O-066 Transdermal testosterone prior to ovarian stimulation for in vitro fertilization in women with poor ovarian response. A multicenter multinational double-blind placebo-controlled randomized trial (The T-TRANSPORT)

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Abstract Study question Does administration of 2 months of transdermal testosterone prior to ovarian stimulation for IVF/ICSI increase clinical pregnancy rates in Bologna criteria poor ovarian responders? Summary answer Pre-treatment with 5.5mg testosterone for 2 months prior to ovarian stimulation for IVF/ICSI does not increase clinical pregnancy rates as compared with placebo. What is known already The role of androgens in the treatment of infertile women has been extensively investigated over the last 20 years. Early animal studies and small human studies supported a potentially beneficial role of androgen pretreatment for the management of poor ovarian responders. Still, available evidence regarding androgen administration remains inconclusive, and clinical guidelines do not support their use in infertile women, mainly due to the lack of robust evidence regarding efficacy, the small sample sizes, the lack of data regarding safety, and the lack of uniform dose and duration of testosterone pretreatment for poor ovarian responders. Study design, size, duration T-TRANSPORT is the first multicenter multinational superiority phase III, double-blind placebo-controlled randomized trial aiming to detect differences in clinical pregnancy rates between testosterone transdermal gel or placebo for the treatment of poor responders. A sample size of 400 women was calculated, with an interim analysis prespecified to be performed after 70% of recruitment, to determine continuation, sample size re-calculation, or early termination for futility, based on the conditional power reached (≥80%, 40-80% and <20%, respectively). Participants/materials, setting, methods T-TRANSPORT included women 18-43 years old from 10 centers and 4 European countries (Spain, Belgium, Denmark and Switzerland) randomized between 2015-2022. Women with poor ovarian response according to the Bologna criteria were randomly assigned 1:1 (stratified by center and age group (<36, 36-39 and ≥40 years old)) to receive either 5.5mg of transdermal testosterone or placebo for ∼60 days prior to initiation of ovarian stimulation for IVF/ICSI. Main results and the role of chance Overall, 316 poor responders were included and 290 patients were randomized. Based on the prespecified interim analysis, recruitment stopped when 70% of the patients have completed their treatment and blinded data were analyzed. Patients were categorized as group A and Group B until the decision of the DSMB board to break the randomization code is taken. Ovarian stimulation outcomes did not differ between groups, with a (mean ± SD) number of oocytes retrieved 3.42±2.25 vs. 3.69±2.72, number of MII oocytes 2.75±2.06 vs. 2.83±1.91 and number of embryos 1.46±1.22 vs. 1.90±1.92, for the comparison of Group A vs. Group B, respectively. Clinical pregnancy rates were comparable between groups, Group A: 17.42% vs. Group B 16.30%, RR (95%CI):1.07(0.64-1.79). Analysis of the results per-age strata also failed to demonstrate significant differences between groups in women <36 (Group A:24% vs. Group B: 17.9%), 36-39 (A: 21.4% vs. B:20%) and ≥40 years old (A:10% vs. B:12.3%) Finally, no severe adverse events were observed in any of the groups that led to treatment discontinuation. Comparison of androgenic adverse events showed differences for hirsutism A:7.10% vs. B:14.07% and acne A:16.13% vs. B:21.48%, whereas very few cases of alopecia A:1.29% vs. B:2.22% and voice deepening (A:1.29% vs. B:0%) were reported. Limitations, reasons for caution All patients, per protocol, underwent D3 embryo transfer. In addition, the study duration exceeded 7 years, owing to a temporary halt during the COVID-19 pandemic. Finally, the results presented here are blinded data which will be unblinded by the time of presentation based on the interim analysis performed. Wider implications of the findings Testosterone pre-treatment prior to IVF/ICSI does not increase clinical pregnancy rates in poor ovarian responders. Planned posthoc analyses within the T-TRANSPORT trial aim to investigate whether testosterone may affect ovarian reserve markers, follicular fluid biomarkers, cumulus cells gene expression, and libido in women with poor ovarian response. Study funding Yes. Funding source Funding by commercial/corporate company(ies). The study received Unrestricted grants by Ferring Pharmaceuticals, BESINS international and Roche Diagnostics. Testosterone and placebo gel were provided by BESINS INTERNATIONAL. Trial registration number NCT02418572