Sample size requirements in trials using repeated measurements and the impact of trial design

Abstract

Objective:

Sample size calculations for clinical trials generally use expected changes between groups, and variances obtained from the literature. However, this approach neglects the impact of differences in trial design. We studied the effects of variations in trial design on the required sample size.

Methods:

Data were used from the METEOR (Measuring Effects on Intima–Media Thickness: an Evaluation of Rosuvastatin) trial in which carotid intima–media thickness (CIMT) measurements were performed twice at baseline, at 6, 12 and 18 months, and twice at the end of 2-year study treatment. A sample size formula for continuous outcome measures that incorporates between- and within-individual variance components was used to evaluate the impact of differences in the length of follow-up, and the number of CIMT examinations.

Results:

Trial designs with a shorter duration of follow-up have increased within-individual variance and require larger sample sizes to detect the same treatment effect. Reduction in the number of examinations within a trial with a given duration, i.e. by using single rather than duplicate baseline and end-of-study scans or by not performing intermediate scans, also increased the required sample size to maintain the same power.

Conclusion:

A longer trial duration and/or more frequent examinations within a trial which has repeated measures of an outcome variable substantially increase study power and reduce the required sample size. In situations where the costs of recruiting, retaining and examining individual participants are known, the sample size, study length and number of examinations can be balanced to optimize the trial design relative to costs or other study objectives.

Keywords::

• Carotid intima
• media thickness
• Repeated measures
• Sample size
• Trial design

Transparency

Declaration of funding

The METEOR study was funded by AstraZeneca.

Declaration of financial/other relationships

S.A.E.P. has disclosed that she received an unrestricted grant from AstraZeneca. H.M.d.R. has disclosed that she has no significant relationships with or financial interests in any commercial companies related to this study or article. M.K.P. is a former employee of AstraZeneca and is now a consultant for Boehringer-Ingelheim and AstraZeneca. D.E.G. has received grant support from, and delivered lectures for, Pfizer, AstraZeneca, Organon, Servier, and Merck. J.R.C. has received grant or salary support from Merck, Merck-Schering Plough, Pfizer, AstraZeneca, and Kos Pharmaceuticals. He has delivered lectures for Merck, Merck-Schering Plough, Pfizer, AstraZeneca, Abbott, and Kos Pharmaceuticals. D.H.O’L. serves on data safety and monitoring boards for Pfizer and AstraZeneca. He serves as a consultant to Pfizer, Sankyo Pharma, Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, Schering-Plough, Esperion Therapeutics and Merck. He is an equity partner in Imagepace LLC. G.W.E. has received grant support and honoraria from AstraZeneca, Organon, and Pfizer, and has served as a consultant for AstraZeneca and Pfizer. J.S.R. is an employee of AstraZeneca. M.L.B. has received study grants for studies on CIMT and/or honoraria for professional input on CIMT issues from AstraZeneca, Boeringer, Organon, Pfizer, Servier, and Unilever.

The sponsor participated in discussions regarding the design and conduct of the study, and provided logistical support during the trial. The manuscript was prepared by the author group. The sponsor was permitted to review the manuscript and suggest changes, but the final approval of content was exclusively retained by the authors.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

The authors would like thank all the METEOR investigators and the individuals involved in this study. Belgium: Marcelo Goldstein, Anderlecht; Jan Staessen, Leuven; Guy Marchal, Leuven. Czech Republic: Ales Linhart, Prague. Finland: Jukka T Salonen, Kuopio. France: Alain Simon, Paris Cedex; Patrick Audouy, Paris; Charles Baranes, Paris; Jean-Philippe Brugnaux, Paris; Eric Chabaud, Ivry sur Seine; Daniel Delbecq, Paris; Jean Claude Mouchet, Meudon; Andre Sebbah, Paris; Gilles Bertrand, Metz; Marcel Frohn, Moutiers; Jean-Luc Jacques, Mars la Tour; Dominique Richter, Jarney; Jean-Louis Doubet, Thionville; Philippe Martin, Yutz; Alain Prochasson, Metz; Eric De Ste Lorette, Paris; Jean-Claude Ingrand, Les Lilas; Denis Smila, Yerres; Genevieve Arcizet, Bangolet; Pascal Didi, Paris; Albert Cohen, Les Lilas; Mohamed Oulmekki, Drancy; Karima Allouache, Bangolet; Serge Kownator, Thionville. Germany: Raimund Erbel, Essen; Clemens Von Shacky, Munich. Norway: Leiv Ose, Oslo; Knut Risberg, Skedsmokorset; Andreas Tandberg, Bekkestua; Olyvind Aabo, Oslo; Jon Christensen, Oslo; Anne C Poole, Oslo; David Russell, Oslo. The Netherlands: Annette Bak, Utrecht; Jan Jonker, Rotterdam. USA: Thomas W Littlejohn, Winston-Salem, NC; David M Capuzzi, Philadelphia, PA; John Morgan, Philadelphia, PA; Robert Davidson, Los Angeles, CA; Michael Davidson, Chicago, IL; Alan Hirsch, Minneapolis, MN; Stephen Glasser, Minneapolis, MN; Leslie Miller, Minneapolis, MN; Daniel Duprez, Minneapolis, MN; Donald Hunninghake, Minneapolis, MN; Robert Knopp, Seattle, WA; Christie Ballantyne, Houston, TX; William Insull, Houston, TX; Daniel Edmundowicz, Pittsburgh, PA; Alan Gradman, Pittsburgh, PA; Neville Bittar, Madison, WI; Laurence Yellen, San Diego, CA; David Cameron, Kirkland, WA; Evan Stein, Cincinnati, OH; Eli Roth, Cincinnati, OH; Tasneem Z Naqvi, Los Angeles, CA; Cecil Farrington, Salisbury, NC; Bernard Mizok, Chicago, IL; Zane P Osborne, Chicago, IL; Monica Perlman, La Jolla, CA; Margaret Drehobl, San Diego, CA; Dean Kereiakes, Cincinnati, OH; Norman M Lunde, Brooklyn Center, MN; Stephen Pomeranz, Cincinnati, OH; Steven Feinstein, Chicago, IL; Charles McCollum, Houston, TX; James Stein, Madison, WI; Laurence Needleman, Philadelphia, PA; Kim Sutton-Tyrell, Pittsburgh, PA; Shirley Otis, La Jolla, CA; Kirk Beach, Seattle, WA. CIMT core laboratory USA: Wake Forest University School of Medicine, Winston-Salem, USA. Gregory Evans, MA; Ward Riley, PhD (co-chairs). CIMT core laboratory Europe: Vascular Imaging Center, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. Anne-Marie Bos; Michiel Bots, MD, PhD (co-chair); Corine van Everdingen; Marrij Geurtsen; Frank Leus; Corry Loffveld; Rudy Meijer MSc; Dicky Mooiweer-Bogaerdt; Karin Nijssen (co-chair) BSc, Hannie Noordzij; Anneke Rutgers; Els Stooker; Brigitte van der Vlist; Lucienne van der Vlist; Arthur Waterschoot; Elise Wineke.