
Hide Arm/Group Description 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). 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. Total of all reporting groups
Overall Number of Baseline Participants 40 44 84
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 40 participants 44 participants 84 participants
58.3  (10.2) 55.5  (11.9) 56.24  (11.16)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 44 participants 84 participants
Female
10
  25.0%
20
  45.5%
30
  35.7%
Male
30
  75.0%
24
  54.5%
54
  64.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 44 participants 84 participants
Hispanic or Latino
0
   0.0%
2
   4.5%
2
   2.4%
Not Hispanic or Latino
40
 100.0%
42
  95.5%
82
  97.6%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 44 participants 84 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   2.5%
2
   4.5%
3
   3.6%
White
39
  97.5%
42
  95.5%
81
  96.4%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
ALS Functional Rating Scale-Revised (ALSFRS-R)   [1] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 40 participants 44 participants 84 participants
38.4  (4.6) 36.5  (5.7) 37.43  (5.24)
[1]
Measure Description: ALSFRS-R is an ordinal rating scale questionnaire (rating 0-4) used to determine subject's assessment of their capability and independence in 12 functional activities (i.e. this is a patient-reported questionnaire scale of disability). Each question has a rating of 0-4 with 4 being the most functional and 0 being the least functional. The most functional total score is 48.
Vital Capacity   [1] 
Mean (Standard Deviation)
Unit of measure:  Percent of predicted normal
Number Analyzed 40 participants 44 participants 84 participants
94.0  (18.1) 86.9  (16.9) 90.18  (18.20)
[1]
Measure Description: Vital capacity (VC) testing is a measure of lung function that is performed using a standard spirometer and the Slow VC method. Three trials were required (5 maximum); the best of 3 was used.
1.Primary Outcome
Title Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire (ALSFRS-R)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Lithium + Riluzole Placebo + Riluzole
Hide Arm/Group Description:
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).
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.
Overall Number of Participants Analyzed 40 44
Measure Type: Number
Unit of Measure: Participants
18 14
2.Secondary Outcome
Title Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire(ALSFRS-R)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Lithium + Riluzole Placebo + Riluzole
Hide Arm/Group Description:
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).
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.
Overall Number of Participants Analyzed 40 44
Mean (Standard Error)
Unit of Measure: Scores on a scale
-1.24  (0.21) -1.09  (0.20)
3.Secondary Outcome
Title Vital Capacity (VC) (Percent of Predicted Normal)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Lithium + Riluzole Placebo + Riluzole
Hide Arm/Group Description:
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).
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.
Overall Number of Participants Analyzed 40 44
Mean (Standard Error)
Unit of Measure: Percent of predicted normal
-1.89  (0.45) -3.12  (0.47)
Time Frame Adverse events (AEs) were collected for the duration of the study period: January 2009 to October 2009. Each subject was followed for AEs from consent signing to the end of their study participation. The AEs reported here are treatment emergent AEs.
Adverse Event Reporting Description The study was terminated early after the first interim analysis for futility. The first interim analysis was conducted in September 2009. The first subject was randomized in January 2009 and the last follow-up for study subjects was in October 2009.
 
Arm/Group Title Lithium + Riluzole Placebo + Riluzole
Hide Arm/Group Description 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). 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.
All-Cause Mortality
Lithium + Riluzole Placebo + Riluzole
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Lithium + Riluzole Placebo + Riluzole
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/40 (25.00%)      8/44 (18.18%)    
Cardiac disorders     
Cardiac arrest  1 [1]  1/40 (2.50%)  1 0/44 (0.00%)  0
Cardiac pain  1  0/40 (0.00%)  0 1/44 (2.27%)  1
Eye disorders     
Retro-orbital pain  1  1/40 (2.50%)  1 0/44 (0.00%)  0
Gastrointestinal disorders     
Nausea  1  0/40 (0.00%)  0 1/44 (2.27%)  1
General disorders     
Chest/thorax pain  1  1/40 (2.50%)  1 0/44 (0.00%)  0
Infections and infestations     
Bronchitis  1  0/40 (0.00%)  0 1/44 (2.27%)  1
Pneumonia  1  1/40 (2.50%)  1 1/44 (2.27%)  1
Musculoskeletal and connective tissue disorders     
Fracture  1  1/40 (2.50%)  1 1/44 (2.27%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Benign tumor  1  1/40 (2.50%)  1 0/44 (0.00%)  0
Nervous system disorders     
Encephalopathy  1  1/40 (2.50%)  1 0/44 (0.00%)  0
Fall  1  1/40 (2.50%)  1 0/44 (0.00%)  0
Hemorrhage, CNS  1 [2]  1/40 (2.50%)  1 0/44 (0.00%)  0
Somnolence  1  0/40 (0.00%)  0 1/44 (2.27%)  1
Speech impairment/dysphagia  1  1/40 (2.50%)  1 0/44 (0.00%)  0
Syncope/fainting  1  1/40 (2.50%)  1 0/44 (0.00%)  0
Psychiatric disorders     
Depression  1 [3]  1/40 (2.50%)  1 0/44 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Chest congestion  1  1/40 (2.50%)  2 0/44 (0.00%)  0
Dyspnea  1  1/40 (2.50%)  1 2/44 (4.55%)  4
Pneumothorax  1  0/40 (0.00%)  0 1/44 (2.27%)  1
Vascular disorders     
Thrombosis/embolism  1  1/40 (2.50%)  1 2/44 (4.55%)  2
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE version 3.0
[1]
Secondary to suspected pulmonary embolism
[2]
Traumatic subdural hematoma
[3]
Depression with suicide attempt
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Lithium + Riluzole Placebo + Riluzole
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   39/40 (97.50%)      43/44 (97.73%)    
Blood and lymphatic system disorders     
Bruising (in absence of grade 3 or 4 thrombocytopenia)  1  5/40 (12.50%)  7 1/44 (2.27%)  2
Edema (limb)  1  6/40 (15.00%)  12 7/44 (15.91%)  8
Gastrointestinal disorders     
Anorexia  1  6/40 (15.00%)  7 2/44 (4.55%)  4
Constipation  1  5/40 (12.50%)  7 8/44 (18.18%)  9
Diarrhea  1  5/40 (12.50%)  5 5/44 (11.36%)  6
Drooling  1  7/40 (17.50%)  7 6/44 (13.64%)  7
Heartburn  1  4/40 (10.00%)  5 5/44 (11.36%)  6
Nausea  1  10/40 (25.00%)  14 9/44 (20.45%)  13
Stomach discomfort  1  2/40 (5.00%)  5 0/44 (0.00%)  0
Vomiting  1  0/40 (0.00%)  0 3/44 (6.82%)  5
General disorders     
Fatigue  1  14/40 (35.00%)  24 9/44 (20.45%)  13
Headache  1  7/40 (17.50%)  7 8/44 (18.18%)  11
Muscle weakness (generalized)  1  4/40 (10.00%)  8 7/44 (15.91%)  10
Pain (chest)  1  4/40 (10.00%)  5 2/44 (4.55%)  2
Weight loss  1  3/40 (7.50%)  3 6/44 (13.64%)  6
Infections and infestations     
Infection (sinus)  1  3/40 (7.50%)  5 1/44 (2.27%)  1
Infection (upper airway)  1  4/40 (10.00%)  6 3/44 (6.82%)  3
Musculoskeletal and connective tissue disorders     
Joint pain  1  7/40 (17.50%)  8 7/44 (15.91%)  8
Muscle weakness (trunk)  1  5/40 (12.50%)  5 3/44 (6.82%)  4
Pain (back)  1  6/40 (15.00%)  10 1/44 (2.27%)  1
Pain (extremity)  1  5/40 (12.50%)  6 5/44 (11.36%)  6
Nervous system disorders     
Dizziness  1  5/40 (12.50%)  6 1/44 (2.27%)  1
Dysarthria/voice changes  1  7/40 (17.50%)  7 4/44 (9.09%)  5
Dysphagia (difficulty swallowing)  1  6/40 (15.00%)  9 9/44 (20.45%)  9
Dysphasia/speech impairment  1  4/40 (10.00%)  5 2/44 (4.55%)  2
Fall  1  8/40 (20.00%)  17 2/44 (4.55%)  7
Fasciculations  1  7/40 (17.50%)  12 4/44 (9.09%)  7
Insomnia  1  5/40 (12.50%)  5 5/44 (11.36%)  5
Muscle atrophy (wasting)  1  3/40 (7.50%)  3 2/44 (4.55%)  7
Muscle cramps  1  4/40 (10.00%)  5 3/44 (6.82%)  4
Muscle weakness (facial)  1  2/40 (5.00%)  2 2/44 (4.55%)  3
Muscle weakness (lower extremity)  1  16/40 (40.00%)  25 17/44 (38.64%)  29
Muscle weakness (upper extremity)  1  20/40 (50.00%)  24 17/44 (38.64%)  25
Pyramidal tract dysfunction (increased muscle tone and/or brisk reflexes)  1  8/40 (20.00%)  9 3/44 (6.82%)  4
Somnolence  1  2/40 (5.00%)  2 2/44 (4.55%)  3
Tremor  1  6/40 (15.00%)  7 3/44 (6.82%)  3
Psychiatric disorders     
Depression  1  6/40 (15.00%)  9 4/44 (9.09%)  6
Renal and urinary disorders     
Urinary frequency/urgency  1  7/40 (17.50%)  9 2/44 (4.55%)  2
Respiratory, thoracic and mediastinal disorders     
Chest congestion  1  6/40 (15.00%)  8 5/44 (11.36%)  5
Dyspnea  1  8/40 (20.00%)  13 6/44 (13.64%)  10
Skin and subcutaneous tissue disorders     
Pruritis  1  3/40 (7.50%)  6 0/44 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE version 3.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Elizabeth Simpson
Organization: Massachusetts General Hospital
Phone: 617-726-3430
EMail: esimpson1@partners.org
Layout table for additonal information
Responsible Party: Merit Cudkowicz, MD, MSc, Co-Director, Neurology Clinical Trials Unit, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00818389     History of Changes
Other Study ID Numbers: U01NS049640 ( U.S. NIH Grant/Contract )
3U01NS049640-04S1 ( U.S. NIH Grant/Contract )
First Submitted: January 6, 2009
First Posted: January 7, 2009
Results First Submitted: May 10, 2010
Results First Posted: April 19, 2011
Last Update Posted: April 19, 2011