Clinical Safety Study of the Progesterone Vaginal Ring in Women Undergoing Assisted Reproductive Technology Procedures

Frequency of participants with spontaneous abortions on or before 12 weeks post-oocyte retrieval and undergoing fresh embryo transfer was presented.

Spontaneous abortion was defined as two positive beta-human chorionic gonadotropin (β-hCG) tests occurring at least two days apart on or after 2 weeks post-oocyte retrieval, but followed by observation of any empty intrauterine gestational sac (blighted ovum), intrauterine gestation without a fetal heart beat, or absence of viable fetuses, as documented by transvaginal ultrasound (TVUS).

Frequency of participants with spontaneous abortions at 6 weeks post-oocyte retrieval was presented.

Frequency of participants with spontaneous abortions at 10 weeks post-oocyte retrieval was presented.

Frequency of participants with biochemical abortions within 6 weeks post-oocyte retrieval was presented.

Biochemical abortion was defined as a positive β-hCG test at 2 weeks and 2 weeks +3-4 days post-oocyte retrieval, but followed by no observed gestational sac on a later TVUS, or followed by a negative β-hCG test.

Frequency of participants with biochemical abortions within 10 weeks post-oocyte retrieval was presented.

Frequency of participants with positive β-hCG rate at 2 weeks and 2 weeks +3-4 Days was presented. Positive β-hCG was defined as a positive serum β-hCG test at 2 weeks and 2 weeks +3-4 Days post-oocyte retrieval.

Frequency of participants with clinical pregnancy at 6 weeks was presented. Clinical pregnancy was defined as a TVUS showing at least 1 intrauterine gestational sac with fetal heart-beat at 6 weeks post-oocyte retrieval.

Frequency of participants with clinical pregnancy at 10 weeks was presented.

Frequency of participants with ectopic and heterotopic pregnancies was presented.

Participants with at least one abnormal finding in clinical laboratory tests (i.e. abnormal clinical significant [CS] values: as assessed by investigator) were reported. Clinical chemistry included: glucose, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, potassium, sodium, chloride, calcium, estimated glomerular filtration rate, and gamma-glutamyl transferase; hematology included: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils, platelets, erythrocytes, and leukocytes; urinalysis included: specific gravity, ketones, pH, protein, blood, and glucose.

Participants with at least one abnormal finding (i.e. abnormal CS values: as assessed by investigator) in vital signs were reported. Vital signs includes: Weight (kg): decrease of >=7% from baseline (BL) or increase of >=7% from BL; Systolic Blood Pressure (SBP): <=90 mmHg and decrease of >=20 mmHg from BL or >=180 mmHg and increase of >= 20 mmHg from BL; Diastolic Blood Pressure (DBP): <= 50 mmHg and decrease of >= 15 mmHg from BL or >=105 mmHg and increase of >=15 mmHg from BL; Heart Rate: <=50 (beats per minute [bpm]) and decrease of >= 15 bpm from BL or >=120 bpm and increase of >=15 from BL; Temperature >= 38.3 degree Celsius.

The frequency of participants with total AEs, AEs by categories of intensity (mild, moderate, severe), seriousness and relatedness was presented. An AE is any untoward medical occurrence in a participant participating in a clinical trial. The intensity of an AE was classified using the following 3-point scale: mild=awareness of signs or symptoms, but no disruption of usual activity; moderate=event sufficient to affect usual activity (disturbing); or severe= inability to work or perform usual activities (unacceptable). Seriousness refers to death, hospitalization/ prolongation of existing hospitalization, a life-threatening experience, persistent or significant disability/incapacity, or congenital anomaly. The possibility of whether the IMP caused the AE would be classified as: reasonable possibility, no reasonable possibility. All the reasonable possible causality to the IMP were referred to as adverse drug reactions (ADRs). Relatedness of AEs to IMP was assessed by the investigator.

Frequency of participants with vaginal bleeding/spotting was presented in total and by categories of intensity/grade (mild, moderate and severe). Vaginal bleeding was recorded in a bleeding log by the participant. The severity of the bleeding was determined using a Pictorial Blood Loss Assessment chart.

Frequency of participants with vaginal hemorrhage was presented in total and by categories of intensity/grade (mild, moderate and severe). Vaginal hemorrhage was defined as a) blood loss of greater than 500 mL based on the opinion of the Investigator or b) hemoglobin post-treatment lesser than 10 gm/dL or c) blood loss requiring transfusion.

The frequency of participants with vaginal pain was presented in total and by categories of intensity/grade.

The intensity of vaginal pain was evaluated as symptoms score of pain and dyspareunia (pain with sexual activity) as: Grade 1 (mild) - Pain causing no or minimal inference with usual social & functional activities; Grade 2 (moderate) - Pain causing greater than minimal inference with usual social & functional activities or the need for non-narcotic medication; Grade 3 (severe) - Pain causing inability to perform usual social & functional activities or the need for narcotic medication; Grade 4 (potentially life threatening) - Disabling pain causing inability to perform basic self-care functions OR hospitalization (other than emergency room visit) indicated.

Dyspareunia (pain with sexual activity): Grade 1 (mild) - Pain causing no or minimal inference with sexual function; Grade 2 (moderate) - Pain causing greater than minimal inference with sexual function.

Frequency of participants with vaginal infection was presented in total and by categories of intensity/grade (mild, moderate and severe).

The frequency of participants with vaginal irritation was presented in total and by categories of intensity/grade. The intensity of vaginal irritation evaluated as symptoms score of vaginal itching, vaginal dryness, and vaginal discharge. Vaginal itching: Grade 1 (mild)-itching causing no, mild or moderate inference with usual social & functional activities; Grade 2 (moderate)-itching causing inability to perform usual social & functional activities; may require intervention such as antihistamine or bathing. Vaginal dryness: Grade 1 (mild)-dryness causing no or minimal inference with usual sexual, social & functional activities; Grade 2 (moderate)-dryness causing greater than minimal inference with usual sexual, social & functional activities. Vaginal discharge by participant report: Grade 1 (mild)-mild-moderate increase in amount above participant BL-no sanitary protection required; Grade 2 (moderate)-profuse increase in discharge requiring pad use or other hygienic intervention.

Frequency of participants with AEs associated with vaginal and cervical abrasions and lesions, by intensity, seriousness, & relatedness was presented. Intensity was evaluated as symptoms score: Vaginal/cervical lesions:Grade 0 (Normal)- Normal variants including skin tags, moles, scars, etc; Grade 1 (mild) - Blisters, ulcerations, or pustules, no treatment indicated; Grade 2 (moderate)- Blisters, ulcerations, or pustules with treatment indicated; Grade 3 (severe) - Severe epithelial disruption requiring hospitalization; Vaginal/cervical abrasions: Grade 0 (Normal) - None; Grade 1 (mild)- Superficial disruptions and disruptions extending through the mucosa with minimal impact on life; Grade 2 (moderate)- Large disruptions extending through the mucosa or large superficial disruptions, hospitalization not indicated; Grade 3 (severe)- Large disruptions extending through the mucosa or large superficial disruptions, hospitalization indicated. Relatedness to IMP was assessed by investigator.

The frequency of participants with AEs associated with vaginal adhesion (total), by categories of intensity, seriousness, and relatedness was presented.

The intensity was evaluated as symptoms score of vaginal adhesion as: Grade 0 (Normal) - None; Grade 1 (mild) - asymptomatic, manual removal of ring possible; Grade 2 (moderate) - Symptomatic (eg: irritation reported by participant), manual removal of ring possible; Grade 3 (severe) - Surgical intervention (eg: adhesiolysis) required to resolve; Grade 4 (potentially life threatening) - urgent intervention indicated. The AEs associated with vaginal adhesion of Grade 4 intensity were considered to be serious. Relatedness to IMP was assessed by investigator.

Frequency of participants who prematurely discontinued PVR (i.e. did not fulfill 10 weeks of PVR treatment) was presented by reason.