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

This study has been terminated.
(NINDS DSMB recommended trial be terminated for futility after reviewing an interim analysis of 84 subjects.)
Sponsor:
Collaborators:
ALS Association
ALS Society of Canada
University of Toronto
State University of New York - Upstate Medical University
Columbia University
University of Kentucky
Information provided by:
Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT00818389
First received: January 6, 2009
Last updated: March 18, 2011
Last verified: March 2011
Results First Received: May 10, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Crossover Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Amyotrophic Lateral Sclerosis
Interventions: Drug: Lithium Carbonate
Drug: Riluzole
Drug: placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
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).
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.

Participant Flow:   Overall Study
    Lithium + Riluzole     Placebo + Riluzole  
STARTED     40     44  
COMPLETED     36 [1]   38 [2]
NOT COMPLETED     4     6  
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.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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).
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.
Total Total of all reporting groups

Baseline Measures
    Lithium + Riluzole     Placebo + Riluzole     Total  
Number of Participants  
[units: participants]
  40     44     84  
Age  
[units: Years]
Mean ± Standard Deviation
  58.3  ± 10.2     55.5  ± 11.9     56.24  ± 11.16  
Gender  
[units: participants]
     
Female     10     20     30  
Male     30     24     54  
Ethnicity (NIH/OMB)  
[units: Participants]
     
Hispanic or Latino     0     2     2  
Not Hispanic or Latino     40     42     82  
Unknown or Not Reported     0     0     0  
Race (NIH/OMB)  
[units: Participants]
     
American Indian or Alaska Native     0     0     0  
Asian     0     0     0  
Native Hawaiian or Other Pacific Islander     0     0     0  
Black or African American     1     2     3  
White     39     42     81  
More than one race     0     0     0  
Unknown or Not Reported     0     0     0  
ALS Functional Rating Scale-Revised (ALSFRS-R) [1]
[units: Scores on a scale]
Mean ± Standard Deviation
  38.4  ± 4.6     36.5  ± 5.7     37.43  ± 5.24  
Vital Capacity [2]
[units: Percent of predicted normal]
Mean ± Standard Deviation
  94.0  ± 18.1     86.9  ± 16.9     90.18  ± 18.20  
[1] 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.
[2] 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.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire (ALSFRS-R)   [ Time Frame: 9 months: Baseline to study termination (January 2009 - October 2009) ]

2.  Secondary:   Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire(ALSFRS-R)   [ Time Frame: 9 months: Baseline to study termination (January 2009 - October 2009) ]

3.  Secondary:   Vital Capacity (VC) (Percent of Predicted Normal)   [ Time Frame: 9 months: Baseline to study termination (January 2009- October 2009) ]


  Serious Adverse Events


  Other Adverse Events
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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.
Additional 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.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
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).
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.

Other Adverse Events
    Lithium + Riluzole     Placebo + Riluzole  
Total, other (not including serious) adverse events      
# participants affected / at risk     39/40     43/44  
Blood and lymphatic system disorders      
Bruising (in absence of grade 3 or 4 thrombocytopenia) † 1    
# participants affected / at risk     5/40 (12.50%)     1/44 (2.27%)  
# events     7     2  
Edema (limb) † 1    
# participants affected / at risk     6/40 (15.00%)     7/44 (15.91%)  
# events     12     8  
Gastrointestinal disorders      
Anorexia † 1    
# participants affected / at risk     6/40 (15.00%)     2/44 (4.55%)  
# events     7     4  
Constipation † 1    
# participants affected / at risk     5/40 (12.50%)     8/44 (18.18%)  
# events     7     9  
Diarrhea † 1    
# participants affected / at risk     5/40 (12.50%)     5/44 (11.36%)  
# events     5     6  
Drooling † 1    
# participants affected / at risk     7/40 (17.50%)     6/44 (13.64%)  
# events     7     7  
Heartburn † 1    
# participants affected / at risk     4/40 (10.00%)     5/44 (11.36%)  
# events     5     6  
Nausea † 1    
# participants affected / at risk     10/40 (25.00%)     9/44 (20.45%)  
# events     14     13  
Stomach discomfort † 1    
# participants affected / at risk     2/40 (5.00%)     0/44 (0.00%)  
# events     5     0  
Vomiting † 1    
# participants affected / at risk     0/40 (0.00%)     3/44 (6.82%)  
# events     0     5  
General disorders      
Fatigue † 1    
# participants affected / at risk     14/40 (35.00%)     9/44 (20.45%)  
# events     24     13  
Headache † 1    
# participants affected / at risk     7/40 (17.50%)     8/44 (18.18%)  
# events     7     11  
Muscle weakness (generalized) † 1    
# participants affected / at risk     4/40 (10.00%)     7/44 (15.91%)  
# events     8     10  
Pain (chest) † 1    
# participants affected / at risk     4/40 (10.00%)     2/44 (4.55%)  
# events     5     2  
Weight loss † 1    
# participants affected / at risk     3/40 (7.50%)     6/44 (13.64%)  
# events     3     6  
Infections and infestations      
Infection (sinus) † 1    
# participants affected / at risk     3/40 (7.50%)     1/44 (2.27%)  
# events     5     1  
Infection (upper airway) † 1    
# participants affected / at risk     4/40 (10.00%)     3/44 (6.82%)  
# events     6     3  
Musculoskeletal and connective tissue disorders      
Joint pain † 1    
# participants affected / at risk     7/40 (17.50%)     7/44 (15.91%)  
# events     8     8  
Muscle weakness (trunk) † 1    
# participants affected / at risk     5/40 (12.50%)     3/44 (6.82%)  
# events     5     4  
Pain (back) † 1    
# participants affected / at risk     6/40 (15.00%)     1/44 (2.27%)  
# events     10     1  
Pain (extremity) † 1    
# participants affected / at risk     5/40 (12.50%)     5/44 (11.36%)  
# events     6     6  
Nervous system disorders      
Dizziness † 1    
# participants affected / at risk     5/40 (12.50%)     1/44 (2.27%)  
# events     6     1  
Dysarthria/voice changes † 1    
# participants affected / at risk     7/40 (17.50%)     4/44 (9.09%)  
# events     7     5  
Dysphagia (difficulty swallowing) † 1    
# participants affected / at risk     6/40 (15.00%)     9/44 (20.45%)  
# events     9     9  
Dysphasia/speech impairment † 1    
# participants affected / at risk     4/40 (10.00%)     2/44 (4.55%)  
# events     5     2  
Fall † 1    
# participants affected / at risk     8/40 (20.00%)     2/44 (4.55%)  
# events     17     7  
Fasciculations † 1    
# participants affected / at risk     7/40 (17.50%)     4/44 (9.09%)  
# events     12     7  
Insomnia † 1    
# participants affected / at risk     5/40 (12.50%)     5/44 (11.36%)  
# events     5     5  
Muscle atrophy (wasting) † 1    
# participants affected / at risk     3/40 (7.50%)     2/44 (4.55%)  
# events     3     7  
Muscle cramps † 1    
# participants affected / at risk     4/40 (10.00%)     3/44 (6.82%)  
# events     5     4  
Muscle weakness (facial) † 1    
# participants affected / at risk     2/40 (5.00%)     2/44 (4.55%)  
# events     2     3  
Muscle weakness (lower extremity) † 1    
# participants affected / at risk     16/40 (40.00%)     17/44 (38.64%)  
# events     25     29  
Muscle weakness (upper extremity) † 1    
# participants affected / at risk     20/40 (50.00%)     17/44 (38.64%)  
# events     24     25  
Pyramidal tract dysfunction (increased muscle tone and/or brisk reflexes) † 1    
# participants affected / at risk     8/40 (20.00%)     3/44 (6.82%)  
# events     9     4  
Somnolence † 1    
# participants affected / at risk     2/40 (5.00%)     2/44 (4.55%)  
# events     2     3  
Tremor † 1    
# participants affected / at risk     6/40 (15.00%)     3/44 (6.82%)  
# events     7     3  
Psychiatric disorders      
Depression † 1    
# participants affected / at risk     6/40 (15.00%)     4/44 (9.09%)  
# events     9     6  
Renal and urinary disorders      
Urinary frequency/urgency † 1    
# participants affected / at risk     7/40 (17.50%)     2/44 (4.55%)  
# events     9     2  
Respiratory, thoracic and mediastinal disorders      
Chest congestion † 1    
# participants affected / at risk     6/40 (15.00%)     5/44 (11.36%)  
# events     8     5  
Dyspnea † 1    
# participants affected / at risk     8/40 (20.00%)     6/44 (13.64%)  
# events     13     10  
Skin and subcutaneous tissue disorders      
Pruritis † 1    
# participants affected / at risk     3/40 (7.50%)     0/44 (0.00%)  
# events     6     0  
Events were collected by systematic assessment
1 Term from vocabulary, CTCAE version 3.0



  More Information
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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.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.  


Results Point of Contact:  
Name/Title: Elizabeth Simpson
Organization: Massachusetts General Hospital
phone: 617-726-3430
e-mail: esimpson1@partners.org


Publications:
Fornai, F., et al., Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA, 2008. 105(6): p. 2052-7.

Publications automatically indexed to this study:

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, 3U01NS049640-04S1
Study First Received: January 6, 2009
Results First Received: May 10, 2010
Last Updated: March 18, 2011
Health Authority: United States: Federal Government
Canada: Health Canada