An updated version of the Investigator’s Brochure was released in January 2015. The clinical trial protocol was updated to reflect that the reference safety information for the expectedness assessment was the Investigator’s Brochure and not the Summary of Product Characteristics (SPC) for Duphaston issued on 29 April 2011, which was mentioned in the protocol. For the comparative study drug, Crinone 8% intravaginal gel 90 mg, the reference safety information was the current SPC issued in the United Kingdom.

The following main changes were included: • Inclusion Criterion #8: the wording for the negative pregnancy test was changed to reflect that it was not the only method used to confirm that the subject was not pregnant: most of the IVF centers did not routinely perform a serum or urine pregnancy test before they started the downregulation process with either gonadotropin agonists or antagonists; for them, the vaginal exam, which was performed prior to any IVF-related procedures, was the basis for further treatment decisions/options. • The protocol was adjusted to the current more frequently used long (downregulation/ovarian stimulation) protocol by increasing the screening and enrollment phase from 14 to 40 days prior to the oocyte retrieval/randomization visit. • Due to the delay in the start of recruitment, the study dates and duration were updated. • Wording was added to explain the expectedness of early miscarriages before presence of fetal heart beats at 12 weeks of gestation (10 weeks of pregnancy), to explain AE/serious AE reporting of pregnancy, and to include definitions of biochemical pregnancy and miscarriage. • The fasting requirement for some laboratory tests was changed to “if possible fasting,” as the Investigators informed that many subjects were not fasting when they went to the study sites, particularly for the end of treatment at Week 10, when subjects were pregnant. • The timing of posttreatment visits was adapted to the visit days in the study flow chart.

For subject eligibility (Inclusion Criterion #5), a selection of hormones, including luteinizing hormone (LH), prolactin (PRL), testosterone, and thyrotropin (TSH), had to be within the normal limits for the clinical laboratory, or considered not clinically significant by the Investigator within 6 months prior to screening. During the study progress it became clear that most of the Asian IVF centers participating in this study were not routinely performing this hormone testing prior to any IVF cycles. Therefore, the assessment of some hormone values (follicle-stimulating hormone, estradiol, LH, PRL, testosterone, and TSH) was added as a requirement at screening for those subjects who did not have available values prior to screening. Wording of Inclusion Criteria #4 and #5, the flow chart of study assessments, and some other sections in the protocol were updated accordingly.