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Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.

Author(s): 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.

Collaborators: D'Amour M, Souchon F, Lefebvre C, Blais L, Cardin E, Allard L, Quessy G, Limbo A, Cabral K, Spinelli N, Robertson G, Lewis P, Grant IA, Benstead TJ, Reidy SL, Hebert SL, Bouchard JP, Dionne A, Dupre N, Morel L, Roy G, Tran TV, Turnbull J, Martin J, Genge A, Lavoie D, Wang JW, Bertone D, Normandin K, Melanson M, McBride EV, O'Connell C, Worley S, Brophy-LeBlanc S, Zinman L, McKinley J, Pinto H, Friedman Y, Iazzetta J, Chrichton B, Johnston W, Kalra S, Sekhon R, Briemberg H, Krieger C, Fabros M, Poirier B, White C, Korngut L, Mawani S, Munro S, Cameron C, Casey A, Ethans K, Olafson T, Shan RL, Hader W, Ridley S, Bruce L, Munchinsky J, Dal Bello-Haas V, Shoesmith C, Strong M, Row A, Findlater K, Verheyden J, Muthukumaran A, Tsimerinov E, Gruendler H, Kaufmann P, Andrews J, Vecchio D, Heiman-Patterson T, Deboo A, Rojas L, Feldman S, Mazurek M, Barr C, Deitch J, Bedlack R, Harward-Grace K, Boyette C, Tiryaki E, Bundlie S, Leviton T, Rohde C, Swanson S, Pascuzzi RM, Kincaid JC, Snook RJ, Bodkin CL, Guingrich S, Micheels A, Humma KG, Morrison BM, Rothstein J, Kimball RM, Clawson LL, Riley KM, David WS, Wills AM, Atassi N, Goldenberg AR, Pulley DE, Berndt JL, Castrillo-Viguera Mdel C, Bellanich M, Jaffa MN, Reilly-Tremblay C, Boylan K, Kennelly K, Johnston A, DeSaro P, Fuqua P, Wright T, Ward C, Schoenberger S, Swan A, DeOliveira G, Huser A, Kissel JT, Nash SM, Kolb SJ, Quick AD, Chelnick SA, King WM, Fudge RP, Reynold J, Bartlett A, Scott K, Simmons Z, Clardy SL, Brothers A, Schaeffer C, Stephens HE, Heisey H, Mottilla S, Saperstein D, Levine T, Hank N, Clarke K, Simionescu L, Bradshaw D, Watson ML, Grosso M, Boevin T, Heitzman D, Spears B, Hand SL, White L, Lomen-Hoerth C, Ahmed F, Kasarskis E, Vanderpool K, Taylor D, Wells RS, Sitzlar SC, Sharma KR, Koggan D, Valdez S, Gonzalez G, Perez M, Palomeque M, Weiss E, Tandan R, Singh P, Potter C, Phillips LH, Burns TM, Solorzano G, Keller K, Warder J, Caress JB, Cartwright MS, Marandi M, O'Neil C, Pestronk A, Harms M, Florence J, Townsend P, Vehe K, Malkus E, Jani-Acsadi A, Lewis RA, Masse S, Mariani M, MacDonald JL, Genge A, Turnbull J, Zinman L, Shoesmith C, Kaufmann P, Rothstein J, Aggarwal S, Cudkowicz M, Schoenfeld D, Boylan KB, Conwit R, Shefner J, Brown R, Kasarskis E, Aggarwal S, Cudkowicz M, Simpson E, Jackson KE, Sherman A, Yu H, Lanka V, Schnupp L, Deng J, Padilla O, Badayan I, Yerramilli-Rao P, Rosenbaum E, Kearney M, Maloutas M, Zinman I, McKinley J, Pinto H, Shefner J, Watson ML, Tindall K, Money K, Varghese B, Lew B, Markis K, Hand H, Kaufman P, Andrews J, Vecchio D, Coffey C, Benatar M, Joyce C, Trivedi M, Wisniewski S, Leventhal C, Russell J.

Affiliation(s): Neurology Clinical Trials Unit, Massachusetts General Hospital, Charlestown, MA, USA. spaggarwal@partners.org

Publication date & source: 2010, Lancet Neurol. , 9(5):481-8

BACKGROUND: In a pilot study, lithium treatment slowed progression of amyotrophic lateral sclerosis (ALS). We aimed to confirm or disprove these findings by assessing the safety and efficacy of lithium in combination with riluzole in patients with ALS. METHODS: We did a double-blind, placebo-controlled trial with a time-to-event design. Between January and June, 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned (1:1) by a centralised computer to receive either lithium or placebo. Patients, caregivers, investigators, and all site study staff with the exception of site pharmacists were masked to treatment assignment. The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death. Interim analyses were planned for when 84 patients had been allocated treatment, 6 months later or after 55 events, and after 100 events. Analysis was by intention to treat. The stopping boundary for futility at the first interim analysis was a p value of at least 0.68. We used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. This trial is registered with ClinicalTrials.gov, NCT00818389. FINDINGS: At the first interim analysis, 22 of 40 patients in the lithium group had an event compared with 20 of 44 patients in the placebo group (log rank p=0.51). The hazard ratio of reaching the primary endpoint was 1.13 (95% CI 0.61-2.07). The study was stopped at the first interim analysis because criterion for futility was met (p=0.78). The difference in mean decline in the ALS functional rating scale score between the lithium group and the placebo group was 0.15 (95% CI -0.43 to 0.73, p=0.61). There were no major safety concerns. Falls (p=0.04) and back pain (p=0.05) were more common in the lithium group than in the placebo group. INTERPRETATION: We found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone. The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly. This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS. FUNDING: National Institute of Neurological Disorders and Stroke, ALS Association, and ALS Society of Canada.

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