Subcutaneous Progesterone in Frozen- Thawed Single Euploid Blastocyst Transfer.

A Multicenter, Randomized, Controlled, Double-blind, Double-dummy Study to Evaluate the Safety and Efficacy of Subcutaneous Progesterone Compared to Vaginal Progesterone for Luteal Phase Supplementation in Modified Natural Frozen Euploid Blastocyst Transfer.

This is a multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority clinical study in women aged 35 to 42 years. This study will investigate the safety and efficacy of Progesterone-IBSA to support euploid embryo blastocyst implantation and early pregnancy after frozen embryo transfer (FET) in a modified natural cycle as a treatment for infertile women. Subjects will be randomized to receive either active Progesterone-IBSA or Crinone 8% for luteal and early pregnancy support and these two groups will be compared.

Inclusion Criteria:

• subject has given written informed consent;
• Premenopausal women 35 to 42 years of age at the time of consent (at least 35 [including day of birthday] and no more than 42 [up to the day before their 43rd birthday]);
• Valid indication for IVF treatment (i.e. history of infertility according to ASRM definition, single women or same-sex couples);
• Consistent, regular spontaneous ovulatory menstrual cycle with normal length (24-38 days included);
• Body mass index (BMI) < 38 kg/m2;
• Subject with at least one euploid frozen blastocyst from a previous IVF treatment cycle;
• Less than 3 previous consecutive euploid blastocyst transfers without a life birth;
• Baseline Follicle Stimulating Hormone (FSH) < 15 mIU/mL, and Anti Muellerian Hormone (AMH) >0.7 ng/mL (within 6 months from screening for subjects requiring a stimulation cycle to obtain a euploid embryo); and Estradiol (E2) < 90 pg/mL and Progesterone (P4)< 1.5 ng/mL at Visit 1 (for all subjects);
• Semen used during IVF(for subjects requiring a stimulation cycle to obtain a euploid embryo) was produced by ejaculation (not surgically derived sperm) from either the partner or from a sperm donor. Donor must be 18-40 years of age at the time of collection and compliant with 21 Code of Regulations (CFR) section 1271 Subpart C;
• Hysterosalpingography, hysteroscopy, 3D ultrasound or sonohysterogram documenting a normal uterine cavity within the last year;
• Normal cervical cytology/High Risk human papillomavirus (HPV) testing per American College of Obstetricians and Gynecologists guidelines.

Exclusion Criteria:

• Oligo or anovulation (spontaneous menses > 39 days apart);
• Breastfeeding or Pregnancy;
• Contraindication to pregnancy (i.e. an active, uncontrolled clinically significant medical condition or abnormality of the sexual organs determined by the provider);
• Known family history of major congenital anomalies;
• Moderate to severe current endometriosis (stage 3 or 4);
• Presence of a unilateral or bilateral hydrosalpinx that communicates with the uterus, that has not been ligated prior to treatment;
• Recurrent pregnancy loss (RPL) as defined by the American Society of Reproductive Medicine (ASRM) as two or more consecutive failed clinical pregnancies;
• Presence of a submucosal or intramural fibroid > 4 cm which distorts the uterine cavity or are > 5 cm in diameter;
• Untreated uterine pathology that could impair embryo implantation (i.e. scarring/Asherman's syndrome or intra uterine polyps > 1 cm in size);
• Type 1 or 2 diabetes mellitus based on American Diabetes Association (ADA) criteria3;
• Uncontrolled adrenal or thyroid dysfunction;
• History of conditions (i.e. toxic shock syndrome) that would contraindicate use of a vaginal progesterone product;
• Subjects with hepatic impairment (liver function tests > 2x upper limit of normal);
• Subjects with renal impairment (estimated creatinine clearance <60 mL/min/1.73 m2);
• History of an active or treated autoimmune disease (i.e. systemic lupus erythematosus);
• History of arterial disease (i.e. Prior or active thrombophlebitis, thromboembolic disorder or known thrombophilia);
• Neoplasias (current) or history of neoplasia that may be responsive to progesterone;
• High grade cervical dysplasia;
• Undiagnosed vaginal bleeding (i.e. at the time of screening);
• Use of donor eggs or plans to use a gestational carrier;
• Use of endometrial receptivity array (ERA) test to postpone or anticipate the embryo transfer (ET) day;
• Use of epididymal, testicular , electro-ejaculated or chemotherapy exposed sperm;
• Known allergy to progesterone preparations or their excipients;
• Current dependence on alcohol, tobacco (must not be smoking/using tobacco x 2 months before the study) or drugs or psychotropic medications labeled as Pregnancy Categories D and X;
• Use of concomitant medications within 1 month previous the start of the FET cycle preparation up to gestational week 12 that might interfere with the study evaluation (use of insulin sensitizing agents, vaginal medications/preparations, any drugs for luteal support other than those specified in the protocol, aspirin, any hormonal treatment, with the exception of levothyroxine);
• Participation in a concurrent clinical trial or in another investigational drug trial within the past 2 months-