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Meta-Analysis
. 2012 Mar 14;2012(3):CD001447.
doi: 10.1002/14651858.CD001447.pub3.

Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)

Robert G Miller  1 , J D Mitchell, Dan H Moore
Affiliations
Meta-Analysis

Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)

Robert G Miller et al. Cochrane Database Syst Rev. .

Abstract

Background: Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy.

Objectives: To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health.

Search methods: We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field.

Selection criteria: Types of studies: randomized controlled trials

Types of participants: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events.

Data collection and analysis: One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible.

Main results: The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31).

Authors' conclusions: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.

PubMed Disclaimer

Conflict of interest statement

Both Drs Miller and Mitchell were investigators in the second large trial of riluzole in ALS, but neither participated in data analysis or manuscript preparation. Dr Mitchell participated in other scientific activities (Consensus conferences, ALS CARE National database and ALS Practice Parameters) where financial support came from Aventis.

Dr Miller is a consultant for several pharmaceutical entities, but none are related to riluzole.

Dan H Moore, PhD received an honorarium for his participation in the ALS CARE program, supported by Aventis. He is a biostatistical consultant for several pharmaceutical entities, but none are related to riluzole.

For Dr Mitchell (deceased), declarations of interest are as published in the previous update of this review.

Figures

1
1
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
2
2
Pooled survival time in months. Solid lines show pooled results from the two trials that were homogeneous.
1.1
1.1. Analysis
Comparison 1 Riluzole 100 mg versus placebo, Outcome 1 Per cent mortality at 12 months.
2.1
2.1. Analysis
Comparison 2 Riluzole 100 mg versus placebo, Outcome 1 Per cent mortality at 18 months.
3.1
3.1. Analysis
Comparison 3 Riluzole all doses versus placebo, Outcome 1 Per cent mortality at 12 months.
4.1
4.1. Analysis
Comparison 4 Muscle strength, Outcome 1 Manual muscle testing.
5.1
5.1. Analysis
Comparison 5 Functional scales, Outcome 1 Rate of decline of Norris Scale.
6.1
6.1. Analysis
Comparison 6 Functional scales, Outcome 1 Rate of decline of Norris Scale.
7.1
7.1. Analysis
Comparison 7 Adverse effects from riluzole 100 mg, Outcome 1 Clinical.
8.1
8.1. Analysis
Comparison 8 Adverse effects from riluzole 100 mg, Outcome 1 Clinical.
9.1
9.1. Analysis
Comparison 9 Adverse effects from riluzole 100 mg, Outcome 1 Laboratory.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Bensimon 1994 {published and unpublished data}
    1. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. The ALS/Riluzole Study Group. New England Journal of Medicine 1994;330(9):585‐91. [PUBMED: 8302340] - PubMed
Bensimon 2002 {published data only}
    1. Bensimon G, Lacomblez L, Delumeau JC, Bejuit R, Truffinet P, Meininger V. A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis. Journal of Neurology 2002;249(5):609‐15. [PUBMED: 12021952] - PubMed
    1. Meininger V, Lacomblez L, Bensimon G. Unpublished report: controlled trial of riluzole in patients with advanced ALS. RP 54272‐302 1995.
Lacomblez 1996 {published and unpublished data}
    1. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V, and the Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Dose‐ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 1996;347(9013):1425‐31. [PUBMED: 8676624] - PubMed
Yanagisawa 1997 {published data only}
    1. Yanagisawa N, Tashiro K, Tohgi H, Mizuno Y, Kowa H, Kimuma J, et al. Efficacy and safety of riluzole in patients with amyotrophic lateral sclerosis: double‐blind placebo‐controlled study in Japan. Igakuno Ayumi 1997;182:851‐66.

References to studies excluded from this review

Arriada‐Mendicoa 1999 {published data only}
    1. Arriada‐Mendicoa N, Otero‐Siliceo E, Burbano G, Corona‐Vazquez T. Open label study of riluzole for the treatment of amyotrophic lateral sclerosis. Revista Ecuatoriana de Neurologia 1999;8:33‐6.
Couratier 2000 {published data only}
    1. Couratier P, Druet‐Cabanac M, Truong CT, Bernet‐Bernady P, Dumas M, Vallat JM, et al. Interest of a computerized ALS database in the diagnosis and follow‐up of patients with ALS [Interets d'une base de donnees informatisee dans le diagnostic et le suivi de patients atteints de la sclerose laterale amyotrophique]. Revue Neurologique 2000;156(4):357‐63. - PubMed
Desiato 1999 {published data only}
    1. Desiato MT, Palmieri MG, Giacomini P, Scalise A, Arciprete F, Caramia MD. The effect of riluzole in amyotrophic lateral sclerosis: a study with cortical stimulation. Journal of Neurological Sciences 1999;169(1‐2):98‐107. - PubMed
Graf 2005 {published data only}
    1. Graf M, Ecker D, Horowski R, Kramer B, Riderer P, Gerlach M, et al. High dose vitamin E therapy in amyotrophic lateral sclerosis as add‐on therapy to riluzole: results of a placebo‐controlled double‐blind study. Journal of Neural Transmission 2005;112(5):649‐60. - PubMed
Kalra 1998 {published data only}
    1. Kalra S, Cashman NR, Genge A, Arnold DL. Recovery of N‐acetylaspartate in corticomotor neurons of patients with ALS after riluzole therapy. Neuroreport 1998;9(8):1757‐61. - PubMed
Meininger 2004 {published data only}
    1. Meininger V, Bensimon G, Bradley WG, Brooks BR, Douillet P, Eisen AA, et al. Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: Results of two phase III trials. Amyotrophic Lateral Sclerosis & Other Motor Neuron Disorders 2004;5(2):107‐17. - PubMed
Mitchell 2006 {published data only}
    1. Mitchell JD, O'Brien MR, Joshi M. Audit of outcomes in motor neuron disease (MND) patients treated with riluzole. Amyotrophic lateral sclerosis and other motor neuron disorders 2006;7:67‐71. - PubMed
Palma 2000 {published data only}
    1. Palma V, Brescia Morra V, Polverino M, Santoro L, Caruso G. An open study of riluzole versus riluzole plus gabapentin in amyotrophic lateral sclerosis. Journal of the Peripheral Nervous System 2000;5(1):46.
Pongratz 1999 {published data only}
    1. Pongratz D, Neundorfer B. Open‐label trial of riluzole 50 mg b.i.d. in treatment of amyotrophic lateral sclerosis (ALS). Aktuelle Neurologie 1999;26(5):225‐9. - PubMed
Riviere 1998 {published data only}
    1. Riviere M, Meininger V, Zeisser P, Munsat T. An analysis of extended survival in patients with amyotrophic lateral sclerosis treated with riluzole. Archives of Neurology 1998;55(4):526‐8. - PubMed
Sojka 1997 {published data only}
    1. Sojka P, Anderson PM, Forsgren L. Effects of riluzole on symptom progression in amyotrophic lateral sclerosis. Lancet 1997;349(9046):176‐7. - PubMed
Zoccolella 2007 {published data only}
    1. Zoccolella S, Beghi E, Palagano G, Fraddosio A, et al. Riluzole and amyotrophic lateral sclerosis survival: a population based study in Southern Italy. European Journal of Neurology 2007;14(3):262‐8. - PubMed

Additional references

Booth‐Clibborn 1997
    1. Booth‐Clibborn N, Best L, Stein K. Riluzole for motor neurone disease. Southampton: Wessex Institute for Health Research & Development (DEC Report 73). Southampton, 1997.
Borderias‐Clau 2006
    1. Borderías‐Clau L, Garrapiz‐López J, Val‐Adán P, Tordesillas‐Lía C, Alcacera‐López A, Bru‐Martín JL. Strong suspicion of lung toxicity due to riluzole [Alta sospecha de toxicidad pulmonar por riluzol]. Archivos de Bronconeumologia 2006;42(1):42‐4. - PubMed
Bourke 2006
    1. Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non‐invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurology 2006;5:140‐7. - PubMed
Brooks 1994
    1. Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors. Journal of Neurological Sciences 1994;124(Suppl):96‐107. - PubMed
Brooks 2001
    1. Brooks BR, Belden DS, Roelke K, Parnell J, Peper S, Houdek A, et al. Survival in non‐riluzole treated amyotrophic lateral sclerosis (ALS) ‐ Motor neuron disease (MND) patients with disease onset before and since 1996 is identical: a clinic‐based epidemiological study. ALS and other motor neuron diseases 2001;2:60‐1.
Cassiman 2003
    1. Cassiman D, Thomeer M, Verbeken E, Robberecht W. Hypersensitivity pneumonitis possibly caused by riluzole therapy in ALS. Neurology 2003;61(8):1150‐1. - PubMed
Chilcott 1997
    1. Chilcott J, Golightly P, Jefferson D, McCabe CJ, Walters S. The use of riluzole in the treatment of Amyotrophic Lateral Sclerosis (Motor Neurone Disease). Working Group on Acute Purchasing. Trent Institute for Health Services Research, Universities of Leicester, Nottingham and Sheffield 1997.
CPMP 1999
    1. Committee for Proprietary Medicinal Products. European Public Assessment Report (EPAR) Rilutek. The European Agency for the Evaluation of Medicinal Products 1997 (CPMP/290/96).
Higgins 2008
    1. Higgins JPT, Altman DG (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors) editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Chichester (UK): John Wiley & Sons, 2008.
HTA 2001
    1. Stewart A, Sandercock J, Bryan S, Hyde C, Barton PM, Fry‐Smith A, et al. The clinical effectiveness and cost‐effectiveness of riluzole for motor neurone disease: a rapid and systematic review. Health Technology Assessment 2001;5(2):1‐97. - PubMed
Hugon 1996a
    1. Hugon J. Riluzole and ALS therapy. Weiner Medizinische Wochenschrift 1996;146(9‐10):185‐7. - PubMed
Hugon 1996b
    1. Hugon J. ALS therapy: targets for the future. Neurology 1996;47:251‐4. - PubMed
Lacomblez 1989
    1. Lacomblez L, Bouche P, Bensimon G, Meininger V. A double‐blind, placebo‐controlled trial of high doses of gangliosides in amyotrophic lateral sclerosis. Neurology 1989;39(12):1635‐7. - PubMed
Logroscino 2007
    1. Logroscino G, Zoccolella S. Efficacy of riluzole: Who are the patients enrolled in the studies?. Amyotrophic Lateral Sclerosis 2007;8:124‐5. - PubMed
McGuire 1996
    1. McGuire D, Garrison L, Miller RG. Relationship of the Tufts Quantitative Neuromuscular Exam (TQNE) and the Sickness Impact Profile (SIP) in measuring progression of ALS. Neurology 1996;46(5):1442‐4. - PubMed
Meininger 1997
    1. Meininger V, Dib M, Aubin F, Jourdain G, Zeisser P. The Riluzole Early Access Programme: descriptive analysis of 844 patients in France. ALS/Riluzole Study Group III. Neurology 1997;244(Suppl 2):S22‐5. - PubMed
Meininger 2000
    1. Meininger V, Bensimon G, Bradley WG, Brooks BR, Douillet P, Eisen AA, et al. Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials. Amyotrophic lateral sclerosis and other motor neuron disorders 2004;5(2):107‐17. - PubMed
Miller 1996
    1. Miller RG, Bouchard JP, Duquette P, Eisen A, Gelinas D, Harati Y, et al. Clinical trials of riluzole in patients with amyotrophic lateral sclerosis. Neurology 1996;47(4 Suppl 2):S86‐S92. - PubMed
Miller 1999
    1. Miller RG, Rosenberg JA, Gelinas DF, Mitsumoto H, Newman D, Sufit R, et al. Practice parameter: The care of the patient with amyotrophic lateral sclerosis (an evidence‐based review). Neurology 1999;52(7):1311‐23. - PubMed
Miller 2009
    1. Miller RG, Jackson CE, Kasarkis EJ, England JD, Forshew D, Johnston W, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence‐based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2009;73(15):1218‐26. - PMC - PubMed
Neurology 1997
    1. Quality Standards Subcommittee of the American Academy of Neurology. Practice advisory on the treatment of amyotrophic lateral sclerosis with riluzole. Neurology 1997;49:657‐9. - PubMed
NICE 2001
    1. National Institute for Clinical Excellence. Guidance on the use of riluzole (Rilutek) for the treatment of motor neurone disease. Technology Appraisal Guidance 2001; Vol. 20.
Parmar 1998
    1. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta‐analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17(24):2815‐34. - PubMed
Remy 1999
    1. Remy AJ, Camu W, Ramos J, Blanc P, Larrey D. Acute hepatitis after riluzole administration. Journal of Hepatology 1999;30(3):527‐30. - PubMed
Review Manager 2011 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Rodrigo 2001
    1. Rodrigo L, Moreno M, Calleja S, Mateos V, Andrade RJ, Lucena MI. Riluzole‐induced acute pancreatitis. American Journal of Gastroenterology 2001;96(7):2268‐9. - PubMed
Rothstein 1996
    1. Rothstein JD. Therapeutic horizons for amyotrophic lateral sclerosis. Current Opinion in Neurobiology 1996;6:679‐87. - PubMed
Rowland 1994
    1. Rowland LP. Riluzole for the treatment of amyotrophic lateral sclerosis ‐ too soon to tell?. New England Journal of Medicine 1994;330(9):636‐7. - PubMed
Sorenson 2008
    1. Sorenson EJ. An acute, life‐threatening, hypersensitivity reaction to riluzole. Neurology 2006;67(12):2260‐1. - PubMed
Stambler 1998
    1. Stambler N, Charatan M, Cedarbaum J and the ALS CNTF Treatment Study Group. Prognostic indicators of survival in ALS. Neurology 1998;50(1):66‐72. - PubMed
Traynor 2001
    1. Traynor BJ, Alexander M, Corr B, Frost E, Mahon L, Hardiman O. Riluzole and prognosis in ALS: Findings of the Irish ALS register over a five year study period (1999‐2000). Amyotrophic lateral sclerosis and other motor neuron disorders 2001;2(Suppl 2):43‐4.
Turner 2001
    1. Turner MR, Bakker M, Sham P, Shaw CE, Leigh PN, Al‐Chalabi A. The Kings' Database 1999‐2000: an analysis of the effect on survival of interventions in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis and other motor neuron disorders 2001;2(Suppl 2):43. - PubMed
Weber 2004
    1. Weber G, Bitterman H. Riluzole‐induced neutropenia. Neurology 2004;62(9):1648. - PubMed
Wokke 1996
    1. Wokke J. Riluzole. Lancet 1996;348(9030):795‐9. - PubMed

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