Trial Outcomes & Findings for Clinical Safety Study of the Progesterone Vaginal Ring in Women Undergoing Assisted Reproductive Technology Procedures (NCT NCT03565211)

NCT ID: NCT03565211

Last Updated: 2020-11-23

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 352 participants
• Primary outcome timeframe: On or before 12 weeks post-oocyte retrieval
• Results posted on: 2020-11-23

Participant Flow

The trial was conducted at 14 trial centers in the United States (US) between 26 July 2018 to 29 July 2019.

In total 352 participants were screened. Of these, 98 were screening failures and 254 participants were treated with investigational medicinal product (IMP), progesterone vaginal ring (PVR).

Participant milestones

Measure	Progesterone Vaginal Ring Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Overall Study STARTED	254
Overall Study Modified Intention-to-treat (mITT)	243
Overall Study COMPLETED	206
Overall Study NOT COMPLETED	48

Reasons for withdrawal

Measure	Progesterone Vaginal Ring Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Overall Study Withdrawal by Subject	2
Overall Study Lost to Follow-up	1
Overall Study Adverse Event	44
Overall Study Personal issues	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Age, Continuous	30.8 years STANDARD_DEVIATION 2.72 • n=5 Participants
Sex: Female, Male Female	254 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	30 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	224 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=5 Participants
Race (NIH/OMB) Asian	22 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	2 Participants n=5 Participants
Race (NIH/OMB) Black or African American	17 Participants n=5 Participants
Race (NIH/OMB) White	210 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: On or before 12 weeks post-oocyte retrieval

Population: The mITT analysis set consisted of all participants who had successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo transfer.

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).

Outcome measures

Measure	Progesterone Vaginal Ring n=243 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Cumulative Rate of Spontaneous Abortions Occurring on or Before 12 Weeks Post-oocyte Retrieval	7.4 percentage of participants Interval 4.4 to 11.5

SECONDARY outcome

Timeframe: At 6 weeks post-oocyte retrieval

Population: The mITT analysis set consisted of all participants who had successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo transfer.

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

Outcome measures

Measure	Progesterone Vaginal Ring n=243 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Cumulative Rate of Spontaneous Abortions Occurring at 6 Weeks Post-oocyte Retrieval	5.8 percentage of participants Interval 3.2 to 9.5

SECONDARY outcome

Timeframe: At 10 weeks post-oocyte retrieval

Population: The mITT analysis set consisted of all participants who had successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo transfer.

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

Outcome measures

Measure	Progesterone Vaginal Ring n=243 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Cumulative Rate of Spontaneous Abortions Occurring at 10 Weeks Post-oocyte Retrieval	7.4 percentage of participants Interval 4.4 to 11.5

SECONDARY outcome

Timeframe: Within 6 weeks post-oocyte retrieval

Population: The mITT analysis set consisted of all participants who had successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo transfer.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=243 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Cumulative Rate of Biochemical Abortion Within 6 Weeks Post-oocyte Retrieval	10.3 percentage of participants Interval 6.8 to 14.8

SECONDARY outcome

Timeframe: Within 10 weeks post-oocyte retrieval

Population: The mITT analysis set consisted of all participants who had successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo transfer.

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

Outcome measures

Measure	Progesterone Vaginal Ring n=243 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Cumulative Rate of Biochemical Abortion Within 10 Weeks Post-oocyte Retrieval	10.3 percentage of participants Interval 6.8 to 14.8

SECONDARY outcome

Timeframe: At 2 weeks and 2 weeks +3-4 Days post oocyte retrieval

Population: The mITT analysis set consisted of all participants who had successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo transfer.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=243 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Positive β-hCG Rate at 2 Weeks and 2 Weeks +3-4 Days Post Oocyte Retrieval	60.9 percentage of participants Interval 54.5 to 67.1

SECONDARY outcome

Timeframe: At 6 weeks post-oocyte retrieval

Population: The mITT analysis set consisted of all participants who had successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo transfer.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=243 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Clinical Pregnancy Rate at 6 Weeks	44.9 percentage of participants Interval 38.5 to 51.3

SECONDARY outcome

Timeframe: At 10 weeks post-oocyte retrieval

Population: The mITT analysis set consisted of all participants who had successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo transfer.

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

Outcome measures

Measure	Progesterone Vaginal Ring n=243 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Clinical Pregnancy Rate at 10 Weeks	43.2 percentage of participants Interval 36.9 to 49.7

SECONDARY outcome

Timeframe: At 4 weeks +3-4 Days after oocyte retrieval

Population: The mITT analysis set consisted of all participants who had successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo transfer.

Frequency of participants with ectopic and heterotopic pregnancies was presented.

Outcome measures

Measure	Progesterone Vaginal Ring n=243 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Rate of Ectopic and Heterotopic Pregnancies Following Oocyte Retrieval Ectopic pregnancy	0.4 percentage of participants Interval 0.0 to 2.3
Rate of Ectopic and Heterotopic Pregnancies Following Oocyte Retrieval Heterotopic pregnancy	0.0 percentage of participants Interval 0.0 to 1.5

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Rate of Abnormal Findings in Clinical Laboratory Tests (Clinical Chemistry, Hematology, and Urinalysis) Potassium (mmol/L)<3.5->5.3	1 participants
Rate of Abnormal Findings in Clinical Laboratory Tests (Clinical Chemistry, Hematology, and Urinalysis) Blood, traces	1 participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Rate of Abnormal Findings in Vital Signs Weight (kg), decrease of >=7% from BL	4 participants
Rate of Abnormal Findings in Vital Signs Weight (kg), increase of >=7% from BL	23 participants
Rate of Abnormal Findings in Vital Signs SBP (mmHg), <=90 and decrease >=20 from BL	2 participants
Rate of Abnormal Findings in Vital Signs DBP (mmHg), <=50 and decrease of>=15 from BL	3 participants
Rate of Abnormal Findings in Vital Signs DBP(mmHg),>=105 and increase of>=15 from BL	1 participants
Rate of Abnormal Findings in Vital Signs Heart Rate(bpm) <=50 and decrease of>= 15 from BL	1 participants
Rate of Abnormal Findings in Vital Signs Heart Rate(bpm) >=120 and increase of>= 15 from BL	1 participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Frequency, Intensity/Grade, Seriousness, and Relatedness of Adverse Events (AEs) Any AE	124 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of Adverse Events (AEs) Mild AE	100 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of Adverse Events (AEs) Moderate AE	46 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of Adverse Events (AEs) Severe AE	9 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of Adverse Events (AEs) Serious AE	4 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of Adverse Events (AEs) ADRs	25 participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Frequency and Intensity/Grade of Vaginal Bleeding/Spotting Any vaginal bleeding	4 participants
Frequency and Intensity/Grade of Vaginal Bleeding/Spotting Mild vaginal bleeding	3 participants
Frequency and Intensity/Grade of Vaginal Bleeding/Spotting Moderate vaginal bleeding	1 participants
Frequency and Intensity/Grade of Vaginal Bleeding/Spotting Severe vaginal bleeding	1 participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Frequency and Intensity/Grade of Vaginal Hemorrhage	0 participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Frequency and Intensity/Grade of Vaginal Pain Any vaginal pain	2 participants
Frequency and Intensity/Grade of Vaginal Pain Mild vaginal pain	2 participants
Frequency and Intensity/Grade of Vaginal Pain Moderate vaginal pain	1 participants
Frequency and Intensity/Grade of Vaginal Pain Severe vaginal pain	0 participants
Frequency and Intensity/Grade of Vaginal Pain Potentially life threatening vaginal pain	0 participants
Frequency and Intensity/Grade of Vaginal Pain Any dyspareunia	1 participants
Frequency and Intensity/Grade of Vaginal Pain Mild dyspareunia	0 participants
Frequency and Intensity/Grade of Vaginal Pain Moderate dyspareunia	1 participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Frequency and Intensity/Grade of Vaginal Infection Any vaginal infection	4 participants
Frequency and Intensity/Grade of Vaginal Infection Mild vaginal infection	3 participants
Frequency and Intensity/Grade of Vaginal Infection Moderate vaginal infection	1 participants
Frequency and Intensity/Grade of Vaginal Infection Severe vaginal infection	0 participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Frequency and Intensity/Grade of Vaginal Irritation Any vaginal itching	2 participants
Frequency and Intensity/Grade of Vaginal Irritation Mild vaginal itching	2 participants
Frequency and Intensity/Grade of Vaginal Irritation Moderate vaginal itching	0 participants
Frequency and Intensity/Grade of Vaginal Irritation Any vaginal dryness	1 participants
Frequency and Intensity/Grade of Vaginal Irritation Mild vaginal dryness	0 participants
Frequency and Intensity/Grade of Vaginal Irritation Moderate vaginal dryness	1 participants
Frequency and Intensity/Grade of Vaginal Irritation Any vaginal discharge	3 participants
Frequency and Intensity/Grade of Vaginal Irritation Mild vaginal discharge	3 participants
Frequency and Intensity/Grade of Vaginal Irritation Moderate vaginal discharge	0 participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Frequency, Intensity/Grade, Seriousness, and Relatedness of AEs Associated With Vaginal and Cervical Abrasions and Lesions Any Vaginal lesions	1 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of AEs Associated With Vaginal and Cervical Abrasions and Lesions Mild vaginal lesion	1 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of AEs Associated With Vaginal and Cervical Abrasions and Lesions Moderate vaginal lesion	0 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of AEs Associated With Vaginal and Cervical Abrasions and Lesions Severe vaginal lesion	0 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of AEs Associated With Vaginal and Cervical Abrasions and Lesions Serious vaginal lesion	0 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of AEs Associated With Vaginal and Cervical Abrasions and Lesions Related vaginal lesion	0 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of AEs Associated With Vaginal and Cervical Abrasions and Lesions Any vaginal abrasion	0 participants
Frequency, Intensity/Grade, Seriousness, and Relatedness of AEs Associated With Vaginal and Cervical Abrasions and Lesions Any cervical lesion	0 participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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.

Outcome measures

Measure	Progesterone Vaginal Ring n=253 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Frequency, Intensity/Grade, Seriousness, and Relatedness of AEs Associated With Vaginal Adhesions	0 Participants

SECONDARY outcome

Timeframe: From Day 1 of PVR treatment (day after oocyte retrieval) up to end-of-trial (12 weeks post-oocyte retrieval)

Population: The safety analysis set comprised of all participants treated with IMP.

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

Outcome measures

Measure	Progesterone Vaginal Ring n=254 Participants Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Frequency and Reason for PVR Discontinuation Personal issue	1 participants
Frequency and Reason for PVR Discontinuation Withdrawal by participant	2 participants
Frequency and Reason for PVR Discontinuation Lost to follow-up	1 participants
Frequency and Reason for PVR Discontinuation Adverse event	44 participants

Adverse Events

Progesterone Vaginal Ring

Serious events: 4 serious events

Other events: 72 other events

Deaths: 0 deaths

Serious adverse events

Measure	Progesterone Vaginal Ring n=254 participants at risk Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Pregnancy, puerperium and perinatal conditions Ectopic pregnancy	0.39% 1/254 • Number of events 1 • Adverse events were monitored from the time of obtaining informed consent until the last visit (end of trial) (up to approximately 4.5 months) . Adverse events with onset after the start of the IMP administration were considered treatment-emergent and are presented for the safety analysis set.
Psychiatric disorders Suicidal ideation	0.39% 1/254 • Number of events 1 • Adverse events were monitored from the time of obtaining informed consent until the last visit (end of trial) (up to approximately 4.5 months) . Adverse events with onset after the start of the IMP administration were considered treatment-emergent and are presented for the safety analysis set.
Reproductive system and breast disorders Adnexal torsion	0.39% 1/254 • Number of events 1 • Adverse events were monitored from the time of obtaining informed consent until the last visit (end of trial) (up to approximately 4.5 months) . Adverse events with onset after the start of the IMP administration were considered treatment-emergent and are presented for the safety analysis set.
Reproductive system and breast disorders Ovarian cyst ruptured	0.39% 1/254 • Number of events 1 • Adverse events were monitored from the time of obtaining informed consent until the last visit (end of trial) (up to approximately 4.5 months) . Adverse events with onset after the start of the IMP administration were considered treatment-emergent and are presented for the safety analysis set.

Other adverse events

Measure	Progesterone Vaginal Ring n=254 participants at risk Treatment started on the day following oocyte retrieval and could be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval), depending on the participants pregnancy assessment. A new PVR was inserted every 7 days with up to 10 PVRs used.
Gastrointestinal disorders Nausea	8.7% 22/254 • Number of events 22 • Adverse events were monitored from the time of obtaining informed consent until the last visit (end of trial) (up to approximately 4.5 months) . Adverse events with onset after the start of the IMP administration were considered treatment-emergent and are presented for the safety analysis set.
Nervous system disorders Headache	5.1% 13/254 • Number of events 17 • Adverse events were monitored from the time of obtaining informed consent until the last visit (end of trial) (up to approximately 4.5 months) . Adverse events with onset after the start of the IMP administration were considered treatment-emergent and are presented for the safety analysis set.
Pregnancy, puerperium and perinatal conditions Biochemical pregnancy	9.8% 25/254 • Number of events 25 • Adverse events were monitored from the time of obtaining informed consent until the last visit (end of trial) (up to approximately 4.5 months) . Adverse events with onset after the start of the IMP administration were considered treatment-emergent and are presented for the safety analysis set.
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	7.1% 18/254 • Number of events 18 • Adverse events were monitored from the time of obtaining informed consent until the last visit (end of trial) (up to approximately 4.5 months) . Adverse events with onset after the start of the IMP administration were considered treatment-emergent and are presented for the safety analysis set.

Additional Information

Global Clinical Compliance

Ferring Pharmaceuticals

Phone: +1 833-548-1402

Email: DK0-Disclosure@ferring.com

Results disclosure agreements

• Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript. Additional time may be required to allow Ferring to seek patent protection of the invention.
• Publication restrictions are in place

Restriction type: OTHER