To the Editor:
Mansour et al. (1) report a positive effect of intrauterine injections of human chorionic gonadotropin (hCG) on implantation and clinical pregnancy rates (CPR) after in vitro fertilization with intracytoplasmic sperm injection (1). We congratulate the authors for exploring this intervention in considerable detail. We wish to comment on the interim analyses conducted in this randomized controlled trial and the completeness of their registration at clinicaltrials.gov.
Two doses of the intervention (injection of 40 ul of tissue culture media with 100 IU or 200 IU of hCG) were initially tested against the control (no injection of tissue culture media). With 80% power and a type I error rate of 5% for each comparison, the stated 10% absolute difference (effect size) in CPR that the authors wished to test would require 1161 participants with complete information on the outcome of interest (387 per arm). When the effect size is a change from a high baseline success rate (here 50%), and the study has three arms, a very large sample size is to be expected. After the first 280 participants, an interim analysis was conducted, no difference was found between 100IU or 200 IU and the controls, and the study testing these two interventions was terminated. It was not specified if this interim analysis was pre-planned, whether it was done to check for harm, and if the trial was stopped for lack of any trend toward benefit. We can readily understand when the previous human study was done with injection of 500 IU in 1,000 ul that they may have chosen the lower doses and done an early interim analysis to mitigate against harm. We can also sympathize with terminating the study when there was no trend toward benefit. Read the rest of this entry »