Multicenter, 2-dose single-group controlled trial of tacrolimus for the severe infertility patients

Abstract

Introduction: Infertility is estimated to affect 8% to 12% of reproductive-aged couples worldwide. While approximately 85% of infertile couples have an identified cause, the remaining 15% suffer physically and emotionally from unexplained intractable infertility. In recent years, maternal-to-fetal immunological abnormalities have attracted attention as mechanisms that differ from the conventional factors contributing to infertility and pregnancy loss. A T-helper 2 (Th2)-dominant immune state has been proposed as a maternal immune alteration to eliminate rejection and induce tolerance to a semi-allogeneic fetus. An imbalance in Th1 responses would not induce adequate maternal immune tolerance to the fetus or early embryos. Tacrolimus, widely used as an immunosuppressant agent in solid organ transplant recipients, is expected to suppress maternal rejection and promote tolerance to early embryos after assisted reproductive technology by modulating the immunological environment of the preimplantation endometrium. We planned an exploratory clinical trial to determine the efficacy, safety, and dosage of tacrolimus in women with intractable infertility. Methods and analysis: This is a multicenter, 2-dose, single-group controlled trial in infertile women who failed to achieve a chemical pregnancy despite multiple in vitro fertilization (IVF) and embryo transfer (ET) treatment cycles. The following 2 key selection criteria were set: no underlying factors of infertility despite appropriate evaluation and presence of Th1-dominant immune state, defined as a Th1/Th2 cell ratio ≥ 10.3 in the peripheral blood. A total of 26 eligible participants are randomly assigned (in a 2:1 ratio) to receive immunosuppressive therapy with oral tacrolimus at a daily dose of 2 mg or 4 mg. Tacrolimus is administered for 16 days starting from 2 days before ET. The primary endpoint is the presence of clinical pregnancy 3 weeks after IVF/ET treatment, and the secondary endpoint is the presence of biochemical pregnancy 2 weeks after IVF/ET treatment. Safety evaluation and biomarker discovery for tacrolimus treatment in infertile women will be conducted simultaneously. Trial registration number: Japan Registry of Clinical Trials (jRCT; jRCTs031220235).