Clinical trial NCT03565211
Conditions: Progesterone Supplementation in Women Undergoing ART
Keywords: Progesterone vaginal ring (PVR) Vaginal progesterone ring Assisted reproductive technology (ART) Infertility
Sponsor: Ferring Pharmaceuticals
Start date: 2018-07-26; Completion date: 2019-07-29
Enrollment: 352 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to assess the safety of Progesterone Vaginal Ring (PVR) in women undergoing fresh embryo transfer (ART).

Detailed description:

Arms: arm 1: 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.
Interventions: intervention 1: Progesterone vaginal ring
Intervention descriptions: intervention 1: A flexible, non-degradable PVR containing progesterone in micronized formulation and dispersed evenly throughout the ring.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
Protocol 
 
 
Title of trial:  
A Prospective, Multi-Center, Non-Comparative Trial of the Clinical Safety of 
the Progesterone Vaginal Ring in Women Undergoing Assisted Reproductive 
Technology (ART) Procedures 
Sponsor trial code: 
000293 
Date:  
09 Aug 2019 
 
 
 
 
 


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CLINICAL TRIAL PROTOCOL
A Prospective, Multi-Center, Non-Comparative Trial of the Clinical Safety of 
the Progesterone Vaginal Ring in Women Undergoing Assisted Reproductive 
Technology (ART) Procedures
Trial 000293
SARA
Safety Assessment of Progesterone Vaginal Ring in Women Undergoing ART
IND Number:
070785
Investigational Medicinal Product:
Progesterone vaginal ring (PVR)
Indication:
Progesterone supplementation in women undergoing 
ART
Phase:
3b
Name and Address of Sponsor:
Ferring Pharmaceuticals Inc.
100 Interpace Parkway
Parsippany, NJ 07054
United States
Tel: (+1) 973-796-1600
GCP Statement:
This trial will be performed in compliance with GCP.
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group.


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SYNOPSIS
TITLE OF TRIAL
A Prospective, Multi-Center, Non-Comparative Trial of the Clinical Safety of the Progesterone 
Vaginal Ring in Women Undergoing Assisted Reproductive Technology (ART) Procedures
Short title: SARA (Safety Assessment of Progesterone Vaginal Ring in Women Undergoing 
ART)
SIGNATORY INVESTIGATOR
Laurel Stadtmauer, MD, PhD.
The Jones Institute for Reproductive Medicine, Norfolk, Virginia.
TRIAL SITE(S)
Approximately 15 sites in the United States
PLANNED TRIAL PERIOD
First subject first visit:
Q3 2018
Last subject last visit:
Q3 2019
CLINICAL PHASE
3b
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE 
TRIAL
Successful human reproduction is dependent upon the influence of progesterone on endometrial 
structure and receptivity. Once the corpus luteum is formed after ovulation, it begins to secrete 
progesterone, which is necessary and sufficient to decidualize the endometrium to facilitate 
implantation. If conception and implantation occur, increasing concentrations of human chorionic 
gonadotropin (hCG) drive continued secretion of progesterone from the corpus luteum, which is 
critical for the maintenance of the endometrium. Progesterone continues to be produced by the 
corpus luteum until the seventh or eighth week of gestation, at which time the placenta becomes 
the primary site of production for the remainder of pregnancy.
Administration of exogenous progesterone to support luteal function has been utilized in the 
treatment of infertility, particularly with ART. A number of studies have demonstrated that the 
use of gonadotrophin-releasing hormone analogs during controlled ovarian stimulation is 
associated with defects in corpus luteal function. Progesterone supplementation after the transfer 
of a fresh, autologous embryo has been shown to improve pregnancy rates.
Vaginal routes of progesterone administration have been shown to allow effective targeted 
delivery for various indications, including supplementation of corpus luteal function. The vaginal 
route offers several important advantages over other methods: it is convenient and acceptable for 


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many subjects, is not painful, does not require any special equipment, systemic levels are low, 
and it rarely produces allergic or other adverse reactions.
A flexible, non-degradable progesterone vaginal ring (PVR) has been developed, releasing an 
average of 11 mg progesterone/day consistently over 7 days. The progesterone (20% w/w) is in a 
micronized formulation and dispersed evenly throughout the ring. 
In a pivotal phase 3 trial (Teva Women’s Health, Inc. Study DR-PGN-302) evaluating the 
efficacy and safety of PVR used for luteal phase support in women undergoing in vitro 
fertilization (IVF), the primary endpoint was clinical pregnancy rate at 8 and 12 weeks of 
pregnancy. Once-weekly PVR was statistically non-inferior to the active comparator, daily 8% 
progesterone vaginal gel, in women 18-34 years of age. Secondary efficacy analyses included 
evaluations of live birth rate, cycle cancellation rate, rate of spontaneous abortion, rate of 
biochemical pregnancy, and rate of ectopic pregnancy for each treatment group. These rates were 
similar between the 2 active treatment groups and consistent with reported background rates.
Weekly PVR insertion appeared to be safe and well tolerated. Adverse events (AEs) and serious 
adverse events (SAEs) were similar for both active treatment groups, and no significant safety 
trends were noted for PVR. Treatment-related AEs were generally similar between the 2 active 
treatment groups and consistent with the known safety profile of progesterone. Rates of subject
discontinuation due to an AE were similar between the treatment groups. AEs related to vaginal 
bleeding were similar between the 2 active treatment groups. No subject discontinued because of 
vaginal bleeding, and no subject was switched to an alternative progesterone product because of a 
bleeding issue. There were no increased rates of cervical/vaginal abrasions or irritation associated 
with use of a vaginal ring compared with vaginal gel.
Manufacturing enhancements for the PVR were implemented subsequent to the pivotal phase 3 
trial. Therefore, a bioequivalence trial was conducted to compare the PVR manufactured using 
the new process to the ring manufactured by the legacy process (the phase 3 clinical trial 
material). The results from the pharmacokinetic trial (DR201-BE-10021) demonstrated that the 
PVR manufactured with the new process was bioequivalent to the PVR produced from the legacy 
process. The safety data indicated that both rings were similarly safe and well tolerated by 
healthy, postmenopausal female subjects who were pretreated with estrogen.
The present trial assesses the safety and tolerability of the PVR manufactured with the new 
process when used for luteal phase support in women undergoing ART. While the design of the 
proposed trial is similar to that of the pivotal phase 3 trial for the PVR, changes to the way in 
which AEs are collected and scored have been implemented as requested by the Agency.


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OBJECTIVES
Primary objective

To estimate the cumulative rate of any spontaneous abortion, including spontaneous 
clinically recognized pregnancy loss and blighted ovum during the trial (up to Week 12 
following oocyte retrieval), in subjects treated with PVR following fresh embryo transfer.
Secondary objectives

To describe the cumulative rate of spontaneous abortions determined at 6 and 10 weeks 
post-oocyte retrieval, including spontaneous clinically recognized pregnancy loss and 
blighted ovum, in all subjects treated with PVR.

To describe the cumulative rate of biochemical abortions determined at 6 and 10 weeks 
post-oocyte retrieval in all subjects treated with PVR.

To describe the rate of ectopic and heterotopic pregnancy in all subjects treated with PVR 
following oocyte retrieval.

To describe the safety of PVR through the collection of clinical laboratory tests and vital 
signs in all subjects treated with PVR.

To assess the safety and tolerability of PVR in all subjects treated with PVR.

To determine the positive β-hCG rate of subjects treated with PVR following oocyte 
retrieval.

To determine the clinical pregnancy rate of subjects treated with PVR following oocyte 
retrieval.
ENDPOINTS
Primary endpoint

Cumulative 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.
Note: spontaneous abortion is defined as two positive 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).
Secondary endpoints

Cumulative rate of spontaneous abortions determined at 6 and 10 weeks post-oocyte 
retrieval in all subjects treated with PVR.

Cumulative rate of biochemical abortions determined at 6 and 10 weeks post-oocyte 
retrieval in all subjects treated with PVR. Biochemical abortion is defined as a positive 


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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.

Rate of ectopic and heterotopic pregnancies in all subjects treated with PVR following 
oocyte retrieval.

Rate of abnormal findings in clinical laboratory tests and vital signs for all subjects 
treated with PVR.

Frequency, intensity/grade, seriousness, and relatedness of adverse events (AEs) for all 
subjects treated with PVR.

Frequency, intensity/grade of vaginal bleeding/spotting, vaginal hemorrhage, pain, 
vaginal infection, and vaginal irritation for all subjects treated with PVR.

Frequency, intensity/grade, seriousness, and relatedness of AEs associated with vaginal 
and cervical abrasions and lesions and with vaginal adhesions for all subjects treated with 
PVR.

Frequency and reason for PVR discontinuation.

Positive β-hCG rate (positive serum β-hCG test) at 2 weeks and 2 weeks + 3-4 days post-
oocyte retrieval in all subjects treated with PVR.

Clinical pregnancy rate (TVUS showing at least 1 intrauterine gestational sac with fetal 
heart beat) at 6 and 10 weeks post-oocyte retrieval in all subjects treated with PVR.
METHODOLOGY
This is an open-label, single-arm, safety trial of PVR for luteal phase support in women 
undergoing IVF with fresh oocytes. Women between the ages of 18 and 34 years with tubal, 
idiopathic, male factor, ovulatory dysfunction, or endometriosis-linked infertility, who agree to 
be considered for inclusion in the trial, will be invited to be seen at the trial site.
Once informed consent is obtained, eligible subjects will be started on an ovarian down-
regulation / suppression protocol utilizing combined oral contraceptives supplied by the site for 
≥14 days to ≤21 days (based upon the site standard of care), with leuprolide acetate at a dose of 
0.1 mL (500 µg)/day beginning 4 days prior to the last birth control pill and for ≥10 days to 
≤20 days; ovarian suppression is to begin in the cycle immediately prior to the ovarian 
stimulation cycle. After suppression, an ovarian stimulation protocol will begin on the second or 
third day after the start of menses with a reduction in leuprolide acetate dose to 0.05 mL 
(250 µg/day) followed by an individually determined ovarian stimulation protocol with highly 
purified, human menopausal gonadotropin (HP-hMG; MENOPUR) at an initial dose of 
225 IU/day for 5 days according to label. Based on clinical monitoring, subsequent dosing should 
be adjusted according to individual subject response. Dose adjustments should not be made more 
frequently than once every two days and should not exceed 150 IU per adjustment. The 
maximum daily dose of MENOPUR should not exceed 450 IU and the minimum daily dose 
should not be lower than 75 IU. MENOPUR dosing should not continue for >20 days and 
coasting is not allowed. Subjects will be monitored to determine when to trigger ovulation with 


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hCG. A TVUS will be performed to assess follicle size and serum estradiol levels will be
determined. A subject must have at least 2 follicles ≥17 mm (mean of 2 dimensions) to receive 
the hCG trigger. Subjects who do not reach this threshold after 20 days of stimulation are to be 
discontinued from the trial. If the estradiol level is ≥5000 pg/mL, hCG should not be 
administered and the subject should be discontinued from the trial.
Oocyte retrieval will occur approximately 35-37 hours after hCG administration. On the day after 
oocyte retrieval, the subject will begin treatment with the Investigational Medicinal Product 
(IMP), PVR. Following instruction on PVR insertion and removal, the subject will insert the first 
PVR (PVR1) at the trial site. The PVR will remain in place a minimum of 23 hours/day. The 
subject will remove PVR1 before fresh embryo transfer and reinsert it after the transfer. Fresh 
embryo transfer will occur 5 days after oocyte retrieval per the trial site’s protocol. The number 
of embryos to transfer must be guided by the 2017 American Society for Reproductive Medicine 
(ASRM) and the Society for Assisted Reproductive Technology (SART) guidelines 
(SART/ASRM 2017): women with the expectation of one or more high-quality embryo(s)
available for cryopreservation, and women with previous live birth after an IVF cycle, will have
transfer of a single blastocyst. All other women will have transfer of no more than two 
blastocysts. Additional PVRs will be distributed for weekly insertion, with the second PVR 
(PVR2) to be inserted at home 7 days following the initial insertion of the first PVR (PVR1), and 
the third PVR (PVR3) to be inserted either at home or at the site 7 days following the insertion of 
PVR2.
Two weeks after oocyte retrieval, a blood draw will be performed to measure serum levels of 
progesterone and β-hCG. Subjects with a β-hCG level <5 mIU/mL will be discontinued from the 
trial. Those with a β-hCG level ≥5 mIU/mL will insert their next PVR and continue in the trial
for up to a total of 10 weeks (up to a total of 10 PVRs). Additional serum pregnancy tests will be 
performed at 2 weeks + 3-4 days and at 3 weeks. Subjects who are no longer pregnant will be 
discontinued from the trial. Subjects with positive β-hCG results at 3 weeks will insert PVR4 and 
receive PVR5 and PVR6 to be inserted weekly.
A TVUS will be performed to document the presence of an intrauterine gestational sac 4 weeks + 
3-4 days after oocyte retrieval. If it is determined that the subject has an ectopic pregnancy, the 
subject will be treated according to the site’s standard protocol and will be withdrawn from the 
trial. Six weeks after oocyte retrieval, a TVUS will be performed to determine the presence and 
number of gestational sacs with/without fetal heart beat. Pregnant subjects will insert PVR7 and 
receive additional PVRs to be inserted weekly (PVR8, PVR9, and PVR10). Ten weeks after 
oocyte retrieval (if the subject is pregnant), an ultrasound (either transvaginal or abdominal) will 
be performed to determine the number of gestational sacs present with and without fetal heart 
beat and the estimated gestational age.
Safety will be monitored throughout the trial. Standardized criteria will be applied to AEs of 
special interest (vaginal bleeding, vaginal pain, and vaginal irritation etc.) to establish grade 
(intensity). Patient-reported vaginal pain and/or irritation should be recorded as an AE if 


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considered clinically significant by the physician. The physician can perform an unscheduled 
pelvic examination at his or her discretion based upon these AEs at any time. A scheduled pelvic 
examination will be performed at screening, on day 1 of PVR treatment, and at 4 weeks + 3-4 
days, 6, 10, and 12 weeks post-oocyte retrieval (Visits 4, 7P, 8, 9 and 10) to document the 
presence and grade (intensity) of any pain, irritation, abrasions, or lesions on the cervix or vagina 
and the presence and grade (intensity) of vaginal adhesions using standardized criteria. If any 
lesions or abrasions are found on the cervix or vagina or vaginal adhesions are noted, another 
examination will be performed 2-4 days later. Subjects will be followed until the 
lesions/abrasions resolve or until the final assessment at the End-of-trial visit, whichever comes 
first. Any clinically significant finding will be reported as an AE.
Post-trial procedures will be performed 2 weeks after the last exposure to IMP (12 weeks after 
oocyte retrieval). An overview of the trial is provided below: 
Screening
Suppression
Stimulation
Oocyte 
Retrieval
Treatment 
Period
Post Treatment 
Period
Consent and 
Screening
Down-regulation
Visits 1 and 2
Visit 3
Visits 4-9:
Day after oocyte 
retrieval and 
ongoing pregnancy 
(~10 weeks)
PVR1 through 
PVR10
Visit 10:
End-of-trial visit 
(2 weeks after last 
exposure to 
Investigational 
Medicinal Product)
NUMBER OF SUBJECTS
Approximately 240 subjects will be needed to complete the controlled ovarian stimulation cycle, 
undergo oocyte retrieval, be treated with PVR, and receive fresh embryo transfer.
CRITERIA FOR INCLUSION / EXCLUSION
Inclusion Criteria
Subjects must meet the following inclusion criteria:
Informed consent signed and dated prior to any trial related procedures.
Pre-menopausal females aged 18-34 years old at time of consent.
Documentation of a normal uterine cavity by hysteroscopy, hydrosonogram, or 
hysterosalpingogram within 1 year of screening.
Documentation of normal Pap smear test within 24 months of screening.


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Documentation of negative testing within 6 months of the start of screening for serum 
Hepatitis B surface antigen, Hepatitis C antibody, human immunodeficiency virus 
antibody, rapid plasma reagin/venereal disease research laboratory.
Documentation of rubella antibody, ABO grouping, Rho typing, and normal prolactin 
and thyroid function within 6 months of screening.
At least 1 cycle without reproductive hormone medication prior to the screening follicle 
stimulating hormone (FSH) and estradiol blood draw.
Tubal, idiopathic, male factor, ovulatory dysfunction, or endometriosis-linked infertility.
For fresh sperm: sperm assessed for leukospermia (≥2 million white blood cells/mL or 
round cells/mL) is required within 2 months of pituitary down regulation OR male 
partner empirically treated with antibiotics prior to the IVF cycle.
Semen analysis within 1 year of screening by standard World Health Organization 
and/or Kruger criteria. Frozen sperm, including donor sperm, may be used, as long as 
testing done at the time of freezing meets standard criteria. Male partners with 
obstructive azoospermia will not be required to have this semen analysis.
Able to understand, read, and sign an informed consent after the nature of the trial has 
been fully explained.
Able to complete all trial procedures.
Exclusion Criteria
The presence of any of the following excludes a subject from trial enrollment:
Contraindications to the use of progesterone, which include:

Known sensitivity to progesterone or related drugs

Undiagnosed vaginal bleeding

Significant liver dysfunction or disease (including liver function tests >2 times 
the upper limit of normal)

Known or suspected malignancy of the breast or genital organs

Active thrombophlebitis or thromboembolic disorders, or a history of 
hormone-associated thrombophlebitis or thromboembolic disorders
Significant psychiatric disease that is not well-controlled.
Body mass index >38 kg/m2.
Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood 
pressure >100 mmHg).
FSH >15 IU/L during the early follicular phase (Day 2-4). For those subjects with 
polycystic ovarian syndrome, a Day 2-4 FSH level can be obtained following a 
progestogen withdrawal or spontaneous menses.


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Clinically significant gynecologic pathology, such as submucosal fibroids, intramural 
fibroids >5 cm, communicating hydrosalpinx, uncorrected uterine septum, endometrial 
cancer or endometrial atypia, scar tissue inside the cavity or poorly developed uterine 
lining from prior uterine surgery, pelvic tuberculosis, or any other conditions that could 
adversely affect pregnancy success.
Uncontrolled hyperprolactinemia or hypothyroidism.
History of pelvic radiation. Subjects with a history of cancer within the last 5 years, 
except for squamous or basal cell cancer of the skin.
Currently pregnant or breastfeeding.
Current gonorrhea or chlamydia.
History of human immunodeficiency virus/acquired immunodeficiency virus.
Known hypersensitivity or previous intolerance to silicone or to any active ingredient or 
excipients in the medicinal products used in this trial.
History of toxic shock syndrome.
Known or suspected substance abuse within 1 year prior to screening.
Use of any investigational drug or device within 30 days prior to screening.
Undergoing donor oocyte cycle, embryo biopsy, or preimplantation genetic testing.
History of more than 1 failed fresh IVF cycle. Note: an ART cycle is started when a 
woman begins taking medication to stimulate the ovaries to develop eggs or, if no drugs 
are given, when the woman begins ovarian follicular monitoring (using ultrasound or 
blood tests) for natural egg production (Centers for Disease Control, 2005). A failed 
cycle is defined as having started a cycle and not becoming pregnant or pregnancy loss 
prior to the 20th week of pregnancy.
More than 2 consecutive clinical miscarriages (gestational sac observed on ultrasound).
Insulin-sensitizing agents, ART cycle, or ovarian stimulation with gonadotropins within 
30 days or clomiphene stimulation within 90 days prior to the screening FSH and 
estradiol blood draw.
Tobacco use within 3 months prior to screening.
For fresh sperm: male partners with non-obstructive azoospermia.
Any abnormal finding or condition deemed clinically significant by the Investigator on 
history, screening, physical examination, or pelvic examination that contraindicates 
pregnancy or the use of progesterone or a vaginal ring, including the presence of any 
vaginal or cervical abrasions/lesions.
Any condition the Investigator believes would interfere with the subject’s ability to 
provide informed consent, to comply with trial instructions, or which might confound 
the interpretation of the trial results or put the subject at risk.


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MEDICINAL PRODUCTS
Investigational Medicinal Product (IMP)
The IMPs in the present trial will be supplied as vaginal rings, which releases an average of 11 
mg progesterone/day consistently over 7 days. The progesterone (20% w/w) is in a micronized 
formulation and dispersed evenly throughout the ring. 
Non-Investigational Medicinal Products (NIMPs)
The non-investigational medicinal products (NIMPs) to be used are combined oral contraceptives
(CYCLAFEM 1/35, Qualitests Pharmaceuticals), GnRH agonist (LEUPROLIDE ACETATE, 
Sandoz), HP-hMG (MENOPUR, Ferring Pharmaceuticals), and hCG (NOVAREL, Ferring 
Pharmaceuticals).
DURATION OF TREATMENT
Eligible subjects will receive up to 10 weeks of progesterone treatment if the subject becomes 
and remains pregnant. Treatment will be stopped if it is determined the subject has a failed 
attempt at becoming pregnant or is found to no longer be pregnant.
STATISTICAL METHODS
Primary Analysis
At the final analysis, the cumulative rate of any spontaneous abortion, including spontaneous 
clinically recognized pregnancy loss and blighted ovum during the trial (up to Week 12 following 
oocyte retrieval), in subjects treated with PVR following fresh embryo transfer will be estimated
(i.e., modified intention-to-treat [mITT] population). 
The number and rate of any spontaneous abortions (occurring on or before 12 weeks following 
oocyte retrieval) for subjects in the mITT cohort will be summarized and the associated two-
sided exact 95% confidence interval will be generated. Upon generating the two-sided exact 
95% confidence interval, the upper bound of the interval will be assessed for whether it excludes 
or fails to exclude a spontaneous abortion rate of 15%.
Determination of Sample Size
Statistical simulations have been performed to understand the operating characteristics under 
varying assumptions for both the sample size of the mITT analysis population and the “true” 
proportion of spontaneous abortions. For each simulation repetition, a sample of subjects was 
simulated using the binomial distribution and a given pair of sample size and “true” proportion of 
spontaneous abortions assumptions. A two-sided 95% exact confidence interval was then created 
based on the simulated data and the upper bound of this confidence interval was compared to the 
threshold of 0.15 (corresponding to a spontaneous abortion rate of 15%). If the upper bound of 
the two-sided 95% exact confidence interval was less than 0.15, the simulation repetition was 


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declared a “success”. If, however, the upper bound of the two-sided 95% exact confidence 
interval was greater than or equal to 0.15, the simulation repetition was declared a “failure”. This 
process was repeated 10,000 times for each combination of assumed sample size and “true” 
proportion of spontaneous abortions. The proportion of simulation repetition successes to the 
total number of simulation repetitions then described the power of the proposed trial given the 
pair of assumptions.
If the “true” spontaneous abortion rate is 8%, 9%, or 10%, the sample size required to achieve 
80% power to exclude the possibility of a 15% spontaneous abortion rate after the use of PVR is 
180, 240, or 365, respectively. Taking the middle of this range, a trial with 240 subjects in the 
mITT analysis population is considered as being adequately powered under a relevant 
assumption in the target population.
Assessment of Primary and Secondary Endpoints
There are 3 analysis cohorts for this trial. The mITT cohort consists of all subjects who had 
successful oocyte retrieval, received at least 1 dose of IMP, and had completed fresh embryo 
transfer. The safety cohort comprises all subjects treated with IMP. The eligible subjects (ES) 
cohort consists of all subjects who were deemed eligible for trial participation based on inclusion 
and exclusion criteria at screening and treated with oral contraceptives, leuprolide acetate, or 
MENOPUR.
The primary objective is to estimate the cumulative rate of any spontaneous abortion, including 
spontaneous clinically recognized pregnancy loss and blighted ovum during the trial (up to 
Week 12 following oocyte retrieval) for subjects in the mITT cohort. The number and rates of 
any spontaneous abortions will be summarized and associated exact 95% confidence intervals 
will be generated. Furthermore, as part of a Bayesian sensitivity analysis, a 95% credible interval
will be generated. The spontaneous abortion rate, biochemical abortion rate, clinical pregnancy 
rate, and positive β-hCG rate will be similarly analyzed for the mITT and safety cohort, for 
subjects that had oocyte(s) retrieved. However, for these endpoints, credible intervals will not be 
derived. Furthermore, safety will be assessed by summarizing treatment-emergent AEs for the 
safety and ES cohorts. Treatment-emergent AEs will be summarized overall, by grade (intensity), 
seriousness, and drug relatedness by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities. A treatment-emergent AE is any AE that occurs after the 
start of PVR and through the end of the trial, or a pretreatment AE/medical condition that 
worsens in intensity after the start of PVR. Furthermore, a separate treatment-emergent AE 
summary table will be generated for AEs of special interest, such as vaginal pain and irritation,
vaginal infection, vaginal bleeding/spotting, vaginal hemorrhage, vaginal adhesions and vaginal 
or cervical abrasions and lesions. These events will also be further analyzed by grade (intensity).
Tolerability for the safety cohort will be assessed by summarizing the total number of subjects 
who prematurely discontinued PVR and the associated reasons for discontinuation. This 
summary will be based on the safety cohort.


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For the safety and ES cohorts, the number of subjects with abnormal clinical laboratory and vital 
sign assessments will be summarized.


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TABLE OF CONTENTS
SYNOPSIS....................................................................................................................................................... 2
LIST OF TABLES........................................................................................................................................ 18
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 19
1
INTRODUCTION ............................................................................................................................. 20
1.1
Background............................................................................................................................. 20
1.2
Scientific Justification for Conducting the Trial..................................................................... 21
1.3
Benefit / Risk Aspects............................................................................................................. 22
2
TRIAL OBJECTIVES AND ENDPOINTS..................................................................................... 23
2.1
Objectives ............................................................................................................................... 23
2.2
Endpoints ................................................................................................................................ 23
3
INVESTIGATIONAL PLAN ........................................................................................................... 25
3.1
Overall Trial Design................................................................................................................ 25
3.1.1
Trial Design Diagram................................................................................................. 25
3.1.2
Overall Design and Control Methods ........................................................................ 25
3.1.3
Trial Schedule............................................................................................................ 27
3.2
Planned Number of Trial Sites and Subjects........................................................................... 27
3.3
Interim Analysis...................................................................................................................... 27
3.4
Data Monitoring Committee (DMC) ...................................................................................... 27
3.5
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 27
3.5.1
Trial Design ............................................................................................................... 27
3.5.2
Selection of Endpoints ............................................................................................... 27
3.5.3
Blinding...................................................................................................................... 28
3.5.4
Selection of Doses in the Trial................................................................................... 28
3.5.5
Selection and Timing of Dose for Each Subject........................................................ 28
3.5.6
Discontinuation and Trial Stopping Criteria.............................................................. 28
3.5.7
Follow-up Procedures ................................................................................................ 29
4
SELECTION OF TRIAL POPULATION ...................................................................................... 30
4.1
Trial Population....................................................................................................................... 30
4.1.1
Inclusion Criteria ....................................................................................................... 30
4.1.2
Exclusion Criteria ...................................................................................................... 30
4.2
Method of Assigning Subjects to Treatment Groups.............................................................. 32
4.2.1
Recruitment................................................................................................................ 32
4.2.2
Randomization........................................................................................................... 32
4.3
Restrictions ............................................................................................................................. 32
4.3.1
Prior and Concomitant Therapies .............................................................................. 32
4.3.2
Prohibited Therapy..................................................................................................... 32
4.4
Withdrawal Criteria................................................................................................................. 33
5
TREATMENTS ................................................................................................................................. 34
5.1
Treatments Administered........................................................................................................ 34
5.1.1
Investigational Medicinal Product (IMP)................................................................... 34
5.1.2
Non-Investigational Medicinal Product (NIMP) ....................................................... 34
5.2
Characteristics and Source of Supply ..................................................................................... 35
5.3
Packaging and Labelling......................................................................................................... 35


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5.4
Conditions for Storage and Use .............................................................................................. 36
5.5
Blinding / Unblinding ............................................................................................................. 36
5.5.1
Blinding...................................................................................................................... 36
5.5.2
Unblinding of Individual Subject Treatment ............................................................. 36
5.6
Treatment Compliance............................................................................................................ 36
5.6.1
Dispensing and Accountability.................................................................................. 36
5.6.2
Assessment of Compliance........................................................................................ 37
5.7
Auxiliary Supplies................................................................................................................... 37
5.8
Return and Destruction of Medicinal Products....................................................................... 37
6
TRIAL PROCEDURES .................................................................................................................... 38
6.1
Screening and Ovarian Suppression (Down-regulation)......................................................... 41
6.2
Ovarian Stimulation and Oocyte Retrieval ............................................................................. 42
6.2.1
Visit 1: Start of Ovarian Stimulation ......................................................................... 42
6.2.2
Visit 2: End of Ovarian Stimulation .......................................................................... 42
6.2.3
Visit 3: Oocyte Retrieval............................................................................................ 43
6.3
Treatment with PVR ............................................................................................................... 43
6.3.1
Visit 4: Initiation of Treatment with PVR.................................................................. 43
6.3.2
Visit 5: Embryo Transfer ........................................................................................... 44
6.3.3
Visit 6: 2 Weeks After Oocyte Retrieval ................................................................... 45
6.3.4
Visit 6P: Procedural Visit .......................................................................................... 45
6.3.5
Visit 7: Week 5 of Pregnancy (3 Weeks After Oocyte Retrieval)............................. 46
6.3.6
Visit 7P: Procedural Visit .......................................................................................... 46
6.3.7
Visit 8: Week 8 of Pregnancy (6 Weeks After Oocyte Retrieval)............................. 47
6.3.8
Visit 9: Week 12 of Pregnancy (10 Weeks After Oocyte Retrieval) / Early-
withdrawal Visit......................................................................................................... 48
6.4
End-of-trial.............................................................................................................................. 48
7
TRIAL ASSESSMENTS ................................................................................................................... 50
7.1
Assessments Related to Primary Endpoint ............................................................................. 50
7.1.1
Pregnancy Monitoring................................................................................................ 50
7.1.1.1
β-hCG Test...................................................................................................50
7.1.1.2
Transvaginal Ultrasound ..............................................................................50
7.1.1.3
Ectopic and Heterotopic Pregnancies...........................................................50
7.1.2
Spontaneous Abortion................................................................................................ 50
7.2
Assessments Related to Secondary Endpoints........................................................................ 50
7.2.1
Positive β-hCG........................................................................................................... 50
7.2.2
Clinical Pregnancy..................................................................................................... 51
7.2.3
Biochemical Abortion................................................................................................ 51
7.2.4
Bleeding Log.............................................................................................................. 51
7.2.5
Vaginal Hemorrhage.................................................................................................. 51
7.2.6
Clinical Laboratory Variables.................................................................................... 51
7.2.7
Vital Signs.................................................................................................................. 52
7.2.8
Pelvic Examination .................................................................................................... 52
7.2.9
Adverse Events .......................................................................................................... 52
7.2.9.1
Adverse Events of Special Interest...............................................................52
7.3
Other Assessments.................................................................................................................. 53
7.3.1
Demographics ............................................................................................................ 53


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7.3.2
Medical/Gynecological History................................................................................. 53
7.3.3
Physical Examination................................................................................................. 53
7.3.4
Height, Weight, and Body Mass Index Calculation................................................... 53
7.3.5
Pelvic Examination and Pap Smear at Screening ...................................................... 53
7.3.6
PVR Diary.................................................................................................................. 53
7.3.7
Number and Size of Follicles..................................................................................... 54
7.3.8
Oocyte Retrieval ........................................................................................................ 54
7.3.9
Endometrial Thickness............................................................................................... 54
7.3.10 Embryo Transfer........................................................................................................ 54
7.3.11 Concomitant Medication............................................................................................ 54
8
ADVERSE EVENTS ......................................................................................................................... 55
8.1
Adverse Event Definition........................................................................................................ 55
8.2
Collection and Recording of Adverse Events......................................................................... 55
8.2.1
Collection of Adverse Events .................................................................................... 55
8.2.2
Recording of Adverse Events .................................................................................... 56
8.3
Adverse Events of Special Interest ......................................................................................... 58
8.3.1
Vaginal Pain and Irritation......................................................................................... 59
8.3.2
Vaginal or Cervical Abrasions and Lesions............................................................... 59
8.3.3
Vaginal Adhesions..................................................................................................... 59
8.3.4
Vaginal Infection ....................................................................................................... 59
8.3.5
Vaginal Bleeding/Spotting......................................................................................... 59
8.3.6
Vaginal Hemorrhage.................................................................................................. 59
8.3.7
Pregnancy Losses....................................................................................................... 59
8.4
Serious Adverse Events .......................................................................................................... 60
8.4.1
Serious Adverse Event Definition.............................................................................. 60
8.4.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 61
8.5
Follow-up of Adverse Events and Serious Adverse Events.................................................... 62
8.5.1
Follow-up of Adverse Events with Onset during the Trial........................................ 62
8.5.2
Follow-up of Adverse Events on Non-Investigational Medicinal Products 
During the Trial.......................................................................................................... 62
8.5.3
Collection of Serious Adverse Events with Onset after Last Visit in the Trial ......... 62
9
STATISTICAL METHODS ............................................................................................................. 63
9.1
Primary Analysis..................................................................................................................... 63
9.2
Determination of Sample Size ................................................................................................ 63
9.3
Subject Disposition ................................................................................................................. 64
9.4
Protocol Deviations................................................................................................................. 64
9.5
Analysis Sets........................................................................................................................... 64
9.5.1
mITT Cohort.............................................................................................................. 64
9.5.2
Safety Cohort ............................................................................................................. 64
9.5.3
Eligible Subjects (ES) Cohort.................................................................................... 65
9.6
Trial Population....................................................................................................................... 65
9.6.1
Demographics and other Baseline Characteristics..................................................... 65
9.6.2
Medical History, Concomitant Medication and Other Safety Evaluations................ 65
9.6.3
Prior and Concomitant Medications .......................................................................... 65
9.7
Endpoint Assessments............................................................................................................. 66
9.7.1
General Considerations.............................................................................................. 66


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9.7.2
Primary Endpoint....................................................................................................... 66
9.7.3
Secondary Endpoints ................................................................................................. 66
9.7.3.1
Spontaneous Abortion within 6 and 10 Weeks of Oocyte Retrieval............66
9.7.3.2
Biochemical Abortions within 6 and 10 Weeks of Oocyte Retrieval ..........66
9.7.3.3
Ectopic and Heterotopic Pregnancies...........................................................67
9.7.3.4
Positive β-hCG.............................................................................................67
9.7.3.5
Clinical Pregnancy .......................................................................................67
9.7.4
Other Assessments..................................................................................................... 67
9.7.4.1
Number and Size of Follicles during Stimulation........................................67
9.7.4.2
E2 and Progesterone Profiles .......................................................................68
9.7.4.3
Oocytes.........................................................................................................68
9.7.4.4
Characterization of Fertilized Oocytes one Day (Day 1) after Oocyte 
Retrieval.......................................................................................................68
9.7.4.5
Quality of Blastocysts 5 Days (Day 5) after Oocyte Retrieval ....................68
9.7.4.6
Endometrial Thickness.................................................................................70
9.8
Extent of Exposure and Treatment Compliance ..................................................................... 71
9.8.1
PVR............................................................................................................................ 71
9.8.2
Oral Contraceptives ................................................................................................... 71
9.8.3
MENOPUR, Leuprolide Acetate, and hCG............................................................... 71
9.9
Safety ...................................................................................................................................... 71
9.9.1
General Considerations.............................................................................................. 71
9.9.2
Adverse Events .......................................................................................................... 72
9.9.2.1
Treatment-Emergent AEs of Special Interest...............................................72
9.9.3
Safety Laboratory Variables ...................................................................................... 72
9.9.4
Vital Signs.................................................................................................................. 73
9.9.5
Bleeding Log.............................................................................................................. 73
9.9.6
Vaginal Hemorrhage.................................................................................................. 73
9.9.7
Pelvic Examination.................................................................................................... 73
9.10
Interim Analyses ..................................................................................................................... 73
10
DATA HANDLING ........................................................................................................................... 74
10.1
Source Data and Source Documents....................................................................................... 74
10.2
eCRF/Case Report Form......................................................................................................... 75
10.3
Data Management ................................................................................................................... 75
10.4
Provision of Additional Information....................................................................................... 76
11
MONITORING PROCEDURES ..................................................................................................... 77
11.1
Periodic Monitoring................................................................................................................ 77
11.2
Audit and Inspection............................................................................................................... 77
11.3
Confidentiality of Subject Data............................................................................................... 77
12
CHANGES IN THE CONDUCT OF THE TRIAL........................................................................ 79
12.1
Protocol Amendments............................................................................................................. 79
12.2
Deviations from the Protocol .................................................................................................. 79
12.3
Premature Trial Termination................................................................................................... 79
13
REPORTING AND PUBLICATION .............................................................................................. 80
13.1
Clinical Trial Report ............................................................................................................... 80
13.2
Confidentiality and Ownership of Trial Data.......................................................................... 80
13.3
Publications and Public Disclosure......................................................................................... 80


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13.3.1 Publication Policy...................................................................................................... 80
13.3.2 Public Disclosure Policy............................................................................................ 81
14
ETHICAL AND REGULATORY ASPECTS................................................................................. 82
14.1
Institutional Review Board ..................................................................................................... 82
14.2
Regulatory Authority Authorization/Approval/Notification................................................... 82
14.3
End-of-Trial and End-of-Trial Notification ............................................................................ 82
14.4
Ethical Conduct of the Trial.................................................................................................... 82
14.5
Subject Information and Consent............................................................................................ 82
14.6
Subject Participation Card ...................................................................................................... 83
14.7
Compliance Reference Documents......................................................................................... 83
15
LIABILITIES AND INSURANCE .................................................................................................. 84
15.1
ICH-GCP Responsibilities...................................................................................................... 84
15.2
Liabilities and Insurance......................................................................................................... 84
16
ARCHIVING...................................................................................................................................... 85
16.1
Investigator File ...................................................................................................................... 85
16.2
Trial Master File...................................................................................................................... 85
17
REFERENCES................................................................................................................................... 86
APPENDICES............................................................................................................................................... 87
Appendix 1
Sample Subject Instructions For Use .........................................................................87
Appendix 2
Pelvic Examination, Grade, and Criteria....................................................................90
Appendix 3
Assessment of AEs of Special Interest: Vaginal Pain and Vaginal Irritation.............93
Appendix 4
Bleeding Log..............................................................................................................94
Appendix 5
Scoring of Bleeding Log Information ........................................................................95
Appendix 6
Primary Analysis Simulation Code and the Sensitivity Analysis Operating 
Characteristics ............................................................................................................96


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LIST OF TABLES
Table 3-1
Trial Flow Overview.......................................................................................................25
Table 5-1
Non-investigational Medicinal Products.........................................................................34
Table 5-2
Characteristics of Medicinal Products ............................................................................35
Table 5-3
Packaging of Medicinal Products ...................................................................................36
Table 6-1
Trial Schedule .................................................................................................................39
Table 9-1
Power Achieved over Varying Sample Sizes and Assumed Spontaneous Abortion 
Rates................................................................................................................................64
Table 9-2
Good-Quality Blastocysts ...............................................................................................70


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
ART
Assisted Reproductive Technology
eCRF
electronic case report form
EOT
End-of-trial
ES
eligible subjects
ET
embryo transfer
EudraCT
European Union Clinical Trial Database
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GnRH
gonadotrophin-releasing hormone
hCG
human chorionic gonadotropin
HP-hMG
highly purified, human menopausal gonadotropin
HPV
human papilloma virus
ICH
International Council for Harmonisation
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRT
interactive response technology
IVF
in vitro fertilization
LH
luteinizing hormone
mITT
modified intention-to-treat
NIMP
Non-Investigational Medicinal Product
P
procedural visit
PVR
progesterone vaginal ring
OR
oocyte retrieval
OS
ovarian stimulation
SAE
serious adverse event
TVUS
transvaginal ultrasound


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1
INTRODUCTION
1.1
Background
Successful human reproduction is dependent upon the influence of progesterone on endometrial 
structure and receptivity. Once the corpus luteum is formed after ovulation, it begins to secrete 
progesterone, which is necessary and sufficient to decidualize the endometrium to facilitate 
implantation. If conception and implantation occur, increasing concentrations of human chorionic 
gonadotropin (hCG) drive continued secretion of progesterone from the corpus luteum, which is 
critical for the maintenance of early pregnancy and the endometrium (Penzias, 2002). Progesterone 
continues to be produced by the corpus luteum until the seventh or eighth week of gestation, at 
which time the placenta becomes the primary site of production for the remainder of pregnancy.
Unfortunately, not all women of reproductive age are able to become pregnant or maintain a 
pregnancy; indeed, 12 percent of women of reproductive age in the United States have received an 
infertility service at some time in their lives. The administration of exogenous progesterone to 
support luteal function has been utilized in the treatment of infertility, particularly with assisted 
reproductive technology (ART). Assisted reproductive technology generally involves the surgical 
removal of eggs from a woman’s ovaries, fertilizing them with sperm in the laboratory, and then 
returning them to either the donor woman’s or another woman’s uterus 
(Centers for Disease Control, 2005). For many women, in conjunction with ART, steps must be 
taken to prime the uterus for implantation and to sustain the pregnancy after implantation. Many 
tools have been developed to aid in this process.
In the middle of the 1980s, gonadotrophin-releasing hormone (GnRH) agonists were incorporated 
into ovarian stimulation regimens and are associated with improved outcomes after in vitro 
fertilization (IVF) and other ARTs. These GnRH agonists work by suppressing the pituitary and 
preventing premature surges of endogenous luteinizing hormone (LH) during IVF cycles and 
allowing time for a larger number of oocytes to reach maturity prior to harvesting. However, GnRH 
agonists inhibit the corpora lutea in these cycles and may create an iatrogenic luteal phase defect.
Use of a GnRH agonist causes suppression of pituitary LH secretion for as long as 10 days after the 
last dose, and pituitary function may not return completely until 2-3 weeks after the end of therapy.
Without this LH signal, the corpus luteum may be dysfunctional, and subsequent progesterone and 
estrogen secretion may be abnormal, compromising endometrial receptivity and potentially leading 
to decreased implantation and pregnancy rates (Pritts, 2002).
Various hormones, including estrogens, progesterone, and hCG have been used during the luteal 
phase and beyond in IVF cycles for luteal phase support. A 1994 meta-analysis showed that the use 
of hCG or progesterone led to significantly higher pregnancy rates than placebo (Soliman, 1994).
Most treatment protocols advocate the use of progesterone throughout the first trimester of 
pregnancy, since corpus luteum activity has been demonstrated up to Week 10 of pregnancy, 
although progesterone supplementation continuing beyond a positive serum pregnancy test may not 
be needed. The goal of progesterone supplementation is to assist a corpus luteum that may have 
become compromised during ovulation induction or oocyte retrieval (Penzias, 2002).


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Moreover, the vaginal route of progesterone administration has been shown to allow effective 
targeted delivery for various indications, including supplementation of corpus luteal function. The 
vaginal route offers several important advantages over other methods: it is convenient and 
acceptable for many patients, is not painful, does not require any special equipment, systemic levels 
are low, and it rarely produces allergic or other adverse reactions. Therefore, a flexible, 
non-degradable progesterone vaginal ring (PVR) has been developed, releasing an average of 
11 mg progesterone/day consistently over 7 days. The progesterone (20% w/w) is in a micronized 
formulation and dispersed evenly throughout the ring.
1.2
Scientific Justification for Conducting the Trial
In a pivotal phase 3 trial (Teva Women’s Health, Inc. Study DR-PGN-302) evaluating the efficacy 
and safety of a progesterone vaginal ring (PVR) used for luteal phase support in women undergoing 
IVF, the primary endpoint was clinical pregnancy rate at 8 and 12 weeks of pregnancy. Once 
weekly PVR was statistically non-inferior to the active comparator, daily 8% progesterone vaginal 
gel, in women 18-34 years of age. Secondary efficacy analyses included evaluations of live birth 
rate, cycle cancellation rate, rate of spontaneous abortion, rate of biochemical pregnancy, and rate 
of ectopic pregnancy for each treatment group. These rates were similar between the 2 active 
treatment groups and consistent with reported background rates. Weekly PVR insertion appeared to 
be safe and well tolerated. Adverse events (AEs) and serious adverse events (SAEs) were similar 
for both active treatment groups, and no significant safety trends were noted for PVR. Treatment-
related AEs were generally similar between the 2 active treatment groups and consistent with the 
known safety profile of progesterone. Rates of subject discontinuation due to an AE were similar 
between the treatment groups. AEs related to vaginal bleeding were similar between the 2 active 
treatment groups. No subject discontinued because of vaginal bleeding, and no subject was 
switched to an alternative progesterone product because of a bleeding issue. There were no 
increased rates of cervical/vaginal abrasions or irritation associated with use of a vaginal ring 
compared with vaginal gel.
Manufacturing enhancements for the PVR were implemented subsequent to the pivotal phase 3 
trial. Therefore, a bioequivalence trial was conducted to compare the PVR manufactured using the 
new process to the ring manufactured by the legacy process (the phase 3 clinical trial material). The 
results from the pharmacokinetic trial (DR201-BE-10021) demonstrated that the PVR 
manufactured with the new process was bioequivalent to the PVR produced from the legacy 
process. The safety data indicated that both rings were similarly safe and well tolerated by healthy, 
postmenopausal female subjects who were pretreated with estrogen.
The present trial assesses the safety and tolerability of the PVR manufactured with the new process 
when used for luteal phase support in women undergoing ART. While the design of the proposed 
trial is similar to that of the pivotal phase 3 trial for the PVR, changes to the way in which AEs are 
collected and scored have been implemented as requested by the Agency.


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1.3
Benefit / Risk Aspects
The benefit/risk aspects are expected to be similar to what is outlined in the Investigator’s Brochure 
for the Investigational Medicinal Product (IMP), PVR, and in the appropriate package inserts for 
the non-investigational medicinal products: oral contraceptives, leuprolide acetate, hCG, and 
MENOPUR (menotropins for injection [package insert], 2016). The PVR offers patients a 
convenient, once-weekly option for luteal phase support as an alternative to twice-daily dosing or 3-
times daily dosing of the progesterone vaginal insert, once-daily dosing of the progesterone vaginal 
gel, or once-daily intramuscular injection of progesterone in oil that are in current clinical use in the 
United States.


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2
TRIAL OBJECTIVES AND ENDPOINTS
In this safety trial the assessment of the trial will be on the totality of safety information collected. 
Hence, the purpose of categorizing the endpoints as primary and secondary is for prioritising the 
endpoints of interest rather than tying the trial’s success to the outcome of the primary objective.
2.1
Objectives
Primary Objective

To estimate the cumulative rate of any spontaneous abortion, including spontaneous 
clinically recognized pregnancy loss and blighted ovum during the trial (up to Week 12 
following oocyte retrieval), in subjects treated with PVR following fresh embryo transfer.
Secondary Objectives

To describe the cumulative rate of spontaneous abortions determined at 6 and 10 weeks 
post-oocyte retrieval, including spontaneous clinically recognized pregnancy loss and 
blighted ovum, in all subjects treated with PVR.

To describe the cumulative rate of biochemical abortions determined at 6 and 10 weeks 
post-oocyte retrieval in all subjects treated with PVR.

To describe the rate of ectopic and heterotopic pregnancy in all subjects treated with PVR 
following oocyte retrieval.

To describe the safety of PVR through the collection of clinical laboratory tests and vital 
signs in all subjects treated with PVR.

To assess the safety and tolerability of PVR in all subjects treated with PVR.

To determine the positive β-hCG rate of subjects treated with PVR following oocyte 
retrieval.

To determine the clinical pregnancy rate of subjects treated with PVR following oocyte 
retrieval.
2.2
Endpoints
Primary Endpoint

Cumulative 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.
Note: spontaneous abortion is defined as two positive 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).


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Secondary Endpoints

Cumulative rate of spontaneous abortions determined at 6 and 10 weeks post-oocyte 
retrieval in all subjects treated with PVR.

Cumulative rate of biochemical abortions determined at 6 and 10 weeks post-oocyte 
retrieval in all subjects treated with PVR. Biochemical abortion is 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.

Rate of ectopic and heterotopic pregnancies in all subjects treated with PVR following 
oocyte retrieval.

Rate of abnormal findings in clinical laboratory tests and vital signs for all subjects treated 
with PVR.

Frequency, intensity/grade, seriousness, and relatedness of adverse events (AEs) for all 
subjects treated with PVR.

Frequency, intensity/grade of vaginal bleeding/spotting, vaginal hemorrhage, pain, vaginal 
infection, and vaginal irritation for all subjects treated with PVR.

Frequency, intensity/grade, seriousness, and relatedness of AEs associated with vaginal and 
cervical abrasions and lesions and with vaginal adhesions for all subjects treated with PVR.

Frequency and reason for PVR discontinuation.

Positive β-hCG rate (positive serum β-hCG test) at 2 weeks and 2 weeks + 3-4 days post-
oocyte retrieval in all subjects treated with PVR.

Clinical pregnancy rate (TVUS showing at least 1 intrauterine gestational sac with fetal 
heart beat) at 6 and 10 weeks post-oocyte retrieval in all subjects treated with PVR.


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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Trial Design Diagram
A trial flow overview is provided in Table 3-1.
Table 3-1
Trial Flow Overview
Screening
Suppression
Stimulation
Oocyte 
Retrieval
Treatment Period
Post Treatment 
Period
Consent and Screening Down-regulation
Visits 1 and 2
Visit 3
Visits 4-9:
Day after oocyte 
retrieval and 
ongoing pregnancy 
(~10 weeks)
PVR1 through 
PVR10
Visit 10:
End-of-trial visit
(2 weeks after last 
exposure to 
Investigational 
Medicinal Product)
3.1.2
Overall Design and Control Methods
This is an open-label, single-arm, safety trial of PVR for luteal phase support in women undergoing 
IVF with fresh oocytes. Women between the ages of 18 and 34 years with tubal, idiopathic, male 
factor, ovulatory dysfunction, or endometriosis-linked infertility, who agree to be considered for 
inclusion in the trial, will be invited to be seen at the trial site.
Once informed consent is obtained, eligible subjects will be started on an ovarian down-regulation /
suppression protocol utilizing combined oral contraceptives supplied by the site for ≥14 days to 
≤21 days (based upon the site standard of care), with leuprolide acetate at a dose of 0.1 mL 
(500 µg)/day beginning 4 days prior to the last birth control pill and for ≥10 days to ≤20 days; 
ovarian suppression is to begin in the cycle immediately prior to the ovarian stimulation cycle.
After suppression, an ovarian stimulation protocol will begin on the second or third day after the 
start of menses with a reduction in leuprolide acetate dose to 0.05 mL (250 µg/day) followed by an 
individually determined ovarian stimulation protocol with highly purified, human menopausal 
gonadotropin (HP-hMG; MENOPUR) at an initial dose of 225 IU/day for 5 days according to label.
Based on clinical monitoring, subsequent dosing should be adjusted according to individual subject
response. Dose adjustments should not be made more frequently than once every two days and 
should not exceed 150 IU per adjustment. The maximum daily dose of MENOPUR should not 
exceed 450 IU and the minimum daily dose should not be lower than 75 IU. MENOPUR dosing 
should not continue for >20 days and coasting is not allowed. Subjects will be monitored to 
determine when to trigger ovulation with hCG. A TVUS will be performed to assess follicle size 
and serum estradiol levels will be determined. A subject must have at least 2 follicles ≥17 mm 
(mean of 2 dimensions) to receive the hCG trigger. Subjects who do not reach this threshold after 
20 days of stimulation are to be discontinued from the trial. If the estradiol level is ≥5000 pg/mL, 
hCG should not be administered and the subject should be discontinued from the trial.


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Oocyte retrieval will occur approximately 35-37 hours after hCG administration. On the day after 
oocyte retrieval, the subject will begin treatment with the IMP, PVR. Following instruction on PVR
insertion and removal (see Appendix 1), the subject will insert the first PVR (PVR1) at the trial site
The PVR will remain in place a minimum of 23 hours/day. The subject will remove PVR1 before 
embryo transfer and reinsert it after the transfer. Fresh embryo transfer will occur 5 days after 
oocyte retrieval per the trial site’s protocol. The number of embryos to transfer must be guided by 
the 2017 American Society for Reproductive Medicine (ASRM) and the Society for Assisted 
Reproductive Technology (SART) guidelines (SART/ASRM 2017): women with the expectation of 
one or more high-quality embryo(s) available for cryopreservation, and women with previous live 
birth after an IVF cycle, will have transfer of a single blastocyst. All other women will have transfer 
of no more than two blastocysts. Additional PVRs will be distributed for weekly insertion, with the 
second PVR (PVR2) to be inserted at home 7 days following the initial insertion of the first PVR
(PVR1), and the third PVR (PVR3) to be inserted either at home or at the site 7 days following the 
insertion of PVR2.
Two weeks after oocyte retrieval, a blood draw will be performed to measure serum levels of 
progesterone and β-hCG. Subjects with a β-hCG level <5 mIU/mL will be discontinued from the 
trial. Those with a β-hCG level ≥5 mIU/mL will insert their next PVR and continue in the trial for 
up to a total of 10 weeks (up to a total of 10 PVRs). Additional serum pregnancy tests will be 
performed at 2 weeks + 3-4 days and at 3 weeks. Subjects who are no longer pregnant will be 
discontinued from the trial. Subjects with positive β-hCG results at 3 weeks will insert PVR4 and 
receive PVR5 and PVR6 to be inserted weekly.
A TVUS will be performed to document the presence of an intrauterine gestational sac 4 weeks 
+ 3-4 days after oocyte retrieval. If it is determined that the subject has an ectopic pregnancy, the 
subject will be treated according to the site’s standard protocol and will be withdrawn from the 
trial. Six weeks after oocyte retrieval, a TVUS will be performed to determine the presence and 
number of gestational sacs with/without fetal heart beat. Pregnant subjects will insert PVR7 and 
receive additional PVRs to be inserted weekly (PVR8, PVR9, and PVR10). Ten weeks after oocyte 
retrieval (if the subject is pregnant), an ultrasound (either transvaginal or abdominal) will be 
performed to determine the number of gestational sacs present with and without fetal heart beat and 
the estimated gestational age.
Safety will be monitored throughout the trial. Standardized criteria will be applied to AEs of special 
interest (vaginal bleeding, vaginal pain, and vaginal irritation etc., see section 8.3) to establish grade 
(intensity). Patient-reported vaginal pain and/or irritation (Appendix 3) should be recorded as an 
AE if considered clinically significant by the physician. The physician can perform an unscheduled 
pelvic examination at his or her discretion based upon these AEs at any time (see Appendix 2). A 
scheduled pelvic examination will be performed at screening, on day 1 of PVR treatment, and 4
weeks + 3-4 days, 6, 10, and 12 weeks post-oocyte retrieval (Visits 4, 7P, 8, 9 and 10) to document 
the presence and grade (intensity) of any pain, irritation, abrasions, or lesions on the cervix or 
vagina and the presence and grade (intensity) of vaginal adhesions using standardized criteria 
(Appendix 2). If any lesions or abrasions are found on the cervix or vagina or vaginal adhesions are 


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noted, another examination will be performed 2-4 days later. Subjects will be followed until the 
lesions/abrasions resolve or until the final assessment at the End-of-trial visit, whichever comes 
first. Any clinically significant finding will be reported as an AE.
Post-trial procedures will be performed 2 weeks after the last exposure to investigational medicinal 
product (IMP) (12 weeks after oocyte retrieval).
3.1.3
Trial Schedule
The estimated first subject, first visit is Q3 2018 with last subject, last visit during Q3 2019.
3.2
Planned Number of Trial Sites and Subjects
Approximately 240 subjects will be needed to complete the controlled ovarian stimulation cycle, 
undergo oocyte retrieval, be treated with PVR, and receive fresh embryo transfer.
3.3
Interim Analysis
No interim analysis is planned.
3.4
Data Monitoring Committee (DMC)
No data monitoring committee is planned.
3.5
Discussion of Overall Trial Design and Choice of Control Groups
3.5.1
Trial Design
This is an open-label, single-arm trial of progesterone supplementation (luteal phase support) in 
women undergoing IVF with fresh oocytes. Each trial center will follow the trial center’s standard 
practice for ART unless otherwise noted in this protocol. On the day after oocyte retrieval, the 
subject will begin treatment with the IMP, PVR. Embryo transfer will occur 5 days after oocyte 
retrieval. A serum pregnancy test will be conducted 2 weeks after the oocyte retrieval. Subjects 
with a β-hCG level <5 mIU/mL will be discontinued from the trial. Those with a β-hCG level 
≥5 mIU/mL will continue dosing with PVR for up to a total of 10 weeks.
The primary objective is to estimate the cumulative rate of any spontaneous abortion, including 
spontaneous clinically recognized pregnancy loss and blighted ovum during the trial (up to 
Week 12 following oocyte retrieval), in subjects treated with PVR following fresh embryo transfer. 
Approximately 240 subjects will be enrolled in the trial in order to ensure that 215 subjects undergo 
fresh embryo transfer.
3.5.2
Selection of Endpoints
The endpoints in this trial (rate of any spontaneous abortion, biochemical abortion, ectopic and 
heterotopic pregnancies as well as rate of clinical pregnancy and positive β-hCG) are typical 
endpoints to demonstrate the safety of products used for progesterone supplementation in women 
undergoing ART. AEs of special interest due to the vaginal administration are also included as 
secondary endpoints, and cover vaginal bleeding/spotting, vaginal hemorrhage, pain, vaginal 


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infection, vaginal irritation, vaginal and cervical abrasions and lesions, and vaginal adhesions. 
Finally, typical safety endpoints such as laboratory results and vital signs are also included.
3.5.3
Blinding
This is an open-label trial.
3.5.4
Selection of Doses in the Trial
Subjects will be instructed to insert the first PVR on the day after oocyte retrieval, which contains 
11 mg progesterone/day and remains in place a minimum of 23 hours/day for 7 days.
3.5.5
Selection and Timing of Dose for Each Subject
A new PVR will be inserted every 7 days, with up to 10 PVRs used through Week 12 of pregnancy 
(10 weeks post-oocyte retrieval).
3.5.6
Discontinuation and Trial Stopping Criteria
Discontinuation Criteria
Two days prior to oocyte retrieval, a TVUS will be performed to assess follicle size. A subject must 
have at least 2 follicles ≥17 mm (mean of 2 dimensions) to receive the hCG trigger. Subjects who 
do not reach this threshold after 20 days of stimulation are to be discontinued from the trial. If the 
estradiol level is ≥5000 pg/mL, hCG should not be administered and the subject should be 
discontinued from the trial.
A serum pregnancy test will be conducted 2, 2.5, and 3 weeks after the oocyte retrieval. Subjects 
with a β-hCG level <5 mIU/mL will be discontinued from the trial. A TVUS will be performed to 
document the presence of an intrauterine gestational sac 4.5 weeks after oocyte retrieval. If it is 
determined that the subject has an ectopic pregnancy, the subject will be treated according to the 
site’s standard protocol and will be withdrawn from the trial.
Subjects who discontinue the trial are to complete an Early Withdrawal Visit (section 6.3.8) no later 
than 1 week after the last dose of the IMP. An End of Trial Visit (section 6.4) is required 2 weeks 
after the last dose of IMP.
Trial Stopping Criteria
Occurrence of the following may warrant consideration of trial termination:
Life-threatening SAEs with suspected causality to the IMP, but not limited to those with grade 4 as 
detailed in Appendix 2 and Appendix 3.
Ferring’s internal Safety Committee will review each occurrence and provide a recommendation as 
to whether to discontinue the trial. The responsibilities and composition of the internal Safety 
Committee are provided in a separate charter document, available before the first subject’s first 
visit.


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3.5.7
Follow-up Procedures
Two weeks after the last exposure to the IMP, subjects will return for an End-of-trial Visit. Physical 
and pelvic examinations will be performed; vital signs will be measured; blood and urine will be 
collected for hematology, chemistry and urinalysis; and AEs will be assessed. If any lesions or 
abrasions are found on the cervix or vagina or vaginal adhesions are noted, another examination 
will be performed 2-4 days later until the lesions/abrasions or vaginal adhesions resolve or until the 
final assessment at the End-of-trial visit, whichever comes first. Vaginal adhesions observed can be 
surgically addressed based on the Investigator’s judgement.


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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
Subjects must meet the following inclusion criteria:
1. Informed consent signed and dated prior to any trial related procedures.
2. Pre-menopausal females aged 18-34 years old at time of consent.
3. Documentation of a normal uterine cavity by hysteroscopy, hydrosonogram, or 
hysterosalpingogram within 1 year of screening.
4. Documentation of normal Pap smear test within 24 months of screening.
5. Documentation of negative testing within 6 months of the start of screening for serum 
Hepatitis B surface antigen, Hepatitis C antibody, human immunodeficiency virus antibody, 
rapid plasma reagin/venereal disease research laboratory.
6. Documentation of rubella antibody, ABO grouping, Rho typing, and normal prolactin and 
thyroid function within 6 months of screening.
7. At least 1 cycle without reproductive hormone medication prior to the screening follicle 
stimulating hormone (FSH) and estradiol blood draw.
8. Tubal, idiopathic, male factor, ovulatory dysfunction, or endometriosis-linked infertility.
9. For fresh sperm: sperm assessed for leukospermia (≥2 million white blood cells/mL or 
round cells/mL) is required within 2 months of pituitary down regulation OR male partner 
empirically treated with antibiotics prior to the IVF cycle.
10. Semen analysis within 1 year of screening by standard World Health Organization and/or 
Kruger criteria. Frozen sperm, including donor sperm, may be used, as long as testing done 
at the time of freezing meets standard criteria. Male partners with obstructive azoospermia 
will not be required to have this semen analysis.
11. Able to understand, read, and sign an informed consent after the nature of the trial has been 
fully explained.
12. Able to complete all trial procedures.
4.1.2
Exclusion Criteria
The presence of any of the following excludes a subject from trial enrollment:
Contraindications to the use of progesterone, which include:

Known sensitivity to progesterone or related drugs

Undiagnosed vaginal bleeding

Significant liver dysfunction or disease (including liver function tests >2 times the 
upper limit of normal)


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
Known or suspected malignancy of the breast or genital organs

Active thrombophlebitis or thromboembolic disorders, or a history of 
hormone-associated thrombophlebitis or thromboembolic disorders
Significant psychiatric disease that is not well-controlled.
Body mass index >38 kg/m2.
Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood 
pressure >100 mmHg).
FSH >15 IU/L during the early follicular phase (Day 2-4). For those subjects with 
polycystic ovarian syndrome, a Day 2-4 FSH level can be obtained following a 
progestogen withdrawal or spontaneous menses.
Clinically significant gynecologic pathology, such as submucosal fibroids, intramural 
fibroids >5 cm, communicating hydrosalpinx, uncorrected uterine septum, endometrial 
cancer or endometrial atypia, scar tissue inside the cavity or poorly developed uterine 
lining from prior uterine surgery, pelvic tuberculosis, or any other conditions that could 
adversely affect pregnancy success.
Uncontrolled hyperprolactinemia or hypothyroidism.
History of pelvic radiation. Subjects with a history of cancer within the last 5 years, except 
for squamous or basal cell cancer of the skin.
Currently pregnant or breastfeeding.
Current gonorrhea or chlamydia.
History of human immunodeficiency virus/acquired immunodeficiency virus.
Known hypersensitivity or previous intolerance to silicone or to any active ingredient or 
excipients in the medicinal products used in this trial.
History of toxic shock syndrome.
Known or suspected substance abuse within 1 year prior to screening.
Use of any investigational drug or device within 30 days prior to screening.
Undergoing donor oocyte cycle, embryo biopsy, or preimplantation genetic testing.
History of more than 1 failed fresh IVF cycle. Note: an ART cycle is started when a 
woman begins taking medication to stimulate the ovaries to develop eggs or, if no drugs 
are given, when the woman begins ovarian follicular monitoring (using ultrasound or 
blood tests) for natural egg production (Centers for Disease Control, 2005). A failed cycle 
is defined as having started a cycle and not becoming pregnant or pregnancy loss prior to 
the 20th week of pregnancy.
More than 2 consecutive clinical miscarriages (gestational sac observed on ultrasound).
Insulin-sensitizing agents, ART cycle, or ovarian stimulation with gonadotropins within 
30 days or clomiphene stimulation within 90 days prior to the screening FSH and estradiol 
blood draw.
Tobacco use within 3 months prior to screening.


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For fresh sperm: male partners with non-obstructive azoospermia.
Any abnormal finding or condition deemed clinically significant by the Investigator on 
history, screening, physical examination, or pelvic examination that contraindicates 
pregnancy or the use of progesterone or a vaginal ring, including the presence of any 
vaginal or cervical abrasions/lesions.
Any condition the Investigator believes would interfere with the subject’s ability to 
provide informed consent, to comply with trial instructions, or which might confound the 
interpretation of the trial results or put the subject at risk.
4.2
Method of Assigning Subjects to Treatment Groups
4.2.1
Recruitment
Sites will recruit subjects based on the inclusion/exclusion criteria and local recruitment practices.
Recruitment materials cannot be used prior to Institutional Review Board (IRB) approval.
4.2.2
Randomization
This trial is not randomized.
4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
Any concomitant therapies used during the trial or within 1 month prior to screening will be 
recorded in the source documents and electronic case report form (eCRF), along with the main 
reason for their prescription/use.
4.3.2
Prohibited Therapy
Use of any medications other than the trial medication provided for this trial should be avoided 
from the screening period until completion of the trial. Occasional use of over-the-counter 
medications or prescription drugs may be allowed, except for those listed below and in 
section 4.1.2.

Vaginal medications other than the PVR described in this protocol

Estrogens or progestogens, other than those outlined in the protocol, administered by any 
route (oral, IM, vaginal). However, for those subjects with PCOS, a progestogen may be 
used to induce a progestogen-withdrawal bleeding episode to obtain FSH on cycle days 2-4 
prior to suppression.

Chronic, systemic corticosteroid

Herbal remedies

Aspirin

OVIDREL (choriogonadotropin alfa injection)


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
VIAGRA, CIALIS, LEVITRA

Insulin-sensitizing agents (eg, metformin)

Any medications the Investigator believes could adversely affect endometrial thickness, 
embryo transfer, or pregnancy

Acupuncture
4.4
Withdrawal Criteria
Withdrawal from Trial
Every subject has the right to withdraw from the trial at any time for any reason, without the need 
to justify their decision. A subject's participation is to terminate immediately upon her request.
However, the Investigator should record the reason for the subject’s withdrawal, if possible.
If, at the time of discontination, a dose of the IMP has already been administered, the subject must 
be advised to consider follow-up safety investigations, which will include all procedures outlined 
for the Early Withdrawal Visit (section 6.3.8).
The subject can also be withdrawn from the trial at any time at the discretion of the Investigator; the 
reason should be discussed with the Sponsor prior to discontinuation. For any discontinuation, the 
Investigator will obtain all the required details and document the date of the premature termination 
and the main reason in the source documents and eCRF.
A subject who withdraws from the trial after embryo transfer will not be replaced.
Withdrawal of Consent
If the subject withdraws her consent, data collected up to withdrawal will remain in the database, 
but no further data will be collected. Samples and recordings obtained before withdrawal may be 
analyzed. This will be described in the Informed Consent Documents. The subject can request 
destruction of samples which would otherwise have been kept in storage.


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5
TREATMENTS
5.1
Treatments Administered
5.1.1
Investigational Medicinal Product (IMP)
The IMPs in the present trial will be supplied as vaginal rings, which releases an average of 11 mg 
progesterone/day consistently over 7 days. The progesterone (20% w/w) is in a micronized 
formulation and dispersed evenly throughout the ring. Subjects will be instructed to insert the first 
PVR on the day after oocyte retrieval. A new PVR will be inserted every 7 days, and each PVR will 
remain in place a minimum of 23 hours/day. Depending on the subject’s pregnancy assessments, 
PVR treatment can be continued through Week 12 of pregnancy (10 weeks post-oocyte retrieval).
For information on warnings, precautions and treatment of overdose, please refer to the 
Investigator’s Brochure for PVR (Progesterone (FE 999913) Vaginal Ring, Investigator’s 
Brochure).
5.1.2
Non-Investigational Medicinal Product (NIMP)
The non-investigational medicinal products (NIMPs) to be used are listed in Table 5-1.
Table 5-1
Non-investigational Medicinal Products
NIMP
Trade name
Dose
Combined oral 
contraceptives
CYCLAFEM 1/35 
(norethindrone [1 mg] and 
ethinyl estradiol [0.035 mg])
1 mg/0.035 mg (1 tablet) daily for at least 14 days 
but no more than 21 days during the downregulation 
period.
GnRH agonist
LEUPROLIDE ACETATE
(leuprolide acetate)
0.1 mL (500 µg)/day administered as subcutaneous 
injections during the downregulation period for at 
least 10 days but no more than 20 days, followed by 
0.05 mL (250 µg/day) throughout the gonadotropin 
treatment period.
HP-hMG
MENOPUR (menotropin)
225 IU/day administered as subcutaneous injections
for 5 days. Subsequent dosing should be adjusted 
according to individual subject response. Dose 
adjustments should not be made more frequently 
than once every two days and should not exceed 
150 IU per adjustment. The maximum daily dose of 
MENOPUR should not exceed 450 IU and the
minimum daily dose should not be lower than 
75 IU. MENOPUR dosing should not continue for
>20 days and coasting is not allowed.
hCG
NOVAREL
(chorionic gonadotropin)
1 mL (2 x 5,000 IU) administered by intramuscular 
injection according to label as soon as 2 follicles of 
≥17 mm are observed on transvaginal ultrasound.


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All NIMPs are to be used in line with the recommendations in the respective products’ labelling for 
the indication ART and/or standard clinical practice supported by literature.
For information on warnings, precautions and treatment of overdose, please refer to FDA approved 
Prescribing Information for CYCLAFEM 1/35, LEUPROLIDE ACETATE, MENOPUR, and
NOVAREL.
5.2
Characteristics and Source of Supply
All medicinal products are provided by Ferring and will be handled according to the principles of 
Good Manufacturing Practice (GMP). Table 5-2 provides an overview of the presentation of each 
medicinal product.
Table 5-2
Characteristics of Medicinal Products
IMP / NIMP
Presentation
PVR (progesterone)
Ferring Pharmaceuticals
PVR (progesterone) is provided as vaginal rings. Each ring 
releases an average of 11 mg progesterone/day consistently 
over 7 days.
CYCLAFEM 1/35
Qualitests Pharmaceuticals
CYCLAFEM 1/35 (norethindrone [1 mg] and ethinyl 
estradiol [0.035 mg]) is provided as oral tablets.
LEUPROLIDE ACETATE (GnRH agonist), 
Sandoz
LEUPROLIDE ACETATE (leuprolide acetate), is 
provided as a vial with sterile solution (14 mg/2.8 mL).
MENOPUR powder (menotrophin HP),
Ferring Pharmaceuticals
MENOPUR powder is provided as vials with lyophilized 
powder and vials with diluent. After reconstitution, each 
vial delivers 75 IU of FSH activity and 75 IU of LH 
activity.
NOVAREL (hCG),
Ferring Pharmaceuticals
NOVAREL (chorionic gonadotropin) is provided as vials 
with lyophilized powder and vials with diluent. After 
reconstitution, each vial delivers 5,000 IU chorionic 
gonadotropin.
5.3
Packaging and Labelling
Packaging and labeling of the medicinal products will be performed under the responsibility of the 
Clinical Trial Supply department at Ferring in accordance with GMP and national regulatory 
requirements. Details on the packaging of each medicinal product is provided in Table 5-3.


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Table 5-3
Packaging of Medicinal Products
IMP / NIMP
Presentation
PVR
(progesterone)
PVR is provided in pouches containing 1 vaginal ring.
CYCLAFEM 1/35
(combined oral contraceptive)
CYCLAFEM 1/35 is provided in boxes containing 3 blister packs, 
each with 28 tablets.
LEUPROLIDE ACETATE
(GnRH agonist)
LEUPROLIDE ACETATE is provided in boxes containing a vial.
MENOPUR powder
(menotrophin HP)
MENOPUR powder is provided in boxes containing five vials with 
powder and five vials with diluent.
NOVAREL
(hCG)
NOVAREL is provided in boxes containing one vial with powder and 
one vial with diluent.
All NIMPs are commercially available and will be purchased centrally. No modification from the 
usual commercial state of the NIMPs will be made, except for trial-specific labelling.
All products (IMPs and NIMPs) will be labelled with trial-specific labels, which contain 1 self-
adhesive tear-off portion to be affixed to the subject dispensing log maintained at the trial site.
5.4
Conditions for Storage and Use
The Investigator will ensure that the medicinal products will be stored in appropriate conditions in a 
secure location with controlled access as per the label for each drug. The storage compartment shall 
be monitored regularly and the temperature shall be documented. Deviations in storage temperature 
must be reported to Ferring as instructed in the IMP/NIMP handling guideline. The IMP/NIMP 
must not be used until authorization to proceed from the Sponsor is received.
Specific storage and use instructions for the IMP and all NIMPs are described in the package inserts 
and/or trial specific/commercial box labelling.
5.5
Blinding / Unblinding
5.5.1
Blinding
This is an open-label trial.
5.5.2
Unblinding of Individual Subject Treatment
This is an open-label trial.
5.6
Treatment Compliance
5.6.1
Dispensing and Accountability
The IMP (PVR) will only be dispensed to subjects who meet the eligibility criteria and are enrolled 
in the trial. The Investigator or designee will use the interactive response technology (IRT) system


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to assign IMP and NIMP kits and record the dates and quantities dispensed to and returned by each 
subject, as well as manage the overall drug accountability for each subject. The monitor will review 
and verify the drug accountability of the IMPs and NIMPs during the trial. Any discrepancies will 
be documented.
5.6.2
Assessment of Compliance
In order to monitor compliance with IMP treatment, the subjects are to return all used and unused 
PVRs, with the exception of unused replacement ring, to the Investigator at each visit. Any unused 
replacement ring is to be returned at Visit 9. Used PVRs are to be returned in the provided bio-
hazard bag. The Investigator or designee will reconcile and document the return in the IRT system
along with the reason for missing rings, if applicable. Any physical damage to the ring should be 
noted by the subject in the PVR diary and collected in the eCRF. Any discrepancies should be 
recorded and discussed with the subject at the time of the return. Used rings are to be stored at the 
trial site until drug accountability has been performed by the trial monitor.
5.7
Auxiliary Supplies
Ferring will provide the sites with sanitary napkins to be used by subjects for any vaginal bleeding 
occurring during the trial.
5.8
Return and Destruction of Medicinal Products
The Monitor will check the supplies, the drug accountability, and inventory records at the trial site.
Following this check, the Investigator will sign off on the records.
Used IMP/NIMP can be destroyed at the trial site after the drug accountability has been finalized 
and signed off by the Investigator, and the Sponsor has issued a written approval. Any destruction 
document must clearly identify the trial code and kit numbers involved, and the quantities of 
IMP/NIMP destroyed, including treatment visits, if applicable.
Any unused IMP/NIMP will be returned for destruction, as instructed by the Clinical Trial Supply 
department, Ferring Pharmaceuticals, and in accordance with local requirements, after the drug 
accountability has been finalized, verified by the monitor, signed off by the Investigator, and 
approved by the Sponsor. All unused medicinal products will be accounted for and must be 
destructed in a certified way.


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6
TRIAL PROCEDURES
The schedule of assessments is presented in Table 6-1.


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Table 6-1
Trial Schedule
Visit:
Screen
(0)a
Down-
reg.
1
2
3
OR
4
5
ET
6
6P
7
7P
8
9
End-
of-
trial
10
Oocyte Retrieval + X Weeks:
-2 
days
0
+1 day
+5 
days
1
2
2+3-4
days
3
4
4+3-4
days
5
6
7
8
9
10
12
X Weeks of Pregnancy + X days b:
2
3
4
4+3-4
5
6
6+3-4
7
8
9
10
11
12
14
Written informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical/gynecological history
X
Physical examination
X
X
X
Pelvic examination
X
X
X
X
X
X
Heightc, weight and BMI
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Suppression treatment
X
Stimulation treatmentd
Start Stop
Ovulation induction (human chorionic gonadotropin)
X
Oocyte retrieval (OR)
X
Embryo transfer (ET)
X
Bleeding log (subject assessment of vaginal bleeding and blood 
loss)e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vaginal hemorrhage assessment
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY/DIAGNOSTIC TESTS
Pap smearf
X
Chemistry and hematology panel
X
Xg
X
X
Gonorrhea/chlamydia testing
X
Urinalysis
X
X
X
FSH and AMH serum levels
Xh
Beta human chorionic gonadotropin serum levels
X
X
X
X
Progesterone serum levels
X
X
X
X
Estradiol serum levels
Xh
Xi
Xi
X
X
Transvaginal ultrasound
X
X
X
Xj
X
X
Xj
Xj
Abdominal ultrasound
PVR TREATMENT
Ring placement
PVR1k,l
PVR2 PVR3
PVR4m PVR5
PVR6 PVR7n PVR8 PVR9 PVR10
Ring removal
PVR1 PVR2
PVR3 PVR4
PVR5 PVR6 PVR7 PVR8 PVR9 PVR10


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Visit:
Screen
(0)a
Down-
reg.
1
2
3
OR
4
5
ET
6
6P
7
7P
8
9
End-
of-
trial
10
Oocyte Retrieval + X Weeks:
-2 
days
0
+1 day
+5 
days
1
2
2+3-4
days
3
4
4+3-4
days
5
6
7
8
9
10
12
X Weeks of Pregnancy + X days b:
2
3
4
4+3-4
5
6
6+3-4
7
8
9
10
11
12
14
PVR diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
AMH = Anti-Müllerian hormone; BMI = Body Mass Index; FSH = follicle-stimulating hormone; OR = oocyte retrieval; ET = embryo transfer; P = procedural visit; PVR = progesterone vaginal ring
a.
The Screening Period may last up to 90 days from the time of signing the consent form to the start of ovarian suppression.
b.
In this trial, pregnancy is defined as beginning 2 weeks prior to egg retrieval.
c.
Height only measured at screening
d.
Stimulation will be with MENOPUR, dosed according to the label and individualized based upon subject response at the Investigator’s discretion.
e.
Vaginal bleeding since the previous visit will be recorded after the start of progesterone administration until the End-of-trial visit.
f.
A Pap smear done within 24 months of the Screening Visit is acceptable, provided the results are normal and a copy is obtained.
g.
If Visit 4 occurs on a day where shipment to the central laboratory is not feasible, e.g. during the weekend, the subject will return to the site for blood collection on the next possible day
h.
Follicle-stimulating hormone (FSH) and estradiol serum levels will be measured on Cycle Day 3 ±1 day, sampling for Anti-Müllerian hormone (AMH) serum levels must be performed prior to start of ovarian 
suppression.
i.
Analysis by local laboratory
j.
Assessment of endometrial thickness by transvaginal ultrasound at Visit 5. The ultrasounds for the embryo transfer procedure at Visit 5 and the pregnancy assessments at Visit 9 and Visit 10 can be either vaginal or 
abdominal. If Visit 9 is an Early Withdrawal Visit due to the subject being no longer pregnant, an ultrasound is not required.
k.
Ring replacement training/confirmation training will occur.
l.
PVR1, PVR2, PVR3 and PVR4 will be distributed to each subject.
m.
PVR5, PVR6, PVR7 and PVR-R will be distributed to each subject.
n.
PVR8, PVR9, and PVR10 will be distributed to each subject.


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6.1
Screening and Ovarian Suppression (Down-regulation)
Potential participants will be scheduled to come to the clinic for the screening assessments. The 
screening period may last up to 90 days from the time of signing the informed consent form to the start 
of ovarian suppression. Trial personnel will determine subject eligibility based on the inclusion and 
exclusion criteria. 
The following procedures / assessments must take place during the screening period:

Signed and dated written informed consent must be obtained before any trial-related 
examinations

Check the inclusion and exclusion criteria

Demographics

Medical and gynecological history (including gonorrhoea and chlamydia testing)

Complete physical examination (including height, weight, and BMI calculation)

Pelvic examination (including Pap smear if not performed in the previous 24 months prior to 
screening)

Vital signs

Blood collection for assessment of:
-
Clinical chemistry and hematology parameters
-
Endocrine parameters (β-hCG, AMH, FSH, and estradiol (Note: AMH sampling must be 
performed prior to start of ovarian suppression; FSH and estradiol serum levels will be
measured on cycle day 3 ±1 day))

Urinalysis

Recording of use of any concomitant medication

Recording of AEs (from time of signed informed consent)
Subjects considered eligible for the trial may proceed with the following procedures / assessments:

Start ovarian suppression with combined oral contraceptives (≥14 days to ≤21 days based on 
the site standard of care)

Start leuprolide acetate at a dose of 0.1 mL (500 µg)/day 4 days prior to the last birth control 
pill (≥10 days to ≤20 days).


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6.2
Ovarian Stimulation and Oocyte Retrieval
6.2.1
Visit 1: Start of Ovarian Stimulation
After suppression, subjects will attend the start of ovarian stimulation visit (Visit 1). Ovarian 
stimulation will begin on the second or third day after the start of menses in the subsequent cycle.
The following must take place at the visit:

TVUS of ovaries (number and size of follicles)

Blood collection for local laboratory assessment of:
-
Endocrine parameters (estradiol)

Reduction of leuprolide acetate dose to 0.05 mL (250 µg/day)

Start ovarian stimulation protocol with MENOPUR.
MENOPUR will be at an initial dose of 225 IU/day for 5 days according to label. Subsequent 
dosing should be adjusted according to individual subject response. Dose adjustments should 
not be made more frequently than once every two days and should not exceed 150 IU per 
adjustment. The maximum daily dose of MENOPUR should not exceed 450 IU and the 
minimum daily dose should not be lower than 75 IU. MENOPUR dosing should not continue 
for >20 days and coasting is not allowed.

Recording of use of any concomitant medication

Recording of AEs
During stimulation, subjects will be monitored to determine when to trigger ovulation with hCG.
6.2.2
Visit 2: End of Ovarian Stimulation
The end-of-stimulation visit (Visit 2) takes place when the subject reaches the criterion for triggering 
of final follicular maturation. Subjects who do not reach the triggering criteria after 20 days of 
stimulation are to be discontinued from the trial.
Criterion for triggering of final follicular maturation with hCG: 

at least 2 follicles ≥17 mm (mean of 2 dimensions)
The following must take place at the visit:

Blood collection for local laboratory assessment of:
-
Endocrine parameters (estradiol)
If the estradiol level is ≥5000 pg/mL, the hCG trigger should not be administered and the 
subject should be discontinued from the trial.


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
TVUS of ovaries (number and size of follicles)

Dispensing/administration of hCG

Recording of use of any concomitant medication

Recording of AEs
6.2.3
Visit 3: Oocyte Retrieval
Oocyte retrieval (Visit 3) will take place approximately 35-37 hours after hCG administration.
The following must take place at the visit:

Oocyte retrieval (performed under TVUS guidance)

Vital signs

Recording of use of any concomitant medication

Recording of AEs
6.3
Treatment with PVR
6.3.1
Visit 4: Initiation of Treatment with PVR
Treatment with PVR will be initiated one day after oocyte retrieval (Visit 4). 
The following must take place at the visit:

Vital signs

Blood collection for assessment of:
-
Clinical chemistry and hematology parameters (Note: if Visit 4 occurs on a day where 
shipment to the central laboratory is not feasible, e.g. during the weekend, the subject will 
return to the site for blood collection on the next possible day)
-
Endocrine parameters (progesterone and estradiol)

Assessment of vaginal hemorrhage

Pelvic examination (documentation of presence and grade [intensity] of any pain, irritation, 
abrasions, or lesions on the cervix or vagina or vaginal adhesions, see Appendix 2).

Dispensing of IMP: the first 4 PVRs will be distributed (PVR1, PVR2, PVR3 and PVR4).
Subjects will be instructed in the proper method for PVR insertion and removal (see Appendix 
1). The subject will insert PVR1 while at the trial site. Subjects will be allowed to remove the 


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PVR for up to 1 hour/day; this includes removal for sexual intercourse, although this is not 
necessary.

Provide subjects with PVR diary and instructions on how to complete the diary. Subjects will 
be asked to fill out the diary at home for each PVR used and bring it to each subsequent visit.

Provide subjects with bleeding log and instructions as to how to differentiate between vaginal 
discharge and bleeding (to capture the frequency and intensity of any bleeding).
Subjects will be asked to fill in the bleeding log at home and bring it to each subsequent visit.

Provide subjects with sanitary napkins.
Subjects will be instructed to use only sanitary napkins provided by the trial site for any 
bleeding that occurs during the trial.

Recording of use of any concomitant medication

Recording of AEs
6.3.2
Visit 5: Embryo Transfer
Embryo transfer (Visit 5) will occur 5 days after oocyte retrieval at the discretion of the Investigator.
The following must take place at the visit:

Vital signs

Blood collection for assessment of:
-
Endocrine parameters (progesterone and estradiol)

Removal of PVR1 before embryo transfer and re-insertion of PVR1 after embryo transfer.
If for any reason the PVR is not reinserted within one hour in order to accommodate transfer, 
this is to be documented.

Review of PVR diary

Recording of any vaginal bleeding noted in the subject’s bleeding log since the previous visit

Assessment of vaginal hemorrhage

TVUS of uterus (endometrial thickness)

Embryo transfer.
The transfer will be guided by ultrasound (abdominal or transvaginal) and the procedure will be 
completed per the trial site’s protocol.

Assessment of drug accountability 

Recording of use of any concomitant medication

Recording of AEs


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
Subjects will be instructed to remove PVR1 and insert PVR2 at home, 7 days following the 
initial insertion of PVR1.
6.3.3
Visit 6: 2 Weeks After Oocyte Retrieval
Visit 6 will occur 2 weeks (14±2 days) after oocyte retrieval.
The following must take place at the visit:

Vital signs

Blood collection for assessment of:
-
Endocrine parameters (progesterone and β-hCG)
If the subject has a negative β-hCG (<5 mIU/mL), treatment will be stopped and the subject 
will be withdrawn from the trial.

Removal of PVR2 and insertion of PVR3 (for subjects with a positive β-hCG (≥5 mIU/mL))
Insertion of PVR3 can be performed either at the trial site or at home.

Review of PVR diary

Assessment of drug accountability

Recording of any vaginal bleeding noted in the subject’s bleeding log since the previous visit

Assessment of vaginal hemorrhage

Recording of use of any concomitant medication

Recording of AEs
6.3.4
Visit 6P: Procedural Visit
Subjects will attend a a procedural visit (Visit 6P), 3-4 days after Visit 6.
The following must take place at the visit:

Blood collection for assessment of:
-
Endocrine parameters (β-hCG)
If the subject has a negative β-hCG (<5 mIU/mL), treatment will be stopped and the subject
will be withdrawn from the trial and the early withdrawal visit is to occur (section 6.3.8).

Review of PVR diary

Recording of any vaginal bleeding noted in the subject’s bleeding log since the previous visit

Assessment of vaginal hemorrhage

Recording of use of any concomitant medication


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
Recording of AEs
6.3.5
Visit 7: Week 5 of Pregnancy (3 Weeks After Oocyte Retrieval)
Subjects will attend Visit 7, 3 weeks (21±2 days) after oocyte retrieval.
The following must take place at the visit:

Vital signs

Blood collection for assessment of:
-
Endocrine parameters (β-hCG)
If the subject has a negative β-hCG (<5 mIU/mL), treatment will be stopped and the subject
will be withdrawn from the trial and the early withdrawal visit is to occur (section 6.3.8).

Removal of PVR3 and insertion of PVR4 (for subjects with a positive β-hCG (≥5 mIU/mL))
Insertion of PVR4 can be performed either at the trial site or at home.

Review of PVR diary

Assessment of drug accountability

Recording of any vaginal bleeding noted in the subject’s bleeding log since the previous visit

Assessment of vaginal hemorrhage

Recording of use of any concomitant medication

Recording of AEs

Dispensing of IMP: the next 3 PVRs and a replacement PVR to be used in the event of ring loss 
or damage (PVR5, PVR6, PVR7 and PVR-R) will be distributed.
The subjects will remove and insert the PVRs at home. Subjects will be instructed to replace 
the PVR every 7 days. If the replacement PVR is used, the subject should obtain another 
replacement PVR from the trial site as soon as possible.
6.3.6
Visit 7P: Procedural Visit
Subjects will attend a procedural visit (Visit 7P), one week + 3-4 days after Visit 7.
The following must take place at the visit:

TVUS to document the presence of an intrauterine gestational sac.
In case of an ectopic pregnancy the subject will be treated according to the site’s standard 
protocol. Treatment with PVR will be stopped and the subject will be withdrawn from the trial
and the early withdrawal visit is to occur (section 6.3.8).

Pelvic examiniation (documentation of presence and grade [intensity] of any pain, irritation, 
abrasions, or lesions on the cervix or vagina or vaginal adhesions).


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If any lesions or abrasions are found on the cervix or vagina or vaginal adhesions are noted, 
another examination will be performed 2-4 days later.

Review of PVR diary

Recording of any vaginal bleeding noted in the subject’s bleeding log since the previous visit

Assessment of vaginal hemorrhage

Recording of use of any concomitant medication

Recording of AEs
6.3.7
Visit 8: Week 8 of Pregnancy (6 Weeks After Oocyte Retrieval)
Subjects will attend Visit 8, 6 weeks (42±2 days) after oocyte retrieval.
The following must take place at the visit:

Vital signs

TVUS to determine the presence and number of gestational sacs with/without fetal heart beat

Pelvic examiniation (documentation of presence and grade [intensity] of any pain, irritation, 
abrasions, or lesions on the cervix or vagina or vaginal adhesions).
If any lesions or abrasions are found on the cervix or vagina or vaginal adhesions are noted, 
another examination will be performed 2-4 days later.

Recording of any vaginal bleeding noted in the subject’s bleeding log since the previous visit

Assessment of vaginal hemorrhage

Removal of PVR6 and insertion of PVR7.
Insertion of PVR7 can be performed either at the trial site or at home.

Review of PVR diary

Assessment of drug accountability

Recording of use of any concomitant medication

Recording of AEs

Dispensing of IMP: the next 3 PVRs (PVR8, PVR9, and PVR10) will be distributed.
will be distributed.
The subjects will remove and insert the PVRs at home. Subjects will be instructed to replace 
the PVR every 7 days.


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6.3.8
Visit 9: Week 12 of Pregnancy (10 Weeks After Oocyte Retrieval) / Early-withdrawal
Visit
Visit 9 will occur 10 weeks (70±2 days) after oocyte retrieval. If a subject discontinues the trial 
prematurely an Early-withdrawal visit should be scheduled as soon as possible and within 1 week after 
last dose of the IMP.
The following procedures / assessments must take place at Visit 9 / the Early-withdrawal visit, 
irrespective of whether the subject discontinues the trial prematurely or continues:

Vital signs

Blood collection for assessment of:
-
Clinical chemistry and hematology parameters
-
Endocrine parameters (progesterone)

Urinalysis

Complete physical examination (including weight and BMI calculation)

Pelvic examination (documentation of presence and grade [intensity] of any pain, irritation, 
abrasions, or lesions on the cervix or vagina or vaginal adhesions).
If any lesions or abrasions are found on the cervix or vagina or vaginal adhesions are noted, 
another examination will be performed 2-4 days later.

TVUS or abdominal ultrasound (pregnant subjects only) to determine the number of gestational 
sacs with/without fetal heart beat and estimate gestational age

Recording of any vaginal bleeding noted in the subject’s bleeding log since the previous visit

Assessment of vaginal hemorrhage

Review of PVR diary

Assessment of drug accountability

Recording of use of any concomitant medication

Recording of AEs
6.4
End-of-trial
The End-of-trial visit (Visit 10) occurs 12 weeks (84±2 days) after oocyte retrieval (week 14 of 
pregnancy) / 2 weeks (14±2 days) after the last exposure to IMP.
The following end-of-trial procedures / assessments must take place:

Vital signs


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
Blood collection for assessment of:
-
Clinical chemistry and hematology parameters

Urinalysis

Complete physical examination (including weight, and BMI calculation)

Pelvic examination (documentation of presence and grade [intensity] of any pain, irritation, 
abrasions, or lesions on the cervix or vagina or vaginal adhesions).
If any lesions or abrasions are found on the cervix or vagina or vaginal adhesions are noted, 
another examination will be performed 2-4 days later.

TVUS or abdominal ultrasound (pregnant subjects only) to determine the number of gestational 
sacs with/without fetal heart beat and estimate gestational age

Recording of any vaginal bleeding noted in the subject’s bleeding log since the previous visit

Assessment of vaginal hemorrhage

Recording of use of any concomitant medication

Recording of AEs
After completion of the End-of-trial visit, subjects will be referred to their obstetricians for further care.


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7
TRIAL ASSESSMENTS
7.1
Assessments Related to Primary Endpoint
7.1.1
Pregnancy Monitoring
7.1.1.1
β-hCG Test
Serum pregnancy tests will be obtained at 2 weeks, 2 weeks + 3-4 days, and 3 weeks after oocyte 
retrieval (i.e. at Visits 6, 6P, and 7). Subjects with a β-hCG level <5 mIU/mL will be discontinued from 
the trial.
7.1.1.2
Transvaginal Ultrasound
A TVUS will be performed at 4 weeks + 3-4 days after oocyte retrieval (Visit 7P) to document the 
presence of an intrauterine gestational sac, and at 6 weeks after oocyte retrieval (Visit 8) to determine 
the presence and number of gestational sacs with/without fetal heart beat. Ten weeks after oocyte 
retrieval (Visit 9), either a TVUS or abdominal ultrasound will be performed in pregnant subjects to 
determine the presence and number of gestational sacs with/without fetal heart beat and to estimate 
gestational age.
7.1.1.3
Ectopic and Heterotopic Pregnancies
If, at the TVUS performed 4 weeks + 3-4 days after oocyte retrieval, it is determined that the subject 
has an ectopic pregnancy, the subject will be treated according to the site’s standard protocol and will 
be withdrawn from the trial. 
If it is determined that the subject has a heterotopic pregnancy, the subject will be treated according to 
the site’s standard protocol and may remain in the trial at the discretion of the Investigator.
7.1.2
Spontaneous Abortion
Spontaneous abortion is defined as two positive 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 ultrasound.
7.2
Assessments Related to Secondary Endpoints
7.2.1
Positive β-hCG
Positive β-hCG is defined as a positive serum β-hCG test at 2 weeks and 2 weeks + 3-4 days post-
oocyte retrieval (Visit 6 and Visit 6P).


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7.2.2
Clinical Pregnancy
Clinical pregnancy is defined as a TVUS showing at least 1 intrauterine gestational sac with fetal heart 
beat at 6 and 10 weeks post-oocyte retrieval (Visit 8 and Visit 9). For clinical pregnancies, the number 
of intrauterine sacs and fetal heart beats will be recorded.
7.2.3
Biochemical Abortion
Biochemical abortion is 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.
7.2.4
Bleeding Log
Vaginal bleeding will be recorded in a Bleeding Log by the subject (Appendix 4). The subject will be 
instructed to use only sanitary napkins provided by the trial site for any bleeding/spotting that occurs 
during the trial; tampons are not permitted. This Bleeding Log will be given to all subjects at Visit 4 to 
capture the incidence (frequency and intensity) of any vaginal bleeding/spotting occurring throughout 
the trial i.e. until end-of-trial. For each incidence of bleeding/spotting, subjects will be instructed to 
record the date, time of day (AM versus PM), and the severity of the bleeding using a Pictorial Blood 
Loss Assessment chart (Wyatt, 2001). The grade (intensity) is scored as shown in Appendix 5. 
Bleeding deemed clinically significant in the opinion of the Investigator will be reported as an AE.
7.2.5
Vaginal Hemorrhage 
The presence or absence of vaginal haemorrhage as defined in section 8.3.6 will be assessed by the 
Investigator at all visits starting at Visit 4 where the first distribution of PVR takes place.
7.2.6
Clinical Laboratory Variables
The following laboratory tests will be performed:

Screening and Visits 4, 9, and 10 (End-of-trial): serum chemistry: non-fasting glucose, blood 
urea nitrogen, creatinine, potassium, sodium, chloride, calcium, aspartate aminotransferase, 
alanine aminotransferase, and gamma-glutamyl transferase

Screening and Visits 4, 9, and 10 (End-of-trial): hematology: red blood cell count, white blood 
cell count, hematocrit, hemoglobin, platelet count, and differential count

Screening and Visits 9 and 10 (End-of-trial): urinalysis: specific gravity, ketones, pH, protein, 
blood, and glucose

Screening: (prior to start of ovarian suppression): AMH

Screening (Cycle Day 3 ±1 day): FSH

Screening (Cycle Day 3 ±1 day) and Visits 1, 2, 4, and 5: serum estradiol

Screening and Visits 6, 6P, and 7: β-hCG


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
Visits 4, 5, 6, and 9: progesterone
The Investigator will review the laboratory results and evaluate and document whether the results are 
normal or abnormal and whether or not abnormal results are clinically significant. The laboratory 
report will be signed and dated by the Investigator. Results will be recorded in the subject’s chart and 
eCRF.
7.2.7
Vital Signs
Blood pressure, heart rate, and temperature will be measured at screening and Visits 3, 4, 5, 6, 7, 8, 9, 
and 10 (End-of-trial). Blood pressure and heart rate are to be measured while the subject is seated 
under resting conditions. All blood pressure measurements should be made using the same arm and 
prior to any scheduled blood draws.
The Investigator will review the vital sign results and evaluate and document whether the results are 
normal or abnormal and whether or not abnormal results are clinically significant. Results will be 
recorded in the subject’s chart and eCRF.
7.2.8
Pelvic Examination
A pelvic speculum examination will be performed at screening, Visits 4, 7P, 8, 9, and 10 to document 
the presence and grade (intensity) of any pain, irritation, abrasions, or lesions on the cervix or vagina, 
including the presence and grade (intensity) of any vaginal adhesions, using standardized criteria. An 
unscheduled pelvic speculum examination can be performed at the discretion of the Investigator for 
any visit with an AE reported by the subject for vaginal pain or irritation; the standardized criteria for 
establishing grade (intensity) are to be applied (Appendix 2). If any lesions or abrasions are found on 
the cervix or vagina or vaginal adhesions are noted, another examination will be performed 2-4 days 
later (each of these visits is to be documented as an unscheduled pelvic examination). Subjects will be 
followed until the lesions/abrasions or vaginal adhesions resolve or until the final assessment at the 
End-of-trial visit, whichever comes first. Vaginal adhesions observed can be surgically addressed
based on the Investigator’s judgement.
Any clinically significant finding will be reported as an AE (section 8). Results will be recorded in the 
subject’s chart and eCRF.
7.2.9
Adverse Events
AEs will be recorded from the signed informed consent for participation in the trial at screening until 
the End-of-trial visit (Visit 10).
7.2.9.1
Adverse Events of Special Interest
Assessment of AEs of special interest is discussed in section 8.3.


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7.3
Other Assessments
7.3.1
Demographics
Demographic information will be obtained during the screening period, including the following: date 
of birth, ethnicity (Hispanic or Latino, Not Hispanic or Latino) and race (American Indian or Alaska 
Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White).
7.3.2
Medical/Gynecological History
A complete medical and gynecological history will be obtained at screening and will include a review 
of prior medical history; menstrual history; concurrent conditions by body system; history of alcohol
and tobacco; and female reproductive status. Medical and gynecological history findings will be 
recorded in the subject’s chart and eCRF.
In addition, subjects will undergo gonorrhoea and chlamydia testing at screening.
7.3.3
Physical Examination
A complete physical examination will be performed at screening, Visit 9, and Visit 10. Results will be 
recorded in the subject’s chart and eCRF.
7.3.4
Height, Weight, and Body Mass Index Calculation
Height, weight, and body mass index (BMI) calculation will be performed at screening. In addition,
weight and BMI will be assessed at Visit 9 and Visit 10. Results will be recorded in the subject’s chart 
and eCRF.
7.3.5
Pelvic Examination and Pap Smear at Screening
A pelvic examination, including recording of baseline parameters in the pelvic examination page of the 
eCRF, will be conducted at screening to confirm the subject has no clinically significant gynecologic 
pathology or other conditions that could adversely affect pregnancy success.
In addition, a Pap smear will be performed at screening if not done in the previous 24 months. If done 
in the previous 24 months, the results must have been normal and a copy of the report must be filed in 
the subject’s chart and recorded in the eCRF.
7.3.6
PVR Diary
A diary will be completed by the subject for each PVR used. Subjects will be instructed to record the
date of insertion, date of removal, whether the PVR was inserted for at least 23 hours per day, and if 
the PVR was damaged at insertion or removal.


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7.3.7
Number and Size of Follicles
TVUS will be performed at Visit 1 and Visit 2, before and after ovarian stimulation, to count the 
number of follicles and measure the size of the follicles. Data will be recorded separately for the right 
and left ovary.
7.3.8
Oocyte Retrieval
Oocyte retrieval will performed under TVUS guidance at Visit 3, the procedure will be completed per 
the trial site’s protocol.
7.3.9
Endometrial Thickness
TVUS of the uterus to assess the endometrial thickness will be conducted at Visit 5 prior to or in 
connection with embryo transfer.
Endometrial thickness (composed of both layers of the endometrium) will be measured in the sagittal 
view of the uterus from the proximal and distal interfaces between the echogenic endometrium and the 
hypoechoic inner layer of the myometrium. Care should be taken not to include the hypoechoic 
subendometrial halo and to account for the presence of any fluid in the uterine cavity (not to be 
included in the endometrial thickness value). Endometrial thickness will be recorded in mm.
7.3.10
Embryo Transfer
Embryo transfer will be performed at Visit 5, 5 days after oocyte retrieval. Embryo transfer will be 
guided by TVUS or abdominal ultrasound and the procedure will be completed per the trial site’s 
protocol. The number of embryos to transfer must be guided by the 2017 American Society for 
Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) 
guidelines (SART/ASRM 2017): women with the expectation of one or more high-quality embryo(s)
available for cryopreservation, and women with previous live birth after an IVF cycle, will have
transfer of a single blastocyst. All other women will have transfer of no more than two blastocysts.
The number of embryos transferred will be recorded. Embryos not used for the embryo transfer in this 
trial may be frozen per the site’s protocol.
7.3.11
Concomitant Medication
The use of any concomitant medication within the last 1 month prior to informed consent for 
participation in the trial (except medication used in previous infertility treatment cycles which will be 
recorded as part of the infertility history) and throughout the trial will be recorded. Recording of 
concomitant medication will be performed at all visits. Any changes in concomitant medications or 
treatments must be recorded at each visit.


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An adverse event (AE) is any untoward medical occurrence in a subject participating in a clinical trial.
It includes:

Any unfavourable and unintended sign, symptom or disease temporally associated with the use 
of the IMP, whether or not considered to be caused by the IMP.

AEs commonly observed and AEs anticipated based on the pharmacological effect of the IMP.

Any laboratory abnormality, vital sign, or finding from physical or gynecological examination 
assessed as clinically significant by the Investigator (Note: pre-existing conditions diagnosed 
through assessments and examinations at the screening visit or during the screening period are 
not AEs, but are recorded as medical history).

Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for any 
medical, nursing or pharmacy consultation, or reasons for admission to hospital or surgical 
procedures.

Overdoses and medication errors with and without clinical consequences.
All AEs will be coded by Ferring Global Pharmacovigilance using the Medical Dictionary for 
Regulatory Activities (MedDRA) (the version effective at trial start).
8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The Investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the last visit (End-of-trial).
The sources of AEs cover:

The subject’s response to questions about her health (a standard non-leading question such as 
“How have you been feeling since your last visit?” is asked at each visit).

Symptoms spontaneously reported by the subject.

Investigations and examinations where the findings are assessed by the Investigator to be 
clinically significant changes or abnormalities.

Other information relating to the subject’s health becoming known to the Investigator 
(e.g., hospitalization).


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8.2.2
Recording of Adverse Events
The Investigator must record all AEs in the AE Log provided in each subject’s eCRF with information 
about:

AE description

Date and time of onset (time can be omitted, if not applicable)

Intensity

Causal relationship to IMP

Action taken to IMP

Other action taken

Date and time of outcome (time can be omitted, if not applicable)

Outcome

Seriousness.
Each of the items in the AE Log is described in detail in the following sections.
Adverse Event
AEs should be recorded as diagnoses, if available. If not, separate signs and symptoms should be 
recorded. One diagnosis/symptom should be entered per record.
If a subject suffers from the same AE more than once and the subject recovers in between the events, 
the AEs should be recorded separately. If an AE changes in intensity, a worst-case approach should be 
used when recording the event, i.e., the highest intensity and the longest duration of the event.1
Note the following: a procedure is not an AE; the reason for conducting the procedure is.
Hospitalization is not an AE; the reason for hospitalization is. Death is not an AE, but the cause of 
death is (an exception is sudden death of unknown cause, which is an AE).
                                                
1
Exception: if an AE with onset before the first IMP administration (i.e., a pretreatment AE) worsens in intensity, 
this must be recorded as 2 separate events. The initial AE should be recorded with outcome “not recovered” and 
the date and time of outcome are when the intensity changed. The second AE should be recorded with date and 
time of onset when the intensity changed. 


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Date and Time of Onset
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the AE is an 
abnormal clinically significant laboratory test or outcome of an examination, the onset date is the date 
the sample was taken or the examination was performed. 
Intensity
The intensity of an AE must be 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).
Severe:
Inability to work or perform usual activities (unacceptable).
The grading of AEs of special interest will be based on predefined criteria as discussed in section 8.3.
Causal Relationship to IMP
The possibility of whether the IMP caused the AE must be classified as one of the following:
Reasonable possibility: 
There is evidence or argument to suggest a causal relationship between 
the IMP and the AE. The AE may occur as part of the pharmacological 
action of the IMP or may be unpredictable in its occurrence.
Examples: 

AEs that are uncommon but are known to be strongly associated with IMP exposure.

AEs that are not commonly associated with IMP exposure, but the event occurs in association 
with other factors strongly suggesting causation, such as a strong temporal association or the 
event recurs on rechallenge with the IMP.
No reasonable possibility:
There is no reasonable evidence or argument to suggest a causal 
relationship between the IMP and the AE.
Examples:

Known consequences of the underlying disease or condition under investigation.

AEs common in the trial population, which are also anticipated to occur with some frequency 
during the course of the trial, regardless of IMP exposure.


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Action Taken to IMP
The action taken to the IMP in response to an AE must be classified as 1 of the following:

No change (medication schedule maintained or no action taken)

Withdrawn

Interrupted

Not applicable
Other Action Taken
AEs requiring therapy must be treated with recognized standards of medical care to protect the health 
and well-being of the subject. Appropriate resuscitation equipment and medicines must be available to 
ensure the best possible treatment of an emergency situation.
If medication is administered to treat the AE, this medication should be entered in the Concomitant 
Medication Log.
Date and Time of Outcome
The date and time (time can be deleted/omitted, if not applicable) the subject recovered or died.
Outcome
The outcome of an AE must be classified as one of the following:

Recovered (fully recovered or the condition has returned to the level observed at initiation of 
trial treatment)

Recovered with sequelae (resulted in persistent or significant disability/incapacity)

Recovering (the event is improving)

Not recovered

Fatal.
8.3
Adverse Events of Special Interest
Standardized criteria will be applied to some AEs of special interest to establish intensity/grade (see 
Section 8.2.2) . Mapping of grade to intensity for these AEs is described below; additional details are 
provided in Appendix 2 and Appendix 3.
Grade 1: Mild
Grade 2: Moderate


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Grade 3: Severe
Grade 4: Potentially Life-Threatening
Any finding of grade 4 will be designated as an SAE.
8.3.1
Vaginal Pain and Irritation 
The criteria for the grading of AE’s associated with vaginal pain and irritation is found in Appendix 3.
The mapping of these grades to intensity criteria is described above (section 8.3). For clinical findings 
of pain and irritation during scheduled or unscheduled pelvic examinations the criteria for grading 
provided in Appendix 2 will be applied.
8.3.2
Vaginal or Cervical Abrasions and Lesions
Clinical findings of abrasions or lesions during scheduled or unscheduled pelvic examinations will be 
graded according to the criteria in Appendix 2. The mapping of these grades to intensity criteria is 
described in section 8.3.
8.3.3
Vaginal Adhesions
Clinical findings of vaginal adhesions during scheduled or unscheduled pelvic examinations will be 
graded according to the criteria in Appendix 2. The mapping of these grades to intensity criteria is 
described in section 8.3.
8.3.4
Vaginal Infection
Any occurrence of vaginal infection will be recorded as AEs. 
8.3.5
Vaginal Bleeding/Spotting
Clinically significant findings of vaginal bleeding/spotting will be recorded as AEs. Collection and 
grading of Bleeding Log information is described in Section 7.2.4, Appendix 4 and Appendix 5.
8.3.6
Vaginal Hemorrhage
Vaginal hemorrhage is defined as a) blood loss of > 500 mL based on the opinion of the Investigator or 
b) hemoglobin post-treatment <10 gm/dL or c) blood loss requiring transfusion. The assessment of 
vaginal hemorrhage will be collected in a specific eCRF module. 
8.3.7
Pregnancy Losses
Cases of biochemical abortion, spontaneous abortion, ectopic pregnancy and heterotopic pregnancy 
will be recorded as AEs.


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8.4
Serious Adverse Events
8.4.1
Serious Adverse Event Definition
Serious adverse events (SAEs) during the trial are defined as follows:
An event is defined a SAE if it:
Guidance
results in death
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within 4 weeks after the treatment ends and irrespective 
of the causal relationship to the IMP. The death of a subject enrolled in a trial is per 
se not an event, but an outcome.
is life-threatening
The term life-threatening refers to an AE in which the subject was at immediate risk 
of death at the time of the event. It does not refer to an event that may have caused 
death if it were more severe.
requires inpatient hospitalization 
or prolongation of existing 
hospitalization
The term hospitalization means that the subject was admitted to hospital or that 
existing hospitalization was extended as a result of an event. Hospitalization 
describes a period of at least 24 hours. An overnight stay for observation, a stay at 
an emergency room, or treatment on an outpatient basis does not constitute a 
hospitalization. However, medical judgement must always be exercised, and when 
in doubt, the case should be considered serious (i.e., if case fulfills the criterion for 
a medically important event). Hospitalizations for administrative or social purposes 
do not constitute a SAE. Hospital admissions and/or surgical operations planned 
before trial inclusion are not considered AEs if the illness or disease existed before 
the subject was enrolled in the trial, provided that the condition did not deteriorate 
during the trial.
results in persistent or significant 
disability/incapacity
Disability/incapacity means a substantial disruption of a person’s ability to conduct 
normal life functions. If in doubt, the decision should be left to medical judgement 
by the Investigator.
is a congenital anomaly/birth 
defect
Congenital anomaly/birth defect observed in any offspring of the subject conceived 
during treatment with the IMP.
is an important medical event
Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered serious such as important mgedical events that 
might not be immediately life-threatening or result in death or hospitalization but 
might jeopardize the patient or might require intervention to prevent one of the 
other outcomes listed in the definition above. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.


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8.4.2
Collection, Recording and Reporting of Serious Adverse Events
SAE Reporting by the Investigator
All SAEs must be reported immediately to Ferring United States Pharmacovigilance as soon as it 
becomes known to the Investigator and not later than within 24 hours of knowledge of the occurrence 
of an SAE.
The Investigator is responsible for submitting the completed SAE Report Form with the fullest possible 
details within 3 calendar days of his/her knowledge of the SAE.
SAE Report Form
The SAE Report Form is included in the eCRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the e-CRF cannot be accessed and hence the 
SAE Report Form cannot be filled in within the e-CRF system, a paper SAE Report Form should be 
used and sent to Ferring Pharmacovigilance using the contact details below.
Ferring Pharmacovigilance
E-mail: 
US Fax: 
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log are mandatory for initial reports and for follow-up reports if any relevant changes have 
been made since the initial report. Data entries must have been made in the e-CRF for Ferring 
Pharmacovigilance to access the information.
Additional information relevant to the SAE such as hospital records, results from investigations, e.g., 
laboratory parameters (that are not already uploaded in the eCRF), invasive procedures, scans and x-
rays, and autopsy results can be faxed or scanned and e-mailed to Ferring Pharmacovigilance using the 
contact details in the section above. In any case, this information must be supplied by the Investigator 
upon request from Ferring. On any copies provided, details such as subject’s name, address, and 
hospital identification number should be concealed and instead subject number should be provided.
The Investigator will supply Ferring and the IRB with any additional requested information such as 
results of post-mortem examinations and hospital records.
Ferring will report SAEs according to local regulations.


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8.5
Follow-up of Adverse Events and Serious Adverse Events
8.5.1
Follow-up of Adverse Events with Onset during the Trial
During the trial, from the time of obtaining informed consent until the end-of-trial visit (for each 
subject individually), the Investigator must follow-up on each AE until it is resolved or until the 
medical condition of the subject is stable.
After the subject’s last trial visit, the Investigator must follow-up on any AE classified as serious or 
considered to have a reasonable possible causality to the IMP until it is resolved or until the medical 
condition of the subject is stable. All such relevant follow-up information must be reported to Ferring.
If the event is a chronic condition, the Investigator and Ferring may agree that further follow-up is not 
required.
8.5.2
Follow-up of Adverse Events on Non-Investigational Medicinal Products During the 
Trial
In case an AE is recognised as an adverse drug reaction caused by a concomitant NIMP, investigators 
should report to each Marketing Authorisation Holder. For adverse drug reactions caused by an NIMP 
where Ferring is the Marketing Authorisation Holder, the case will have to be reported to Ferring.
8.5.3
Collection of Serious Adverse Events with Onset after Last Visit in the Trial
If an Investigator becomes aware of an SAE after the subject’s last visit, and he/she assesses the SAE 
to have a reasonable possible causality to the IMP, the case will have to be reported to Ferring, 
regardless of how long after the end of the trial this takes place.


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9
STATISTICAL METHODS
The statistical analyses will be detailed in a separate Statistical Analysis Plan.
9.1
Primary Analysis
At the final analysis, the cumulative rate of any spontaneous abortion, including spontaneous clinically 
recognized pregnancy loss and blighted ovum during the trial (up to Week 12 following oocyte 
retrieval), in subjects treated with PVR following fresh embryo transfer will be estimated (i.e.,
modified intention-to-treat [mITT] population). 
The number and rate of any spontaneous abortions (occurring on or before 12 weeks following oocyte 
retrieval) for subjects in the mITT cohort will be summarized and the associated two-sided exact 95% 
confidence interval will be generated. Upon generating the two-sided exact 95% confidence interval, 
the upper bound of the interval will be assessed for whether it excludes or fails to exclude a 
spontaneous abortion rate of 15%.
9.2
Determination of Sample Size
In this safety trial, the primary assessment of interest is on the number of subjects that experience a 
spontaneous abortion. Because this is a single-arm trial, all subjects that enter the mITT analysis 
population will have been treated with the investigational product, PVR. The primary analysis involves 
the construction of a two-sided 95% exact confidence interval surrounding the proportion of subjects in 
the mITT analysis population that experience a spontaneous abortion. The upper bound of said 
confidence interval is then compared with the threshold of a 15% spontaneous abortion rate.
Statistical simulations have been performed to understand the operating characteristics under varying 
assumptions for both the sample size of the mITT analysis population and the “true” proportion of 
spontaneous abortions. For each simulation repetition, a sample of subjects was simulated using the 
binomial distribution and a given pair of sample size and “true” proportion of spontaneous abortions 
assumptions. A two-sided 95% exact confidence interval was then created based on the simulated data 
and the upper bound of this confidence interval was compared to the threshold of 0.15 (corresponding 
to a spontaneous abortion rate of 15%). If the upper bound of the two-sided 95% exact confidence 
interval was less than 0.15, the simulation repetition was declared a “success”. If, however, the upper 
bound of the two-sided 95% exact confidence interval was greater than or equal to 0.15, the simulation
repetition was declared a “failure”. This process was repeated 10,000 times for each combination of 
assumed sample size and “true” proportion of spontaneous abortions. The proportion of simulation 
repetition successes to the total number of simulation repetitions then described the power of the 
proposed trial given the pair of assumptions.


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The sample size necessary to achieve 80% power to exclude the possibility of a 15% spontaneous 
abortion rate after the use of PVR is described in Table 9-1. If the “true” spontaneous abortion rate is 
8%, 9%, or 10%, the sample size required to achieve 80% power to exclude the possibility of a 15% 
spontaneous abortion rate after the use of PVR is 180, 240, or 365, respectively. 
Table 9-1
Power Achieved over Varying Sample Sizes and Assumed Spontaneous Abortion 
Rates
Required Sample Size
(mITT Analysis Population)
Assumed “True” Spontaneous Abortion Rate
8%
9%
10%
180
80.3%
64.8%
46.1%
240
93.1%
81.8%
63.2%
365
98.9%
94.2%
80.9%
mITT = modified intention-to-treat
Taking the middle of this range, a trial with 240 subjects in the mITT analysis population is considered
as being adequately powered under a relevant assumption in the target population. Full simulation code 
is provided in Appendix 6.
9.3
Subject Disposition
The number and percentage of subjects treated with oral contraceptives, leuprolide acetate, 
MENOPUR, hCG, and IMP, and subjects who underwent a fresh cycle, will be summarized.
Furthermore, the number of subjects that discontinue the trial during the suppression phase, stimulation 
phase, and after start of IMP treatment (treatment phase) will be summarized by reason for 
discontinuation. The subjects screened and not treated with either IMP nor NIMP (oral contraceptives, 
leuprolide acetate, MENOPUR, and hCG) will be presented in a separate data listing.
9.4
Protocol Deviations
Significant protocol deviations will be defined and documented prior to database lock. Details will be 
provided in the Statistical Analysis Plan and/or in the Clean File document.
9.5
Analysis Sets
9.5.1
mITT Cohort
The mITT cohort consists of all subjects who had successful oocyte retrieval, received at least 1 dose 
of IMP, and had completed fresh embryo transfer.
9.5.2
Safety Cohort
The safety cohort comprises all subjects treated with IMP.


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9.5.3
Eligible Subjects (ES) Cohort
The ES cohort consists of all subjects who were deemed eligible for trial participation based on 
inclusion and exclusion criteria at screening and treated with oral contraceptives, leuprolide acetate, 
and MENOPUR.
9.6
Trial Population
9.6.1
Demographics and other Baseline Characteristics
Descriptive statistics for demographics and other baseline characteristics will be presented for the 
subjects in the mITT, safety, and ES cohorts. 
Categorical data will be summarized using frequencies and percentages. The percentages are based on 
the total number of subjects within the given analysis cohort. Continuous data will be presented with 
the number of subjects, mean, standard deviation, median, interquartile range, minimum, and 
maximum. Associated demographic listings will also be produced.
9.6.2
Medical History, Concomitant Medication and Other Safety Evaluations
Medical history will be coded using the latest version of Medical Dictionary for Regulatory Activities 
for the mITT and ES cohorts.
9.6.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by Anatomical Therapeutic Chemical 
classification first level (alphabetically) and Anatomical Therapeutic Chemical classification second 
level (in decreasing order of frequency) using the latest available version of the World Health 
Organization Drug Dictionary. Medications will be tabulated separately for:
Prior medication: medication taken exclusively prior to the first IMP administration (i.e., with 
a stop date before the date of the first IMP administration).
Concomitant medication: medication taken after IMP administration, regardless of whether the 
drug began before the first IMP administration (i.e., medication that was not stopped before the 
date of the first IMP administration) and not started after the End-of-trial visit.
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as a concomitant medication. Prior medication will be 
summarized using the mITT and ES cohorts. In contrast, concomitant medications will be analyzed 
using the mITT cohort.


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9.7
Endpoint Assessments
9.7.1
General Considerations
Continuous variables will be described with the number of non-missing values, mean, standard 
deviation, median, and minimum/maximum values. Categorical variables will be described with the 
number and percentage of subjects within each level. All confidence intervals will be 95% confidence 
intervals.
9.7.2
Primary Endpoint
The primary endpoint is the cumulative 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. Spontaneous abortion is defined as two positive 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 ultrasound.
In addition to the analysis specified in section 9.1, the number and rates of any spontaneous abortions 
(occurring on or before 12 weeks following oocyte retrieval) in all subjects in the mITT cohort will be 
analyzed as a sensitivity analysis using a Bayesian hierarchical model to dynamically borrow 
information from the DR-PGN-302 study. The cumulative rate of any spontaneous abortion from Study 
DR-PGN-302 was 55/549 (10.2%). Dynamic borrowing between this prior data and the current trial’s 
data allow borrowing to occur to the extent indicated by these two observed rates. More borrowing 
occurs when the rates are similar while less when they differ. Full modeling details are provided 
in Appendix 6.
9.7.3
Secondary Endpoints
9.7.3.1
Spontaneous Abortion within 6 and 10 Weeks of Oocyte Retrieval
The frequency and proportion of subjects that have any spontaneous abortion during the trial within 6 
and 10 weeks post-oocyte retrieval will be derived for subjects in the mITT and safety cohorts for 
subjects that had ooctyte retrieved. Associated 95% confidence intervals will also be presented.
9.7.3.2
Biochemical Abortions within 6 and 10 Weeks of Oocyte Retrieval
Biochemical abortion is 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. The frequency and proportion of subjects that have biochemical abortion within 
6 and 10 weeks post-oocyte retrieval will be derived for subjects in the mITT and safety cohorts for 
subjects that had oocyte(s) retrieved. Associated 95% confidence intervals will also be presented.


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9.7.3.3
Ectopic and Heterotopic Pregnancies
Ectopic and heterotopic pregnancies will be reported as AEs. The frequency and proportion of subjects 
with ectopic and heterotopic pregnancies will be summarized.
9.7.3.4
Positive β-hCG
Positive β-hCG is defined as a positive serum β-hCG test at 2 weeks and 2 weeks + 3-4 days post-
oocyte retrieval. The positive β-hCG rate will be derived for subjects in the mITT and safety cohorts 
for subjects that had oocyte(s) retrieved. Associated 95% confidence intervals for these event rate 
estimates will also be presented.
Subjects who do not have both β-hCG tests due to missing data, early withdrawal, or any other reason 
will be counted as not having positive β-hCG unless a positive result is observed at a later pregnancy 
assessment. For example, if the outcome of these β-hCG tests is missing and a TVUS confirms clinical 
pregnancy at a later date then β-hCG will be imputed as ‘positive’.
9.7.3.5
Clinical Pregnancy
Clinical pregnancy is defined as a TVUS showing at least 1 intrauterine gestational sac with fetal heart 
beat at 6 and 10 weeks post-oocyte retrieval. The frequency and proportion of subjects that are 
clinically pregnant at 6 and 10 weeks post-oocyte retrieval will be derived for subjects in the mITT and 
safety cohorts for subjects that had oocyte(s) retrieved. Associated 95% confidence intervals for these 
event rate estimates will also be presented.
For the clinical pregnancy rate derivation at 6 weeks post-oocyte retrieval, if a subject has missing 
TVUS assessment and no other TVUS assessment at a later date, the subject will be counted as not 
having a clinical pregnancy. In contrast, if there is a later assessment with at least 1 intrauterine 
gestational sac with fetal heart beat, the subject will be imputed as having a clinical pregnancy at 6 
weeks post-oocyte retrieval.
9.7.4
Other Assessments
9.7.4.1
Number and Size of Follicles during Stimulation
For each subject, the number of follicles on stimulation day 1 and last day of stimulation will be 
summarized for the mITT and ES cohorts. The summary will include the following:
1. the number of subjects that have follicles of size <10 mm, 10 mm, 11 mm, 12 mm, 13 mm,
14 mm, 15 mm, 16 mm, and ≥17 mm, 
2. a summary of the number of follicles ≥17 mm (the count for each subject will be summarized 
across subjects),
3.
the number of subjects that have at least two folliciles that are ≥17 mm, and 


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4. a summary of the percentage of follicles ≥17 mm, ≥15 mm, and ≥12 mm (for each subject the 
percentage will be first derived and this subject level sammary will be summarized across 
subject using mean, SD, etc.).
9.7.4.2
E2 and Progesterone Profiles
The central laboratory E2 and progesterone profiles will be summarized for mITT and ES cohorts, 
using descriptive statistics by scheduled visit, as well as for the change from screening for 
post-screening visits.
For patients in the mITT population, the local laboratory E2 assessments will be summarized by visit.
9.7.4.3
Oocytes
For each subject, the number of oocytes retrieved, the number of germinal vesicle, metaphase I, 
metaphase II and Degenerated oocytes will be summarized by frequency distribution and by 
descriptive statistics for the mITT and ES cohorts.
9.7.4.4
Characterization of Fertilized Oocytes one Day (Day 1) after Oocyte Retrieval
The status of fertlized oocytes will be summarized 1 day after oocyte retrieval for the mITT and ES 
cohorts. The summary will be both at the subject level and at the oocyte level. 
For the summary at the subject level, for each subject, the percentage of fertilized oocytes with 
pronuclei 2 pn will be derived. The percentage will be derived over the number of oocytes retrieved. 
These percentage will further be summarized using descriptive statastistics (i.e., mean, SD, etc.). The 
percentage of fertilized oocytes with continue destiny will be similarly analyzed. 
For the fertlized oocyte level summary, the number and percentage of fertilized oocytes falling in each 
category of pronuclei will be presented (i.e., >2 pn, 2 pn, 1 pn, 0 pn and damaged). The percentage 
derivation will be over the total number of oocytes classified. 
These summaries will be obtained for mITT and ES cohorts.
9.7.4.5
Quality of Blastocysts 5 Days (Day 5) after Oocyte Retrieval
The quality of blastocysts 5 days after oocyte retrieval will be assessed at both the blastocyst level and 
at the subject level. The evaluation of fertilized oocytes at Day 5 will consist of assessment of embryo
stage and classification of blastocysts according to blastocyst expansion and hatching status, blastocyst 
inner cell mass grading and trophectoderm grading. Furthermore, the destiny of the embryo will be 
recorded.
Embryo stage is classified as blastocyst, morula, degenerated or cleavage stage. For embryos still at the 
cleavage stage the number of blastomeres will be recorded.


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Destiny at Day 5 is either transferred, cryopreserved or out of trial.
The scoring of blastocysts is based on the classification system by Gardner & Schoolcraft (Gardner, 
1999).
Blastocyst expansion and hatching status will be assessed as one of the following:
1. An early blastocyst, blastocoel being less than half volume of that of the embryo
2. A blastocyst with a blastocoel whose volume is half of, or greater than half of, that 
of the embryo
3. A blastocyst with a blastocoel completely filling the embryo
4. An expanded blastocyst with a blastocoel volume larger than that of the early 
embryo, with a thinning zona
5. A hatching blastocyst with the trophectoderm starting to herniate through the zona
6. A hatched blastocyst, in which the blastocyst has completely escaped from the zona
For blastocysts with expansion and hatching status on Day 5, blastocyst inner cell mass grading and 
trophectoderm grading will be evaluated.
Blastocyst inner cell mass grading will be assessed as one of the following:
A. Tightly packed, many cells
B. Loosely grouped, several cells
C. Very few cells
Trophectoderm grading will be assessed as one of the following:
A. Many cells forming a cohesive epithelium
B. Few cells forming a loose epithelium
C. Very few, large cells 
Based on the blastocyst expansion and hatching status, blastocyst inner cell mass grading and 
trophectoderm grading, the embryo will be classified as a good-quality blastocyst if the grade is 3BB 
or above as illustrated in Table 9-2.


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Table 9-2
Good-Quality Blastocysts
3AA
4AA
5AA
6AA
3AB
4AB
5AB
6AB
3AC
4AC
5AC
6AC
3BA
4BA
5BA
6BA
3BB
4BB
5BB
6BB
4BC
5BC
6BC
4CA
5CA
6CA
4CB
5CB
6CB
4CC
5CC
6CC
The embryos on Day 5 will be summarised on both the embryo level and at the subject level.
Embryo Level
At the embryo level all embryos evaluated will be included in the tables when reporting embryo stage 
and destiny of the embryo. For summary of blastocyst expansion and hatching status, blastocyst inner 
cell mass grading and trophectoderm grading all available embryo evaluations will be included. 
Frequency tables will be produced for the embryo stage, destiny, blastocyst expansion and hatching 
status, blastocyst inner cell mass grading and trophectoderm grading. These summaries will be 
obtained for the subjects in the mITT and ES cohorts.
Subject Level
At the subject level the following will be derived for all subjects in the mITT and ES cohorts for the 
subjects that had oocytes retrieved:

Number of blastocysts at Day 5

Number of good-quality blastocysts at Day 5
These counts will be summarized using descriptive statistics of mean, median, SD, minimum and 
maximum.
9.7.4.6
Endometrial Thickness 
Endometrial thickness at the time of blastocyst transfer will be summarized for the mITT and ES 
cohorts.


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9.8
Extent of Exposure and Treatment Compliance
9.8.1
PVR
The total number of PVRs used and the duration of treatment will be summarized. The total number of 
subjects who prematurely discontinued PVR and the associated reasons for discontinuation will also be 
summarized. Furthermore, the drug compliance rate will also be summarized for the mITT and safety 
cohorts. Compliance is defined as follows:
(number of PVRs used)/ (number of PVRs expected to be used).
These summaries will be generated for the safety cohort. Additional information collected in the drug 
accountability eCRF module may be summarized. A detailed associated listing will be produced.
9.8.2
Oral Contraceptives
The type of oral contraceptives used and the duration of treatment will be summarized for the ES and 
safety cohorts.
9.8.3
MENOPUR, Leuprolide Acetate, and hCG
The total dose of MENOPUR and leuprolide acetate administered and the duration of treatment will be 
summarized for the ES and safety cohorts. The number of subjects that receive hCG will also be 
summarized for the ES and safety cohorts.
9.9
Safety
9.9.1
General Considerations
Safety parameters will be evaluated for the ES and safety cohorts. Safety summaries will be presented 
by the 5 phases of the trial. These phases are defined as follows:

Screening Phase: From the date of signing the informed consent through the day before the start 
of the oral contraceptive treatment.

Suppression Phase: From the start of oral contraceptive treatment until the day before the start 
of the stimulation phase (start of MENOPUR treatment).

Stimulation Phase: From the date of the first dose of MENOPUR through the day before the 
start of IMP.

Treatment Phase: From the date of the first dose of IMP (PVR) through the end of the trial.

Study Phase: From the date of the first dose of oral contraceptive through the end of the trial.


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9.9.2
Adverse Events
Treatment-emergent AEs are AEs that occur during the treatment phase or a pre-existing medical 
condition that worsened in intensity during the treatment phase. Treatment-emergent AEs will be 
summarized overall and tabulated by system organ class and preferred term using the latest available 
Medical Dictionary for Regulatory Activities dictionary. The total number of subjects reporting at least 
1 AE, the percentage of subjects with an AE, and the number of events reported will be presented.
Summary tables will be prepared for:

All treatment-emergent AEs

Treatment-emergent AEs by causality (related/unrelated)

Treatment-emergent AEs leading to death

Treatment-emergent AEs by intensity

Treatment-emergent SAEs

Treatment-emergent AEs leading to discontinuation

Treatment-emergent AEs with an incidence of at least 5%

Non-serious treatment-emergent AEs with an incidence of at least 5%
Furthermore, the overall AE summary table by system organ class and preferred term will also be 
produced for the study phase, suppression phase, and the stimulation phase for the ES and safety 
cohorts.
A separate AE listing will be provided for the screening phase, suppression phase, stimulation phase, 
and treatment phase of the trial.
9.9.2.1
Treatment-Emergent AEs of Special Interest
Standardized criteria will be applied to some AEs of special interest to establish intensity/grade. For 
AEs associated with vaginal bleeding/spotting, vaginal pain and irritation, and vaginal or cervical 
abrasions and lesions, standardized criteria will be used by the sites to record the intensity of these AEs 
(see section 8.3 and Appendix 2, Appendix 3, and Appendix 4). For these AEs and AEs associated 
with vaginal haemorrhage, vaginal infection and vaginal adhesions, a summary table of the treatment-
emergent AEs of special interest will be produced by preferred term, grade (intensity), and seriousness 
for subjects in the safety cohort for the treatment phase and the study phase.
9.9.3
Safety Laboratory Variables
For each laboratory parameter (hematology, chemistry, and urinalysis), the number of subjects with 
abnormal laboratory values will be summarized for the study phase and the stimulation phase for the 


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ES and safety cohorts. This summary will also be produced for the treatment phase for the safety 
cohort.
9.9.4
Vital Signs
For each vital sign parameter, the number of subjects with abnormal vital signs will be summarized for 
the study phase and stimulation phase for the ES and safety cohorts. This summary will also be
produced for the treatment phase for the safety cohort.
9.9.5
Bleeding Log
At the start of PVR, each subject will receive a bleeding log (see section 8.3 and Appendix 4). For each 
incidence of sanitary napkin use for bleeding/spotting, subjects will be instructed to record the date, 
time of day, and the severity of the bleeding. For each subject, for each day: the grade (intensity) of 
bleeding associated with each sanitary napkin use will be summed. The sum of the daily grades 
(intensity) of bleeding will be averaged by visit window where the visit window will cover the
subject’s Bleeding Log recording period (i.e., from the start of the PVR to the End-of-trial visit). 
Finally, this subject data will be summarized across all subjects for the safety cohort by visit window. 
The summary will include mean, median, standard deviation, minimum and maximum. Furthermore, 
this analysis will be repeated removing the periods associated with AEs reported as vaginal 
hemorrhage, the primary endpoint of spontaneous abortion, the secondary endpoint of biochemical 
abortion and information collected after the cessation of the use of PVR.
9.9.6
Vaginal Hemorrhage
The number of subjects with vaginal hemorrhage (see Sections 7.2.5 and 8.3.6) will be summarized for 
the safety cohort.
9.9.7
Pelvic Examination
A pelvic examination will be performed at screening, Visits 4, 7P, 8, 9, and 10 to document the 
presence and grade (intensity) of any pain, irritation, abrasions, or lesions on the cervix or vagina using 
standardized criteria, and the presence and grade (intensity) of any vaginal adhesions using 
standardized criteria (Appendix 2). If any lesions or abrasions are found on the cervix or vagina or 
vaginal adhesions are noted, another examination will be performed 2-4 days later. The grade 
(intensity) for each type of assessment will be summarized by visit for the safety cohort. Furthermore, 
a shift table will be presented summarizing the change in grade (intensity) from Visit 4 to the End-of-
trial, where the End-of-trial is defined to be the last assessment in the treatment phase.
An associated listing will also be produced.
9.10
Interim Analyses
No interim analysis is planned.


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10
DATA HANDLING
10.1
Source Data and Source Documents
Source Data – International Council for Harmonisation (ICH) Definition
Source data are defined as all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents (original records or certified 
copies).
Source Documents - ICH Definition
Source documents are defined as original documents, data, and records (e.g., hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-
technical departments involved in the clinical trial).
Trial-specific Source Data Requirements – Ferring
Source documents need to be preserved for the maximum period of time permitted by local 
requirements. For each subject enrolled, the Investigator will indicate in the source documents that the 
subject participates in this trial, and will record at least the following information, if applicable: 

Existence of subject (initials, date of birth) 

Confirmation of participation in trial (trial ID, subject ID)

Informed consent (date and time of oral information, date and time of handing out Informed 
Consent Documents, date and time of obtaining written informed consent)

Eligibility for participation in the trial (documenting all inclusion / exclusion criteria)

Relevant medical and gynecological history

Visit dates

Dates of administration of IMP

Dates and doses of NIMP

Dates and doses of concomitant medication

Results of β-hCG tests and TVUS at Visits 6, 6P, 7, 8, 9 and 10

Adverse events (description as well as start/stop date and time)


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
Reason for discontinuation
The source data for analytical parameters of blood samples will be available at the central laboratory.
The source data for vaginal bleeding/spotting will be the subject´s bleeding log. The source data for 
dates of insertion and removal of each PVR will be the subject´s PVR diary.
No specific protocol data can be recorded directly in the e-CRF without prior written or electronic 
record.
10.2
eCRF/Case Report Form
An eCRF system provided by an independent third-party contract research organization (CRO) will be 
used for data capture. The system is validated and access at all levels to the system is granted/revoked 
following Ferring and vendor procedures, in accordance with regulatory and system requirements.
Trial data should be entered into the eCRF in a timely manner. The time-frame will be specified in the 
investigator agreement as well as in the eCRF guideline.
The Investigator will approve/authorize the eCRF entries for each subject with an electronic signature 
that is equivalent to a handwritten signature. 
The eCRF system and the database will be hosted at the independent third-party CRO. After the trial 
database is declared clean and released to the statistician, a final copy of the database will be stored at 
Ferring. The Investigator will also receive a copy of the trial site’s final and locked data (including 
audit trail, electronic signature, and queries) as write-protected PDF files produced by the independent 
third-party CRO. The PDF files will be stored in an electronic format and will be provided to the 
Investigator before access to the eCRF is revoked.
Entry errors occurring in the eCRF will be corrected electronically. Such corrections or modifications 
will be automatically tracked by an audit trail detailing the date and time of the correction and the 
name of the person making the correction.
10.3
Data Management
A data management plan will be created under the responsibility of the Global Biometrics Department,
Ferring. The data management plan will be issued before data collection begins and will describe all 
functions, processes, and specifications for data collection, cleaning, and validation.
The data management plan will also include information about the intended use of computerised 
systems, a description of the security measures employed to protect the data and a description of the 
electronic data flow.


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10.4
Provision of Additional Information
On request, the Investigator will provide Ferring with additional data relating to the trial, duly 
anonymized and protected in accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
Periodic Monitoring
The monitor will contact and visit the Investigator periodically to ensure adherence to the protocol, 
ICH-Good Clinical Practice (GCP), standard operating procedures and applicable regulatory 
requirements, maintenance of trial-related source records, completeness, accuracy, and verifiability of 
eCRF entries compared to source data, verification of drug accountability, and compliance with safety 
reporting instructions.
The Investigator will permit the monitor direct access to all source data, including electronic medical 
records, and/or documents in order to facilitate data verification. The Investigator will cooperate with 
the monitor to ensure that any discrepancies that may be identified are resolved. The Investigator is 
expected to be able to meet the monitor during these visits. When the first subject is enrolled at the trial 
site, a monitoring visit will take place shortly afterwards. For this trial, the frequency of the monitoring 
visits per site will be determined by the enrolment rate.
The source data verification process and definition of key variables to be monitored and the monitoring 
strategy will be described in detail in the Monitoring Plan for the trial.
11.2
Audit and Inspection
The Investigator will make all the trial-related source data and records available at any time to quality-
assurance auditor(s) mandated by Ferring, or to domestic/foreign regulatory inspectors or 
representatives from IRBs who may audit/inspect the trial.
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP, including the Declaration of Helsinki and all other relevant regulations.
The subjects must be informed by the Investigator and in the informed consent documents that 
authorized Ferring representatives and representatives from regulatory authorities and IRBs may wish 
to inspect their medical records. During audits/inspections, the auditors/inspectors may copy relevant 
parts of the medical records. No personal identification, apart from the screening number, will appear 
on these copies.
The Investigator should notify Ferring without any delay of any inspection by a regulatory authority or 
IRB.
11.3
Confidentiality of Subject Data
The Investigator will ensure that the confidentiality of the subjects’ data will be preserved. In the eCRF
or any other documents submitted to Ferring, the subjects will not be identified by their names, but by 
an identification system, which consists of an assigned number in the trial. Documents that are not for 


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submission to Ferring, e.g., the confidential subject identification code and the signed informed 
consent documents, will be maintained by the Investigator in strict confidence.


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12
CHANGES IN THE CONDUCT OF THE TRIAL
12.1
Protocol Amendments
Any change to this protocol will be documented in a protocol amendment issued by Ferring, and 
agreed upon by the Investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving IRBs and regulatory authorities, in accordance with local 
regulations. Changes to the protocol to eliminate immediate hazard(s) to trial subjects may be 
implemented prior to IRB approval or favourable opinion.
12.2
Deviations from the Protocol
Deviations from the protocol should not occur. If deviations from the protocol occur, the Investigator 
must inform the monitor, and the implications of the deviation must be reviewed and discussed. Any 
deviation must be documented, either as an answer to a query in the eCRF, in a protocol deviation 
report in the eCRF, or a combination of both. A log of significant protocol deviation reports will be 
maintained by Ferring. Protocol deviation reports and supporting documentation must be kept in the 
Investigator’s File and in the trial master file.
12.3
Premature Trial Termination
Both the Investigator (with regard to his/her participation) and Ferring reserve the right to terminate the 
trial at any time. Should this become necessary, the procedures will be agreed upon after consultation 
between the two parties. In terminating the trial, Ferring and the Investigator will ensure that adequate 
consideration is given to the protection of the best interests of the subjects. Regulatory authorities and 
IRBs will be informed.
In addition, Ferring reserves the right to terminate the participation of individual trial sites. Conditions 
that may warrant termination include, but are not limited to, insufficient adherence to protocol 
requirements and failure to enter subjects at an acceptable rate.


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13
REPORTING AND PUBLICATION
13.1
Clinical Trial Report
The data and information collected during this trial will be reported in a clinical trial report prepared by 
Ferring and submitted for comments and signature to the signatory Investigator.
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from the 
trial, will be the exclusive property of Ferring. The Investigator and any other persons involved in the 
trial will protect the confidentiality of this proprietary information belonging to Ferring.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
At the end of the trial, one or more manuscripts for joint publication may be prepared in collaboration 
between the Investigator(s) offered authorship and Ferring. In a multisite trial based on the 
collaboration of many sites, any publication of results must acknowledge all sites. Results from 
multisite trials must be reported in entirety in a responsible and coherent manner and results from 
subsets should not be published in advance or without clear reference to the primary publication of the 
entire trial.
Authorship is granted based on the International Committee of Medical Journal Editors criteria (see 
current official version: http/www.ICMJE.org). The total number of authors is based on the guideline 
from the relevant journal or congress. In the event of any disagreement in the content of a publication, 
both the Investigator’s and Ferring’s opinion will be fairly and sufficiently represented in the 
publication.
Any external CRO or laboratory involved in the conduct of this trial has no publication rights regarding 
this trial.
If the Investigator wishes to independently publish/present any results from the trial, the draft 
manuscript/presentation must be submitted in writing to Ferring for comment prior to submission.
Comments will be given within 4 weeks from receipt of the draft manuscript. This statement does not 
give Ferring any editorial rights over the content of a publication, other than to restrict the disclosure of 
Ferring’s intellectual property. If the matter considered for publication is deemed patentable by 
Ferring, scientific publication will not be allowed until after a filed patent application is published.
Under such conditions, the publication will be modified or delayed at the Investigator’s discretion, to 
allow sufficient time for Ferring to seek patent protection of the invention.


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13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trial-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public clinical trials registry. Thus, it is the 
responsibility of Ferring to register the trial in an appropriate registry, i.e., www.ClinicalTrials.gov, a 
website maintained by the National Library of Medicine at the United States National Institutes of 
Health. Trial registration may occur in other registries in accordance with local regulatory 
requirements. A summary of the trial results is made publicly available in accordance with applicable 
regulatory requirements.


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14
ETHICAL AND REGULATORY ASPECTS
14.1
Institutional Review Board
An IRB will review the protocol and any amendments and advertisements used for recruitment. The 
IRB will review the subject information sheet and the informed consent form, their updates (if any), 
and any written materials given to the subjects. A list of all IRBs to which the protocol has been 
submitted and the name of the committee chairmen will be included in the clinical trial report.
14.2
Regulatory Authority Authorization/Approval/Notification
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility.
14.3
End-of-Trial and End-of-Trial Notification
The end of the trial is defined as the date of LPLV, i.e. when the last subject completes the end-of-trial 
visit. The IRBs and relevant regulatory authorities will be notified about the completion of the clinical 
trial according to local legislation.
In the case of early termination for safety reasons, Ferring must notify the end of the trial to the 
relevant regulatory authorities and the concerned IRBs without delay, clearly explain the reasons, and 
describe follow-up measures, if any.
Within one year of the end of the trial, Ferring shall send the final clinical trial report to the relevant 
regulatory authorities.
14.4
Ethical Conduct of the Trial
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki, in compliance with the approved protocol, ICH-GCP, and applicable 
regulatory requirements.
14.5
Subject Information and Consent
The Investigator (or the person delegated by the Investigator) will obtain a freely given written consent 
from each subject after an appropriate explanation of the aims, methods, sources of funding, any 
possible conflicts of interest, anticipated benefits, potential risks of the trial and the discomfort it may 
entail, post-trial provisions, and any other aspects of the trial that are relevant to the subject’s decision 
to participate. The trial subject must be given ample time to consider participation in the trial, before 
the consent is obtained. The informed consent documents must be signed and dated by the subject and 
the Investigator, or the person delegated by the Investigator, who has provided information to the 
subject regarding the trial before the subject is exposed to any trial-related procedure, including 


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screening tests for eligibility. Subjects must be given the option of being informed about the general 
outcome and the results of the trial.
The Investigator (or the person delegated by the Investigator) will explain that the subject is 
completely free to refuse to enter the trial or to withdraw from it at any time, without any consequences 
for her further care and without the need to justify her decision.
The subject will receive a copy of the subject information and her signed informed consent form.
If new information becomes available that may be relevant to the trial subject’s willingness to continue 
participation in the trial, a new subject information and informed consent form will be forwarded to the 
IRBs (and regulatory authorities, if required). The trial subjects will be informed about this new 
information and re-consent will be obtained.
Each subject will be informed that the monitor(s), quality-assurance auditor(s) mandated by Ferring, 
IRB representatives, or regulatory authority inspector(s), in accordance with applicable regulatory 
requirements, may review her source records and data. Data protection will be handled in compliance 
with national/local regulations.
14.6
Subject Participation Card
Each subject will be provided with a subject participation card bearing the following information:

That she is participating in a clinical trial (including trial code)

That she is being treated with PVR

The name and phone number of the Investigator

The name, address and phone number of a Ferring contact
The subject will be asked to keep the subject participation card in her possession at all times during the 
trial and to return it at the last trial visit, if applicable.
Each subject’s primary care physician will be notified of her participation in the trial by the 
Investigator, if the subject agrees and if applicable.
14.7
Compliance Reference Documents
The Declaration of Helsinki, the consolidated ICH-GCP, and other national law(s) in the country(ies) 
where the trial takes place shall constitute the main reference guidelines for ethical and regulatory 
conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitor, and the Investigator will be defined in the ICH-GCP 
consolidated guideline, and applicable United States regulatory requirements. The Investigator is 
responsible for adhering to the ICH-GCP responsibilities of Investigators, for dispensing and 
reconciliation of the IMP in accordance with the approved protocol or an approved amendment, and for 
its secure storage and safe handling throughout the trial.
15.2
Liabilities and Insurance
Ferring is, as Sponsor, responsible for ensuring appropriate general/product liability insurance and, as 
required in accordance with applicable laws and regulations, United States-specific liability insurance 
coverage for claims made by a trial subject for injury arising from the subject’s participation in the 
trial.


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16
ARCHIVING
16.1
Investigator File
The Investigator is responsible for maintaining all the records, which enable the conduct of the trial at 
the site to be fully understood, in compliance with ICH-GCP. The trial documentation including all the 
relevant correspondence should be kept by the Investigator for at least 15 years after the completion or 
discontinuation of the trial, if no further instructions are given by Ferring.
The Investigator is responsible for the completion and maintenance of the confidential subject 
identification code, which provides the sole link between named subject source records and anonymous 
eCRF data for Ferring. The Investigator must arrange for the retention of this subject identification log 
and signed informed consent documents for at least 15 years after the completion or discontinuation of 
the trial.
No trial site document may be destroyed without prior written agreement between the Investigator and 
Ferring. Should the Investigator elect to assign the trial documents to another party, or move them to 
another location, Ferring must be notified. If the Investigator retires and the documents can no longer 
be archived by the site, Ferring can arrange having the Investigator file archived at an external archive.
16.2
Trial Master File
Ferring will archive the Trial Master File in accordance with ICH-GCP and applicable regulatory 
requirements.


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17
REFERENCES
Center for Disease Control 2005 Assisted Reproductive Technology Success Rates. U.S. Department 
of Health and Human Services; http://www.cdc.gov/ART/ART2005/508PDF/2005ART508.pdf.
Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Towards reproductive 
certainty (Eds Jansen R & Mortimer D). The plenary proceedings of the 11th world congress on in vitro 
fertilization and human reproductive genetics. The Parthenon Publishing Group. 1999. Pp 378-388.
MENOPUR - menotropins for injection. Ferring Pharmaceuticals.
Prescribing Information, Version: July, 2016.
Practice Committee of the Society for Assisted Reproductive Technology and Practice Committee of 
the American Society for Reproductive Medicine. Guidance on the limits to the number of embryos to 
transfer: a committee opinion. Fertil Steril 2017; 107:901–3.
Progesterone (FE 999913) Vaginal Ring Investigator’s Brochure, Ferring Pharmaceuticals, Edition 5, 
2018. 
Penzias AS. Luteal phase support. Fertil Steril. 2002; 77(2):318-23.
Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized 
trials. Hum Reprod. 2002;17(9):2287-99.
Soliman S, Daya S, Collins J et al. The role of luteal phase support in infertility treatment: a meta-
analysis of randomized trials. Fertil Steril. 1994; 61:1068-76.
Wyatt KM, Dimmock PW, Walker TJ, O’Brien PM. Determination of total menstrual blood loss. 
Fertil Steril. 2001;76(1):125-31.


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APPENDICES
Appendix 1
Sample Subject Instructions For Use
How should I use Progesterone Vaginal Ring?
Use progesterone vaginal ring (PVR) exactly as prescribed. The usual dose of PVR is one ring placed 
in your vagina and replaced weekly for up to a total of 10 weeks, unless your Doctor/Investigator 
advises otherwise.
Follow the steps below:
Save foil pouch, bio-hazard plastic bag, and outer carton for later use to return the used ring at 
your next visit.
1. After washing your hands, remove the vaginal ring from its foil pouch.
2. Choose the position that is most comfortable for you (for example: lying down, squatting, or 
standing with one leg up).
3. To insert the ring, hold the ring between your thumb and index finger and gently squeeze the
opposite sides of the ring together.


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4. Use your other hand and hold open the folds of skin around your vagina.
5. Place the tip of the ring in the vaginal opening and then use your index finder to push the folded 
ring gently into your vagina. Push it up towards your lower back as far as you can. If you can
feel the ring, it may not be placed back far enough in your vagina. Use your index finder to push it
back a bit further. There is no danger of the vaginal ring being pushed too far up in the vagina or
getting lost.
This is all you need to do to place the ring in the correct position. The ring will conform to fit
your body. The exact position is not important, as the muscles of your vagina should keep
the ring securely in place. Put the ring where it is comfortable for you. If you have difficulty
inserting the ring, it is fine to rinse it with cool to lukewarm (not hot) water before insertion.
To remove:
1. Wash your hands.
2. Choose the position that is the most comfortable for you.
3. Put a finger into your vagina and hook it through the ring.


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4. Gently pull downwards and forward to remove the ring.
5. Place the used ring in the foil pouch and place the foil pouch in the bio-hazard plastic bag (supplied 
in the carton with the study materials) and seal the bag.
6. Place the sealed bio-hazard bag in the original outer carton and return to the doctor/investigator or 
study personnel at your next visit
7. Keep out of reach of children and pets.
Other Information for Using Progesterone Vaginal Ring

If the vaginal ring is expelled, it should be rinsed with cool to lukewarm (not hot) water and 
reinserted as soon as possible, except if fecally-contaminated. If fecally-contaminated, the vaginal 
ring should be replaced.

The vaginal ring should remain in place for a minimum of 23 hours per day. It may be removed for 
sexual intercourse, although this is not necessary.

If you forgot to remove the vaginal ring at the scheduled time, replace the used ring with a new ring 
as soon as possible.

Do not insert more than one progesterone vaginal ring at a time.

Do not use any other vaginal products when you are using progesterone vaginal ring.

This leaflet summarizes the most important information about the use of the progesterone vaginal 
ring. If you would like more safety information, talk with your Doctor/Investigator or Study 
personnel.


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Appendix 2
Pelvic Examination, Grade, and Criteria
PARAMETER
INDIVIDUAL SIGNS/SYMPTOMS
GRADE 0
NORMAL
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-THREATENING
Pain
None
Pain causing no 
or minimal 
inference with 
usual social & 
functional 
activities
Pain causing 
greater than 
minimal 
inference with 
usual social & 
functional 
activities or the 
need for 
non-narcotic 
medication
Pain causing 
inability to 
perform usual 
social & functional 
activities or the 
need for narcotic 
medication
Disabling pain causing 
inability to perform basic 
self-care functions OR 
hospitalization (other 
than emergency room 
visit) indicated
Dyspareunia (pain 
with sexual 
activity)
None
Pain causing no 
or minimal 
inference with 
sexual function
Pain causing 
greater than 
minimal 
inference with 
sexual function
NA
NA
Tenderness*
(Specify Area: 
Vulvar/Perineum, 
Vagina, Cervix 
(including cervical 
motion 
tenderness), 
Uterus, Adnexae, 
Pelvic/Lower 
Abdominal, or 
Ovulatory) 
None
Mild tenderness
Moderate 
tenderness
Severe tenderness
NA
GENITOURINARY IRRITATION - VULVA
Vulvar/vaginal 
itching
None
Itching causing 
no, mild or 
moderate 
inference with 
usual social & 
functional 
activities
Itching causing 
inability to 
perform usual 
social & 
functional 
activities; may 
require 
intervention such 
as antihistamine 
or bathing to 
provide relief
NA
NA
Vulvar edema
None
Mild, non-pitting 
edema
Moderate, 1-2+ 
pitting edema
3+ pitting edema, 
severe enough to 
require urinary 
drainage, or 
weeping edema ± 
skin breakdown 
NA


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PARAMETER
INDIVIDUAL SIGNS/SYMPTOMS
GRADE 0
NORMAL
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-THREATENING
Vulvar erythema
None
Erythema 
covering <50% of 
vulvar surface
Erythema 
covering >50% 
of vulvar surface
NA
NA
Vulvar rash
None
Rash covering 
<50% of vulvar 
surface
Rash covering 
>50% of vulvar 
surface
Severe epithelial 
disruption with 
hospitalization 
indicated
NA
Bartholin’s or 
Skene’s gland
No findings
Cyst with no 
inflammation
Cyst or abscess 
with outpatient 
intervention 
indicated
Cyst or abscess 
with 
hospitalization 
indicated
Necrotizing fasciitis 
from Bartholin’s abscess
GENITOURINARY LESIONS - VULVA
Vulvar lesions 
(findings seen only 
by colposcopy
should not be 
included here)
Normal 
variants 
including skin 
tags, moles, 
scars, etc.
Blisters, 
ulcerations, or 
pustules – no 
treatment 
indicated
Blisters, 
ulcerations, or 
pustules, with 
treatment 
indicated
Severe epithelial 
disruption with 
hospitalization 
indicated 
NA
GENITOURINARY IRRITATION – VAGINA
Vaginal edema
None
Mild-moderate 
engorgement
Loss of ruggae 
and friability
NA
NA
Vaginal erythema
None
Erythema <50% 
of vaginal surface
Erythema >50% 
of vaginal surface
NA
NA
Vaginal dryness
No complaint 
Dryness causing 
no or minimal 
inference with 
usual sexual, 
social & 
functional 
activities
Dryness causing 
greater than 
minimal 
inference with 
usual sexual, 
social & 
functional 
activities
NA
NA
Vaginal discharge 
by participant 
report 
Participant’s 
usual amount of 
discharge, 
regardless of 
color or 
quantity 
Mild-moderate 
increase in 
amount above 
participant 
baseline – no 
sanitary 
protection 
required
Profuse increase 
in discharge 
requiring pad use 
or other hygienic 
intervention
NA
NA
Vaginal discharge 
as observed by 
clinician 
Slight amount 
of discharge, 
any color
Mild-moderate 
increase in 
amount
Significant 
increase in 
amount with 
pooling in vagina 
on examination 
NA 
NA


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PARAMETER
INDIVIDUAL SIGNS/SYMPTOMS
GRADE 0
NORMAL
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-THREATENING
GENITOURINARY LESIONS, ABRASIONS– VAGINA
Vaginal abrasions 
or laceration 
(including 
probable 
applicator 
injuries)
None
Superficial 
disruptions and 
disruptions 
extending 
through the 
mucosa with 
minimal impact 
on life 
Large disruptions 
extending 
through the 
mucosa or large 
superficial 
disruptions, 
hospitalization 
not indicated
Large disruptions 
extending through 
the mucosa or 
large superficial 
disruptions, 
hospitalization 
indicated
NA
Vaginal lesions 
(findings seen 
only by 
colposcopy 
should not be 
included here)
Normal variants 
including skin 
tags, moles, 
scars, etc. 
Blisters, 
ulcerations, or 
pustules, no 
treatment 
indicated
Blisters, 
ulcerations, or 
pustules with 
treatment 
indicated
Severe epithelial 
disruption 
requiring 
hospitalization 
NA
GENITOURINARY IRRITATION – CERVIX
Cervical edema 
and friability 
None
Edema without 
friability
Friable cervix
NA
NA
Cervical erythema
None
Erythema 
covering <50% of 
cervix
Erythema 
covering >50% 
of cervix
NA
NA
Cervical 
discharge
White or clear 
discharge 
Small amount of 
purulent 
discharge at os
Purulent 
discharge 
extending onto 
cervix or vagina
NA
NA
GENITOURINARY LESIONS – CERVIX
Visible cervical 
lesions (findings 
seen only by 
colposcopy 
should not be 
included here)
Normal variants 
including skin 
tags, moles, 
scars, etc.
Blisters, 
ulcerations, or 
pustules, no 
treatment 
indicated
Blisters, 
ulcerations, or 
pustules with 
treatment 
indicated
NA
NA
VAGINAL ADHESIONS – VAGINA
Vaginal Adhesion
None
Asympotomatic, 
manual removal 
of ring possible
Symptomatic (eg. 
irritation reported 
by patient), 
manual removal 
of ring possible
Surgical 
intervention (eg. 
adhesiolysis) 
required to resolve
Potentially life 
threatening; urgent 
intervention indicated.
* If both pain and tenderness are present, only report the one with the most severe grade
Note: Any finding deemed clinically significant after initiation of treatment is to be reported as an AE.
Adapted from: Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Addendum 1 
(Female Genital Grading Table for Use In Microbicide Studies); November 2007.


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Appendix 3
Assessment of AEs of Special Interest: Vaginal Pain and Vaginal Irritation
INDIVIDUAL SIGNS/SYMPTOMS
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
VAGINAL PAIN
Pain
Pain causing no or 
minimal inference with 
usual social &
functional activities
Pain causing greater 
than minimal inference 
with usual social & 
functional activities or 
the need for non-
narcotic medication
Pain causing inability 
to perform usual 
social & functional 
activities or the need 
for narcotic 
medication
Disabling pain causing 
inability to perform 
basic self-care functions 
OR hospitalization 
(other than emergency 
room visit) indicated
Dyspareunia (pain 
with sexual activity)
Pain causing no or 
minimal inference with 
sexual function
Pain causing greater 
than minimal inference 
with sexual function
NA
NA
VAGINAL IRRITATION
Vaginal itching
Itching causing no, 
mild or moderate 
inference with usual 
social & functional 
activities
Itching causing 
inability to perform 
usual social & 
functional activities; 
may require 
intervention such as
antihistamine or 
bathing to provide 
relief
NA
NA
Vaginal dryness
Dryness causing no or 
minimal inference with 
usual sexual, social & 
functional activities
Dryness causing 
greater than minimal 
inference with usual 
sexual, social & 
functional activities
NA
NA
Vaginal discharge by 
participant report
Mild-moderate 
increase in amount 
above participant 
baseline – no sanitary 
protection required
Profuse increase in 
discharge requiring pad 
use or other hygienic 
intervention
NA
NA
Adapted from: Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Addendum 1 
(Female Genital Grading Table for Use In Microbicide Studies); November 2007.


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Appendix 4
Bleeding Log
Bleeding Log
Please record each use of a sanitary napkin related to vaginal bleeding. Tampons cannot be used.
Date
Time of Day
Sanitary Napkin
     2 0 1 
d   d   m  m  m        y   y    y   y
:     AM 
h   h    m  m              
                  PM 
Adapted from: Wyatt KM, Dimmock PW, Walker TJ, O’Brien PM. Determination of total menstrual blood loss. 
Fertil Steril. 2001;76(1):125-31.


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Appendix 5
Scoring of Bleeding Log Information
Adapted from: Wyatt KM, Dimmock PW, Walker TJ, O’Brien PM. Determination of total menstrual blood loss. 
Fertil Steril. 2001;76(1):125-31.


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Appendix 6
Primary Analysis Simulation Code and the Sensitivity Analysis Operating 
Characteristics
Primary Analysis Simulation Code
Below is the R code that runs the simulation described in the sample size justification.
#################
### LIBRARIES ###
#################
library(ggplot2)
library(tidyverse)
#############
### SETUP ###
#############
### SET THE SEED ###
set.seed(7639216)
### THE NUMBER OF SIMULATION REPS ###
n.sim <- 10000
### THE NUMBER OF SUBJECTS IN THE MODIFIED ITT ANALYSIS POPULATION ###
n.mitt <- seq(from = 100, to = 400, by = 5)
### THE TRUE PR(SPONTANEOUS ABORTION | IN THE MITT ANALYSIS POPULATION) 
###
p.sa <- seq(from = 0.08, to = 0.1, by = 0.01)
### A PLACE TO STORE THE RESULTS ###
sim.res <- matrix(NA, nrow = length(n.mitt), ncol = length(p.sa))
rownames(sim.res) <- n.mitt
colnames(sim.res) <- paste0(p.sa * 100, "%")
##################
### SIMULATION ###
##################
pb <- txtProgressBar(min = 1, max = length(n.mitt), style = 3)
for(a in 1:length(n.mitt)){
  
  setTxtProgressBar(pb, value = a)
  
  for(b in 1:length(p.sa)){


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    sim.sara <- rbinom(n = n.sim, size = n.mitt[a], prob = p.sa[b])
    
    sara.res <- unlist(lapply(X = sim.sara, FUN = function(x, n = n.mitt[a]){
      
      ifelse(binom.test(x = x, n = n, p = 0.15, alternative = c("two.sided"), conf.level = 
0.95)$conf.int[2] < 0.15, 1, 0)
      
    }))
    
    sim.res[a, b] <- mean(sara.res) * 100
    
  }
  
}
########################
### PLOT THE RESULTS ###
########################
### MOLD THE RESULTS FOR PLOTTING ###
sim.res.long <- data.frame(N = as.numeric(rownames(sim.res)), SA8PCT = sim.res[, 1], SA9PCT = 
sim.res[, 2], SA10PCT = sim.res[, 3]) %>%
  gather(key = "SA", value = "POWER", 2:4)
p <- ggplot(sim.res.long, aes(x = N, y = POWER, group = SA)) +
  geom_hline(yintercept = 80, linetype = "dashed", color = "grey", size = 2) +
  geom_line(aes(color = SA), size = 1.5) +
  scale_x_continuous(name = "Sample Size (in MITT Analysis Population)", breaks = seq(from = 
100, to = 400, by = 20)) +
  scale_y_continuous(name = "Power", limits = c(0, 100)) +
  theme(axis.text.x = element_text(angle = 45, hjust = 1)) +
  scale_color_discrete(name = "Spontaneous\nAbortion\nRate",
                       breaks = c("SA8PCT", "SA9PCT", "SA10PCT"),
                       labels = c("8%", "9%", "10%"))
######################
### TABULAR OUTPUT ###
######################
### FIND WHICH RESULTS ARE ABOVE 80% POWER ###
sim.res.80 <- sim.res >= 80
### FIND THE INDICES ###
sim.res.ind <- apply(X = sim.res.80, MARGIN = 2, FUN = function(x){
  


Date: 09 Aug 2019
E-Study Protocol-21625; Ver. 6.0
Supersedes: 5.0
Page 98 of 99
Progesterone, FE 999913
Trial Code:  000293
Vaginal Ring
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
  TEMP <- length(x)
  if(any(x)){
    
    TEMP <- min(which(x))
    
  }
  TEMP
  
})
### REPORT THE POWER FOR THESE INDICES
sim.table <- sim.res[sim.res.ind, ]
Hierarchical Modeling Details
Define n1 as the number of subjects in the current trial and Y1i as the indicator of spontaneous 
abortion for the ith subject in the current trial where Y1 ~ Bin(n1, π1). Let π1 be the true rate of 
spontaneous abortions in the current trial.
The previous trial (Study DR-PGN-302) reported a spontaneous rate of abortion of 55/549. This 
prior information about abortion rate is incorporated into the modeling framework through a 
hierarchical model. Dynamic borrowing between this trial’s results and the current trial’s data 
allows borrowing to occur to the extent indicated by these two data sources. More borrowing occurs 
when the two rates are similar while less borrowing occurs when they differ. This “dynamic” 
borrowing property is distinct from other approaches which use a fixed informative prior or apriori 
assume an amount of borrowing between these two data sources. Let Y0 ~ Bin(n0=549, π0) where π0
is the true rate of spontaneous abortions from the previous trial.
We transform to the logit scale for modeling purposes. Let 1 = log(π1/(1- π1)) and 0 = log(π0/(1-
π0)). The hierarchical model assumes that 0 and 1 have an across studies distribution:
1 , 0  ~ N(, 2)
The across trial mean and variance 2 are unknown and hence have a prior distribution which is 
combined with the data to produce estimates of and 2:
~N(–2.2, 2.25)
2~ IG(0.125,0.005)
The mean parameter assumes a relatively vague prior on the original scale and centered at 10%. 
The variance component 2 controls the degree of borrowing among studies. Small values of 2
result in a greater degree of borrowing while large values of 2 correspond to less borrowing. The 
parameter 2 is estimated using the data, so the observed between studies variation is a key 
component of the model behavior. The prior specification on 2 corresponds to an inverse-gamma 
distribution with mean 0.2 and weight 0.25.


Date: 09 Aug 2019
E-Study Protocol-21625; Ver. 6.0
Supersedes: 5.0
Page 99 of 99
Progesterone, FE 999913
Trial Code:  000293
Vaginal Ring
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
Operating Characteristics
The planned sample size is based only on subjects that undergo fresh embryo transfer. No further 
drop-outs are assumed. The analysis is evaluated across a range of true effects for the current trial’s 
spontaneous abortion rate. For the null scenario where in truth the PVR spontaneous abortion rate is 
15%, 100,000 sets of trials were simulated. For all other assumed scenarios, 5,000 sets of trials 
were simulated.
Overall Success
We evaluated the overall probability that the 95% credible interval is entirely below 15% for each 
scenario of the true PVR rate. If PVR truly maintains an abortion rate below 15%, then this 
represents the power for achieving a credible interval entirely below 15%. If the true rate of 
abortions for PVR is 15%, then obtaining a credible interval entirely below 15% is the type I error. 
Results are provided in the table below.
True PVR Rate 
8%
9%
10%
11%
12%
13%
14%
15%
Trial Success
0.979
0.933
0.830
0.670
0.485
0.297
0.167
0.084
When in truth the PVR spontaneous abortion rate is 9%, the trial has 93.3% power of achieving a 
95% credible interval entirely below 15%. Alternatively, when in truth the spontaneous abortion 
rate is 15%, the trial has a 8.4% rate of success.
Inference Associated with Various Observed Rates
For various observed rates of spontaneous abortions, the corresponding primary analysis based on 
the hierarchical model is described below. The posterior mean, 95% credible interval, effective 
number of borrowed subjects, and the borrowing percentage (out of the n=549 subjects from the 
previous trial) is provided. The effective number of borrowed subjects calculation [E(π1)*(1-
E(π1))/Var(π1)–1–240] is somewhat approximate as it is based on the binomial likelihood. Results 
are provided in the below table.
Observed Data
Estimated Rate (%) 
(95% CI)
Effective Number of 
Borrowed Subjects
Borrowing 
Percentage
19/240 (7.92%)
8.6% (5.7, 11.7)
103
18.9%
24/240 (10.00%)
10.0% (7.2, 13.3)
130
23.7%
36/240 (15.00%)
13.8% (10.1, 18.5)
9
1.7%
Borrowing based on the hierarchical modeling is dynamic, with higher borrowing achieved when 
the current trial’s results are similar to the previous data and minimal borrowing when the current 
trial’s results are at 15%. This is evidenced by both the decreasing number of borrowed subjects 
and the increasing width of the credible intervals. Also, based on 240 subjects being included in the 
analysis, the maximal number of observed responses which maintains a 95% credible interval 
entirely below 15% is 28.

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Date: 09 Aug 2019
E-Statistical Analysis Plan-22442; Ver.4.0
Supersedes: 3.0
Page 1 of 45
Progesterone, FE 999913
Trial Code: 000293 
Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
                                                                                                                             
STATISTICAL ANALYSIS PLAN
A Prospective, Multi-Center, Non-Comparative Trial of the Clinical Safety of 
the Progesterone Vaginal Ring in Women Undergoing Assisted Reproductive 
Technology (ART) Procedures
000293
Investigational Product:
Progesterone vaginal ring (PVR)
Indication:
Progesterone supplementation in women undergoing ART
Phase:
3b
Author:
Date of issue:
09 Aug 2019
Version:
4.0
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group


Date: 09 Aug 2019
E-Statistical Analysis Plan-22442; Ver.4.0
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Page 2 of 45
Progesterone, FE 999913
Trial Code: 000293 
Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes
1.0
2.0
May 11, 2018
Oct 08, 2018
NA
!
To make the SAP consistent with 
the protocol amendment.
!
More detailed analysis of embryo 
quality has been added.
!
More details have been added to 
the analysis of bleeding logs.
!
Typographical and formatting 
errors have been corrected.
None
1.0
3.0
Feb 26, 2019
!
Responded to FDA feedback on 
statistical design by adjusting 
confidence intervals and assuring 
that endpoints align with the DR-
PGN-302 study
!
Updated the document author to 
reflect the new statistician
!
Corrected formatting issues, 
typos, text relating to which drug
was used for hCG triggering, and 
“Other Endpoint(s)” to “Other 
Assessment(s)”
!
Added tabulation of vaginal 
hemorrhage (was in protocol, but 
not SAP)
!
Clarified the use of Preferred 
Terms, how baseline is calculated 
for laboratory and vital signs 
variables, how shift tables are to 
be calculated, and the tabulation 
of bleeding log data for non-
completers.
2.0


Date: 09 Aug 2019
E-Statistical Analysis Plan-22442; Ver.4.0
Supersedes: 3.0
Page 3 of 45
Progesterone, FE 999913
Trial Code: 000293 
Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes
4.0
Aug 09, 2019
!
Responded to FDA feedback on 
statistical design by moving the 
frequentist sensitivity analysis to 
be the primary analysis and the 
Bayesian primary analysis to be 
the sensitivity analysis.
!
Updated the sample size 
justification to reflect the 
frequentist primary analysis.
!
Updated primary endpoint text 
throughout.
!
Updated Appendix 2 to reflect the 
revised sample size justification.


Date: 09 Aug 2019
E-Statistical Analysis Plan-22442; Ver.4.0
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Page 4 of 45
Progesterone, FE 999913
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 4
1
Introduction.......................................................................................................................................... 7
1.1
Definitions/ Abbreviations........................................................................................................ 7
Definition of Terms .................................................................................................. 7
Abbreviations............................................................................................................ 8
2
Trial Objectives and Endpoints.......................................................................................................... 9
2.1
Objectives ................................................................................................................................. 9
2.2
Endpoints .................................................................................................................................. 9
3
Trial design......................................................................................................................................... 11
3.1
General Design Considerations............................................................................................... 11
3.2
Trial Design Diagram.............................................................................................................. 13
3.3
Determination of Sample Size ................................................................................................ 13
4
Subject Disposition ............................................................................................................................ 15
5
Protocol Deviations............................................................................................................................ 16
6
Analysis sets........................................................................................................................................ 17
6.1
Modified Intention-To-Treat (mITT) Cohort.......................................................................... 17
6.2
Safety Cohort .......................................................................................................................... 17
6.3
Eligible Subjects (ES) Cohort................................................................................................. 17
7
Trial population ................................................................................................................................. 18
7.1
Demographics and Other Baseline Characteristics................................................................. 18
Demographics......................................................................................................... 18
Endocrine Profile.................................................................................................... 18
Gynaecological History and Infertility Diagnosis.................................................. 18
Smoking and Alcohol Habits.................................................................................. 18
Transvaginal Ultrasound......................................................................................... 18
7.2
Medical History....................................................................................................................... 18
7.3
Prior and Concomitant Medication......................................................................................... 19
7.4
Physical Examination.............................................................................................................. 19
8
Exposure and Treatment Compliance ............................................................................................. 20
8.1
Extent of Exposure.................................................................................................................. 20
PVR ........................................................................................................................ 20
Oral Contraceptives................................................................................................ 20
Leuprolide Acetate ................................................................................................. 20
MENOPUR Administration ................................................................................... 20
hCG......................................................................................................................... 20
9
Efficacy ............................................................................................................................................... 21
9.1
General Considerations........................................................................................................... 21
9.2
Primary Endpoint.................................................................................................................... 21
9.3
Primary Variable Analysis...................................................................................................... 21
Analysis of the Primary Endpoint........................................................................... 21


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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Hierarchical Modelling Details for the Sensitivity Analyses ................................. 22
9.4
Secondary Endpoints............................................................................................................... 23
Spontaneous Abortion within 6 and 10 Weeks of Oocyte Retrieval ...................... 23
Biochemical Abortions within 6 and 10 Weeks of Oocyte Retrieval..................... 23
Ectopic and Heterotopic Pregnancies..................................................................... 23
Positive β-hCG ....................................................................................................... 23
Clinical Pregnancy.................................................................................................. 24
9.5
Other Assessments.................................................................................................................. 24
Number and Size of Follicles during Stimulation .................................................. 24
E2 and Progesterone Profiles.................................................................................. 24
Oocytes................................................................................................................... 24
Characterization of Fertilized Oocytes one Day (Day 1) after Oocyte 
Retrieval ................................................................................................................. 25
Quality of Blastocysts 5 Days (Day 5) after Oocyte Retrieval............................... 25
Endometrial Thickness ........................................................................................... 27
10
Safety................................................................................................................................................... 28
10.1
General Considerations........................................................................................................... 28
10.2
Adverse Events ....................................................................................................................... 28
Overview of Treatment-Emergent Adverse Events................................................ 28
Incidence of Adverse Events .................................................................................. 28
Treatment-Emergent AEs of Special Interest......................................................... 29
10.3
Safety Laboratory Variables ................................................................................................... 30
Summary Statistics ................................................................................................. 30
Laboratory Variable Shift Tables ........................................................................... 30
Data Listings........................................................................................................... 30
Urinalysis................................................................................................................ 30
Vital Signs .............................................................................................................. 30
10.3.5.1
Summary Statistics.............................................................................31
10.3.5.2
Notable Changes in Vital Signs..........................................................31
10.3.5.3
Data Listings ......................................................................................31
10.4
Other Safety Variables............................................................................................................ 31
Bleeding Log Assessment ...................................................................................... 31
Vaginal Hemorrhage............................................................................................... 32
Pelvic Examination................................................................................................. 32
11
Interim Analyses ................................................................................................................................ 33
12
Deviations from Protocol................................................................................................................... 34
13
References........................................................................................................................................... 35
14
APPENDICES.................................................................................................................................... 36
Appendix 1
Notable Vital Signs................................................................................................................ 37
Appendix 2
Primary Analysis Simulation Code and the Sensitivity Analysis Operating 
Characteristics....................................................................................................................... 38
Appendix 3
Preferred Terms Associated With Spontaneous Abortion and Ectopic pregnancy........ 43


Date: 09 Aug 2019
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
List of Tables
Table 1
Trial Flow Chart..............................................................................................................13
Table 2
Power Achieved over Varying Sample Sizes and Assumed Spontaneous Abortion 
Rates................................................................................................................................14
Table 3
Good-Quality Blastocysts ...............................................................................................26
Table 4
Visits numbers, nominal visit days from oocyte retrieval date and associated visit 
windows ..........................................................................................................................32
Table 5
Notable Criteria for Vital Signs ......................................................................................37


Date: 09 Aug 2019
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Page 7 of 45
Progesterone, FE 999913
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
1
Introduction
This document describes the planned statistical analyses for trial 000293 based on the protocol 
Version 6.0 dated 9 August 2019. 
1.1
Definitions/ Abbreviations
Definition of Terms
Terms
Definitions
Screened
Subject who enters the screening phase
ES cohort
The ES cohort consists of all subjects who were deemed eligible 
for trial participation based on inclusion and exclusion criteria at 
screening and treated with oral contraceptives, leuprolide acetate, 
and MENOPUR
mITT cohort
The mITT cohort consists of all subjects who had successful 
oocyte retrieval, received at least 1 dose of IMP, and had 
completed fresh embryo transfer.
Safety cohort
The safety cohort comprises all subjects treated with IMP.
Screening Phase
From the date of signing the informed consent through the day 
before the start of the oral contraceptive treatment.
Suppression Phase
From the start of oral contraceptive treatment until the day before 
the start of the stimulation phase (start of MENOPUR treatment).
Stimulation Phase
From the date of the first dose of MENOPUR through the day 
before the start of IMP.
Treatment Phase
From the date of the first dose of IMP (PVR) through the end of 
the trial.
Study Phase
From the date of the first dose of oral contraceptive through the 
end of the trial.


Date: 09 Aug 2019
E-Statistical Analysis Plan-22442; Ver.4.0
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Page 8 of 45
Progesterone, FE 999913
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Abbreviations
Abbreviations
Meaning of abbreviations in document
AE
adverse event
ART
Assisted Reproductive Technology
ATC
Anatomical Therapeutic Chemical
eCRF
electronic case report form
EOT
End-of-trial
ES
eligible subjects
E2
Estradiol
FSH
follicle-stimulating hormone
hCG
human chorionic gonadotropin
IMP
Investigational Medicinal Product
IVF
in vitro fertilization
mITT
modified intention-to-treat
NIMP
Non-Investigational Medicinal Product
P
procedural visit
PVR
progesterone vaginal ring
SAE
serious adverse event
SD
Standard deviation
TVUS
transvaginal ultrasound


Date: 09 Aug 2019
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Page 9 of 45
Progesterone, FE 999913
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
2
Trial Objectives and Endpoints
In this safety trial, the assessment of the trial will be on the totality of safety information collected. 
Hence, the purpose of categorizing the endpoints as primary and secondary is for prioritising the 
endpoints of interest rather than tying the trial’s success to the outcome of the primary objective.
2.1
Objectives
Primary Objective
!
To estimate the cumulative rate of any spontaneous abortion, including spontaneous 
clinically recognized pregnancy loss and blighted ovum during the trial (up to Week 12 
following oocyte retrieval), in subjects treated with progesterone vaginal ring (PVR)
following fresh embryo transfer.
Secondary Objectives
!
To describe the cumulative rate of spontaneous abortions determined at 6 and 10 weeks 
post-oocyte retrieval, including spontaneous clinically recognized pregnancy loss and 
blighted ovum, in all subjects treated with PVR.
!
To describe the cumulative rate of biochemical abortions determined at 6 and 10 weeks 
post-oocyte retrieval in all subjects treated with PVR.
!
To describe the rate of ectopic and heterotopic pregnancy in all subjects treated with PVR 
following oocyte retrieval.
!
To describe the safety of PVR through the collection of clinical laboratory tests and vital 
signs in all subjects treated with PVR.
!
To assess the safety and tolerability of PVR in all subjects treated with PVR.
!
To determine the positive β-hCG rate of subjects treated with PVR following oocyte 
retrieval.
!
To determine the clinical pregnancy rate of subjects treated with PVR following oocyte 
retrieval.
2.2
Endpoints
Primary Endpoint
!
Cumulative 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.
Note: spontaneous abortion is defined as two positive 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 
heartbeat, or absence of viable fetuses, as documented by transvaginal ultrasound (TVUS).


Date: 09 Aug 2019
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Page 10 of 45
Progesterone, FE 999913
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Secondary Endpoints
!
Cumulative rate of spontaneous abortions determined at 6 and 10 weeks post-oocyte 
retrieval in all subjects treated with PVR.
!
Cumulative rate of biochemical abortions determined at 6 and 10 weeks post-oocyte 
retrieval in all subjects treated with PVR. Biochemical abortion is 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.
!
Rate of ectopic and heterotopic pregnancies in all subjects treated with PVR following 
oocyte retrieval.
!
Rate of abnormal findings in clinical laboratory tests and vital signs for all subjects treated 
with PVR.
!
Frequency, intensity/grade, seriousness, and relatedness of adverse events (AEs) for all 
subjects treated with PVR.
!
Frequency, intensity/grade of vaginal bleeding/spotting, vaginal hemorrhage, pain, vaginal 
infection, and vaginal irritation for all subjects treated with PVR.
!
Frequency, intensity/grade, seriousness, and relatedness of AEs associated with vaginal and 
cervical abrasions and lesions and with vaginal adhesions for all subjects treated with PVR.
!
Frequency and reason for PVR discontinuation.
!
Positive β-hCG rate (positive serum β-hCG test) at 2 weeks and 2 weeks + 3-4 days post-
oocyte retrieval in all subjects treated with PVR.
!
Clinical pregnancy rate (TVUS showing at least 1 intrauterine gestational sac with fetal 
heartbeat) at 6 and 10 weeks post-oocyte retrieval in all subjects treated with PVR.


Date: 09 Aug 2019
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
3
Trial design
This is an open-label, single-arm, safety trial of PVR for luteal phase support in women undergoing 
IVF with fresh oocytes. Women between the ages of 18 and 34 years with tubal, idiopathic, male 
factor, ovulatory dysfunction, or endometriosis-linked infertility, who agree to be considered for 
inclusion in the trial, will be invited to be seen at the trial site
3.1
General Design Considerations
Once informed consent is obtained, eligible subjects will be started on an ovarian down-regulation / 
suppression protocol utilizing combined oral contraceptives supplied by the site for ≥14 days to 
≤21 days (based upon the site standard of care), with leuprolide acetate at a dose of 0.1 mL 
(500 μg)/day beginning 4 days prior to the last birth control pill and for ≥ 10 days to ≤20 days;
ovarian suppression is to begin in the cycle immediately prior to the ovarian stimulation cycle.
After suppression, an ovarian stimulation protocol will begin on the second or third day after the 
start of menses with a reduction in leuprolide acetate dose to 0.05 mL (250 μg/day) followed by an 
individually determined ovarian stimulation protocol with highly purified, human menopausal 
gonadotropin (HP-hMG; MENOPUR) at an initial dose of 225 IU/day for 5 days according to label. 
Based on clinical monitoring, subsequent dosing should be adjusted according to individual subject 
response. Dose adjustments should not be made more frequently than once every two days and 
should not exceed 150 IU per adjustment. The maximum daily dose of MENOPUR should not 
exceed 450 IU and the minimum daily dose should not be lower than 75 IU. MENOPUR dosing 
should not continue for >20 days and coasting is not allowed. Subjects will be monitored to 
determine when to trigger ovulation with hCG. A TVUS will be performed to assess follicle size 
and serum estradiol levels will be determined. A subject must have at least 2 follicles ≥17 mm 
(mean of 2 dimensions) to receive the hCG trigger. Subjects who do not reach this threshold after 
20 days of stimulation are to be discontinued from the trial. If the estradiol level is ≥5000 pg/mL, 
hCG should not be administered and the subject should be discontinued from the trial.
Oocyte retrieval will occur approximately 35-37 hours after hCG administration. On the day after 
oocyte retrieval, the subject will begin treatment with the investigational medicinal product (IMP), 
PVR. Following instruction on PVR insertion and removal, the subject will insert the first PVR 
(PVR1) at the trial site The PVR will remain in place a minimum of 23 hours/day. The subject will 
remove PVR1 before embryo transfer and reinsert it after the transfer. Fresh embryo transfer will 
occur 5 days after oocyte retrieval per the trial site’s protocol. The number of embryos to transfer 
must be guided by the 2017 American Society for Reproductive Medicine (ASRM) and the Society 
for Assisted Reproductive Technology (SART) guidelines (SART/ASRM 2017): women with the 
expectation of one or more high-quality embryo(s) available for cryopreservation, and women with 
previous live birth after an IVF cycle, will have transfer of a single blastocyst. All other women 
will have transfer of no more than two blastocysts. Additional PVRs will be distributed for weekly 
insertion, with the second PVR (PVR2) to be inserted at home 7 days following the initial insertion 
of the first PVR (PVR1), and the third PVR (PVR3) to be inserted either at home or at the site 
7 days following the insertion of PVR2.


Date: 09 Aug 2019
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Progesterone, FE 999913
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Two weeks after oocyte retrieval, a blood draw will be performed to measure serum levels of 
progesterone and β-hCG. Subjects with a β-hCG level <5 mIU/mL will be discontinued from the 
trial. Those with a β-hCG level ≥5 mIU/mL will insert their next PVR and continue in the trial for 
up to a total of 10 weeks (up to a total of 10 PVRs). Additional serum pregnancy tests will be 
performed at 2 weeks + 3-4 days and at 3 weeks. Subjects who are no longer pregnant will be 
discontinued from the trial. Subjects with positive β-hCG results at 3 weeks will insert PVR4 and 
receive PVR5 and PVR6 to be inserted weekly.
A TVUS will be performed to document the presence of an intrauterine gestational sac 4 weeks 
+ 3-4 days after oocyte retrieval. If it is determined that the subject has an ectopic pregnancy, the 
subject will be treated according to the site’s standard protocol and will be withdrawn from the 
trial. Six weeks after oocyte retrieval, a TVUS will be performed to determine the presence and
number of gestational sacs with/without fetal heartbeat. Pregnant subjects will insert PVR7 and 
receive additional PVRs to be inserted weekly (PVR8, PVR9, and PVR10). Ten weeks after oocyte 
retrieval (if the subject is pregnant), an ultrasound (either transvaginal or abdominal) will be 
performed to determine the number of gestational sacs present with and without fetal heartbeat and 
the estimated gestational age.
Safety will be monitored throughout the trial. Standardized criteria will be applied to AEs of special 
interest (Protocol Section 8.3) to establish grade (intensity). Patient-reported vaginal pain and/or 
irritation should be recorded as an AE if considered clinically significant by the physician. The 
physician can perform an unscheduled pelvic examination at his or her discretion based upon these 
AEs at any time. A scheduled pelvic examination will be performed at screening, on day 1 of PVR 
treatment, and 4 weeks + 3-4 days, 6, 10, and 12 weeks post-oocyte retrieval (Visits 4, 7P, 8, 9 and 
10) to document the presence and grade (intensity) of any pain, irritation, abrasions, or lesions on 
the cervix or vagina and the presence and grade (intensity) of vaginal adhesions using standardized
criteria. If any lesions or abrasions are found on the cervix or vagina or vaginal adhesions are noted, 
another examination will be performed 2-4 days later. Subjects will be followed until the 
lesions/abrasions resolve or until the final assessment at the End-of-trial visit, whichever comes 
first. Any clinically significant finding will be reported as an AE.
Post-trial procedures will be performed 2 weeks after the last exposure to investigational medicinal 
product (IMP) (12 weeks after oocyte retrieval).


Date: 09 Aug 2019
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Progesterone, FE 999913
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
3.2
Trial Design Diagram
Table 1
Trial Flow Chart
Screening
Suppression
Stimulation
Oocyte 
Retrieval
Treatment Period
Post Treatment 
Period
Consent and Screening Down-regulation
Visits 1 and 2
Visit 3
Visits 4-9:
Day after oocyte 
retrieval and 
ongoing pregnancy 
(~10 weeks)
PVR1 through 
PVR10
Visit 10:
End-of-trial visit 
(2 weeks after last 
exposure to 
Investigational 
Medicinal Product)
3.3
Determination of Sample Size
In this safety trial, the primary assessment of interest is on the number of subjects that experience a 
spontaneous abortion. Because this is a single-arm trial, all subjects that enter the mITT analysis 
population will have been treated with the investigational product, PVR. The primary analysis 
involves the construction of a two-sided 95% exact confidence interval surrounding the proportion 
of subjects in the mITT analysis population that experience a spontaneous abortion. The upper 
bound of said confidence interval is then compared with the threshold of a 15% spontaneous 
abortion rate.
Statistical simulations have been performed to understand the operating characteristics under 
varying assumptions for both the sample size of the mITT analysis population and the “true” 
proportion of spontaneous abortions. For each simulation repetition, a sample of subjects was 
simulated using the binomial distribution and a given pair of sample size and “true” proportion of 
spontaneous abortions assumptions. A two-sided 95% exact confidence interval was then created 
based on the simulated data and the upper bound of this confidence interval was compared to the 
threshold of 0.15 (corresponding to a spontaneous abortion rate of 15%). If the upper bound of the 
two-sided 95% exact confidence interval was less than 0.15, the simulation repetition was declared
a “success”. If, however, the upper bound of the two-sided 95% exact confidence interval was
greater than or equal to 0.15, the simulation repetition was declared a “failure”. This process was
repeated 10,000 times for each combination of assumed sample size and “true” proportion of 
spontaneous abortions. The proportion of simulation repetition successes to the total number of 
simulation repetitions then described the power of the proposed trial given the pair of assumptions.
The  sample size necessary to achieve 80% power to exclude the possibility of a 15% spontaneous 
abortion rate after the use of PVR is described in Table 2. If the “true” spontaneous abortion rate is 
8%, 9%, or 10%, the sample size required to achieve 80% power to exclude the possibility of a 
15% spontaneous abortion rate after the use of PVR is 180, 240, or 365, respectively. 


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Table 2
Power Achieved over Varying Sample Sizes and Assumed Spontaneous Abortion 
Rates
Required Sample Size
(mITT Analysis Population)
Assumed “True” Spontaneous Abortion Rate
8%
9%
10%
180
80.3%
64.8%
46.1%
240
93.1%
81.8%
63.2%
365
98.9%
94.2%
80.9%
Taking the middle of this range, a trial with 240 subjects in the mITT analysis population is 
considered as being adequately powered under a relevant assumption in the target population. Full 
simulation code is provided in Appendix 2.


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4
Subject Disposition
The number of subjects that discontinue the trial during the stimulation phase and after start of IMP 
treatment (treatment phase) will be summarized by reason for discontinuation. The subjects 
screened and not treated with both the IMP and the non-investigational medicinal product (NIMP), 
MENOPUR, will be presented in a separate data listing.


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5
Protocol Deviations
Major protocol deviations are a subset of the important protocol deviations that may significantly 
impact the primary endpoint or efficacy parameters of the trial. Major protocol deviations include 
the following criteria:
!
significant deviation in the treatment regimens of IMP and NIMP,
!
use of prohibited medication, and
!
non-compliance with the blastocyst transfer policy
All protocol deviations will be listed however, only major protocol deviations will be summarized 
in a table.


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6
Analysis sets
6.1
Modified Intention-To-Treat (mITT) Cohort
The mITT cohort consists of all subjects who had successful oocyte retrieval, received at least 
1 dose of IMP, and had completed fresh embryo transfer.
6.2
Safety Cohort
The safety cohort comprises all subjects treated with IMP.
6.3
Eligible Subjects (ES) Cohort
The ES cohort consists of all subjects who were deemed eligible for trial participation based on 
inclusion and exclusion criteria at screening and treated with oral contraceptives, leuprolide acetate, 
and MENOPUR


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7
Trial population
7.1
Demographics and Other Baseline Characteristics
Descriptive statistics for demographics and other baseline characteristics will be presented for the 
subjects in the mITT, safety, and ES cohorts.
Categorical data will be summarised using numbers and percentages. The percentages are based on 
the total number of subjects with a corresponding assessment. Continuous data will be presented, 
for example, using the number of subjects (N), mean and standard deviation, median, minimum and 
maximum. All baseline characteristics will be listed. Associated demographic listings will also be 
produced.
Demographics
Descriptive statistics of screening demographics variables (e.g., age, race and ethnic origin, height, 
weight and BMI) will be summarized.
Endocrine Profile
The screening AMH, FSH and E2 assessments will be summarized for the mITT and ES cohorts.
Furthermore, the AMH level will be summarized by categories < 5 ng/mL and ≥ 5 ng/mL. Values 
below the lower limit of quantification (LLOQ) will be included as LLOQ/2.
For stimulation day 1, E2 will be assessed by the sites. This assessment will be summarized. Values 
below the lower limit of quantification (LLOQ) will be included as LLOQ/2.
Gynaecological History and Infertility Diagnosis
Gynaecological history, infertility diagnosis and menstrual history collected at screening will be 
summarized for the mITT and ES cohorts.
Smoking and Alcohol Habits
Smoking and Alcohol consumption history and current habits at screening will be summarised for 
the mITT and ES cohorts.
Transvaginal Ultrasound
Visibility of the Ovaries
The visualization of the left and right ovaries (No/Yes) will be summarized.
Antral Follicles
For summary of antral follicles please see stimulation day 1 analysis in Section 9.5.1
7.2
Medical History
Medical history recorded at screening visit will be coded using MedDRA version 21 or later.


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7.3
Prior and Concomitant Medication
Prior and concomitant medication will be summarised by ATC classification 1st level 
(alphabetically), ATC classification 2nd level (in decreasing order of frequency) and treatment 
group. These medications will be tabulated separately for:
1) Prior medication; i.e. medication taken exclusively prior to treatment with IMP (i.e. with 
stop date before date of first IMP administration);
2) Concomitant medication, i.e. medication taken during the treatment period (phase) i.e. 
medication that was not stopped before date of first IMP-administration and not started after 
the end of trial.
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication. Prior-medication will be 
summarized for the mITT and ES cohorts while concomitant medication will be summarized for the 
mITT cohort.
7.4
Physical Examination
Subjects with abnormalities at any screening, baseline, or post-baseline visit will be listed with all 
physical examination evaluations.


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8
Exposure and Treatment Compliance
8.1
Extent of Exposure
All NIMP summary will be based on the safety and ES cohorts. In contrast, the IMP analysis will
be based on the safety and mITT cohorts.
PVR
The total number of PVRs used and the duration of treatment will be summarized. Furthermore, the 
drug compliance rate will also be summarized. Compliance is defined as follows:
(number of PVRs used) / (number of PVRs expected to be used).
The number of PVRs expected to be used is defined to be the number of weeks from oocyte 
retrieval to either confirmation of no pregnancy via β-hCG test or TVUS assessment or in the case 
of a subject where there is no such confirmation, the end of trial visit. 
The number of times a subject was unable to keep a PVR in for at least 23 hours and the number of 
times a subject recorded a damaged PVR will be summarized. A detailed associated listing will be 
produced.
Oral Contraceptives
In this trial, all subjects will be prescribed the same contraceptives. The total dose and duration of 
treatment will be summarized. Associated listing will also be generated.
Leuprolide Acetate
For Leuprolide, a summary of the total dose and duration of treatment will be generated. 
Furthermore, the start and end date of Leuprolide Acetate from last day of oral contraceptive use
will be summarized. Associated listing will be generated.
MENOPUR Administration
Exposure to MENOPUR will be summarized by the total dose administered and duration of 
treatment (days). The maximum MENOPUR dose, the dose on stimulation day 1, the final dose, 
and the number of dose adjustments will also be summarized. Associated listing will be generated.
hCG
Intramuscular injection of 10,000 IU hCG (NOVAREL) will be administered to induce final 
follicular maturation. A subject must have at least 2 follicles ≥17 mm to receive the hCG trigger. 
The following will be summarized: number of subjects who met the hCG criteria, number of 
subjects that had hCG administered, number of subjects who met the hCG criteria and had hCG 
administered, and the number of days from when the hCG criteria was met (the date of final 
stimulation where at least 2 follicles ≥17 mm is observed) to when the hCG is administered.
Associated listing will be generated.


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9
Efficacy
9.1
General Considerations
All confidence intervals will be two-sided 95% confidence intervals. 
9.2
Primary Endpoint
The primary endpoint, spontaneous abortion, is defined as two positive 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 heartbeat, 
or absence of viable fetuses, as documented by transvaginal ultrasound (TVUS).
The derivation of this endpoint will be as follows:
!
Any subject that has two positive β-hCG tests at least two days apart, and
!
meeting at least one of the following conditions at visit 7P (4 weeks and 3-4 days post 
oocyte retrieval) or at a later visit:
1. the TVUS assessment at a later visit shows that there is no presence of gestational sac,
2. there is a presence of empty gestational sac,
3. there is a gestational sac that has a fetus without a heartbeat, or
4. any AE of pregnancy loss that meets the definition of spontaneous abortion.
In order to clearly identify AEs that are spontaneous abortions, listing of all AEs related to 
pregnancy loss, will be generated and provided to the medical team together with the reported and 
coded terms. Appendix 3 lists the preferred terms associated with pregnancy loss that will be used 
for generating this listing. This listing will be provided periodically throughout the trial. The 
medical team will use these listings to identify AEs that meet the spontaneous abortion definition. 
The identification process will be completed prior to data base lock. Since spontaneous abortion 
can occur outside of scheduled visits, for accurate accounting of all spontaneous abortions, the AE 
eCRF page needs to be included.
9.3
Primary Variable Analysis
The primary endpoint will be analysed for the mITT cohort.
Analysis of the Primary Endpoint
The number and rate of any spontaneous abortions (occurring on or before 12 weeks following 
oocyte retrieval) for subjects in the mITT cohort will be summarized and the associated two-sided 
exact 95% confidence interval will be generated. Upon generating the two-sided exact 95% 
confidence interval, the upper bound of the interval will be assessed for whether it excludes or fails 
to exclude a spontaneous abortion rate of 15%.


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Hierarchical Modelling Details for the Sensitivity Analyses
Define n1 as the number of subjects in the current trial and Y1i as the indicator of spontaneous 
abortion for the ith subject in the current trial where Y1 ~ Bin(n1, π1). Let π1 be the true rate of 
spontaneous abortions in the current trial.
The previous trial (Study DR-PGN-302) reported a spontaneous rate of abortion of 55/549. This 
prior information about abortion rate is incorporated into the modelling framework through a 
hierarchical model. Dynamic borrowing between this trial’s results and the current trial’s data 
allows borrowing to occur to the extent indicated by these two data sources. More borrowing occurs 
when the two rates are similar while less borrowing occurs when they differ. This “dynamic” 
borrowing property is distinct from other approaches which use a fixed informative prior or apriori 
assume an amount of borrowing between these two data sources. Let Y0 ~ Bin(n0=549, π0) where π0
is the true rate of spontaneous abortions from the previous trial.
The parameter is transformed to the logit scale for modelling purposes. Let ∀1 = log(π1/(1- π1)) and 
∀0 = log(π0/(1- π0)). The hierarchical model assumes that ∀0 and ∀1 have an across studies 
distribution:
∀1 , ∀0  ~ N(#, ∃2)
The across trial mean # and variance ∃2 are unknown and hence have a prior distribution which is 
combined with the data to produce estimates of # and ∃2:
# ~N(–2.2, 2.25)
∃2~ IG(0.125,0.005)
The mean parameter # assumes a relatively vague prior on the original scale and centered at 10%. 
The variance component ∃2 controls the degree of borrowing among studies. Small values of ∃2
result in a greater degree of borrowing while large values of ∃2 correspond to less borrowing. The 
parameter ∃2 is estimated using the data, so the observed between studies variation is a key 
component of the model behavior. The prior specification on ∃2 corresponds to an inverse-gamma 
distribution with mean 0.2 and weight 0.25.
At the end of this trial, the Bayesian hierarchical model specified above and the spontaneous 
abortion rate in the current trial together with the spontaneous abortion rate in the previous trial (i.e. 
55 spontaneous abortion among 549 subjects) will be used to estimate the posterior distribution of 
the spontaneous abortion rates in the current trial. This posterior distribution will be used to 
generate a 95% credible interval for spontaneous abortion rate in the current trial. Since this 
posterior distribution is intractable, MCMC method via Openbugs in R (e.g., R2OpenBUGS ) will 
be used to generate samples from the posterior distribution and these samples will be used to 
generate the 95% credible interval. Finally, whether or not the 95% credible interval lies entirely 
below 15% will be assessed.


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9.4
Secondary Endpoints
Spontaneous Abortion within 6 and 10 Weeks of Oocyte Retrieval
The frequency and proportion of subjects that have any spontaneous abortion during the trial within 
6 and 10 weeks (i.e., up to 42 and 70 days) post-oocyte retrieval will be derived for subjects in the 
mITT and safety cohorts for subjects that had oocyte(s) retrieved. Associated 95% confidence 
intervals will also be presented.
Biochemical Abortions within 6 and 10 Weeks of Oocyte Retrieval
Biochemical abortion is 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. Additionally, a biochemical abortion can be defined by an AE that meets the 
definition of biochemical abortion (see Appendix 3). To allow for assessment that might occur 
outside the visit window, a subject will be considered to be biochemically pregnant if there are two 
positive assessments at least two days apart on or after 2 weeks post-oocyte retrieval.
The frequency and proportion of subjects that have biochemical abortion within 6 and 10 weeks 
(i.e., up to 42 and 70 days) post-oocyte retrieval will be derived for subjects in the mITT and safety 
cohorts for subjects that had oocyte(s) retrieved. Associated 95% confidence intervals will also be 
presented.
Ectopic and Heterotopic Pregnancies
At time of TVUS examination, ectopic and heterotopic pregnancies may be detected and recorded 
in the TVUS eCRF. These events may also occur outside such assessment visits and may be 
recorded in the AE CRF. The preferred terms associated with ectopic pregnancy are presented in 
Appendix 3 and will be used to select and check for such terms. The frequency and proportion of 
subjects with ectopic and heterotopic pregnancies will be pooled from the two sources and
summarized.
Positive β-hCG
Positive β-hCG is defined as a positive serum β-hCG test at 2 weeks and 2 weeks + 3-4 days post-
oocyte retrieval. To allow for assessment that might occur outside the visit window, a subject will 
be considered to be biochemically pregnant if there are two positive assessment at least two days 
apart on or after 2 weeks post-oocyte retrieval. The positive β-hCG rate will be derived for subjects 
in the mITT and safety cohorts for subjects that had oocyte(s) retrieved. Associated 95% 
confidence intervals for these event rate estimates will also be presented.
Subjects who do not have two β-hCG tests due to missing data, early withdrawal, or any other 
reason will be counted as not having positive β-hCG unless a positive result is observed at a later 
pregnancy assessment. For example, if the outcome of these β-hCG tests is missing and a TVUS 
confirms clinical pregnancy at a later date then β-hCG will be imputed as ‘positive’.


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Clinical Pregnancy
Clinical pregnancy is defined as a TVUS showing at least 1 intrauterine gestational sac with fetal 
heartbeat at 6 and 10 weeks (i.e., up to 42 and 70 days) post-oocyte retrieval. The frequency and 
proportion of subjects that are clinically pregnant at 6 and 10 weeks post-oocyte retrieval will be 
derived for subjects in the mITT and safety cohorts for subjects that had oocyte(s) retrieved. 
Associated 95% confidence intervals for these event rate estimates will also be presented.
For the clinical pregnancy rate derivation at 6 weeks post-oocyte retrieval, if a subject has missing 
TVUS assessment and no other TVUS assessment at a later date, the subject will be counted as not 
having a clinical pregnancy. In contrast, if there is a later assessment with at least 1 intrauterine 
gestational sac with fetal heartbeat, the subject will be imputed as having a clinical pregnancy at 
6 weeks post-oocyte retrieval.
9.5
Other Assessments
Number and Size of Follicles during Stimulation
For each subject, the number of follicles on stimulation day 1 and last day of stimulation will be 
summarized for the mITT and ES cohorts. The summary will include the following:
1. the number of subjects that have follicles of size <10 mm, 10 mm, 11 mm, 12 mm, 13 mm, 
14 mm, 15 mm, 16 mm, and ≥17 mm,
2. a summary of the number of follicles ≥17 mm (the count for each subject will be 
summarized across subjects),
3.
the number of subjects that have at least two folliciles that are ≥17 mm, and 
4. a summary of the percentage of follicles ≥17 mm, ≥15 mm, and ≥12 mm (for each subject
the percentage will be first derived and this subject level sammary will be summarized 
across subject using mean, SD, etc.).
E2 and Progesterone Profiles
The central laboratory E2 and progesterone profiles will be summarized for mITT and ES cohorts, 
using descriptive statistics by scheduled visit, as well as for the change from screening for post-
screening visits.
For patients in the mITT population, the local laboratory E2 assessments will be summarized by 
visit.
Oocytes
For each subject, the number of oocytes retrieved, the number of germinal vesicle, metaphase I, 
metaphase II and Degenerated oocytes will be summarized by frequency distribution and by 
descriptive statistics for the mITT and ES cohorts.


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Characterization of Fertilized Oocytes one Day (Day 1) after Oocyte Retrieval
The status of fertlized oocytes will be summarized 1 day after oocyte retrieval for the mITT and ES 
cohorts. The summary will be both at the subject level and at the oocyte level. 
For the summary at the subject level, for each subject, the percentage of fertilized oocytes with 
pronuclei 2 pn will be derived. The percentage will be derived over the number of oocytes 
retrieved. These percentage will further be summarized using descriptive statastistics (i.e., mean, 
SD, etc.). The percentage of fertilized oocytes with continue destiny will be similarly analyzed.
For the fertlized oocyte level summary, the number and percentage of fertilized oocytes falling in 
each category of pronuclei will be presented (i.e., > 2 pn, 2 pn, 1 pn, 0 pn and damaged). The 
percentage derivation will be over the total number of oocytes classified. 
These summaries will be obtained for mITT and ES cohorts.
Quality of Blastocysts 5 Days (Day 5) after Oocyte Retrieval
The quality of blastocysts 5 days after oocyte retrieval will be assessed at both the blastocyst level 
and at the subject level. The evaluation of fertilized oocytes at Day 5 will consist of assessment of 
embryo stage and classification of blastocysts according to blastocyst expansion and hatching 
status, blastocyst inner cell mass grading and trophectoderm grading. Furthermore, the destiny of 
the embryo will be recorded.
Embryo stage is classified as blastocyst, morula, degenerated or cleavage stage. For embryos still at 
the cleavage stage the number of blastomeres will be recorded.
Destiny at Day 5 is either transferred, cryopreserved or out of trial.
The scoring of blastocysts is based on the classification system by Gardner & Schoolcraft[3].
Blastocyst expansion and hatching status will be assessed as one of the following:
1. An early blastocyst, blastocoel being less than half volume of that of the embryo
2. A blastocyst with a blastocoel whose volume is half of, or greater than half of, 
that of the embryo
3. A blastocyst with a blastocoel completely filling the embryo
4. An expanded blastocyst with a blastocoel volume larger than that of the early 
embryo, with a thinning zona
5. A hatching blastocyst with the trophectoderm starting to herniate through the 
zona
6. A hatched blastocyst, in which the blastocyst has completely escaped from the 
zona


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For blastocysts with expansion and hatching status on Day 5, blastocyst inner cell mass grading and 
trophectoderm grading will be evaluated.
Blastocyst inner cell mass grading will be assessed as one of the following:
A. Tightly packed, many cells
B. Loosely grouped, several cells
C. Very few cells
Trophectoderm grading will be assessed as one of the following:
A. Many cells forming a cohesive epithelium
B. Few cells forming a loose epithelium
C. Very few, large cells 
Based on the blastocyst expansion and hatching status, blastocyst inner cell mass grading and 
trophectoderm grading, the embryo will be classified as a good-quality blastocyst if the grade is 
3BB or above as illustrated in Table 3.
Table 3
Good-Quality Blastocysts
The embryos on Day 5 will be summarised on both the embryo level and at the subject level.
Embryo Level
At the embryo level all embryos evaluated will be included in the tables when reporting embryo 
stage and destiny of the embryo. For summary of blastocyst expansion and hatching status, 
blastocyst inner cell mass grading and trophectoderm grading all available embryo evaluations will 
be included. Frequency tables will be produced for the embryo stage, destiny, blastocyst expansion 
and hatching status, blastocyst inner cell mass grading and trophectoderm grading. These 
summaries will be obtained for the subjects in the mITT and ES cohorts.
3AA
4AA
5AA
6AA
3AB
4AB
5AB
6AB
3AC
4AC
5AC
6AC
3BA
4BA
5BA
6BA
3BB
4BB
5BB
6BB
4BC
5BC
6BC
4CA
5CA
6CA
4CB
5CB
6CB
4CC
5CC
6CC


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Subject Level
At the subject level the following will be derived for all subjects in the mITT and ES cohorts for the 
subjects that had oocytes retrieved:
!
Number of blastocysts at Day 5
!
Number of good-quality blastocysts at Day 5
These counts will be summarized using descriptive statistics of mean, median, SD, minimum and 
maximum.
Endometrial Thickness 
Endometrial thickness at the time of blastocyst transfer will be summarized for the mITT and ES 
cohorts.


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10
Safety
10.1
General Considerations
Safety parameters will be evaluated for the ES and safety cohorts. Safety summaries will be 
presented by the 5 phases of the trial. These phases are defined as follows:
•Screening Phase: From the date of signing the informed consent through the day before the 
start of the oral contraceptive treatment.
•Suppression Phase: From the start of oral contraceptive treatment until the day before the start 
of the stimulation phase (start of MENOPUR treatment).
•Stimulation Phase: From the date of the first dose of MENOPUR through the day before the 
start of IMP.
•Treatment Phase: From the date of the first dose of IMP (PVR) through the end of the trial.
•Study Phase: From the date of the first dose of oral contraceptive through the end of the trial.
10.2
Adverse Events
Adverse events (AEs) are classified according to the latest available version of Medical Dictionary 
for Regulatory Activities (MedDRA).
Written narratives will be issued for all serious AEs (including deaths). Treatment-emergent AEs 
are AEs that occur during the treatment phase or a pre-existing medical condition that worsened in 
intensity during the treatment phase.
Overview of Treatment-Emergent Adverse Events
A TEAE overview summary table will be prepared including the number of subjects reporting a
TEAE, the percentage of subjects (%) with a TEAE, and the number of events (E) reported, for the 
following categories: 
!
Treatment-emergent adverse events
!
Treatment-emergent Deaths 
!
Treatment-emergent Serious adverse events 
!
Treatment-emergent adverse events leading to withdrawal 
!
Treatment-emergent severe adverse events 
!
Treatment-emergent Adverse drug reactions
Incidence of Adverse Events
Treatment-emergent adverse events will be summarised in a Table by SOC and PT of MedDRA 
using the latest available version. The Table will display the total number of subjects reporting an 
AE, the percentage of subjects (%) with an AE, and the number of events (E) reported. AEs will be 


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presented by system organ class (SOC) sorted alphabetically and preferred term (PT) sorted in 
decreasing frequency of occurrence.
Summary tables will be prepared for:
!
All Treatment-emergent adverse events
!
Treatment-emergent adverse events with an incidence [≥ 5%] of subjects in any treatment 
group
!
Treatment-emergent adverse events by causality (related/unrelated)
!
Treatment-emergent adverse events leading to death
!
Treatment-emergent adverse events by intensity
!
Treatment-emergent Serious adverse events 
!
Treatment-emergent Adverse events leading to withdrawal
!
Non-serious treatment-emergent AEs with an incidence of at least 5%
Furthermore, the overall AE summary table by system organ class and preferred term will also be 
produced for the study phase, suppression phase, and the stimulation phase for the ES and safety 
cohorts.
Supporting data listings will be provided for:
1. All treatment-emergent adverse events sorted by centre and subject number
2. All treatment-emergent adverse events sorted by MedDRA System Organ Class and Preferred 
Term
3. Serious adverse events 
4. Adverse events leading to death
5. Adverse events leading to withdrawal. 
For listings specified in 3-5, there will be a variable that will indicate which phase of the trial each 
event occurred.
A separate AE listing will be provided for the screening phase, suppression phase, stimulation 
phase, and treatment phase of the trial.
Treatment-Emergent AEs of Special Interest
Standardized criteria will be applied to some AEs of special interest to establish intensity/grade. For 
AEs associated with vaginal bleeding/spotting, vaginal pain and irritation, and vaginal or cervical 
abrasions and lesions, standardized criteria will be used by the sites to record the intensity of these 
AEs (Protocol Section 8). For these AEs and AEs associated with vaginal hemorrhage, vaginal 
infection and vaginal adhesions, a summary table of the treatment-emergent AEs of special interest 
will be produced by preferred term, grade (intensity), and seriousness for subjects in the safety 
cohort for the treatment phase and the study phase. These AEs will be identified using preferred 
terms.


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10.3
Safety Laboratory Variables
Baseline for all laboratory analyses will be the values obtained at visit 4.  If visit 4 is missing, then 
the last assessment prior to visit 4 will be used. Treatment-emergent laboratory data will include 
tests completed after the first dose of IMP through the residual time of drug effect. End of trial will 
include the last post-baseline observation during the trial. 
Laboratory variables will be grouped under “Hematology”, “Clinical Chemistry” or “Urinalysis”.
Summary Statistics
For treatment phase of the trial, for the safety cohort, mean change and mean percentage (%) 
change from baseline at end of trial will be presented for each laboratory variable. In addition, 
descriptive statistics, i.e., the number of subjects with data, mean (standard deviation), median, 
minimum, and maximum values, will be presented for observed values and change from baseline at 
each time-point for each laboratory variable. The screening value will also be summarized for both 
the safety and the ES cohorts.
Laboratory Variable Shift Tables
Changes relative to normal ranges are presented with shift tables with total number of subjects, and 
number and percent of subjects who experienced a shift from baseline to their end of trial visit. The 
following categories for shift tables are defined:
!
Low: 
Values which are below the lower reference range limit;
!
Normal: 
Values which are within the lower and upper reference range;
!
High: 
Values which are above the upper reference range limit.
For all hematology and clinical chemistry variables, shift tables will be prepared to show all shifts. 
More specifically, for hematology and clinical chemistry, tables presenting the changes from Low 
or Normal to High and from High or Normal to Low will be provided. 
Data Listings
Data listings will be prepared for all subjects with any abnormal laboratory value at any time-point 
(including screening, baseline). 
Urinalysis
Urinalysis parameters will be summarized by visit for the ES and safety cohorts. For continuous 
variables, mean, standard deviation, median, minimum and maximum will be used to summarize 
the assessment. In contrast, for categorical parameters, percentages and frequencies will be used. 
Furthermore, for each urinalysis parameter the number of subjects with abnormal laboratory values 
will be summarized by visit for the ES and safety cohorts.
Vital Signs
Baseline for all vital signs analyses will be calculated in the same manner as the safety laboratory 
variables in Section 10.3. Treatment-emergent vital signs data will include tests completed after the 


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first dose of IMP through the end of the trial. End of trial assessment is defined to be the last post-
baseline observation during the treatment phase of the trial.
10.3.5.1
Summary Statistics
For the treatment phase of the trial, for the safety cohort, mean change and mean percentage (%) 
change from baseline to the end of trial will be presented for each vital signs variable. In addition, 
descriptive statistics, i.e., the number of subjects with data, mean (standard deviation), median, 
minimum, and maximum values, will be presented for observed values and change from baseline at 
each time-point for each vital signs variable. 
10.3.5.2
Notable Changes in Vital Signs
Summary tables will be prepared displaying the number and percentage of subjects with normal 
baselines who had one or more pre-specified notable treatment-emergent values, according to the 
definition in Appendix 1.
10.3.5.3
Data Listings
Data listings will be prepared by centre for all subjects with any notable vital signs value at any 
time-point (including screening, baseline).
10.4
Other Safety Variables
Bleeding Log Assessment
At the start of PVR, each subject will receive a bleeding log. For each incidence of sanitary napkin 
use for bleeding/spotting, subjects will be instructed to record the date, time of day, and the severity 
of the bleeding. For each subject, for each day: the grade (intensity) of bleeding associated with 
each sanitary napkin use will be summed. The sum of the daily grades (intensity) of bleeding will 
be averaged by visit window (see Table 4) where the visit window will cover the subject’s Bleeding 
Log recording period (i.e., from the start of the PVR to the End-of-trial visit). Finally, this subject 
data will be summarized across all subjects for the safety cohort by visit window. The summary 
will include mean, median, standard deviation, minimum and maximum. 
The analysis outlined above will be repeated removing the date of fresh transfer, periods associated 
with AEs reported as vaginal hemorrhage, the primary endpoint of spontaneous abortion and 
information collected after the cessation of the use of PVR. For vaginal hemorrhaging, spontaneous 
abortion and biochemical abortion, this will be achieved by removing bleeding log assessment 
collected starting from two days prior to the start of such an event up to two days after the end of 
such an event. Furthermore, for subjects with any negative β-hCG result, the bleeding log 
assessment will be summarized.
For subjects that discontinue from PVR early, the bleeding logs will be calculated normally (as per
Table 4) until PVR is discontinued. Bleeding log entries after the visit preceding the Early 
Withdrawal Visit and bleeding log entries after PVR is withdrawn will be assigned to Visit 9. At 
the end of study visit and beyond, bleeding log entries will be assigned to Visit 10.


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Table 4
Visits numbers, nominal visit days from oocyte retrieval date and associated visit 
windows
Visit 
Nominal visit date from date 
of oocyte retrieval (Day 1=
date of oocyte retrieval)
Visit window
(Day 1= date of oocyte 
retrieval)
Visit 3
Day 1
Visit 4
Day 2
Start of IMP  - Day 3
Visit 5
Day 5
Day 4 – Day 9
Visit 6
Day 14±1
Day 10 – Day 15
Visit 6P
Day 17±1
Day 16 – Day 19
Visit 7
Day 21±1
Day 20 – Day 26
Visit 7P
Day 31 ±1
Day 27 – Day 36
Visit 8
Day 42±1
Day 37 – Day 56
Visit 9
Day 70±1
Day 57 – Day 77
Visit 10
Day 84
Day 78 – Day 90
Vaginal Hemorrhage
Vaginal hemorrhage is defined in Section 8.3.6 of the protocol and the assessment of vaginal 
hemorrhage will be collected in a specific eCRF module. Based on the eCRF module, the number 
of subjects with vaginal hemorrhage will be summarized for the Safety cohort.
Pelvic Examination
A pelvic examination will be performed at screening, Visits 4, 7P, 8, 9, and 10 to document the 
presence and grade (intensity) of any pain, irritation, abrasions, or lesions on the cervix or vagina 
using standardized criteria, and the presence and grade (intensity) of any vaginal adhesions using 
standardized criteria. If any lesions or abrasions are found on the cervix or vagina or vaginal 
adhesions are noted, another examination will be performed 2-4 days later. The grade (intensity) for 
each type of assessment will be summarized by visit for the safety cohort. Furthermore, a shift table 
will be presented summarizing the change in grade (intensity) from Visit 4 to the End-of-trial, 
where the End-of-trial is defined to be the last assessment in the treatment phase.
An associated listing will also be produced.


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11
Interim Analyses
No interim analysis is planned for this trial.


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12
Deviations from Protocol 
The following changes and additions from the planned displays and analyses described in the 
previous version of the clinical trial protocol have been implemented in the statistical analysis plan:
!
All 90% confidence intervals have been replaced with 95% confidence intervals based on 
FDA input on the statistical analysis plan.
!
The embryo quality analysis that is described in this SAP was not mentioned in the clinical 
trial protocol.
!
The definition of the Eligible Subjects cohort is taken to be a subject that has received at 
least one dose of oral contraceptives, leuprolide acetate, and MENOPUR. This aligns with 
the analogous cohort from the DR-PGN-302 study. In the clinical trial protocol, an “or” is 
used instead of an “and”.
These revisions have been implemented in the clinical trial protocol version 6.0.


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13
References
[1]
Center for Disease Control 2005 Assisted Reproductive Technology Success Rates. U.S. 
Department of Health and Human Services; 
http://www.cdc.gov/ART/ART2005/508PDF/2005ART508.pdf.
[2]
Practice Committee of the Society for Assisted Reproductive Technology and Practice 
Committee of the American Society for Reproductive Medicine. Guidance on the limits to 
the number of embryos to transfer: a committee opinion. Fertil Steril 2017; 107:901–3.
[3]
Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Towards 
reproductive certainty (Eds Jansen R & Mortimer D). The plenary proceedings of the 11th
world congress on in vitro fertilization and human reproductive genetics. The Parthenon 
Publishing Group. 1999. Pp 378-388


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14
APPENDICES


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Appendix 1
Notable Vital Signs
Table 5
Notable Criteria for Vital Signs*
Variable
Criterion Value
Change from Baseline
Systolic blood pressure
% 180 mmHg
& 90 mmHg
Increase of % 20 mmHg 
Decrease of % 20 mmHg
Diastolic blood pressure
% 105 mmHg 
& 50 mmHg
Increase of % 15 mmHg 
Decrease of % 15 mmHg
Pulse rate
% 120 bpm
& 50 bpm
Increase of % 15 bpm
Decrease of % 15 bpm
Body weight
None
Increase of % 7%
Decrease of % 7%
Body temperature**
> 38.3∋C
* To be identified as notable abnormal, a treatment value must meet the criterion value and also the 
specified change from baseline.
** The notable criteria is met for body temperature whenever this criteria is met.


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Appendix 2
Primary Analysis Simulation Code and the Sensitivity 
Analysis Operating Characteristics
Primary Analysis Simulation Code
Below is the R code that runs the simulation described in the sample size justification.
#################
### LIBRARIES ###
#################
library(ggplot2)
library(tidyverse)
#############
### SETUP ###
#############
### SET THE SEED ###
set.seed(7639216)
### THE NUMBER OF SIMULATION REPS ###
n.sim <- 10000
### THE NUMBER OF SUBJECTS IN THE MODIFIED ITT ANALYSIS POPULATION ###
n.mitt <- seq(from = 100, to = 400, by = 5)
### THE TRUE PR(SPONTANEOUS ABORTION | IN THE MITT ANALYSIS POPULATION) 
###
p.sa <- seq(from = 0.08, to = 0.1, by = 0.01)
### A PLACE TO STORE THE RESULTS ###
sim.res <- matrix(NA, nrow = length(n.mitt), ncol = length(p.sa))
rownames(sim.res) <- n.mitt
colnames(sim.res) <- paste0(p.sa * 100, "%")
##################
### SIMULATION ###
##################
pb <- txtProgressBar(min = 1, max = length(n.mitt), style = 3)
for(a in 1:length(n.mitt)){
  
  setTxtProgressBar(pb, value = a)


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  for(b in 1:length(p.sa)){
    
    sim.sara <- rbinom(n = n.sim, size = n.mitt[a], prob = p.sa[b])
    
    sara.res <- unlist(lapply(X = sim.sara, FUN = function(x, n = n.mitt[a]){
      
      ifelse(binom.test(x = x, n = n, p = 0.15, alternative = c("two.sided"), conf.level = 
0.95)$conf.int[2] < 0.15, 1, 0)
      
    }))
    
    sim.res[a, b] <- mean(sara.res) * 100
    
  }
  
}
########################
### PLOT THE RESULTS ###
########################
### MOLD THE RESULTS FOR PLOTTING ###
sim.res.long <- data.frame(N = as.numeric(rownames(sim.res)), SA8PCT = sim.res[, 1], SA9PCT = 
sim.res[, 2], SA10PCT = sim.res[, 3]) %>%
  gather(key = "SA", value = "POWER", 2:4)
p <- ggplot(sim.res.long, aes(x = N, y = POWER, group = SA)) +
  geom_hline(yintercept = 80, linetype = "dashed", color = "grey", size = 2) +
  geom_line(aes(color = SA), size = 1.5) +
  scale_x_continuous(name = "Sample Size (in MITT Analysis Population)", breaks = seq(from = 
100, to = 400, by = 20)) +
  scale_y_continuous(name = "Power", limits = c(0, 100)) +
  theme(axis.text.x = element_text(angle = 45, hjust = 1)) +
  scale_color_discrete(name = "Spontaneous\nAbortion\nRate",
                       breaks = c("SA8PCT", "SA9PCT", "SA10PCT"),
                       labels = c("8%", "9%", "10%"))
######################
### TABULAR OUTPUT ###
######################
### FIND WHICH RESULTS ARE ABOVE 80% POWER ###
sim.res.80 <- sim.res >= 80
### FIND THE INDICES ###


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sim.res.ind <- apply(X = sim.res.80, MARGIN = 2, FUN = function(x){
  
  TEMP <- length(x)
  if(any(x)){
    
    TEMP <- min(which(x))
    
  }
  TEMP
  
})
### REPORT THE POWER FOR THESE INDICES
sim.table <- sim.res[sim.res.ind, ]
Hierarchical Modelling Details
Define n1 as the number of subjects in the current trial and Y1i as the indicator of spontaneous 
abortion for the ith subject in the current trial where Y1 ~ Bin(n1, π1). Let π1 be the true rate of 
spontaneous abortions in the current trial.
The previous trial (Study DR-PGN-302) reported a spontaneous rate of abortion of 55/549. This 
prior information about abortion rate is incorporated into the modelling framework through a 
hierarchical model. Dynamic borrowing between this trial’s results and the current trial’s data 
allows borrowing to occur to the extent indicated by these two data sources. More borrowing occurs 
when the two rates are similar while less borrowing occurs when they differ. This “dynamic” 
borrowing property is distinct from other approaches which use a fixed informative prior or apriori 
assume an amount of borrowing between these two data sources. Let Y0 ~ Bin(n0=549, π0) where π0 
is the true rate of spontaneous abortions from the previous trial.
We transform to the logit scale for modelling purposes. Let ∀1 = log(π1/(1- π1)) and ∀0 = log(π0/(1-
π0)). The hierarchical model assumes that ∀0 and ∀1 have an across studies distribution:
∀1 , ∀0  ~ N(#, ∃2)
The across trial mean # and variance ∃2 are unknown and hence have a prior distribution which is 
combined with the data to produce estimates of # and ∃2:
# ~N(–2.2, 2.25)
∃2~ IG(0.125,0.005)
The mean parameter # assumes a relatively vague prior on the original scale and centered at 10%. 
The variance component ∃2 controls the degree of borrowing among studies. Small values of ∃2
result in a greater degree of borrowing while large values of ∃2 correspond to less borrowing. The 
parameter ∃2 is estimated using the data, so the observed between studies variation is a key 


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component of the model behavior. The prior specification on ∃2 corresponds to an inverse-gamma 
distribution with mean 0.2 and weight 0.25.
Operating Characteristics
The planned sample size is based only on subjects that undergo fresh embryo transfer. No further 
drop-outs are assumed. The analysis is evaluated across a range of true effects for the current trial’s 
spontaneous abortion rate. For the null scenario where in truth the PVR spontaneous abortion rate is 
15%, 100,000 sets of trials were simulated.  For all other assumed scenarios, 5,000 sets of trials 
were simulated.
Overall Success
We evaluated the overall probability that the 95% credible interval is entirely below 15% for each 
scenario of the true PVR rate. If PVR truly maintains an abortion rate below 15%, then this 
represents the power for achieving a credible interval entirely below 15%. If the true rate of 
abortions for PVR is 15%, then obtaining a credible interval entirely below 15% is the type I error. 
Results are provided in the table below.
True PVR Rate 
8%
9%
10%
11%
12%
13%
14%
15%
Trial Success
0.979
0.933
0.830
0.670
0.485
0.297
0.167
0.084
When in truth the PVR spontaneous abortion rate is 9%, the trial has 93.3% power of achieving a 
95% credible interval entirely below 15%. Alternatively, when in truth the spontaneous abortion 
rate is 15%, the trial has a 8.4% rate of success.
Inference Associated with Various Observed Rates
For various observed rates of spontaneous abortions, the corresponding primary analysis based on 
the hierarchical model is described below. The posterior mean, 95% credible interval, effective 
number of borrowed subjects, and the borrowing percentage (out of the n=549 subjects from the 
previous trial) is provided. The effective number of borrowed subjects calculation [E(π1)*(1-
E(π1))/Var(π1)–1–240] is somewhat approximate as it is based on the binomial likelihood. Results 
are provided in the below table.
Observed Data
Estimated Rate (%) 
(95% CI)
Effective Number of 
Borrowed Subjects
Borrowing 
Percentage
19/240 (7.92%)
8.6% (5.7, 11.7)
103
18.9%
24/240 (10.00%)
10.0% (7.2, 13.3)
130
23.7%
36/240 (15.00%)
13.8% (10.1, 18.5)
9
1.7%
Borrowing based on the hierarchical modelling is dynamic, with higher borrowing achieved when 
the current trial’s results are similar to the previous data and minimal borrowing when the current 
trial’s results are at 15%. This is evidenced by both the decreasing number of borrowed subjects 
and the increasing width of the credible intervals. Also, based on 240 subjects being included in the 


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analysis, the maximal number of observed responses which maintains a 95% credible interval 
entirely below 15% is 28.
R2OpenBUGS Codes for Analysing the Data at the End of the Trial
for (i in 1:N) {
                                 y[i]  ~ dbin(theta[i], n[i])
                                   logit(theta[i]) <- logit.theta[i]
                                   logit.theta[i] ~ dnorm( mu, tau)
                                      }
                mu ~ dnorm(-2.2, 0.4444444)
                tau ~ dgamma(0.125, 0.005)


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Appendix 3
Preferred Terms Associated With Spontaneous Abortion
and Ectopic pregnancy
All the preferred terms associated with Spontaneous abortion are listed below. This is based on 
MedDRA version 21.0. Prior to dry-run and DBL, the dictionary will be checked to make sure there 
is no change of terms with dictionary update. 
Spontaneous abortion associated preferred terms
Abortion
Abortion complete
Abortion complete complicated
Abortion complicated
Abortion early
Abortion incomplete
Abortion incomplete complicated
Abortion induced
Abortion induced complete
Abortion induced complete complicated
Abortion induced complicated
Abortion induced incomplete
Abortion induced incomplete complicated
Abortion infected
Abortion late
Abortion missed
Abortion of ectopic pregnancy
Abortion spontaneous
Abortion spontaneous complete
Abortion spontaneous complete complicated
Abortion spontaneous complicated
Abortion spontaneous incomplete
Abortion spontaneous incomplete complicated


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Abortion threatened
The relevant preferred terms associated with biochemical abortion are listed below. This is based 
on MedDRA version 21.0. Prior to dry-run and DBL, the dictionary will be checked to make sure 
there is no change of terms with dictionary update.
Biochemical abortion associated preferred terms
Biochemical pregnancy
The relevant preferred terms associated with ectopic pregnancy are listed below. This is based on 
MedDRA version 21.0. Prior to dry-run and DBL, the dictionary will be checked to make sure there 
is no change of terms with dictionary update.
Ectopic pregnancy associated preferred terms
Abortion of ectopic pregnancy
Ectopic pregnancy
Ectopic pregnancy termination
Ectopic pregnancy under hormonal
contraception
Ectopic pregnancy with contraceptive device
Ruptured ectopic pregnancy
The relevant preferred terms associated with adverse events of special interest (Appendices 2, 3, 
and 4 of the Protocol) are listed below. This is based on MedDRA version 21.0. Prior to dry-run 
and DBL, the dictionary will be checked to make sure there is no change of terms with dictionary 
update.
Preferred terms associated with adverse events of special interest
Vulvovaginal pain
Dyspareunia
Vulvovaginal discomfort


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Vulvovaginal pruritus
Vulval oedema
Vulvovaginal erythema
Vulvovaginal rash
Bartholin’s cyst
Urethral cyst
Vulval disorder
Vaginal oedema
Vulvovaginal dryness
Vaginal discharge
Vaginal erosion
Vaginal lesion
Cervix oedema
Cervical friability
Cervix erythema
Cervical discharge
Cervix disorder
Vulvovaginal adhesion
Vaginal haemorrhage
Vaginal infection
Uterine cervical erosion