Skip to main content

Advertisement

Log in

A Two-Stage Adaptive Design in Phase 2 Clinical Trials for Acute Treatment of Migraine

  • Statistics
  • Published:
Drug information journal : DIJ / Drug Information Association Aims and scope Submit manuscript

Abstract

In the development of acute migraine treatments, traditional phase 2 dose-finding trial designs are particularly challenging when a wide dose range needs to be investigated. In this article, an adaptive two-stage dose-finding design is introduced. The proposed design combines traditional phase 2a and 2b to serve the dual purpose of proof of concept and dose finding through the use of an unblinded interim analysis that provides an opportunity for adaptation. The design has a fixed total sample size but includes provisions for discontinuation of less effective doses at the interim analysis to allow for the allocation of patients into a more promising range of doses. The interim adaptation is designed to increase the amount of information collected on more effective doses and increase study power as compared to a traditional nonadaptive dose-finding design. On the other hand, despite the interim look and adaptation of the design, conventional statistical analyses of the final data can still be used for the final analysis and provide proper inferences with adequately controlled type I error and an ignorable amount of bias.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Visser WH, Terwindt GM, Reines SA, Jiang K, Lines C, Ferrari C. Rizatriptan (MK-0462) versus sumatriptan in the acute treatment of migraine: a placebo-controlled, dose-ranging study. Arch Neurol. 1996;53:1132–1137.

    Article  CAS  Google Scholar 

  2. Gijsman H. Kramer MS, Sargent J. et al. Double-blind, placebo-controlled, dose-finding study of rizatriptan (MK-0462) in the acute treatment of migraine. Cephalalgia. 1997;17:647–651.

    Article  CAS  Google Scholar 

  3. Dragalin V. Adaptive designs: terminology and classification. Drug Inf J. 2006;40:425–435.

    Article  Google Scholar 

  4. EMEA Committee for Medicinal Products for Human Use. Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive design. Doc. Ref. CHMP/EWP/2459/02.2007.

  5. Food and Drug Administration. Guidance for industry: adaptive design clinical trials for drugs and biologics (draft guidance). 2010.

  6. Bretz F. Hsu J. Pinheiro J. et al. Dose finding—a challenge in statistics. Biometrical f. 2008;50:480–504.

    Article  Google Scholar 

  7. Bornkamp B. Bretz F. Dmitrienko A. et al. Innovative approaches for designing and analyzing adaptive dose-ranging trials. J Biopharm Stat. 2007;17:965–995.

    Article  Google Scholar 

  8. Berry SM, Spinelli W, Littman GS, et al. A Bayesian dose-finding trial with adaptive dose expansion to flexibly assess efficacy and safety of an investigational drug. Clin Trials. 2010;7:121–135.

    Article  Google Scholar 

  9. Thall PF, Nguyen HQ, Estey EH. Patient-specific dose finding based on bivariate outcomes and covariates. Biometrics. 2008;64:1126–1136.

    Article  Google Scholar 

  10. Dragalin V, Fedorov VV, Wu YH. Two-stage design for dose-finding that accounts for both efficacy and safety. Stat Med. 2008;27:5156–5176.

    Article  Google Scholar 

  11. Ivanova A, Bolognese JA. Perevozskaya I. Adaptive dose finding based on t-statistic for dose-response trials. Stat Med. 2008;27:1581–1592.

    Article  Google Scholar 

  12. Hall DB, Meir U, Diener H. A group sequential adaptive treatment assignment design for proof of concept and dose selection in headache trials. Contemp Clin Trials. 2005;26:349–364.

    Article  Google Scholar 

  13. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1–10.

    Article  CAS  Google Scholar 

  14. Proschan MA, Hunsberger SA. Designed extension of studies based on conditional power. Biometrics. 1995;51:1315–1324.

    Article  CAS  Google Scholar 

  15. Posch M. Bauer P. Adaptive two stage designs and the conditional error function. Biometrical J. 1999;41:689–696.

    Article  Google Scholar 

  16. Liu Q. Chi GYH. On sample size and inference for two-stage adaptive designs. Biometrics. 2001; 57:172–177.

    Article  CAS  Google Scholar 

  17. Bischoff W, Miller F. Adaptive two-stage test procedures to find the best treatment in clinical trials. Biometrika. 2005;92:197–212.

    Article  Google Scholar 

  18. Sampson AR, Sill MW. Drop-the-losers design: normal case. Biometrical J. 2005;47:257–268.

    Article  Google Scholar 

  19. Bauer P. Koenig F. Brannath W. Posch M. Selection and bias—two hostile brothers. Stat Med. 2010;29:1–13.

    PubMed  Google Scholar 

  20. Brannath W. Konig F. Bauer P. Estimation in flexible two stage designs. Stat Med. 2006;25:3366–3381.

    Article  Google Scholar 

  21. Stallard N, Todd. S. Point estimates and confidence regions for sequential trials involving selection. J Stat Plan Infer. 2005;135:402–419.

    Article  Google Scholar 

  22. Agresti A, Coull BA. Approximate is better than “exact” for interval estimation of binomial proportions. Am Stat. 1998;52:119–126.

    Google Scholar 

  23. Durham PL. CGRP-receptor antagonists—a fresh approach to migraine therapy? N Engl J Med. 2004;350:1073–1075.

    Article  CAS  Google Scholar 

  24. Brain SD. Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev. 2004;84:903–934.

    Article  CAS  Google Scholar 

  25. Ho TW, Mannix LK, Fan X. et al. A randomized controlled trial of an oral CGRP antagonist. MK-0974. in the treatment of migraine. Neurology, 2007;70:1304–1312.

    Article  Google Scholar 

  26. Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomized controlled clinical trial versus placebo and zolmitriptan. Lancet. 2008;372:2115–2123.

    Article  CAS  Google Scholar 

  27. Connor KM, Shapiro RE, Diener HC, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009; 73:970–977.

    Article  CAS  Google Scholar 

  28. Bauer M. Bauer P. Budde M. A simulation program for adaptive two stage designs. Comp Stat Data Anal. 1998;26:351–371.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xiaoyin Frank Fan PhD.

Additional information

Presented at DIA/FDA Adaptive Design for Clinical Trials: FDA Draft Guidance Symposium. March 26, 2010. Silver Spring, Mayland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fan, X.F., Assaid, C.A., Ge, Y.J. et al. A Two-Stage Adaptive Design in Phase 2 Clinical Trials for Acute Treatment of Migraine. Ther Innov Regul Sci 45, 315–330 (2011). https://doi.org/10.1177/009286151104500311

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/009286151104500311

Key Words

Navigation