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

• ClinicalTrials.gov Identifier: NCT00818389
• Recruitment Status: Terminated
• First Posted: January 7, 2009
• Results First Posted: April 19, 2011
• Last Update Posted: April 19, 2011
• Sponsor: Massachusetts General Hospital
• 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

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.

Arm/Group Title	Lithium + Riluzole	Placebo + Riluzole
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.

Baseline Characteristics

Arm/Group Title		Lithium + Riluzole	Placebo + Riluzole	Total
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
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.

Outcome Measures

1. Primary Outcome

Title	Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Questionnaire (ALSFRS-R)
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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lithium + Riluzole	Placebo + Riluzole
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)
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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lithium + Riluzole	Placebo + Riluzole
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)
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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lithium + Riluzole	Placebo + Riluzole
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)

Adverse Events

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
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	--/--		--/--
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
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

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Elizabeth Simpson
• Organization: Massachusetts General Hospital
• Phone: 617-726-3430
• EMail: esimpson1@partners.org

Publications:

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. Erratum in: Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16404-7.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Merit Cudkowicz, MD, MSc, Co-Director, Neurology Clinical Trials Unit, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00818389
• 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