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

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

ClinicalTrials.gov Identifier:

NCT00818389

First received: January 6, 2009

Last updated: March 18, 2011

Last verified: March 2011

History of Changes

Results First Received: May 10, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double Blind (Participant, Care Provider, 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.
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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

Overall Participants Analyzed
[Units: Participants]

Age
[Units: Years]
Mean (Standard Deviation)

58.3 (10.2)

55.5 (11.9)

56.24 (11.16)

Gender
[Units: Participants]

Female

Male

Ethnicity (NIH/OMB)
[Units: Participants]

Hispanic or Latino

Not Hispanic or Latino

Unknown or Not Reported

Race (NIH/OMB)
[Units: Participants]

American Indian or Alaska Native

Asian

Native Hawaiian or Other Pacific Islander

Black or African American

White

More than one race

Unknown or Not Reported

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)

^[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.

Vital Capacity ^[1]
[Units: Percent of predicted normal]
Mean (Standard Deviation)

94.0 (18.1)

86.9 (16.9)

90.18 (18.20)

^[1]	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

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1. Primary:

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

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2. Secondary:

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

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3. Secondary:

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

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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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
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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.

Results Point of Contact:

Name/Title: Elizabeth Simpson
Organization: Massachusetts General Hospital
phone: 617-726-3430
e-mail: 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 History of Changes
Other Study ID Numbers:	U01NS049640 ( U.S. NIH Grant/Contract ) 3U01NS049640-04S1 ( U.S. NIH Grant/Contract )
Study First Received:	January 6, 2009
Results First Received:	May 10, 2010
Last Updated:	March 18, 2011

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