{'fraction_non_alphanumeric': 0.04060997845184817, 'fraction_numerical': 0.023702967014752198, 'mean_word_length': 5.051654964894684, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 1, 'zh_pornsignals.json': 0}}
Phase III trial of 8% vaginal progesterone gel for luteal phase support in Japanese women undergoing in vitro fertilization and fresh embryo transfer cycles

Abstract Aim This study evaluated the efficacy and safety of vaginal progesterone gel that was administered daily for luteal phase support as part of in vitro fertilization/embryo transfer (IVF/ET) cycles in Japanese women. Methods This was a phase III, multicenter, open‐label, single‐arm trial in Japanese women undergoing IVF/ET, using the Japanese Society of Obstetrics and Gynecology 2009 registry as a historical control. The primary objective was to demonstrate the non‐inferiority, with regard to the clinical pregnancy rate per ET, of vaginal progesterone gel that was administered once daily, compared with the historical standard value in IVF/ET cycles in Japan. The biochemical pregnancy (positive serum β‐hCG pregnancy test but no clinical pregnancy) rate per ET also was investigated, as were the safety and tolerability of the vaginal progesterone gel. Results Of the 178 women who were enrolled, 123 underwent IVF/ET. The clinical pregnancy rate per ET was non‐inferior in the prospective arm, compared with the historical population. The biochemical pregnancy rate per ET was 7.3%. The safety profile of the vaginal progesterone gel was as expected, with no new safety issue identified. Conclusion The vaginal progesterone gel was efficacious, with a safety profile as expected, in this study in Japanese women undergoing IVF/ET cycles.

Progesterone for luteal phase support is typically given from the day of oocyte retrieval up to weeks 7-10 of pregnancy and may be administered orally, vaginally (as a tablet, capsule, or gel), or intramuscularly. Each route of administration has different characteristics in terms of pharmacokinetics and potency, as well as adverse event (AE) profiles. [2][3][4] As such, it is important that an effective and well-tolerated form is used to ensure both optimal outcomes and patient well-being.
Oral progesterone requires the administration of high doses to reach appropriate serum concentrations, which can result in a number of side-effects, including sedation, drowsiness, and nausea. 5,6 Vaginal administration of progesterone delivers high local concentrations to the vagina and uterus with low peripheral serum concentrations, reducing the risk for systemic side-effects that can be observed with oral or intramuscular administration. 3 There is, however, the inconvenience of vaginal discharge, and possibly irritation, following this route of administration. Intramuscular progesterone is typically prepared in oil, is rapidly absorbed following injection, and maintains a steady state for ≤72 hours. [5][6][7] There is the possibility of injection site reactions, including pain, inflammation, and abscesses, with this route of administration, as well as rare complications, including a severe allergic reaction. [5][6][7] Outside of Japan, vaginally administered progesterone is widely used as luteal phase support for IVF/embryo transfer (ET) cycles, whereas in Japan, until recently, there was no approved vaginal progesterone preparation for luteal phase support. Injected progesterone or in-house formulations of progesterone were therefore used. Since 2014, a vaginal tablet containing 100 mg of progesterone has been available in Japan for luteal phase support during assisted reproductive technology (ART) cycles. 8 Previous studies, outside of Japan, that compared vaginal progesterone gel and vaginal progesterone tablets indicated that there were no substantial differences in outcomes with either formulation.
Patient ease-of-use, satisfaction, and convenience were greater with the gel, compared with the tablets, resulting in a better overall impression of the gel formulation, compared with the tablets. [9][10][11][12][13] Here, the results of a phase III trial that was conducted to evaluate the efficacy and safety of 8% vaginal progesterone gel that was administered daily for luteal phase support in IVF/ET cycles in Japanese women are presented. The data from this trial were compared with the historical standard values in Japan from the Japanese Society of Obstetrics and Gynecology (JSOG) 2009 registry. 14

| MATERIALS AND METHODS
This was a phase III, multicenter, open-label, single-arm trial in Japanese women undergoing IVF/ET (ClinicalTrials.gov identifier: NCT01863680), using the JSOG 2009 registry 14 as a historical control, that was designed in line with regulatory requirements. Women were enrolled at 10 centers in Japan and the trial was conducted between July 2013 and October 2014. The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki, the International Conference on Harmonisation-Good Clinical Practice guidelines, and all applicable regulatory requirements, with all the participants providing written informed consent prior to entry into the trial.

| Study participants
Healthy, premenopausal Japanese women (aged between 20 and 45 years, inclusive) with a history of infertility, in whom IVF/ET was indicated and who were to undergo controlled ovarian stimulation with a gonadotropin-releasing hormone (GnRH) analog (either an antagonist or an agonist) in combination with a follicle-stimulating hormone (FSH)-containing preparation, were enrolled in the trial if they met the following criteria: body mass index (BMI) between 17.0 and 25.0 kg/m 2 (inclusive); a negative pregnancy test (urinary β-human chorionic gonadotropin [β-hCG]) prior to starting controlled ovarian stimulation; a normal cervical smear test result within 12 months prior to the date of informed consent; and no clinically significant abnormal findings in the screening hematology, biochemistry, and urinalysis parameters.
The main exclusion criteria included: a history of recurrent pregnancy loss, defined as three or more previous spontaneous abortions; a history of three or more consecutive canceled or failed (no clinical pregnancy) IVF/ET cycles; ovarian enlargement or a cyst of unknown etiology; a uterine myoma requiring treatment; a history of severe OHSS, classified according to the Japan Reproductive/Endocrine Working Group guidance; 15 or a contraindication for pregnancy, controlled ovarian stimulation, or vaginal progesterone gel.

| Study objectives and endpoints
The primary objective of the trial was to demonstrate the non- The other objectives of the trial were to assess the biochemical pregnancy rate per ET, as well as the safety and tolerability of the vaginal progesterone gel being administered once daily.
Biochemical pregnancy was defined as any miscarriage without evidence of a fetal sac on transvaginal ultrasound during the visit 5 weeks after the ET, but with a positive serum β-hCG pregnancy test (serum β-hCG>10 mIU/mL) at the visit 14±3 days after the ET.

| Statistical analysis
Based on the reference clinical pregnancy rate per ET of 24.3% (JSOG 2009 registry) 14 and a 10% non-inferiority margin, overall, 117 participants were planned to be enrolled to demonstrate that the lower limit of the 95% two-sided CI (based on the Clopper-Pearson approach) of the observed rate was ≥14.3%, with a power of at least 80%. Allowing for a drop-out rate of 10%, an estimated total of 130 participants were planned to be enrolled (ie to start controlled ovarian stimulation following successful screening).
The primary efficacy endpoint of clinical pregnancy rate per ET was assessed in both the intention-to-treat (ITT) and per-protocol

| RESULTS
A total of 195 women were screened for inclusion in this trial and 178 were enrolled and entered the screening period (Fig. 2). Of these women, 169 started controlled ovarian stimulation and 162 received an hCG injection to trigger ovulation, with all the women who discontinued before the hCG injection doing so because of risk of OHSS.

| Baseline characteristics and demographics
In the ITT population, the mean (standard deviation [SD]) age of the women who received the vaginal progesterone gel was 34.5 (3.8) years, the mean (SD) weight was 52.4 (5.1) kg, and the mean (SD) BMI was 20.6 (2.0) kg/m 2 ( Table 1). The majority of the women F I G U R E 1 Trial design. β-hCG, β-human chorionic gonadotropin; COS, controlled ovarian stimulation; Max., maximum had primary infertility (69.1%), with 46.3% of the women having female-only infertility and 44.7% having unexplained infertility. The most common cause of female infertility was a tubal factor. The data were similar for the PP population ( Table 1). The baseline demographics and patient characteristics were not available for the historical control data.

| Efficacy evaluation
In the ITT population, the clinical pregnancy rate per ET (95% CI) was 28.5% (20.7%-37.3%), compared with 24.3% in the historical control population ( Table 2). 14 The lower bound of the 95% CI minus 24.3% for the prospective arm (−3.6%) was above the predefined −10% limit for non-inferiority to the historical control. In the PP population the clinical pregnancy rate per ET was 27.8% (19.9%-37.0%) and the lower bound of the 95% CI was also above the predefined −10% limit for non-inferiority to the historical control ( Table 2). The biochemical pregnancy rate per ET (95% CI) was 7.3% (3.4%-13.4%) in the ITT population and 7.8% (3.6%-14.3%) in the PP population.

| Safety evaluation
The safety profile of the vaginal progesterone gel was as expected during this 12 week trial (Table 3). In the safety population, the most frequently reported TEAE was OHSS, which was reported by 32 (21.5%) participants, with mild, moderate, and severe OHSS reported by 24 (16.1%), four (2.7%), and four (2.7%) participants, respectively. None of the cases of OHSS reported was assessed as being related to the study drug.

| DISCUSSION
This open-label, single-arm trial of vaginal progesterone gel demonstrated that the clinical pregnancy rate per ET was non-inferior to that observed in the historical registry data in Japan (28.5% vs 24.3%, respectively). Furthermore, a clinical pregnancy rate of 22.7% was observed in more recent (2013) Japanese registry data. 16 The higher clinical pregnancy rate that was observed in this study, compared with the registry data, is probably related to the younger mean age of the women who were enrolled in the study, compared with the registry associated with the historical data. Nonetheless, the clinical pregnancy rate that was observed in the present trial was similar to that observed in a clinical trial in Japan of a 100 mg vaginal progesterone tablet (22.2%), 17 as well as to that of a trial comparing an oral progestogen (chlormadinone acetate) and intramuscular progesterone for luteal phase support in Japan (20% and 25%, respectively). 18 Moreover, these data are in line with the results of a meta-analysis by Polyzos et al,11 which demonstrated that there is no difference in clinical pregnancy rates following luteal phase support with vaginal progesterone gel compared with all other vaginal progesterone forms. The observed clinical pregnancy rate in the current study is also comparable with that observed in European studies of vaginal progesterone gel in women undergoing IVF/intracytoplasmic sperm injection cycles with oocyte retrieval (32.3%-32.9%). 9,19 The biochemical pregnancy rate in the present trial (7.3%) was low and similar to that reported for the trial comparing an oral progestogen and intramuscular progesterone for luteal phase support in Japan (5% and 10%, respectively). 18 The safety profile of the vaginal progesterone gel was as expected for IVF/ET cycles in Japanese women, with the clinical pregnancy rate per ET observed to be non-inferior to the historical standard value from the JSOG registry. Furthermore, the vaginal progesterone gel demonstrated the expected safety profile, with no new clinical safety issues identified. The once-per-day application makes progesterone gel a highly convenient option for luteal phase support in women undergoing ART.