Reply of the Authors

Abstract

We read with interest the Letter by Su and Sammel (1Su H.I. Sammel M.D. Interim analysis in clinical trials.Fertil Steril. 2012; Google Scholar) and wish to respond to their comments. We also wish to thank them for congratulating the investigators for exploring the intervention of intrauterine injection of human chorionic gonadotrophin (hCG) before embryo transfer (ET) (2Mansour R. Tawab N. Kamal O. El-Faissal Y. Serour A. Aboulghar M. Serour G. Intrauterine injection of human chorionic gonadotropin before embryo transfer significantly improves the implantation and pregnancy rates in in vitro fertilization/intracytoplasmic sperm injection: a prospective randomized study.Fertil Steril. 2011; 96: 1370-1374Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar).An interim analysis was performed after the first 280 participants (100 IU or 200 IU hCG or control), no difference was found and the study using these doses was terminated. This interim analysis was pre-planned, to check for harm, and detect any trend toward benefit. We appreciate the authors’ (1Su H.I. Sammel M.D. Interim analysis in clinical trials.Fertil Steril. 2012; Google Scholar) understanding and sympathizing with terminating the study when there was no trend toward benefit was found.We proceeded to increase the dose to 500 IU which was not mentioned in the original plan, therefore a modification was done on the protocol registered at clinicaltrials.gov but apparently it did not go into the system. For this new dose which unfortunately was not registered, an interim analysis was preplanned to check for harm and see trend toward benefit. We terminated the study after the interim analysis when we found the implantation rate was significant at 0.002.We appreciate that the authors (1Su H.I. Sammel M.D. Interim analysis in clinical trials.Fertil Steril. 2012; Google Scholar) considered this study examining a scientifically plausible and exciting hypothesis which can change clinical care. We are looking forward to see our results reproduced by other IVF colleagues. We agree that clinical trials require large sample size and it is always difficult for clinicians, as investigators, to perform a study and at the same time provide all patients with a helpful intervention.We would like to clarify some details regarding how precisely the hCG was prepared and delivered. The vial of hCG containing 5000 IU was dissolved in 400 μL tissue culture medium (G.2 plus. ref. 10132, vitrolife). It is important to remove the rubber stopper of the vial as it is embryo toxic. During the dummy ET which is done before the actual ET, 40 μL of this solution containing 500 IU hCG is injected in the mid uterine cavity. Before injection, the screw of the vaginal speculum was loosened so as the two valves of the speculum would press on the portio vaginalis of the cervix and prevent leakage of the injected hCG (3Mansour R. Minimizing embryo expulsion after embryo transfer: a randomized controlled study.Hum Reprod. 2005; 20: 170-174Crossref PubMed Scopus (33) Google Scholar). Then the embryologist will load the embryos in another catheter and bring it for the actual ET. We read with interest the Letter by Su and Sammel (1Su H.I. Sammel M.D. Interim analysis in clinical trials.Fertil Steril. 2012; Google Scholar) and wish to respond to their comments. We also wish to thank them for congratulating the investigators for exploring the intervention of intrauterine injection of human chorionic gonadotrophin (hCG) before embryo transfer (ET) (2Mansour R. Tawab N. Kamal O. El-Faissal Y. Serour A. Aboulghar M. Serour G. Intrauterine injection of human chorionic gonadotropin before embryo transfer significantly improves the implantation and pregnancy rates in in vitro fertilization/intracytoplasmic sperm injection: a prospective randomized study.Fertil Steril. 2011; 96: 1370-1374Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). An interim analysis was performed after the first 280 participants (100 IU or 200 IU hCG or control), no difference was found and the study using these doses was terminated. This interim analysis was pre-planned, to check for harm, and detect any trend toward benefit. We appreciate the authors’ (1Su H.I. Sammel M.D. Interim analysis in clinical trials.Fertil Steril. 2012; Google Scholar) understanding and sympathizing with terminating the study when there was no trend toward benefit was found. We proceeded to increase the dose to 500 IU which was not mentioned in the original plan, therefore a modification was done on the protocol registered at clinicaltrials.gov but apparently it did not go into the system. For this new dose which unfortunately was not registered, an interim analysis was preplanned to check for harm and see trend toward benefit. We terminated the study after the interim analysis when we found the implantation rate was significant at 0.002. We appreciate that the authors (1Su H.I. Sammel M.D. Interim analysis in clinical trials.Fertil Steril. 2012; Google Scholar) considered this study examining a scientifically plausible and exciting hypothesis which can change clinical care. We are looking forward to see our results reproduced by other IVF colleagues. We agree that clinical trials require large sample size and it is always difficult for clinicians, as investigators, to perform a study and at the same time provide all patients with a helpful intervention. We would like to clarify some details regarding how precisely the hCG was prepared and delivered. The vial of hCG containing 5000 IU was dissolved in 400 μL tissue culture medium (G.2 plus. ref. 10132, vitrolife). It is important to remove the rubber stopper of the vial as it is embryo toxic. During the dummy ET which is done before the actual ET, 40 μL of this solution containing 500 IU hCG is injected in the mid uterine cavity. Before injection, the screw of the vaginal speculum was loosened so as the two valves of the speculum would press on the portio vaginalis of the cervix and prevent leakage of the injected hCG (3Mansour R. Minimizing embryo expulsion after embryo transfer: a randomized controlled study.Hum Reprod. 2005; 20: 170-174Crossref PubMed Scopus (33) Google Scholar). Then the embryologist will load the embryos in another catheter and bring it for the actual ET. Interim analysis in clinical trialsFertility and SterilityVol. 97Issue 3PreviewMansour and colleagues (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 . Full-Text PDF Remarks from the EditorFertility and SterilityVol. 97Issue 3PreviewIn the July 2011 issue of Fertility and Sterility and in an online supplement we discussed various aspects of study design and the requirements for registry of clinical trials (1, 2). As pointed out by Su and Sammel, when calculating the sample size required for detecting a 20% change from a high baseline, a very large number of subjects is usually required, particularly for a three-arm study. It is always better to limit such a study to only the intervention and control arms to increase its power. Full-Text PDF