Safety evaluation of a novel progesterone vaginal ring (PVR) for luteal phase support: SARA trial

After manufacturing changes, the safety and tolerability of the progesterone vaginal ring (PVR) was compared to findings from the similarly designed phase 3 trial. This prospective, open-label, single-arm, multi-center U.S. trial was conducted with women with tubal, idiopathic, male factor, ovulatory dysfunction, or endometriosis-linked infertility. Women underwent ovarian stimulation with highly purified human menotropin 225 IU/day in a standardized long agonist protocol. Weekly administration of PVR started the day after oocyte retrieval (OR), followed by ICSI and fresh blastocyst transfer, and continued for up to 10 weeks. The primary endpoint was spontaneous abortion rate, defined as 2 positive β-hCG tests and an empty intrauterine gestational sac or lacking a fetal heartbeat, or the absence of a viable fetus up to 12 weeks after OR. 254 women were treated with PVR at 14 sites July 2018–July 2019 (mean age 30.8 years, BMI 26.5 kg/m2, AMH 2.8 ng/mL, FSH 7.0 mIU/mL). Adverse events occurring in ≥ 5% of the population included nausea (8.7%) and headache (5.1%). Incidence of predefined vaginal/cervical adverse events was 2.0%. Fresh embryo transfer was performed in 243 subjects (95.7%). The spontaneous abortion rate was 7.4%, with the upper bound of the 95% confidence interval (11.5%) below the predefined threshold of 15.0%. Clinical pregnancy rates 10 weeks post OR were 43.2%. This trial established a safety bridge between PVR produced via enhanced manufacturing processes and the legacy PVR, with comparable rates of spontaneous abortion. Weekly administration of PVR was well-tolerated with good pregnancy outcomes. Trial registration: NCT03565211 (https://clinicaltrials.gov/study/NCT03565211), registration June 21, 2018, first enrollment July 26, 2018 Similar content being viewed by others

Procedures used in assisted reproductive technologies (ART) potentially disrupt the corpus luteum, which promotes implantation and maintains early pregnancy. Progesterone is typically administered to supplement endogenous progesterone production in fresh embryo transfer cycles [1, 2]. Current progesterone formulations used for luteal phase support include intramuscular (IM), subcutaneous, vaginal, or oral routes of administration, taken at least once daily after oocyte retrieval for 10 weeks. Daily IM injection of progesterone is the predominant formulation used for luteal phase support in the United States [2]. While effective, IM injections have been associated with patient discomfort and injection site pain, cellulitis, and abscesses [3]. Vaginal progesterone for luteal phase support is arguably better tolerated [4, 5] and more easily administered than IM progesterone, with targeted drug delivery of higher progesterone concentrations to the uterus [6, 7]. Current FDA-approved vaginal formulations require administration 1–3 times per day and may be associated with vaginal discharge among other adverse events [8, 9]. The progesterone vaginal ring (PVR; Milprosa, Ferring Pharmaceuticals, Inc.) received FDA approval in 2020 and was designed for weekly administration with continuous release of 11 mg/day of progesterone over 7 days via a silicone ring [10]. The prospective randomized pivotal phase 3 trial of the PVR was conducted at 22 US clinical sites in 1,297 women between February 2008 and January 2009 and compared the efficacy and safety of weekly PVR (n = 646) to daily progesterone 8% vaginal gel (n = 651) [11]. The trial demonstrated similar clinical pregnancy rates at 6 weeks and 10 weeks post-oocyte retrieval, with no significant differences in safety parameters. A post-hoc analysis of patient satisfaction questionnaires collected in the trial found that the PVR interfered less with daily life, social activities, and sexual activities compared to progesterone vaginal gel [12]. After implementation of enhancements to manufacturing of the PVR, the SARA (Safety Assessment of Progesterone Vaginal Ring in Women Undergoing ART) trial was required to re-establish clinical safety and tolerability over the entire treatment duration prior to FDA approval. The trial design and tools used in SARA may provide insights to help guide the clinical development of other treatments for infertility.

Trial design and setting SARA was an open-label, single-arm trial conducted in 14 US centers between July 2018 and July 2019. The trial was performed in compliance with Good Clinical Practice as required by the FDA, and in accordance with the Declaration of Helsinki. Institutional Review Board (IRB) approval was obtained from all study sites before the start of the trial. Patients gave written informed consent to participate using an IRB-approved consent form before undergoing any study-specific procedures. The first subject was enrolled on July 26, 2018, the last subject was enrolled on December 31, 2018, and the database was locked on August 14, 2019. Trial population Eligible subjects included women 18–34 years of age with body mass index (BMI) ≤ 38 kg/m2, history of infertility, Day 2 or 3 serum FSH ≤ 15 IU/L, and documentation of a normal uterine cavity within 1 year and normal pap smear test within 24 months of screening. Documented infertility was specific to tubal, idiopathic, male factor, ovulatory dysfunction, and/or endometriosis-linked infertility. Women with any known contraindication to progesterone or silicone, uncontrolled hypertension, hypothyroidism or hyperprolactinemia, history of more than 1 failed fresh IVF cycle, more than 2 consecutive clinical miscarriages, or clinically significant gynecologic pathology were excluded from the trial. Full inclusion and exclusion criteria are listed in Supplemental Table 1. Trial procedures Eligible subjects started ovarian suppression with combined oral contraceptive (Cyclafem 1/35, Qualitests Pharmaceuticals) ≥ 14 days to ≤ 21 days based on the study site standard of care. Four days prior to the last birth control pill, subjects started GnRH agonist (leuprolide acetate, Sandoz) at a dose of 0.1 mL (500 µg)/day, administered for a minimum of 10 days and maximum of 20 days. Ovarian suppression was confirmed with the start of menses and controlled ovarian stimulation was started after 2–3 days with HP-hMG (Menopur, Ferring Pharmaceuticals, Inc.), administered at a fixed dose of 225 IU/day. The dose of leuprolide acetate was reduced to 0.05 mL (250 µg)/day at the start of ovarian stimulation. HP-hMG was administered at a fixed starting dose for 5 days; on day 6 of stimulation, dose adjustments could be made according to individual response by increments of no more than 150 IU every 2 days, to a minimum daily dose of 75 IU and maximum daily dose of 450 IU. The maximum duration of ovarian stimulation was 20 days and coasting was not permitted. When 2 follicles of ≥ 17 mm were observed by transvaginal ultrasound (TVUS), oocyte maturation was induced by 10,000 IU hCG (Novarel, Ferring Pharmaceuticals). Oocytes were retrieved approximately 35–37 h after hCG administration and insemination was performed predominantly through intracytoplasmic sperm injection (ICSI; 84.8%), IVF, or a combination of both. PVR administration started the day after oocyte retrieval. Subjects were required to keep the PVR inserted for at least 23 h/day for 7 days. The PVR was removed and a new PVR was inserted every 7 days; weekly administration of a new ring was dependent on pregnancy assessments. Fresh embryo transfer was conducted on day 5 after oocyte retrieval at the discretion of the site investigator and in accordance with 2017 ASRM and SART guidelines [13]. Subjects with the expectation of 1 or more high-quality embryo(s) available for cryopreservation, and subjects with previous live birth after an IVF cycle, underwent transfer of a single embryo. All other subjects underwent transfer of no more than 2 embryos. Preimplantation genetic testing was not permitted in the trial. The first pregnancy assessment was serum β-hCG testing 14 ± 2 days post-oocyte retrieval. If the serum β-hCG was ≥ 5 mIU/mL, then the subject continued PVR treatment and proceeded to subsequent pregnancy assessments, including up to 2 additional serum β-hCG tests and 4 TVUS assessments. PVR treatment was continued for 10 weeks post-oocyte retrieval if subjects were observed to be pregnant at each β-hCG and TVUS visit. A final visit was conducted 14 ± 2 days after the last PVR exposure to confirm pregnancy and perform a pelvic examination. Trial endpoints and assessments The primary endpoint was the rate of any spontaneous abortion occurring on or before 12 weeks following oocyte retrieval in all subjects treated with PVR and undergoing fresh embryo transfer. The primary endpoint was selected based on extensive interactions with US regulators. Secondary endpoints included biochemical abortion within 6 and 10 weeks of oocyte retrieval, ectopic and heterotopic pregnancies, positive β-hCG, clinical pregnancy at 6 and 10 weeks post-oocyte retrieval, number and size of follicles during stimulation, estradiol and progesterone profiles, characterization of fertilized oocytes 1 day after oocyte retrieval, quality of blastocysts 5 days after oocyte retrieval, and endometrial thickness. Clinical pregnancy was defined as the visualization of an intrauterine gestation with fetal heart motion present on ultrasound [11]. Safety was assessed based on vital signs, laboratory results, and reports of treatment-emergent adverse events (TEAEs) that occurred from the time of first administration of trial drug to the last end-of-treatment visit. OHSS was classified using Golan’s classification system [14]. Safety and tolerability of the PVR was also monitored through stringent pelvic examinations performed throughout the trial. PVR diaries and a standardized grading table were used to assess vaginal bleeding and the severity of female genitourinary AEs (Supplemental Table 2). Additionally, subjects were instructed to use sanitary napkins provided by the sponsor, and vaginal bleeding was recorded in bleeding logs to capture the frequency and intensity of any vaginal bleeding or spotting from PVR treatment initiation to the end of trial. Severity of bleeding was recorded using a Pictorial Blood Loss Assessment chart (Supplemental Fig. 1) [15]. Pivotal phase 3 trial design The design of the pivotal phase 3 trial of the PVR has been published previously (ClinicalTrials.gov identifier: NCT00615251) [11]. Briefly, a randomized, single-blind study was conducted at 22 sites and included 1,297 women who underwent egg retrievals and were then randomized to weekly PVR or daily progesterone vaginal gel after fresh transfer. The pivotal phase 3 trial protocol and endpoints are similar to those of the SARA trial, with two exceptions. First, the SARA trial used HP-hMG alone and the pivotal trial used a mixed rFSH and HP-hMG protocol for ovarian stimulation. Second, Day 5 single embryo transfers were performed in the SARA trial, whereas both Day 3 and Day 5 transfers of single or multiple embryos were performed in the pivotal trial. Sample size and statistical analysis The trial was powered to exclude the possibility of a 15% spontaneous abortion rate after the use of PVR, based on the upper bound of the two-sided exact confidence interval of 0.15 in the pivotal phase 3 trial. An estimated 240 subjects were needed to achieve 80% power, assuming a true spontaneous abortion rate of 9%. A primary frequentist analysis was applied with a Bayesian sensitivity analysis. A Bayesian hierarchical model was formulated to dynamically borrow from the pivotal phase 3 trial and to determine whether or not the 95% credible interval for the primary endpoint of rate of any spontaneous abortion in the SARA trial was entirely below the 15% threshold. Continuous variables were summarized using mean and SD, while categorical variables were summarized using the number of observations and the corresponding percentage. Analyses of exposure to non-investigational medicinal product (i.e.; HP-hMG), were based on the number of participants that started stimulation. Analyses of exposure to PVR as well as AEs were based on the safety analysis set (i.e.; all participants exposed to PVR) and analyses of spontaneous abortion rate and pregnancy outcomes were based on the modified intent to treat population (mITT) analysis set (i.e.; all exposed participants with embryo transfer).

Trial subjects Of 352 screened subjects, 298 started ovarian suppression, 274 started ovarian stimulation with HP-hMG, 254 were administered the PVR (safety population), and 243 underwent fresh embryo transfer (mITT; Fig. 1). Overall, 48 subjects discontinued the trial after exposure to PVR, and 206 subjects completed the trial. The main reasons for discontinuation were adverse events, of which the majority were biochemical (n = 25) and spontaneous (n = 18) abortions that did not affect analysis of the primary endpoint (rate of any spontaneous abortion). Two subjects withdrew consent: one subject at initiation of PVR treatment and one subject 2 weeks after oocyte retrieval. One subject was lost to follow-up after oocyte retrieval and one subject discontinued due to personal reasons. The mean subject age was 30.8 years, BMI was 26.5 kg/m2, and AMH was 2.8 ng/mL. The majority of subjects were White; the predominant causes of infertility were male factor, idiopathic, and tubal infertility; and the average duration of infertility was 34.7 months (Table 1). Stimulation response The average duration of ovarian stimulation with HP-hMG was 10.1 days, and the mean (SD) daily dose was 258.7 (50.0) IU (Supplemental Table 3). Mean serum estradiol at end of stimulation was 2516 pg/mL. The mean (SD) number of oocytes retrieved in the mITT population was 11.3 (6.0), resulting in an average of 7.0 fertilized oocytes. The mean (SD) number of Day 5 blastocysts was 4.3 (2.9), resulting in 3.0 (2.4) morphologically good quality blastocysts, defined as grade 3BB or above with classification of blastocyst expansion and hatching status, blastocyst inner cell mass, and trophectoderm (Supplemental Table 3). Progesterone profile Mean progesterone serum levels increased from 14.6 ± 8.5 ng/mL at the start of PVR treatment to 62.4 ± 38.0 ng/mL at the time of embryo transfer. Mean progesterone serum levels were 34.0 ± 50.1 ng/mL 2 weeks after oocyte retrieval and 18.6 ± 25.0 ng/mL at week 12 of pregnancy. Pregnancy outcomes Secondary endpoints included positive β-hCG rate and clinical pregnancy rate in the mITT population. The combined rate of positive β-hCG at 2 weeks and 2 weeks + 3–4 days post-oocyte retrieval was 60.9% (n = 148/243) in the SARA trial, compared to 57.7% (n = 317/549) in the pivotal phase 3 trial (Supplemental Table 4). The clinical pregnancy rate at 6 weeks and 10 weeks post-oocyte retrieval was 44.9% (n = 109/243) and 43.2% (n = 105/243), respectively, in the SARA trial, compared to 50.5% (n = 227/549) and 49.2% (n = 270/549), respectively, in the pivotal phase 3 trial. Safety outcomes The primary endpoint, rate of any spontaneous abortion occurring on or before 12 weeks following oocyte retrieval in the mITT population, was 7.4% (95% CI: 4.4%, 11.5%) (n = 18/243) in the SARA trial and 10.0% (95% CI: 7.6%, 12.8%) (n = 55/549) in the pivotal phase 3 trial (Fig. 2A). The upper bound of the two-sided exact 95% CI was 11.5%, below the 15% spontaneous abortion rate threshold, thus meeting the pre-defined trial goal for trial success in the primary statistical analysis. Bayesian sensitivity analysis showed a similar result, with an upper bound of the two-sided 95% credibility interval of 11.3%, also under the spontaneous abortion rate threshold of 15% (Fig. 2A). Frequent adverse events, defined as ≥ 5% incidence in the safety population, included biochemical pregnancy loss (9.8%), nausea (8.7%), spontaneous abortion (7.1%), and headache (5.1%). There were 4 treatment-emergent serious adverse events (Table 2). These events were typical of ART intervention, with the exception of suicidal ideation in a 10 weeks and 3 days pregnant subject with a history of depression. This event was assessed as unrelated to PVR exposure due to the amount of systemic progesterone originating from the corpus luteum and placenta compared to vaginal absorption at that stage of pregnancy. A post-hoc analysis of pregnancy loss included the biochemical abortion rate within 6 weeks after oocyte retrieval per positive β-hCG and the spontaneous abortion rate within 12 weeks after oocyte retrieval per observed gestational sac. The rates of biochemical abortion per positive β-hCG within 6 weeks of oocyte retrieval were 16.9% (95% CI: 11.2%, 23.9%) in the SARA trial and 11.5% (95% CI: 8.3%, 15.3%) in the pivotal phase 3 trial (Fig. 2B). The rates of spontaneous abortion per gestational sac 12 weeks after oocyte retrieval were 14.8% (95% CI: 9.0%, 22.3%) in the SARA trial, and 16.8% (95% CI: 12.7%, 21.6%) in the pivotal trial (Fig. 2C). As the pivotal trial included Day 3 and Day 5 embryo transfer, the spontaneous abortion rate per gestational sac was further analyzed to compare the rate for all Day 5 embryo transfers. The rate per observed sac remained 14.8% in the SARA trial where all transfers were performed 5 days after oocyte retrieval; in the pivotal trial, the rate of biochemical abortions among subjects with a day 5 transfer was 17.0% (Fig. 2D). Supplemental Table 5 summarizes the bleeding log data, which demonstrated that vaginal bleeding was lowest in pregnant subjects. As expected, subjects with biochemical pregnancy reported vaginal bleeding during early pregnancy visits, while subjects with spontaneous abortion experienced vaginal bleeding at later trial pregnancy visits (Supplemental Fig. 2). Few clinically significant events were reported using the grading table developed to capture genitourinary signs and symptoms through pelvic examinations (Supplemental Table 6). There was no trend in observation of pelvic examination events during the trial, and all events were of mild or moderate intensity, including for 2 subjects who reported moderate vaginal discharge.

In this open-label, single-arm, multi-center US trial, we established that weekly administration of the PVR, after initiation of an enhanced manufacturing process, is safe and well-tolerated for luteal phase support in ART for up to 10 weeks in early pregnancy. In the pivotal phase 3 trial, once-weekly administration of the legacy PVR was demonstrated to be efficacious and statistically non-inferior to the active comparator, daily progesterone 8% vaginal gel, in women 18–34 years of age for luteal phase support for the 2 primary endpoints of clinical pregnancy at 6 and 10 weeks post-oocyte retrieval. Prior to the new manufacturing process, the pivotal phase 3 trial included secondary endpoints to evaluate the legacy PVR safety, including live birth rate, rate of spontaneous abortion, rate of biochemical pregnancy, and rate of ectopic pregnancy for both treatment groups. These rates were similar between the two treatment groups and consistent with reported background rates [7]. A pharmacokinetic trial demonstrated that the PVR manufactured with the new process was bioequivalent to the PVR produced from the legacy process [7]. The findings from SARA indicated that both rings were similarly safe and well-tolerated by healthy, postmenopausal female subjects who were pre-treated with estrogen. The SARA trial thus re-established the safety and tolerability of the PVR for the entire duration of treatment after enhancements in the manufacturing process. Positive β-hCG pregnancy outcomes were comparable in SARA and the pivotal phase 3 trial, at 60.9% and 57.7%, respectively. The clinical pregnancy rates at 6 and 10 weeks after oocyte retrieval dropped to 44.9% and 43.2%, respectively, in the SARA trial. In subjects < 35 years of age in the pivotal trial, these rates were higher, at 50.5% and 49.2%, respectively. It is important to note that the high incidence of multiple embryo transfers and pregnancies in the pivotal trial led to some subjects who reported an adverse event of spontaneous abortion while also reaching the study endpoint of clinical pregnancy. In the SARA trial, the rate of any spontaneous abortion occurring on or before 12 weeks after oocyte retrieval was 7.4% (n = 18/243). The Bayesian sensitivity analysis produced a rate of 8.2% based on data from both the pivotal phase 3 trial and SARA trial. The upper bound of the two-sided 95% exact confidence interval for the proportion of spontaneous abortions in the mITT analysis population was below the 15% threshold (11.5%). This finding was supported by the sensitivity analysis, as the upper bound of the two-sided 95% credible interval was also below 15% (11.3%). The point estimate of 8.2% was between the primary endpoint estimate of 7.4% and the estimate from the pivotal trial, 10.0%, reflecting the use of data from the pivotal trial in the sensitivity analysis. Similarly, the primary analysis 95% CI was wider (4.4%, 11.5%) than the sensitivity analysis credible interval (5.3%, 11.3%) because the sensitivity analysis made use of information from both trials whereas the primary analysis only used information from the SARA trial. The non-comparative design of the SARA trial required that it be similar to the pivotal phase 3 trial that used the legacy manufacturing process in order to establish an adequate safety bridge. However, there were two notable differences between the pivotal trial and SARA trial. The first was the ovarian stimulation protocol, with the SARA trial using HP-hMG alone and the pivotal trial using a mixed rFSH and HP-hMG protocol. We found that HP-hMG stimulation outcomes in SARA were favorable, producing an average of 7.0 fertilized oocytes and 4.3 Day 5 blastocysts, of which 3.0 were determined to be good quality. The second difference between the two trials was related to embryo transfer. Although both study protocols specified the use of the ASRM treatment guidelines for the number of embryos to transfer [13], the guidelines were updated in 2017, after the conclusion of the pivotal phase 3 trial and prior to the SARA trial. Consequently, single embryo transfer was performed in 98.9% of subjects in the SARA trial compared to only 7.4% in the pivotal trial. Although single embryo transfer does not change the rate of spontaneous abortion versus multiple embryo transfer [16], a difference in the embryo transfer policy likely accounts for the modest decrease in the pregnancy rate observed in the SARA trial relative to the pivotal trial, consistent with observed outcomes in previous studies [17]. In addition, in the pivotal phase 3 trial, 53.4% of subjects had embryo transfer on day 3, whereas all embryo transfers in the SARA trial were performed on day 5, as per current US standard of care. A 2012 Cochrane review concluded that there was no difference in reported miscarriage rate between early cleavage and blastocyst stage transfers [18]. Therefore, the difference in embryo culture and timing of transfer is unlikely to have had an impact on the difference in spontaneous abortion rate observed in the SARA trial vs. the pivotal trial. The SARA trial rigorously assessed local vaginal and cervical adverse events through pelvic examinations conducted throughout the trial. The intensity of any pain, irritation, abrasions, or lesions on the cervix or vagina, as well as the presence and grade of any vaginal adhesions, were documented using standardized criteria. The overall incidence of these adverse events of special interest remained low (2.0%), and the majority of clinical findings were graded mild. The overall rate of local vaginal and cervical events in the pivotal phase 3 trial was also low (3.7%). Vaginal bleeding was characterized in both trials using a bleeding log, although greater standardization was provided in the SARA trial. All SARA subjects were provided uniform sanitary napkins, and a pictorial blood loss assessment was used to quantify bleeding. In both trials, the highest bleeding grades were observed approximately 2 weeks after oocyte retrieval, which likely reflects the occurrence of menses in non-pregnant subjects. Subjects who were not pregnant had the highest bleeding grades, while pregnant subjects had the lowest bleeding grades, consistent with an absence of menses.

of this study include the restriction of the study population and IVF protocol. Study participants could not have more than one previous failed fresh IVF cycle, and all participants underwent GnRH agonist cycles with HP-hMG for ovarian stimulation. In addition, the SARA trial evaluated safety and tolerability in subjects 18–34 years of age based on FDA guidance, as the pivotal phase 3 trial was not powered to demonstrate non-inferiority for women 35–42 years of age. Future trials will need to examine the safety and tolerability of the PVR manufactured with the enhanced process in women ≥ 35 years of age, as well as in GnRH antagonist cycles. In addition, the SARA trial was not designed to evaluate PVR efficacy in fresh transfer cycles. A recent network meta-analysis of randomized clinical trials suggested that only oral and IM formulations of progesterone for luteal support improved clinical pregnancy and live birth rates after fresh transfer; however, the analysis found significant overlap in confidence intervals and did not include the PVR [19]. The efficacy and safety of the PVR in progesterone replacement cycles (e.g., programmed frozen embryo transfer cycles where there is no corpus luteum) has also not yet been established. Therefore, additional studies are needed to compare the efficacy of the PVR to other treatment regimens in both luteal support and programmed frozen embryo transfer cycles.

The SARA trial supported the safety and tolerability of the PVR for the indication luteal phase support, after implementation of enhanced manufacturing processes. Weekly PVR was well tolerated for up to 10 weeks after oocyte retrieval based on the adverse events profile and low incidence of genitourinary events observed in stringent pelvic safety examinations. As the SARA trial led to the successful FDA registration of the PVR, the study design and application of novel tools for collection of safety data may help inform the clinical development of other treatments in reproductive medicine and infertility. Future studies are needed to evaluate PVR efficacy for luteal support and in replacement cycles using contemporary IVF protocols. Data availability Ferring will provide access to individual de-identified participant data, upon request via a secure portal, to researchers whose proposals meet the research criteria and other conditions. To gain access, data requestors must enter into a data access agreement with Ferring.

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This study was supported by Ferring Pharmaceuticals, Inc. Editorial assistance in the preparation of the manuscript was provided by Stacey Tobin, PhD, who was compensated by Ferring Pharmaceuticals, Inc. Funding This study was supported by Ferring Pharmaceuticals, Inc. Author information Authors and Affiliations Contributions L.S., V.S., J.P., and C.S. provided data curation, investigation, resources, and writing - review and editing; E.F. provided data curation, formal analysis, methodology, validation, and writing - review and editing; S.G. provided data curation, formal analysis, investigation, methodology, supervision, writing - original draft, and writing - review and editing; P.H. provided conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, validation, visualization, writing - original draft, and writing - review and editing. All authors approved the final manuscript for submission and publication. Corresponding author Ethics declarations Competing interests L.S., V.S., J.P., and C.S. were investigators in the SARA trial. P.H. and E.F. were employees of Ferring Pharmaceuticals, Inc. during the design, conduct, and analysis of the SARA trial. S.G. is a full-time employee of Ferring Pharmaceuticals A/S. Informed Consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Stadtmauer, L.A., Schnell, V.L., Park, J.K. et al. Safety evaluation of a novel progesterone vaginal ring (PVR) for luteal phase support: SARA trial. Drug Deliv. and Transl. Res. (2026). https://doi.org/10.1007/s13346-026-02158-x Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s13346-026-02158-x