Increasing the efficiency of clinical trials in neurodegenerative disorders using group sequential trial designs

Published:February 24, 2018DOI:



      Clinical trials in neurodegenerative disorders are facing high futility rates and rising development costs. We aim to review and exemplify the value of group sequential trial designs (i.e., designs with one or more prospectively planned interim analyses) within the field of amyotrophic lateral sclerosis.

      Study Design and Setting

      We reviewed the literature to identify sequentially conducted trials. Subsequently, we reanalyzed the dexpramipexole trial (EMPOWER), a classically designed and conducted trial involving 942 participants, by sequentially monitoring the functional questionnaire and survival endpoint. Finally, we simulated the performance of the sequential methodology under different treatment effects.


      Only six (12%) randomized, placebo-controlled trials incorporated stopping rules for both futility and superiority. Despite its high enrollment rate, sequential reanalysis of the EMPOWER study reduced the total trial duration with 140 days (23.4%, 95% confidence interval [CI] 13.2–34.4%), the number of follow-ups with 2,688 visits (23.6%, 95% CI 11.3–38.6%), and the total drug exposure time with 73,377 days (20.6%, 95% CI 9.8–35.9%). The functional questionnaire considerably increased the heterogeneity in the test statistics, which may negatively affect sequential monitoring.


      Group sequential trials can result in important reductions in the trial duration, which could make clinical trials more ethical by reducing the patients’ exposure to noneffective treatments or by limiting their time on placebo.


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        • Groeneveld G.J.
        • Graf M.
        • van der Tweel I.
        • van den Berg L.H.
        • Ludolph A.C.
        Alternative trial design in amyotrophic lateral sclerosis saves time and patients.
        Amyotroph Lateral Scler. 2007; 8: 266-269
        • Gordon P.H.
        • Cheung Y.K.
        • Levin B.
        • Andrews H.
        • Doorish C.
        • Macarthur R.B.
        • et al.
        A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS.
        Amyotroph Lateral Scler. 2008; 9: 212-222
        • Dorsey E.R.
        • Venuto C.
        • Venkataraman V.
        • Harris D.A.
        • Kieburtz K.
        Novel methods and technologies for 21st-century clinical trials: a review.
        JAMA Neurol. 2015; 72: 582-588
        • Bauer P.
        • Bretz F.
        • Dragalin V.
        • Konig F.
        • Wassmer G.
        Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls.
        Stat Med. 2016; 35: 325-347
        • Bhatt D.L.
        • Mehta C.
        Adaptive designs for clinical trials.
        N Engl J Med. 2016; 375: 65-74
        • van der Tweel I.
        • Roes K.C.
        Ned Tijdschr Geneeskd. 2013; 157 ([Article in Dutch]): A5660
        • Schoenfeld D.A.
        • Cudkowicz M.
        Design of phase II ALS clinical trials.
        Amyotroph Lateral Scler. 2008; 9: 16-23
        • Groeneveld G.J.
        • van der Tweel I.
        • Wokke J.H.
        • van den Berg L.H.
        Sequential designs for clinical trials in amyotrophic lateral sclerosis.
        Amyotroph Lateral Scler Other Motor Neuron Disord. 2004; 5: 202-207
        • Nikolakopoulos S.
        • Roes K.C.
        • van der Tweel I.
        Sequential designs with small samples: evaluation and recommendations for normal responses.
        Stat Methods Med Res. 2016; 27: 1115-1127
        • Stevely A.
        • Dimairo M.
        • Todd S.
        • Julious S.A.
        • Nicholl J.
        • Hind D.
        • et al.
        An investigation of the shortcomings of the CONSORT 2010 statement for the reporting of group sequential randomised controlled trials: a methodological systematic review.
        PLoS One. 2015; 10: e0141104
        • Schoenfeld D.A.
        Pro/con clinical debate: it is acceptable to stop large multicentre randomized controlled trials at interim analysis for futility. Pro: futility stopping can speed up the development of effective treatments.
        Crit Care. 2005; 9 (discussion 34–6): 34-36
        • Piepers S.
        • Veldink J.H.
        • de Jong S.W.
        • van der Tweel I.
        • van der Pol W.L.
        • Uijtendaal E.V.
        • et al.
        Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis.
        Ann Neurol. 2009; 66: 227-234
        • van Eekelen R.
        • de Hoop E.
        • van der Tweel I.
        Simultaneous sequential monitoring of efficacy and safety led to masking of effects.
        J Clin Epidemiol. 2016; 76: 155-165
        • Jennison C.
        • Turnbull B.W.
        Group sequential methods with applications to clinical trials.
        Chapman & Hall/CRC, Boca Raton2000
        • Mitsumoto H.
        • Brooks B.R.
        • Silani V.
        Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved?.
        Lancet Neurol. 2014; 13: 1127-1138
        • Gupta S.
        • Faughnan M.E.
        • Tomlinson G.A.
        • Bayoumi A.M.
        A framework for applying unfamiliar trial designs in studies of rare diseases.
        J Clin Epidemiol. 2011; 64: 1085-1094
        • van der Lee J.H.
        • Wesseling J.
        • Tanck M.W.
        • Offringa M.
        Efficient ways exist to obtain the optimal sample size in clinical trials in rare diseases.
        J Clin Epidemiol. 2008; 61: 324-330
        • Vandemeulebroecke M.
        Group sequential and adaptive designs-a review of basic concepts and points of discussion.
        Biom J. 2008; 50: 541-557
        • Pocock S.J.
        When (not) to stop a clinical trial for benefit.
        JAMA. 2005; 294: 2228-2230
        • Cudkowicz M.E.
        • van den Berg L.H.
        • Shefner J.M.
        • Mitsumoto H.
        • Mora J.S.
        • Ludolph A.
        • et al.
        Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial.
        Lancet Neurol. 2013; 12: 1059-1067
        • Hughes M.D.
        • Pocock S.J.
        Stopping rules and estimation problems in clinical trials.
        Stat Med. 1988; 7: 1231-1242
        • Friedman L.M.
        • Furberg C.
        • DeMets D.L.
        Fundamentals of clinical trials.
        4th ed. Springer, New York2010
        • Todd S.
        • Whitehead A.
        • Stallard N.
        • Whitehead J.
        Interim analyses and sequential designs in phase III studies.
        Br J Clin Pharmacol. 2001; 51: 394-399
        • Elia A.E.
        • Lalli S.
        • Monsurro M.R.
        • Sagnelli A.
        • Taiello A.C.
        • Reggiori B.
        • et al.
        Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis.
        Eur J Neurol. 2016; 23: 45-52
        • de Carvalho M.
        • Pinto S.
        • Costa J.
        • Evangelista T.
        • Ohana B.
        • Pinto A.
        A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis.
        Amyotroph Lateral Scler. 2010; 11: 456-460
        • Kaufmann P.
        • Thompson J.L.
        • Levy G.
        • Buchsbaum R.
        • Shefner J.
        • Krivickas L.S.
        • et al.
        Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.
        Ann Neurol. 2009; 66: 235-244
        • Sorenson E.J.
        • Windbank A.J.
        • Mandrekar J.N.
        • Bamlet W.R.
        • Appel S.H.
        • Armon C.
        • et al.
        Subcutaneous IGF-1 is not beneficial in 2-year ALS trial.
        Neurology. 2008; 71: 1770-1775
        • DeSouza C.M.
        • Legedza A.T.
        • Sankoh A.J.
        An overview of practical approaches for handling missing data in clinical trials.
        J Biopharm Stat. 2009; 19: 1055-1073
        • Mandrioli J.
        • Biguzzi S.
        • Guidi C.
        • Sette E.
        • Terlizzi E.
        • Ravasio A.
        • et al.
        Heterogeneity in ALSFRS-R decline and survival: a population-based study in Italy.
        Neurol Sci. 2015; 36: 2243-2252
        • Aggarwal S.P.
        • Zinman L.
        • Simpson E.
        • McKinley J.
        • Jackson K.E.
        • Pinto H.
        • et al.
        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; 9: 481-488
        • Cudkowicz M.E.
        • Titus S.
        • Kearney M.
        • Yu H.
        • Sherman A.
        • Schoenfeld D.
        • et al.
        Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial.
        Lancet Neurol. 2014; 13: 1083-1091
        • Dupuis L.
        • Dengler R.
        • Heneka M.T.
        • Meyer T.
        • Zierz S.
        • Kassubek J.
        • et al.
        A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.
        PLoS One. 2012; 7: e37885
        • Groeneveld G.J.
        • Veldink J.H.
        • van der Tweel I.
        • Kalmijn S.
        • Beijer C.
        • de Visser M.
        • et al.
        A randomized sequential trial of creatine in amyotrophic lateral sclerosis.
        Ann Neurol. 2003; 53: 437-445
        • Verstraete E.
        • Veldink J.H.
        • Huisman M.H.
        • Draak T.
        • Uijtendaal E.V.
        • van der Kooi A.J.
        • et al.
        Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial.
        J Neurol Neurosurg Psychiatry. 2012; 83: 557-564
        • Graf M.
        • Ecker D.
        • Horowski R.
        • Kramer B.
        • Riederer 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.
        J Neural Transm (Vienna). 2005; 112: 649-660
        • Martin L.
        • Hutchens M.
        • Hawkins C.
        • Radnov A.
        How much do clinical trials cost?.
        Nat Rev Drug Discov. 2017; 16: 381-382
        • van der Lee J.H.
        • Wesseling J.
        • Tanck M.W.
        • Offringa M.
        Sequential design with boundaries approach in pediatric intervention research reduces sample size.
        J Clin Epidemiol. 2010; 63: 19-27
        • LeBlanc M.
        • Crowley J.
        Using the bootstrap for estimation in group sequential designs: an application to a clinical trial for nasopharyngeal cancer.
        Stat Med. 1999; 18: 2635-2644
        • Bacci E.D.
        • Staniewska D.
        • Coyne K.S.
        • Boyer S.
        • White L.A.
        • Zach N.
        • et al.
        Item response theory analysis of the amyotrophic lateral sclerosis functional rating scale-revised in the pooled resource open-access ALS clinical trials database.
        Amyotroph Lateral Scler Frontotemporal Degener. 2016; 17: 157-167
        • Franchignoni F.
        • Mora G.
        • Giordano A.
        • Volanti P.
        • Chio A.
        Evidence of multidimensionality in the ALSFRS-R Scale: a critical appraisal on its measurement properties using Rasch analysis.
        J Neurol Neurosurg Psychiatry. 2013; 84: 1340-1345
        • van Eijk R.P.A.
        • Jones A.R.
        • Sproviero W.
        • Shatunov A.
        • Shaw P.J.
        • Leigh P.N.
        • et al.
        Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.
        Neurology. 2017; 89: 1915-1922