Abstract
Objectives
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.
Results
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.
Conclusion
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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Clinical EpidemiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Alternative trial design in amyotrophic lateral sclerosis saves time and patients.Amyotroph Lateral Scler. 2007; 8: 266-269
- A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS.Amyotroph Lateral Scler. 2008; 9: 212-222
- Novel methods and technologies for 21st-century clinical trials: a review.JAMA Neurol. 2015; 72: 582-588
- Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls.Stat Med. 2016; 35: 325-347
- Adaptive designs for clinical trials.N Engl J Med. 2016; 375: 65-74
- Ned Tijdschr Geneeskd. 2013; 157 ([Article in Dutch]): A5660
- Design of phase II ALS clinical trials.Amyotroph Lateral Scler. 2008; 9: 16-23
- Sequential designs for clinical trials in amyotrophic lateral sclerosis.Amyotroph Lateral Scler Other Motor Neuron Disord. 2004; 5: 202-207
- Sequential designs with small samples: evaluation and recommendations for normal responses.Stat Methods Med Res. 2016; 27: 1115-1127
- 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
- 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
- Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis.Ann Neurol. 2009; 66: 227-234
- Simultaneous sequential monitoring of efficacy and safety led to masking of effects.J Clin Epidemiol. 2016; 76: 155-165
- Group sequential methods with applications to clinical trials.Chapman & Hall/CRC, Boca Raton2000
- Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved?.Lancet Neurol. 2014; 13: 1127-1138
- A framework for applying unfamiliar trial designs in studies of rare diseases.J Clin Epidemiol. 2011; 64: 1085-1094
- Efficient ways exist to obtain the optimal sample size in clinical trials in rare diseases.J Clin Epidemiol. 2008; 61: 324-330
- Group sequential and adaptive designs-a review of basic concepts and points of discussion.Biom J. 2008; 50: 541-557
- When (not) to stop a clinical trial for benefit.JAMA. 2005; 294: 2228-2230
- Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial.Lancet Neurol. 2013; 12: 1059-1067
- Stopping rules and estimation problems in clinical trials.Stat Med. 1988; 7: 1231-1242
- Fundamentals of clinical trials.4th ed. Springer, New York2010
- Interim analyses and sequential designs in phase III studies.Br J Clin Pharmacol. 2001; 51: 394-399
- Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis.Eur J Neurol. 2016; 23: 45-52
- A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis.Amyotroph Lateral Scler. 2010; 11: 456-460
- Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.Ann Neurol. 2009; 66: 235-244
- Subcutaneous IGF-1 is not beneficial in 2-year ALS trial.Neurology. 2008; 71: 1770-1775
- An overview of practical approaches for handling missing data in clinical trials.J Biopharm Stat. 2009; 19: 1055-1073
- Heterogeneity in ALSFRS-R decline and survival: a population-based study in Italy.Neurol Sci. 2015; 36: 2243-2252
- 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
- Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2014; 13: 1083-1091
- A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.PLoS One. 2012; 7: e37885
- A randomized sequential trial of creatine in amyotrophic lateral sclerosis.Ann Neurol. 2003; 53: 437-445
- Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial.J Neurol Neurosurg Psychiatry. 2012; 83: 557-564
- 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
- How much do clinical trials cost?.Nat Rev Drug Discov. 2017; 16: 381-382
- Sequential design with boundaries approach in pediatric intervention research reduces sample size.J Clin Epidemiol. 2010; 63: 19-27
- Using the bootstrap for estimation in group sequential designs: an application to a clinical trial for nasopharyngeal cancer.Stat Med. 1999; 18: 2635-2644
- 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
- 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
- Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.Neurology. 2017; 89: 1915-1922
Article info
Publication history
Published online: February 24, 2018
Accepted:
February 16,
2018
Footnotes
Authors' contributions: R.P.A.v.E. and S.N. contributed to study concept, design, analysis, interpretation of data, and drafting manuscript. T.A.F., D.L., and M.J.C.E. contributed to critical revision of the manuscript for intellectual content. L.H.v.d.B. contributed to study supervision and critical revision of manuscript for intellectual content.
Funding: This work was funded by the Netherlands ALS Foundation (Project TryMe) and the European Union Seventh Framework Programme (grand number: Health-F5-2013-603160; Project Asterix).
Disclosures: T.A.F. and D.L. are employees of Biogen Idec and hold shares in Biogen Idec. L.H.v.d.B. serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen Idec, and Cytokinetics; received an educational grant from Baxter International Inc.; serves on the editorial board of Amyotrophic Lateral Sclerosis and the Journal of Neurology, Neurosurgery and Psychiatry; and receives research support from the Prinses Beatrix Spierfonds, Netherlands ALS Foundation, The European Community's Health Seventh Framework Programme (grant agreement n° 259867), and The Netherlands Organization for Health Research and Development (Vici Scheme, JPND [SOPHIA, STRENGTH]). All the other authors have no conflicts to interest to disclose.
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
