T Friede1, H Schmidli. 1. Abteilung Medizinische Statistik, Universitätsmedizin Göttingen, Humboldtallee 32, 37073 Göttingen, Germany. tim.friede@med.uni-goettingen.de
Abstract
BACKGROUND: In the planning of clinical trials with count outcomes such as the number of exacerbations in chronic obstructive pulmonary disease (COPD) often considerable uncertainty exists with regard to the overall event rate and the level of overdispersion which are both crucial for sample size calculations. OBJECTIVES: To develop a sample size reestimation strategy that maintains the blinding of the trial, controls the type I error rate and is robust against misspecification of the nuisance parameters in the planning phase in that the actual power is close to the target. METHODS: The operation characteristics of the developed sample size reestimation procedure are investigated in a Monte Carlo simulation study. RESULTS: Estimators of the overall event rate and the overdispersion parameter that do not require unblinding can be used to effectively adjust the sample size without inflating the type I error rate while providing power values close to the target. CONCLUSIONS: If only little information is available regarding the size of the overall event rate and the overdispersion parameter in the design phase of a trial, we recommend the use of a design with sample size reestimation as the one suggested here. Trials in COPD are expected to benefit from the proposed sample size reestimation strategy.
BACKGROUND: In the planning of clinical trials with count outcomes such as the number of exacerbations in chronic obstructive pulmonary disease (COPD) often considerable uncertainty exists with regard to the overall event rate and the level of overdispersion which are both crucial for sample size calculations. OBJECTIVES: To develop a sample size reestimation strategy that maintains the blinding of the trial, controls the type I error rate and is robust against misspecification of the nuisance parameters in the planning phase in that the actual power is close to the target. METHODS: The operation characteristics of the developed sample size reestimation procedure are investigated in a Monte Carlo simulation study. RESULTS: Estimators of the overall event rate and the overdispersion parameter that do not require unblinding can be used to effectively adjust the sample size without inflating the type I error rate while providing power values close to the target. CONCLUSIONS: If only little information is available regarding the size of the overall event rate and the overdispersion parameter in the design phase of a trial, we recommend the use of a design with sample size reestimation as the one suggested here. Trials in COPD are expected to benefit from the proposed sample size reestimation strategy.
Authors: Gabriella Marx; Tina Mallon; Nadine Janis Pohontsch; Franziska Schade; Judith Dams; Manuel Zimansky; Thomas Asendorf; Silke Böttcher; Christiane A Mueller; Michael Freitag; Eva Hummers; Hendrik van den Bussche; Ingmar Schäfer; Hans-Helmut König; Stephanie Stiel; Nils Schneider; Friedemann Nauck; Tim Friede; Martin Scherer Journal: BMJ Open Date: 2022-07-25 Impact factor: 3.006