Clinical trial NCT01976728
Conditions: Primary Amenorrhea With Hypogonadotropic Hypogonadism
Sponsor: Ferring Pharmaceuticals
Start date: 2014-04-01; Completion date: 2018-02-23
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare the ovulation rate in women with primary amenorrhea with hypogonadotropic hypogonadism following pulsatile gonadotropin-releasing hormone (GnRH) treatment using the OmniPod pump versus placebo

Detailed description:

Arms: arm 1: Gonadorelin acetate 10 µg/pulse arm 2: Gonadorelin acetate 15 µg/pulse arm 3: Gonadorelin acetate 20 µg/pulse arm 4: Placebo
Interventions: intervention 1: Gonadorelin acetate subcutaneous (SC) 10 μg/pulse as a fixed dose, administered via. OmniPod pump intervention 2: Gonadorelin acetate SC 15 μg/pulse as a fixed dose, administered via. OmniPod pump intervention 3: Gonadorelin acetate SC 20 μg/pulse as a fixed dose, administered via. OmniPod pump intervention 4: Placebo (SC 10, 15, or 20 μg/pulse as a fixed dose, administered via. OmniPod pump)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Protocol 
 
 
Title of trial:  
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating Three Doses of Subcutaneous Pulsatile GnRH Administered via 
OmniPod Pump for Ovulation Induction in Female Subjects with Primary 
Amenorrhea with Hypogonadotropic Hypogonadism  
NCT number: 
NCT01976728 
Sponsor trial code: 
000070 
Date:  
06 Dec 2017 
 
 
 
 
 


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Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Evaluating Three Doses 
of Subcutaneous Pulsatile GnRH Administered via OmniPod Pump for Ovulation Induction 
in Female Subjects with Primary Amenorrhea with Hypogonadotropic Hypogonadism 
 
Trial Code 000070 
 
Consolidated Protocol Incorporating Amendments 1-7 
 
 
IND Number: 
22,278 
Investigational Medicinal Product: 
LutrePulse OmniPod  
Indication: 
Primary Hypothalamic Amenorrhea 
Phase: 
III 
Name and Address of Sponsor: 
Ferring International Pharmascience Center U.S., Inc. 
100 Interpace Parkway 
Parsippany, NJ 07054 
P: 973-796-1600  
F: 973-796-1660 
GCP Statement: 
This trial will be performed in compliance with GCP. 
 
 
 
 
 
The information in this document is confidential and is proprietary to Ferring International Pharmascience Center U.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 authorized officer of Ferring International Pharmascience 
Center U.S. or another company within the Ferring Group. 


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CONFIDENTIAL 
SYNOPSIS 
TITLE OF TRIAL 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Evaluating Three Doses of 
Subcutaneous Pulsatile GnRH Administered via OmniPod Pump for Ovulation Induction in 
Female Subjects with Primary Amenorrhea with Hypogonadotropic Hypogonadism 
TRIAL SITES 
The study will be conducted at approximately 50 sites in the United States and Canada. 
PLANNED TRIAL PERIOD 
First subject first visit (FSFV)  March 2014 
Last subject last visit (LSLV)   June 2019 
CLINICAL PHASE 
III 
OBJECTIVES 
Primary objective  
• To compare the ovulation rate in women with primary amenorrhea with hypogonadotropic 
hypogonadism (HH) following each of three doses (10 g, 15 g, and 20 g per pulse) of 
subcutaneous (SC)  pulsatile gonadotropin-releasing hormone (GnRH) administered with 
the LutrePulse OmniPod Pump versus placebo  
Secondary objectives 
• To evaluate clinical pregnancy rate  
• To evaluate biochemical pregnancy rate  
• To evaluate LH surge rate 
• To evaluate ovarian follicular development  
• To evaluate luteal phase support with GnRH   
• To evaluate pharmacodynamic parameters 
• To evaluate the safety of LutrePulse OmniPod SC 


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Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
ENDPOINTS 
Primary endpoint  
• Ovulation rate, calculated as a proportion of subjects with at least 1 post-baseline 
progesterone (P4) level ≥ 6 ng/mL or a confirmed positive serum β-hCG (i.e., 2 positive 
results) or presence of a gestational sac documented by transvaginal ultrasound (TVUS) 
Secondary endpoints 
Progesterone levels: 
• Proportion of subjects with at least 1 post-baseline P4 level ≥ 10 ng/mL 
Pregnancy: 
 
Clinical pregnancy rate: 
• Proportion of subjects with presence of gestational sac and fetal heart movement (FHM) 
on transvaginal ultrasound (TVUS) at approximately 2 to 4 weeks after a second positive 
serum beta human chorionic gonadotropin (-hCG) test 
 
Biochemical pregnancy rate:  
• Proportion of subjects with a confirmed positive serum -hCG (i.e., 2 positive results) 
14 + 4 days post luteinizing hormone (LH) surge 
LH Surge Detection:  
• Proportion of subjects with a positive detection of LH surge on a Clearblue test 
Ovarian Follicular Development:  
• Number of follicles with a mean diameter ≥ 14 mm 
• Number of dominant follicles with a mean diameter ≥ 18 mm  
Luteal Phase Support: 
• Maximum P4 levels from Days 19, 21, 23, 25, and 27 
• Mean P4 levels from Days 19, 21, 23, 25, and 27 
Pharmacodynamic Endpoints: 
• Follicle-stimulating hormone (FSH) and LH change from baseline in relation to the first 
GnRH pulse on Day 1 and Day 10  
• Mean serum FSH and LH levels on Day 1 and Day 10 


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Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• Estradiol (E2) serum levels on Day 1 and Day 10 
Safety Endpoints: 
• Adverse events (type, frequency, intensity, and seriousness) 
• Clinical chemistry, hematology, urinalysis 
• Frequency and severity of ovarian hyperstimulation syndrome (OHSS) 
METHODOLOGY  
This multicenter, randomized, double-blind, placebo-controlled study will be performed in 
approximately 60 women with primary amenorrhea with HH who desire pregnancy.  The 
treatment duration with LutrePulse OmniPod SC or placebo can be approximately 7 weeks.  It is 
expected that the response to treatment will occur within 2 to 3 weeks after therapy initiation.  
When LH surge is detected by LH urine kit test, therapy should be continued for approximately 
another 2 weeks to maintain corpus luteum function (continue until confirmatory serum 
pregnancy test).  Subjects will discontinue treatment either at the onset of menses or after having 
two (2) negative or two (2) positive confirmatory serum pregnancy tests. Subjects will be 
required to return to the study site for pharmacodynamic blood draws, TVUS, serum pregnancy 
tests, and safety follow-up assessments. 
The study will consist of 3 periods: Screening (includes progestin challenge test), Treatment 
(includes pituitary priming and treatment phase), and Follow-up. 
Screening (Day -60 to Day -1): Only subjects with diagnosed primary amenorrhea with HH 
should be screened.  Only subjects who desire pregnancy will be eligible to participate in the trial. 
The site will obtain written informed consent before any study-related procedures begin.  Upon 
signing the Informed Consent Form, subjects will be screened based on inclusion/exclusion 
criteria.  The assessments during the screening period will include medical/gynecologic history, 
safety laboratory tests (chemistry, hematology, urinalysis), other laboratory tests (serum 
pregnancy, LH, FSH, E2, P4, prolactin [PRL], and thyroid-stimulating hormone [TSH] levels), 
vital signs (blood pressure, heart rate, body temperature),  Papanicolaou (PAP) smear (if not done 
within the last 24 months; PAP smear may be performed at Screening and for every patient if 
warranted, per investigator discretion), TVUS documenting normal uterus and adnexa, and a 
physical/gynecological examination.  A normal or stable computed tomography (CT) scan or 
magnetic resonance imaging (MRI) scan of the hypothalamic pituitary region must be on file to 
exclude other causes for the disease.  The male partner should have a recent normal semen 
analysis (within 1 year). A progestin challenge test will also be initiated to confirm HH. 


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Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Rescreening will be allowed at the investigators’ discretion for subjects who exhibit laboratory 
tests outside of the normal or required range.  No subject may be rescreened more than once.  
Rescreening for the progestin challenge test is not allowed. 
Progestin challenge test:  After confirmed negative serum pregnancy test, subjects will be 
dispensed 10 mg of medroxyprogesterone acetate (Provera®) once daily for 10 days.  
Subjects who do not have uterine bleeding 5 days after the last dose of progestin will 
continue to the treatment period.  Per investigator’s discretion, occasional spotting is not 
considered withdrawal bleeding.  Subjects with uterine bleeding are considered screen 
failures and will be ineligible for study participation.  Rescreening for the progestin 
challenge test is not allowed. 
Treatment (Day 1 to approximately Day 37): Subjects who do not have uterine bleeding within 
5 days after the last dose of progestin will return to the clinic; a negative urine pregnancy test 
result is required and then the subject will be randomly assigned to 1 of 4 treatment arms: 
LutrePulse OmniPod SC 10 μg/pulse, 15 μg/pulse, 20 μg/pulse, or placebo (10, 15, or 20 μg/pulse 
delivery setting) every 90 minutes. 
Subjects will be instructed on the application of the OmniPod pump.  The first OmniPod pump 
will be applied on Day 1.  Each OmniPod pump will be worn for 3 days (Days 1-3, 4-6, 7-9, etc. 
to approximately Day 37).  The subject will apply subsequent OmniPod pumps every 4th day at 
approximately the same time as the 1st application (±1 hour). 
Pharmacodynamic assessments:  A blood sample for E2, LH and FSH will be taken on 
Day 1 (pre-treatment baseline) prior to dosing.  Additional blood samples for only LH and 
FSH will be taken 5, 15, 30, 60, and 90 minutes after the first dose is administered.   
A blood sample for E2, LH and FSH will be taken on Day 10 at the same time as the Day 1 
initial sample (±1 hour) and before the first dose is administered by the Day 10 pump.  
Additional blood samples for only LH and FSH will be taken 5, 15, 30, 60, and 90 minutes 
after the first dose is administered. 
 
 
 
 


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Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follicular and endometrial development: Follow-up will begin on Day 10 of treatment.  
Follicular and endometrial development will be monitored by TVUS every other day or per the 
investigator’s discretion (minimum of 3 TVUS), until a dominant follicle of ≥ 18 mm mean 
diameter and normal endometrium (thickness and pattern) are confirmed. If a dominant follicle ≥ 
18 mm mean diameter is not observed after 21 full days of treatment, the therapy will be 
discontinued.  However, the treatment may be continued for a maximum of 39 days at the 
discretion of the investigator if the patient has growing follicle(s).  After Day 10, a single blood 
sample for E2 assessment will be collected each time the subject returns for TVUS.  A subject 
who has an increased risk of developing multiple gestation/OHSS (4 or more follicles with a 
mean diameter ≥ 15 mm by TVUS and E2 levels ≥ 1200 pg/mL) will be discontinued from 
treatment.  
LH surge detection: Clearblue® digital ovulation urine test will begin when follicles with a 
mean diameter ≥ 14 mm are documented on TVUS.  The subject will administer a 
Clearblue test daily, between 8 and 11 AM at approximately the same time each morning, 
until a positive test result occurs.  Subjects should document the date of their first Clearblue 
test and the date of their first positive test result on the subject diary card (Appendix II). 
The subject should notify the site immediately once the surge has been detected to schedule 
a visit within 72 hours for a confirmatory TVUS.  Subjects will be advised to engage in 
sexual intercourse on the day of LH surge, the day following LH surge, and per 
investigator’s discretion thereafter. The subject should also document the date(s) of sexual 
intercourse on the subject diary card.  
If LH surge is not detected after 21 full treatment days, the subject will be discontinued.  
However, the treatment may be continued for a maximum of 39 days at the discretion of the 
investigator if the patient has growing follicle(s).The subject will be instructed to visit the 
site to return all study drug and the OmniPod System. 
Blood samples for progesterone (P4) levels: A single blood sample for P4 will be taken on 
Day 1 (pre-treatment baseline) prior to dosing.  Blood samples will also be obtained on Day 
19, Day 21, Day 23, Day 25 and Day 27.  For subjects who have discontinued the study 
early and ended treatment on or after Day 14, a blood sample will also be taken at the End-
of-Study Visit.   
Menses Onset:  Subjects who begin menstruating after treatment was initiated will be 
instructed to stop the treatment and to visit the site to return all study drug and the OmniPod 
System.  The site will record the first day of menses and duration of menses for all non-
pregnant subjects.   


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Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Serum pregnancy tests (-hCG): will be performed 14 days (+ 4 days) after LH surge and 
3 days thereafter.  Two positive pregnancy tests are required to confirm biochemical 
pregnancy.  If only one of the 2 tests is positive, the subject will return within 5 days 
(unscheduled visit) to confirm pregnancy with another test. 
After obtaining two (2) negative or two (2) positive confirmed serum pregnancy test results, the 
treatment will complete.   
All subjects will be assessed for an End-of-Study visit and return all study drug and the OmniPod 
System. 
Follow-up:  TVUS for pregnancy outcome:  Subjects who achieve pregnancy (2 positive serum 
pregnancy tests) will be followed up for clinical pregnancy (gestational sac and fetal heart 
movement) 2 to 4 weeks after second positive pregnancy test and will complete an End-of-Study 
visit the day of documented fetal heart movement on TVUS.  If the fetal heartbeat is not detected, 
the subject will return within 7 days for a follow-up ultrasound to confirm fetal heartbeat.  Sites 
will contact these subjects to collect data for ongoing pregnancy rate (fetal heart movement at 
gestational Week 11 or Week 12), including safety follow-up of the subjects for miscarriage, fetal 
anomalies and live birth rate. 
NUMBER OF SUBJECTS 
Approximately 60 female subjects will be randomized.   


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Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
MAIN CRITERIA FOR INCLUSION / EXCLUSION 
Inclusion Criteria:  
1 
Signed written informed consent prior to any study-related procedure 
2 
Women 18 - 40 years old 
3 
Body mass index (BMI) between 18 and 38 kg/m2 
4 
Documented clinical history or recently diagnosed with primary amenorrhea with 
hypogonadotropic hypogonadism 
5 
Hormonal values in a centrally analyzed fasting blood sample: FSH < 5 IU/L and mean 
LH < 5 IU/L 
6 
Desire to become pregnant 
7 
Discontinued estrogen-progesterone replacement therapy at least 1 month before 
screening 
8 
Negative progestin challenge test performed during screening 
9 
Normal PAP smear within 24 months of the initial visit (PAP smear can be performed at 
Screening, per investigator discretion and standard of practice if warranted, even if results 
within 24 months are available) 
10 
Normal or stable CT scan or MRI scan of the hypothalamic pituitary region on file 
11 
Prolactin and TSH within normal limits for the clinical laboratory at the Screening Visit 
12 
Male partner with normal semen analysis, including volume, liquefaction time, sperm 
count, and motility, according to the local laboratory normal criteria, within the past year 
13 
Normal TVUS at Screening with respect to uterus and adnexa (presence of both ovaries 
and tubes, without evidence of clinically significant abnormality) and with normal uterine 
cavity, normal cervix 
14 
Tube patency on saline tubal perfusion, hysterosalpingography or laparoscopy on file 
within the past 2 years 
15 
Willing and able to comply with the protocol for the duration of the study 
 
Exclusion Criteria:  
1 
Any medical condition that, in the judgment of the investigator, may interfere with the 
absorption, distribution, metabolism, or excretion of the drug 
2 
A history of or currently diagnosed with clinically important cardiovascular, pulmonary 
(e.g., serious corticosteroid-dependent asthma), gastrointestinal, hepatic, metabolic, renal, 
endocrinological (e.g., insulin-dependent diabetes mellitus), or neurological (e.g., 
epilepsy, serious migraine, central nervous system [CNS] lesions [in cases where HH is 
secondary to a CNS lesion or its treatment]) abnormality   
3 
A history of adrenal or uncontrolled thyroid disorders, or hyperprolactinemia 
4 
Prior treatment cycle with gonadotropins or GnRH within the last 2 months 
5 
Known allergy to study drug or its components 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
6 
Infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C 
7 
Ovarian enlargement or cyst of unknown etiology 
8 
Abnormal gynecological bleeding of undetermined origin 
9 
Previous or current hormone-dependent tumor 
10 
Known active substance abuse  
11 
Planning to undergo in vitro fertilization procedure in the course of a study treatment 
cycle 
12 
Currently undergoing treatment with gonadotropin hormones (FSH and LH), psychotropic 
medication, sex hormones, or any other medication known to interfere with normal 
reproductive function or that can affect GnRH secretion (e.g., neuroleptics, dopamine 
antagonists, spironolactone, levodopa, phenothiazine, digoxin) 
13 
Ongoing pregnancy or lactation 
14 
Participation in any experimental drug study within 30 days prior to screening 
15 
Previously randomized in this study 
16 
The patient is considered by the investigator to be unsuitable to participate in the trial for 
any other reason 
17 
The patient has a mental incapacity or language barrier precluding adequate understanding 
or cooperation. 
MEDICINAL PRODUCTS 
LutrePulse (gonadorelin acetate) for subcutaneous (SC) pulsatile injection via OmniPod System, 
delivering 10 μg, 15 μg, or 20 μg of GnRH or placebo per pulse every 90 minutes. 
Investigational Medicinal Product (IMP): 
• Lutrelef 3.2 mg, lyophilized powder for reconstitution 
• Solvent in vials of 10 ml for reconstitution of Lutrelef 3.2 mg, or to serve as placebo 
Non- Investigational Medicinal Product (NIMP): 
• Provera® (medroxyprogesterone acetate tablets, USP) 10 mg 
Device: 
• Delivery pump (OmniPod) for administration of IMP 
• Managers for programming of the delivery pump 
• Syringes, needles and adaptors used for reconstitution and loading of delivery pump 


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Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
DURATION OF TREATMENT 
LutrePulse (gonadorelin acetate) delivered via pulsatile injection every 90 minutes (1-minute 
delivery followed by an 89-minute gap) for a total of approximately 16 administrations over a 24-
hour period for up to approximately 7 weeks.  Duration of treatment depends on subject response; 
it is expected that follicular response to LutrePulse will occur within 2 to 3 weeks after therapy 
initiation.  However, the treatment may be continued for a maximum of 39 days at the discretion 
of the investigator if the patient has growing follicle(s).   Additionally, when ovulation occurs, 
therapy should be continued for approximately another 2 weeks to maintain corpus luteum 
function (continue until confirmatory serum pregnancy test).   
STATISTICAL METHODS 
Sample size:  
The sample size was determined based on the original fixed parallel group study design. The true 
ovulation rate for LutrePulse OmniPod SC 20 μg, 15 μg, 10 μg, and placebo was assumed to be 
70%, 65%, 60%, and 1%, respectively.  Under these assumptions, a sample size of 14 subjects 
per group (total 56 subjects) will provide at least 80% power to detect differences between 
LutrePulse OmniPod SC 20 μg and placebo, 15 μg and placebo, and 10 μg and placebo in 
ovulation rate separately  using stratified one-sided Fisher’s exact tests19 at an overall one-sided 
significance level of 0.025  with the closed testing procedure (Kong et al., 2005)18 to be used for 
the primary efficacy analysis.   
Approximately 60 subjects will be randomized, assuming up to 4 subjects may be ineligible for 
the full analysis set (FAS). 
Efficacy:  
The primary efficacy analysis will be based on all randomized subjects who received at least 14 
days of study drug for pituitary priming (i.e., FAS). 
The primary efficacy endpoint will be ovulation rate calculated as the proportion of subjects who 
had at least 1 post-baseline value of P4 level ≥ 6 ng/mL or pregnancy confirmed by a positive 
serum β-hCG (i.e., 2 positive results) or presence of a gestational sac documented by transvaginal 
ultrasound (TVUS).  A Bayesian adaptive design is adopted to address the following objectives: 
1. Demonstrate superiority of the pooled middle and high doses over placebo in the 
ovulation rate 
2. Evaluate the dose-response relationship 
The adaptive design includes two interim analyses, conducted after approximately 9 and 12 
patients per arm enrolling in the study, respectively. The interim analysis provides an opportunity 
for stopping the trial early due to efficacy success utilizing the group sequential strategy or due to 
efficacy futility through Bayesian predictive probability of success. Furthermore, it allows the 


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Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
low dose to be dropped following the interim look if it shows a much lower response rate 
compared with the middle and high doses.  
Each interim analysis will result in one of the following possible outcomes: 
1. Continue the trial with all arms 
2. Continue the trial without the low dose 
3. Declare early success, but continue the trial without placebo 
4. Declare early success and stop the trial (both placebo and low dose dropped) 
5. Stop the trial for futility 
When the primary efficacy analysis is not successful at the interim analysis, and if the ovulation 
rate in the low-dose arm is sufficiently low, satisfying 
                                           Rlow < (Rhigh +middle) – 0.2,                                                      (1) 
then the trial will continue without the low dose, resulting in outcome #2 listed above. Note that 
Rlow and Rhigh +middle in inequality (1) are the observed ovulation rates in the low dose arm and the 
combined middle- and high-dose arms, respectively. However, if inequality (1) is not satisfied, 
then the trial will continue with all arms (outcome #1 listed above).  
Conversely, when success on the primary efficacy analysis is declared at an interim analysis, if 
the response rate in the low-dose arm meets the condition in inequality (1), then the trial is 
completed at this point (outcome #4 listed above) with dose selection using the ED80 rule (see 
below).   
In the case the primary efficacy analysis is successful, but the response rate in the low-dose arm 
is within 20% from the combined low- and high-dose success rate, the trial is not stopped 
immediately. Rather, the trial will continue to enroll additional patients into the low-, middle- and 
high-dose arms to further assess dose responses.  
Finally, the trial may terminate (outcome #5 listed above) as a result of a low predictive 
probability of success (<0.05) given the data collected at the interim analysis.  
At the end of the study, for a trial that achieves efficacy success, the dose to be selected as the 
lowest effective dose is the ED80 dose, defined as the lowest dose that retains at least 80% of the 
largest treatment effect, i.e.  
                                  (RED80 – Rplacebo) ≥ (Rmaximum – Rplacebo) ×0.8,                                   (2) 
where Rmaximum is the observed ovulation rate in the most effective dose arm, Rplacebo is the 
observed ovulation rate in the placebo arm, and RED80 is the observed ovulation rate in the 
selected dose arm. 
The primary efficacy analysis will compare the pooled ovulation rate of LutrePulse OmniPod SC 
20 g and 15 g to placebo. Let Phigh+middle and Pplacebo be the underlying ovulation rates in the 
combined middle- and high-dose arms and the placebo arm, respectively. The hypotheses for the 
one-sided statistical testing are: 
 


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CONFIDENTIAL 
𝐻0: 𝑃ℎ𝑖𝑔ℎ+𝑚𝑖𝑑𝑑𝑙𝑒≤ 𝑃𝑝𝑙𝑎𝑐𝑒𝑏𝑜, 
vs. 
𝐻0:𝑃ℎ𝑖𝑔ℎ+𝑚𝑖𝑑𝑑𝑙𝑒> 𝑃𝑝𝑙𝑎𝑐𝑒𝑏𝑜. 
The hypotheses are tested using a stratified one-sided Fisher’s exact test (Jung et al., 2014) in the 
FAS including the randomization scheme as the stratification factor. The SAS PROC FREQ with 
permutation-based Cochran-Mantel-Haenszel test with exact p-value derived from all possible 
permutations will be employed for the calculation of p-value for the stratified Fisher’s exact test. 
To account for the multiplicities introduced by early success interim analyses, Pocock boundaries 
are used. Thus, the success threshold at each analysis corresponds to a nominal p-value < 0.0131 
to maintain an overall one-sided type I error rate of 0.025.  
Sensitivity analysis: 
• 
will be performed on the PPS  
• 
will be performed on the mITT 
For the secondary efficacy analyses, clinical and biochemical pregnancy rates will be compared 
between the pooled middle- and high-dose arms vs. the placebo arm using the same statistical 
method to be applied to the primary efficacy analysis.  Numbers of follicles with a mean diameter 
≥ 14 mm and dominant follicles with a mean diameter ≥18 mm will be compared using 
Wilcoxon’s rank sum test by stratifying based on the randomization scheme.  The maximum P 4 
level and the mean P4 level from Days 19, 21, 23, 25, and 27 values will be compared using an 
analysis of covariance (ANCOVA) model including the treatment group and randomization 
scheme as factors and mean baseline value as covariate.  The proportion of subjects with at least 
1 post-baseline progesterone (P4) level ≥ 10 ng/mL will be compared to placebo using the same 
statistical method to be applied to the primary efficacy analysis. The mean FSH and LH on Day 
10, as well as the change from baseline, will be compared using ANCOVA model including the 
treatment group and randomization scheme as factors and mean baseline value as covariate.  The 
E2 levels on Day 10, as well as the change from baseline, will be compared using a similar 
ANCOVA model.  The change in the maximum value of FSH, LH, and E2 levels on Day 1 and 
Day 10 from the first value taken on Day 1 and Day 10, respectively, will be presented with 
descriptive statistics by treatment group.  The FSH, LH, and E2 levels on Day 1 and Day 10 will 
be presented graphically by treatment group. 
Safety:  
Safety parameters will be summarized by treatment group for all subjects who received at least 1 
pulsatile injection delivery of study drug. 


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TABLE OF CONTENTS 
 
Page 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
17 
1 
INTRODUCTION 
19 
1.1 
Background .............................................................................................................19 
1.2 
Scientific Justification for Conducting the Study ...........................................................20 
2 
STUDY OBJECTIVES AND ENDPOINTS 
21 
3 
INVESTIGATIONAL PLAN AND STUDY DESIGN 
23 
3.1 
Overall Design and Plan – Description.........................................................................23 
3.2 
Number of Centers and Subjects .................................................................................26 
3.3 
Discussion of Study Design and Choice of Control Groups .............................................26 
4 
SELECTION OF STUDY POPULATION 
27 
4.1 
Inclusion Criteria......................................................................................................27 
4.2 
Exclusion Criteria .....................................................................................................28 
4.3 
Prior and Concomitant Therapies ................................................................................29 
4.4 
Withdrawal Criteria ..................................................................................................29 
4.5 
Subject Replacement .................................................................................................29 
5 
TREATMENTS 
30 
5.1 
Treatments Administered ...........................................................................................30 
5.1.1 
Investigational Medicinal Product (IMP) .......................................................... 30 
5.1.2 
Non-Investigational Medicinal Product (NIMP) ................................................. 32 
5.2 
Packaging and Labeling.............................................................................................32 
5.2.1 
Investigational Medicinal Product.................................................................... 33 
5.2.2 
Non-Investigational Medicinal Product............................................................. 33 
5.3 
Conditions for Storage and Use...................................................................................33 
5.4 
Blinding / Unblinding................................................................................................34 
5.4.1 
Blinding ...................................................................................................... 34 
5.4.2 
Unblinding of Individual Subject Treatment ...................................................... 35 
5.5 
Selection of Doses in the Study...................................................................................36 
5.6 
Treatment Compliance ..............................................................................................37 
5.6.1 
Dispensing and Accountability ........................................................................ 37 
5.6.2 
Assessment of Compliance ............................................................................. 37 
5.7 
Auxiliary Supplies ....................................................................................................37 
5.8 
Return and Destruction of Medicinal Products and Auxiliary Supplies ..............................37 
6 
STUDY FLOW CHART AND STUDY PROCEDURES 
39 
6.1 
Schedule of Activities ...............................................................................................39 
6.2 
Study Procedures......................................................................................................42 
6.2.1 
Screening/Pre-treatment ................................................................................. 42 
6.2.2 
Treatment Day 1 through Day 10..................................................................... 43 
6.2.3 
Treatment Day 11 until LH Surge .................................................................... 44 
6.2.4 
Progesterone and Pregnancy Monitoring........................................................... 45 
7 
STUDY ASSESSMENTS 
48 


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7.1 
Pharmacodynamic Assessments ..................................................................................48 
7.2 
Transvaginal Ultrasound ............................................................................................48 
7.3 
Detection of LH Surge ..............................................................................................49 
7.4 
Progesterone Evaluations ...........................................................................................49 
7.5 
Pregnancy Assessments .............................................................................................49 
7.5.1 
Serum Pregnancy Tests .................................................................................. 49 
7.5.2 
Pregnancy and Pregnancy Outcome ................................................................. 49 
7.6 
Safety Assessments...................................................................................................49 
7.6.1 
Medical History ............................................................................................ 49 
7.6.2 
Physical and Gynecological Examination.......................................................... 50 
7.6.3 
Vital Signs ................................................................................................... 50 
7.6.4 
ECG Evaluation............................................................................................ 50 
7.6.5 
Clinical Laboratory Tests ............................................................................... 50 
7.6.6 
Ovarian Hyperstimulation Syndrome Monitoring ............................................... 52 
7.7 
Concomitant Medications ..........................................................................................53 
8 
ADVERSE EVENTS AND UNANTICIPATED ADVERSE DEVICE EFFECTS 
54 
8.1 
Adverse Event Definition...........................................................................................54 
8.2 
Collection and Recording of Adverse Events ................................................................54 
8.2.1 
Collection of Adverse Events .......................................................................... 54 
8.2.2 
Recording of Adverse Events .......................................................................... 55 
8.3 
Serious Adverse Events .............................................................................................58 
8.3.1 
Serious Adverse Event Definition .................................................................... 58 
8.3.2 
Collection, Recording and Reporting of Serious Adverse Events .......................... 60 
8.4 
Follow-up of Adverse Events and Serious Adverse Events ..............................................61 
8.4.1 
Follow-up of Adverse Events with Onset during the Trial.................................... 61 
8.4.2 
Collection of Serious Adverse Events with Onset after Last Visit ......................... 61 
8.5 
Unanticipated Adverse Device Effects .........................................................................61 
9 
STATISTICAL METHODS 
62 
9.1 
Determination of Sample Size ....................................................................................62 
9.2 
Subject Disposition ...................................................................................................62 
9.3 
Protocol Deviations ..................................................................................................62 
9.4 
Analysis Sets ...........................................................................................................62 
9.4.1 
Intent-to-Treat (ITT) Analysis Set.................................................................... 62 
9.4.2 
Full Analysis Set (FAS) ................................................................................. 62 
9.4.3 
Modified Intent-to-Treat (mITT) Analysis Set ................................................... 62 
9.4.4 
Per Protocol Set (PPS) ................................................................................... 63 
9.4.5 
Safety Population .......................................................................................... 63 
9.5 
Trial Population .......................................................................................................63 
9.5.1 
Demographic and Baseline Characteristics ........................................................ 63 
9.5.2 
Medical History and Concomitant Medications.................................................. 63 
9.6 
Efficacy Endpoint Assessments ..................................................................................63 
9.6.1 
General Considerations .................................................................................. 63 
9.6.2 
Primary Efficacy Endpoint ............................................................................. 64 
9.6.3 
Secondary Efficacy Endpoints......................................................................... 65 


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9.7 
Extent of Exposure ...................................................................................................66 
9.8 
Safety Analysis ........................................................................................................66 
9.8.1 
General Considerations .................................................................................. 66 
9.8.2 
Adverse Events............................................................................................. 66 
9.8.3 
Clinical Laboratory Variables ......................................................................... 66 
9.9 
Interim Analyses ......................................................................................................67 
10 
DATA HANDLING 
68 
10.1 
Source Data and Source Documents ............................................................................68 
10.2 
eCRF ......................................................................................................................69 
10.3 
Data Management.....................................................................................................70 
10.4 
Provision of Additional Information ............................................................................70 
11 
MONITORING PROCEDURES 
71 
11.1 
Periodic Monitoring ..................................................................................................71 
11.2 
Audit and Inspection .................................................................................................71 
11.3 
Confidentiality of Subject Data ...................................................................................71 
12 
CHANGES IN THE CONDUCT OF THE TRIAL 
72 
12.1 
Protocol Amendments ...............................................................................................72 
12.2 
Deviations from the Protocol ......................................................................................72 
12.3 
Premature Trial Termination ......................................................................................72 
13 
REPORTING AND PUBLICATION 
73 
13.1 
Clinical Trial Report .................................................................................................73 
13.2 
Confidentiality and Ownership of Trial Data.................................................................73 
13.3 
Publications and Public Disclosure ..............................................................................73 
13.3.1 Publication Policy ......................................................................................... 73 
13.3.2 Public Disclosure Policy ................................................................................ 73 
14 
ETHICAL AND REGULATORY ASPECTS 
74 
14.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ........................74 
14.2 
Regulatory Authorities Authorization / Approval / Notification .......................................74 
14.3 
End-of-Trial and End-of-Trial Notification ...................................................................74 
14.4 
Ethical Conduct of the Trial .......................................................................................74 
14.5 
Subject Information and Consent ................................................................................74 
14.6 
Compliance Reference Documents ..............................................................................75 
15 
LIABILITIES AND INSURANCE 
76 
15.1 
ICH-GCP Responsibilities .........................................................................................76 
15.2 
Liabilities and Insurance ............................................................................................76 
16 
ARCHIVING 
77 
16.1 
Investigator File .......................................................................................................77 
16.2 
Trial Master File.......................................................................................................77 
17 
REFERENCES 
78 
18 
APPENDICES 
80 
 


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List of Tables 
Table 1 
Schedule of Activities................................................................................................40 
Table 2 
Classification of Mild, Moderate and Severe OHSS....................................................52 
 
List of Figures 
Figure 1: The OmniPod Drug Delivery System ............................................................................32 
 
Appendices 
Appendix I – Subject’s Confidential Non-Disclosure Affidavit .....................................................80 
Appendix II – Subject Diary Card................................................................................................81 
 


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CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
Meaning of abbreviations in document 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
anatomical-therapeutic-chemical 
-hCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
E2 
estradiol 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FHM 
fetal heart movement 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
HCP 
Healthcare Professional 
HH 
hypogonadotropic hypogonadism 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
ICMA 
immunochemiluminometric assay 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
intravenous 
LSLV 
last subject last visit 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NIMP 
Non-Investigational Medicinal Product 
OHSS 
ovarian hyperstimulation syndrome 
P4 
progesterone 
PAP 
Papanicolaou 
PD 
pharmacodynamic 
PPS 
Per Protocol Set 


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Ferring Pharmaceuticals 
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Abbreviations 
Meaning of abbreviations in document 
PRL 
prolactin 
PT 
preferred term 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
TVUS 
transvaginal ultrasound 
UADE 
unanticipated adverse device effect 
US 
United States 
 


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1 
INTRODUCTION 
1.1 
Background 
Pulsatile gonadotropin-releasing hormone (GnRH) has been widely used in the United States (US) 
and Europe for over 25 years, with an estimated 12,000 cases treated annually.  It has an excellent 
safety record and a high degree of effectiveness in treating primary hypothalamic amenorrhea and 
in inducing ovulation and pregnancy in a variety of infertile patients.  Pulsatile GnRH is safer than 
other parenteral preparations and has a much lower incidence of inducing multiple pregnancies or 
ovarian hyperstimulation than other therapies such as anti-estrogens or gonadotropins.1,2  
Hypogonadotropic hypogonadism (HH), characterized by inappropriately low serum concentrations 
of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the setting of 
hypogonadism, may be amenable to treatment with GnRH.   
Several investigations utilizing subcutaneous (SC) administration of GnRH, including 
pharmacokinetic studies conducted by Ferring, showed favorable GnRH and LH profiles and 
ovulation and pregnancy rates comparable to intravenous (IV) regimens.3,4,5,6,7  Favorable results 
were obtained in women with hypothalamic amenorrhea, with pregnancy rates comparable to those 
achieved with exogenous gonadotropins, with a much lower risk of ovarian hyperstimulation and 
multiple pregnancy.  When a physiological replacement regimen of pulsatile GnRH is used, a high 
rate of ovulation and conception can be anticipated in women with complete GnRH deficiency and 
hypothalamic amenorrhea.8 
Gonadorelin acetate is a synthetic decapeptide that is identical in amino acid sequence to 
endogenous GnRH synthesized in the human hypothalamus and in various neurons terminating in 
the hypothalamus.  Therapeutic pulsatile GnRH for treatment of primary hypothalamic amenorrhea 
was first approved in Europe as Lutrelef® in 1983 and as LutrePulse™ in the US in 1989 and in 
Canada in 1993 with different pumps. 
LutrePulse (gonadorelin acetate) was approved in the US for use in patients with primary 
hypothalamic amenorrhea administered IV via the Zyklomat® pump, but was later withdrawn from 
the market for commercial reasons.  Therefore, no approved GnRH product is currently available 
for ovulation induction and treatment of primary hypothalamic amenorrhea patients in the US.  
LutrePulse (known as Lutrelef) with OmniPod for subcutaneous use was approved in France 
(2009), Netherlands (2010) and Germany (2011) to treat both men and women with GnRH 
deficiency or GnRH impairment.  In 2012, LutrePulse (gonadorelin acetate) with the OmniPod 
device for subcutaneous administration was also approved and re-introduced in Canada for 
ovulation induction in patients with primary hypothalamic amenorrhea. 
The OmniPod® pump is a disposable SC delivery pump for LutrePulse with a hand-held wireless 
controller (the Manager).9  The OmniPod has been demonstrated to provide similar volume and 
similar bolus/pulse accuracy as the Zyklomat IV pump (data on file).  In addition, the stability of 


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CONFIDENTIAL 
LutrePulse solution over the intended period of use was demonstrated for the OmniPod pump (data 
on file).  Compared to the IV pumps, the OmniPod SC pump with LutrePulse (Gonadorelin Acetate) 
represents a technologically advanced and more patient-friendly solution for pulsatile drug delivery.  
If a successful efficacy and safety profile is established for GnRH with the OmniPod, this will 
address the current unmet need in the very rare population of patients with HH in the US. 
1.2 
Scientific Justification for Conducting the Study 
There is an unmet medical need for a replacement GnRH treatment of patients with primary 
hypothalamic amenorrhea in the US.  Good results for ovulation induction, with similar ovulation 
results, have been previously reported in the literature for two IV doses of pulsatile GnRH 
administered to GnRH-deficient women:  75 ng/kg (~3-4 µg/pulse) and 100 ng/kg (~5 µg/pulse).8  
The recommended GnRH dose for primary hypothalamic amenorrhea women in the previously 
approved label for LutrePulse with IV pump was 5 µg IV every 90 minutes, which could be 
increased up to 20 µg in stepwise fashion if there was no response.  The efficacy and safety of 10 
and 20 µg/pulse administered SC in terms of ovulation induction were studied and published in 
literature in the past (See Section 5.5 for more details) but there is currently a need for a well-
powered and well-controlled, randomized clinical trial to confirm the efficacy and safety profile of 
LutrePulse with OmniPod subcutaneous delivery pump.   
In addition to the 10 and 20 µg/pulse doses, an intermediate dose of 15 µg/pulse has been added to 
better understand the dose range.  This study is expected to provide much needed efficacy and 
safety information in this very rare HH population of patients. 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective 
• To compare the ovulation rate in women with primary amenorrhea with hypogonadotropic 
hypogonadism (HH) following each of three doses (10 g, 15 g, and 20 g per pulse) of 
subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) administered with the 
LutrePulse OmniPod Pump versus placebo  
Secondary Objectives 
• To evaluate clinical pregnancy rate  
• To evaluate biochemical pregnancy rate 
• To evaluate LH surge rate  
• To evaluate ovarian follicular development  
• To evaluate luteal phase support with GnRH 
• To evaluate pharmacodynamic parameters  
• To evaluate the safety of LutrePulse OmniPod SC 
Primary Endpoint  
• Ovulation rate, calculated as a proportion of subjects with at least 1 post-baseline 
progesterone (P4) level ≥ 6 ng/mL or a confirmed positive serum β-hCG (i.e., 2 positive 
results) or presence of a gestational sac documented by transvaginal ultrasound (TVUS) 
Secondary Endpoints 
Progesterone levels: 
• Proportion of subjects with at least 1 post-baseline P4 level ≥ 10 ng/mL 
 
Pregnancy: 
 
 
Clinical pregnancy rate: 
• 
Proportion of subjects with presence of gestational sac and fetal heart movement 
(FHM) on transvaginal ultrasound (TVUS) at approximately 2 to 4 weeks after 
second positive serum beta human chorionic gonadotropin (-hCG) test 
 
 
Biochemical pregnancy rate:  
• 
Proportion of subjects with a confirmed positive (i.e., 2 positive results) serum 
-hCG 14 + 4 days post LH surge  


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LH Surge Detection:  
• Proportion of subjects with a positive detection of LH surge on a Clearblue test 
Ovarian Follicular Development:  
• Number of follicles with a mean diameter ≥ 14 mm 
• Number of dominant follicles with a mean diameter ≥ 18 mm 
 
Luteal Phase Support: 
• Maximum P4 levels from Days 19, 21, 23, 25, and 27  
• Mean P4 levels from Days 19, 21, 23, 25, and 27  
 
Pharmacodynamic (PD) Endpoints: 
• FSH and LH change from baseline in relation to the first GnRH pulse on Day 1 and Day 
10  
• Mean serum FSH and LH levels on Day 1 and Day 10 
• Estradiol (E2) serum levels on Day 1 and Day 10 
 
Safety Endpoints: 
• Adverse events (type, frequency, intensity, and seriousness) 
• Clinical chemistry, hematology, urinalysis 
• Frequency and severity of ovarian hyperstimulation syndrome (OHSS) 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
3 
 INVESTIGATIONAL PLAN AND STUDY DESIGN 
3.1 
Overall Design and Plan – Description  
This multicenter, randomized, double-blind, placebo-controlled study will be performed in 
approximately 60 women with primary amenorrhea with HH who desire pregnancy.  The treatment 
duration with LutrePulse OmniPod SC or placebo can be approximately 7 weeks.  It is expected that 
the response to treatment will occur within 2 to 3 weeks after therapy initiation.  When LH surge is 
detected by LH urine kit test, therapy should be continued for approximately another 2 weeks to 
maintain corpus luteum function (continue until confirmatory serum pregnancy test).  Subjects will 
discontinue treatment either at the onset of menses or after having two (2) negative or two (2) 
positive confirmatory serum pregnancy tests.  Subjects will be required to return to the study site for 
pharmacodynamic blood draws, TVUS, serum pregnancy tests, and safety follow-up assessments. 
The study will consist of 3 periods: Screening (includes progestin challenge test), Treatment 
(includes pituitary priming up to 14 days and treatment phase), and Follow-up. 
Screening (Day -60 to Day -1): Only subjects with diagnosed primary amenorrhea with HH should 
be screened for this trial.  Only subjects who desire pregnancy will be eligible to participate in this 
trial. 
The site will obtain written informed consent before any study-related procedures begin.  Upon 
signing the Informed Consent Form, subjects will be screened based on inclusion/exclusion criteria.  
The assessments during the screening period will include medical/gynecologic history, safety 
laboratory tests (chemistry, hematology, urinalysis), other laboratory tests (serum pregnancy, LH, 
FSH, E2, P4, prolactin [PRL], and thyroid-stimulating hormone [TSH] levels), vital signs (blood 
pressure, heart rate, body temperature), Papanicolaou (PAP) smear (if not done within the last 
24 months; PAP smear may be performed at Screening and for every patient if warranted, per 
investigator discretion), TVUS documenting normal uterus and adnexa, and a 
physical/gynecological examination.  A normal or stable computed tomography (CT) scan or 
magnetic resonance imaging (MRI) scan of the hypothalamic pituitary region must be on file to 
exclude other causes for the disease.  The male partner should have a documented recent normal 
semen analysis (within 1 year).  A progestin challenge test will be initiated to confirm HH.   
Rescreening will be allowed at the investigators’ discretion for subjects who exhibit laboratory tests 
outside of the normal or required range.  No subject may be rescreened more than once.  
Rescreening for the progestin challenge test is not allowed. 


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Progestin challenge test:  After confirmed negative serum pregnancy test, subjects will be 
dispensed 10 mg of medroxyprogesterone acetate (Provera®)10 once daily for 10 days.  Subjects 
who do not have uterine bleeding 5 days after the last dose of progestin will continue to the 
treatment period.  Per investigator’s discretion, occasional spotting is not considered withdrawal 
bleeding.  Subjects with uterine bleeding are considered screen failures and will be ineligible for 
study participation.  Rescreening for the progestin challenge test is not allowed. 
Treatment (Day 1 to approximately Day 37): Subject who do not have uterine bleeding within 
5 days after the last dose of progestin will return to the clinic; a negative urine pregnancy test result 
is required and then the subject will be randomly assigned to 1 of 4 treatment arms: LutrePulse 
OmniPod SC 10 μg/pulse, 15 μg/pulse, 20 μg/pulse, or placebo (10, 15, and 20 μg/pulse delivery 
setting) every 90 minutes.   
Subjects will be instructed on the application of the OmniPod pump (See Instructions for Use 
[IFU]).11,12  The first OmniPod pump will be applied on Day 1.  Each OmniPod pump will be worn 
for 3 days (Days 1-3, 4-6, 7-9, etc. to approximately Day 37).  The subject will apply subsequent 
OmniPod pumps every 4th day at approximately the same time as the first application (±1 hour).   
Pharmacodynamic (PD) assessments:  A blood sample for E2, LH and FSH will be taken on Day 1 
(pretreatment baseline) prior to dosing.  Additional blood samples for only LH and FSH will be 
taken 5, 15, 30, 60, and 90 minutes after the first dose is administered.   
A blood sample for E2, LH and FSH will be taken on Day 10 at the same time as the Day 1 initial 
sample (±1 hour) and before the first dose is administered by the Day 10 pump.  Additional blood 
samples for only LH and FSH will be taken 5, 15, 30, 60, and 90 minutes after the first dose is 
administered.   
Follicular and endometrial development: Follow-up will begin on Day 10 of treatment.  
Follicular and endometrial development will be monitored by TVUS every other day or per the 
investigator’s discretion (minimum of 3 TVUS), until a dominant follicle of ≥ 18 mm mean 
diameter and normal endometrium (thickness and pattern) are confirmed.  If a dominant follicle ≥ 
18 mm mean diameter is not observed after 21 full days of treatment, the therapy will be 
discontinued.  However, the treatment may be continued for a maximum of 39 days at the discretion 
of the investigator if the patient has growing follicle(s).  After Day 10, a single blood sample for E2 
assessment will be collected each time the subject returns for TVUS.  A subject who has an 
increased risk of developing multiple gestation/OHSS (4 or more follicles with a mean diameter ≥ 
15 mm by TVUS and E2 levels ≥ 1200 pg/mL) will be discontinued from treatment. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
LH surge detection with Clearblue® digital ovulation urine test 13 will begin when follicles with a 
mean diameter ≥ 14 mm are documented on TVUS.  The Clearblue test will be administered daily, 
between 8 and 11 AM at approximately the same time each morning, until a positive test result 
occurs.  Subjects should document the date of their first Clearblue test and the date of their first 
positive test result on the subject diary card (Appendix II). The subject should notify the site 
immediately once the surge has been detected to schedule a visit within 72 hours for confirmatory 
TVUS.  Subjects will be advised to engage in sexual intercourse on the day of LH surge, the day 
following LH surge, and per investigator’s discretion thereafter.  The subject should also document 
the date(s) of sexual intercourse on the subject diary card. 
If LH surge is not detected after 21 full treatment days, the subject will be discontinued.  However, 
the treatment may be continued for a maximum of 39 days at the discretion of the investigator if the 
patient has growing follicle(s).  The subject will be instructed to visit the site to return all study drug 
and the OmniPod System. 
Blood samples for progesterone (P4) levels: A single blood sample for P4 will be taken on Day 1 
(pre-treatment baseline) prior to dosing.  Blood samples will also be obtained on Day 19, Day 21, 
Day 23, Day 25, and Day 27 after initiation of study drug.  For subjects who have discontinued the 
study early and ended treatment on or after Day 14, a blood sample will also be taken at the End-of-
Study Visit.  
Menses Onset:  Subjects who begin menstruating after treatment was initiated will be instructed to 
stop the treatment and to visit the site to return all study drug and the OmniPod System.  The site 
will record the first day of menses and duration of menses for all non-pregnant subjects.  
Serum pregnancy tests (-hCG): will be performed 14 days (+ 4 days) after LH surge and 3 days 
thereafter.  Two positive pregnancy tests are required to confirm biochemical pregnancy.  If only 
one of the 2 tests is positive, the subject will return within 5 days (unscheduled visit) to confirm 
pregnancy with another test.   
After obtaining two (2) negative or two (2) positive confirmed serum pregnancy test results, the 
treatment will complete.     
All subjects will be assessed for an End-of-Study visit and return all study drug and the OmniPod 
System. 
 
 
 


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CONFIDENTIAL 
Follow-up:  
TVUS for pregnancy outcome:  Subjects who achieve pregnancy (2 positive serum pregnancy tests) 
will be followed up for clinical pregnancy (gestational sac and fetal heart movement) 2 to 4 weeks 
after second positive pregnancy test and will complete an End-of-Study visit the day of documented 
fetal heart movement on TVUS.  If the fetal heartbeat is not detected, the subject will return within 
7 days for a follow-up ultrasound to confirm fetal heartbeat.  Sites will contact these subjects to 
collect data for ongoing pregnancy rate (fetal heart movement at gestational Week 11 or Week 12), 
including safety follow-up of the subjects for miscarriage, fetal anomalies and live birth rate.  
3.2 
Number of Centers and Subjects 
The study will be conducted in approximately 50 sites in the United States and Canada.  
Approximately 60 female subjects will be randomized. 
3.3 
Discussion of Study Design and Choice of Control Groups 
This is a multicenter, randomized, double-blind, placebo-controlled trial.  Subjects with primary 
amenorrhea with HH will be treated with 1 of 3 doses of pulsatile GnRH, or placebo, administered 
SC via the OmniPod pump manufactured by Insulet. 
The three active dose regimens of GnRH and placebo will be administered using indistinguishable 
vials to maintain the blind.  Insulet is a leader in wearable insulin pump technology with its 
OmniPod Insulin Management System.  The OmniPod Insulin Management System, a 
revolutionary, discreet and easy-to-use insulin infusion system, features 2 easy-to-use parts with no 
tubing and fully automated cannula insertion.  Insulet worked with Ferring Pharmaceuticals to 
develop a system for the delivery of gonadorelin acetate.  A custom version of the OmniPod's 
Personal Diabetes Manager was developed, which was the first non-diabetes drug delivery 
application for the OmniPod System.  The OmniPod System is expected to be an effective platform 
technology for the delivery of various drugs that require continuous or frequent infusions, including 
GnRH. 


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CONFIDENTIAL 
4 
SELECTION OF STUDY POPULATION 
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible for the study: 
1. 
Signed written informed consent prior to any study-related procedure 
2. 
Women 18 - 40 years old 
3. 
Body mass index (BMI) between 18 and 38 kg/m2 
4. 
Documented clinical history or recently diagnosed with primary amenorrhea with 
hypogonadotropic hypogonadism 
5. 
Hormonal values in a centrally analyzed fasting blood sample: FSH < 5 IU/L and mean 
LH < 5 IU/L 
6. 
Desire to become pregnant 
7. 
Discontinued estrogen-progesterone replacement therapy at least 1 month before 
screening   
8. 
Negative progestin challenge test performed during screening 
9. 
Normal PAP smear within 24 months of the initial visit (PAP smear can be performed at 
Screening, per investigator discretion and standard of practice if warranted, even if 
results within 24 months are available) 
10. 
Normal or stable CT scan or MRI scan of the hypothalamic pituitary region on file 
11. 
Prolactin and TSH within normal limits for the clinical laboratory at the Screening Visit 
12. 
Male partner with normal semen analysis, including volume, liquefaction time, sperm 
count, and motility, according to the local laboratory normal criteria, within the past 
year 
13. 
Normal TVUS at Screening with respect to uterus and adnexa (presence of both ovaries 
and tubes, without evidence of clinically significant abnormality) and with normal 
uterine cavity, normal cervix  
14. 
Tube patency on saline tubal perfusion, hysterosalpingography or laparoscopy on file 
within the past 2 years 
15. 
Willing and able to comply with the protocol for the duration of the study 
 
 
 
 
 


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4.2 
Exclusion Criteria 
The presence of any of the following excludes a subject from study enrollment: 
1. 
Any medical condition that, in the judgment of the investigator, may interfere with the 
absorption, distribution, metabolism, or excretion of the drug 
2. 
A history of or currently diagnosed with clinically important cardiovascular, pulmonary 
(e.g., serious corticosteroid-dependent asthma), gastrointestinal, hepatic, metabolic, 
renal, endocrinological (e.g., insulin-dependent diabetes mellitus), or neurological (e.g., 
epilepsy, serious migraine, CNS lesions [in cases where HH is secondary to a CNS 
lesion or its treatment]) abnormality   
3. 
A history of adrenal or uncontrolled thyroid disorders or hyperprolactinemia 
4. 
Prior treatment cycles with gonadotropins or GnRH within the last 2 months 
5. 
Known allergy to study drug or its components 
6. 
Infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C 
7. 
Ovarian enlargement or cyst of unknown etiology 
8. 
Abnormal gynecological bleeding of undetermined origin 
9. 
Previous or current hormone-dependent tumor 
10. 
Known active substance abuse  
11. 
Planning to undergo in vitro fertilization procedure in the course of a study treatment 
cycle 
12. 
Currently undergoing treatment with gonadotropin hormones (FSH and LH), 
psychotropic medication, sex hormones, or any other medication known to interfere 
with normal reproductive function or that can affect GnRH secretion (e.g., neuroleptics, 
dopamine antagonists, spironolactone, levodopa, phenothiazine, digoxin) 
13. 
Ongoing pregnancy or lactation 
14. 
Participation in any experimental drug study within 30 days prior to screening 
15. 
Previously randomized in this study 
16. 
The patient is considered by the investigator to be unsuitable to participate in the trial 
for any other reason 
17. 
The patient has a mental incapacity or language barrier precluding adequate 
understanding or cooperation.  
 
 
 
 
 


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4.3 
Prior and Concomitant Therapies 
Use of any medication other than study medication provided for this study should be avoided from 
the Screening/Pre-treatment Period until the completion of the study.   
Details of all concomitant medications (and other therapies) including the main reason for their 
prescription must be recorded in the medical source data and the electronic case report form (eCRF) 
for all eligible patients within 14 days of the Screening Visit until the completion of the study.  This 
information should include name of the drug, route of administration, indication, and duration of 
treatment. Any changes (including new therapies) must be recorded at each subsequent trial visit. 
4.4 
Withdrawal Criteria 
Every subject has the right to refuse further participation in the study at any time and without 
providing a reason(s).  A subject’s participation is to terminate immediately upon her request.  The 
investigator should seek to obtain the reason(s) if possible and record this in the eCRF. 
If, at the time of refusal, a dose of the investigational product has already been administered, the 
subject must be advised to agree to follow-up safety investigations, which will include all 
procedures outlined in the End-of-Study Visit. Any early term subjects should complete this visit 
within 3 days of discontinuation.   
A subject may be withdrawn from the study at any time at the discretion of the investigator; the 
reason should be discussed with the sponsor prior to discontinuing the subject and the reason fully 
documented in the eCRF.  Should the subject, during the course of the study, develop conditions 
that would have prevented her entry into the study according to the exclusion criteria, she must be 
withdrawn immediately.   
A subject who has an increased risk of developing multiple gestation/OHSS (4 or more follicles 
with a mean diameter ≥ 15 mm by TVUS and E2 levels ≥ 1200 pg/mL) will be discontinued from 
treatment.   
In addition, any clinically important adverse physical or symptomatic findings/events and/or 
abnormal laboratory findings that are above the pre-specified critical values defined in the 
laboratory manual will be grounds for discontinuation from the study.    
Subjects who do not become pregnant following treatment (2 negative serum pregnancy tests) will 
be discontinued from the study and must complete an End-of-Study Visit on the day of the second 
negative serum pregnancy test. 
4.5 
Subject Replacement 
Subjects discontinued from the study will not be replaced. 


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CONFIDENTIAL 
5 
TREATMENTS 
5.1 
Treatments Administered 
5.1.1 
Investigational Medicinal Product (IMP) 
Subjects will be randomly assigned to 1 of 4 treatment arms:  
• LutrePulse OmniPod SC 10 μg/pulse as a fixed dose (Test Product) 
• LutrePulse OmniPod SC 15 μg/pulse as a fixed dose (Test Product) 
• LutrePulse OmniPod SC 20 μg/pulse as a fixed dose (Test Product) 
• Placebo (10, 15, or 20 μg/pulse as a fixed “dose”)    
Subjects will receive consecutive pulses of GnRH or placebo, each delivered at 90-minute intervals, 
for approximately 37 days of treatment.  Each OmniPod will be worn for 3 full days (Days 1-3, 4-6, 
7-9, etc. to approximately Day 37) and will be replaced every 4th day (i.e., Day 4, Day 7, Day 10, 
etc.).  New OmniPod pumps should be applied at approximately the same time as the first pump 
(±1 hour). 
Test Product - LutrePulse (gonadorelin acetate)  
LutrePulse is a white lyophilized powder that is highly soluble in water and is intended for SC 
pulsatile injection with the OmniPod pump after reconstitution.  LutrePulse is manufactured by the 
sponsor.  Each vial with 13.2 mg powder contains 3.2 mg of lyophilized gonadorelin acetate, 
equivalent to 2.91 mg gonadorelin; each vial with 10 mL solvent (pH 4.0 – 5.0) contains sodium 
chloride, water for injection, and hydrochloric acid 10%.  Randomized fixed doses of either 10 μg, 
15 μg, or 20 μg will be programmed into the OmniPod Manager and subcutaneously delivered to 
the subject.  For every 10 μg, 15 μg, or 20 μg dose, the subject will receive 10 μL, 15 μL, or 20 μL 
amount of volume with the same concentration of drug per pulsatile injection. 
Test Product – Placebo   
The placebo product is a vial with solvent (pH 4.0 – 5.0) containing sodium chloride, water for 
injection, and hydrochloric acid 10%.  Placebo is manufactured by the sponsor.  Each vial of 
placebo will appear similar to the LutrePulse 3.2 mg reconstituted vials. Randomized fixed doses to 
match 10 μg, 15 μg, or 20 μg will be programmed into the OmniPod Manager and subcutaneously 
delivered to the subject.  Placebo doses will be the same amount of volume respectively, either 10, 
15 μg, or 20 μg/pulse, as the LutrePulse OmniPod dose without active drug substance.   


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CONFIDENTIAL 
Drug Delivery System 
The OmniPod Drug Delivery system is a disposable delivery pump (OmniPod) with a handheld 
wireless controller (the Manager) for SC drug delivery (see Figure 1).  The OmniPod is a discreet 
and easy-to-use delivery pump featuring two parts, with no tubing and fully automated cannula 
insertion manufactured by Insulet Corporation (located at 9 Oak Park Dr., Bedford, MA, US).  A 
custom version of the originally developed OmniPod's Manager (wireless controller for insulin 
delivery) was subsequently modified for use with LutrePulse. 
The OmniPod is a small (1.530” wide × 2.055” long × 0.575” high), lightweight (< 1.1 oz.), self-
adhesive device filled with LutrePulse or placebo and worn directly on the body.  The OmniPod 
delivers precise doses of LutrePulse or placebo through a small flexible subcutaneous cannula, 
based on instructions programmed into its wireless controller, the Drug Delivery Manager.  The 
deliverable reservoir volume is 2000 μL.  The cannula insertion depth is between 6 and 7 mm at 
≤ 50° insertion angle when measured from the perpendicular axis to the skin, and the cannula is 
inserted only once with each OmniPod. 
The OmniPod’s adhesive keeps it securely in place for up to 3 days.  Body lotion, creams, or oils 
should not be used near the infusion site, as these products may loosen the adhesive.  The infusion 
site should be changed each time a new OmniPod is applied; the new site should be at least 1 inch 
away from the last site.  To avoid infusion-site infection, subjects will be instructed to use an aseptic 
technique such as an alcohol swab to prepare the infusion site before applying an OmniPod. 
The Manager is a wireless, handheld device that programs the OmniPod with the subject’s 
LutrePulse or placebo delivery instructions and wirelessly monitors the OmniPod’s operation.  The 
Manager is 2.5” wide × 4.5” long × 1.0” high, and it weighs 4.4 oz. with batteries.  The Manager is 
powered by 2 AAA alkaline batteries that have a battery life of approximately 3 weeks. Additional 
batteries will be supplied in order to cover the entire trial length.   
With its two parts, OmniPod provides all the functionality and benefits of continuous pulsatile drug 
delivery.  In addition, OmniPod provides safety, convenience, and freedom, with no tubing, no 
record keeping, and automated cannula insertion. 


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The OmniPod is applied to the skin with an 
adhesive backing, similar to an adhesive bandage. 
        The Manager 
Figure 1: The OmniPod Drug Delivery System 
 
More detailed characteristics of the investigational product, dosage and administration can be found 
in the Investigator’s Brochure.14  An abbreviated version of the LutrePulse User Guide for the 
OmniPod Pump9 is provided in the LutrePulse™ Healthcare Professional (HCP) Quick Reference 
Guide and LutrePulse™ Guide for the Patient.11, 12 
5.1.2 
Non-Investigational Medicinal Product (NIMP) 
During the progestin challenge, subjects will be dispensed 10 mg medroxyprogesterone acetate 
(Provera®) for oral administration, a derivative of progesterone used to induce menstrual onset.  
Provera 10 mg tablets will be dispensed via prescription in the US.  For Canada, Provera will be 
provided by Ferring as either 5 mg (2) tablets or 10 mg tablets.   
More detailed characteristics can be found in the package insert for medroxyprogesterone acetate.10  
5.2 
Packaging and Labeling 
Packaging and labelling of the medicinal products will be performed under the responsibility of the 
IMP Department at Ferring Pharmaceuticals A/S in accordance with GMP and national regulatory 
requirements.  


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CONFIDENTIAL 
5.2.1 
Investigational Medicinal Product 
Reconstituted vials, SC pumps, and accessories will be supplied in subject kits on Treatment Day 1, 
Treatment Day 10, and Treatment Day 25 (if applicable).  Subjects will receive a sharps container 
for safe disposal of needles.  The OmniPod Managers will also be supplied to the subjects on 
Treatment Day 1.   
The active and placebo study drug will be identical in appearance and labeling.  The IMP will be 
packaged and distributed using a secure system assuring full traceability from production to site.  
The unblinded coordinator will program the Manager to deliver the assigned dose, according to the 
randomization schedule (but will remain blinded to assigned study drug, whether active or placebo).  
Each subject study kit will contain the following: 
• OmniPod Manager (initial shipment only) 
• Replacement batteries for Manager (initial shipment only) 
• OmniPod pump(s) (2 mL syringe and needle included) 
• Vial adapter(s) 
• Vial(s) of LutrePulse or Placebo 
• One (1) sharps container 
• Alcohol swab(s) 
Each subject study kit will have a study specific label uniquely numbered assuring traceability with 
one self-adhesive tear-off portion to be affixed to the source document form and maintained at the 
trial site.   
5.2.2 
Non-Investigational Medicinal Product 
Provera® will have a study specific label uniquely numbered assuring traceability.  No modification 
will be made from the usual commercial state, other than application of trial specific labelling.  
5.3 
Conditions for Storage and Use 
The investigator or designee will ensure that the investigational product and Non-Investigational 
medicinal product is stored in appropriate conditions in a reasonably secure, substantially 
constructed locked cabinet with controlled access.  The temperature in the storage compartment 
shall be constantly monitored with a minimum/maximum thermometer and the values shall be 
controlled regularly and documented.  Deviations in storage temperature must be reported to the 
sponsor without delay and the IMP cannot be used until acceptance from the sponsor is received.  
The investigator or designee will also ensure the subject has an understanding of the proper storage 
conditions for IMP at home. 


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CONFIDENTIAL 
All LutrePulse products and supplies (including unopened pumps) should be stored in a cool, dry 
place.  Medication vials should not be stored above 25°C (77°F). The OmniPod’s operating 
temperature is 5-40°C (40-104°F).  Extreme heat or cold can damage the OmniPod and the 
Manager, causing them to malfunction.  The OmniPod should not be exposed to direct sunlight for 
long periods of time and should be removed prior to using hot tubs, whirlpools, or saunas.  The 
Manager should not be left inside a car or other places where it could be exposed to extreme 
temperatures.  If Pods are exposed to extreme temperatures, they should first be returned to room 
temperature and inspected carefully before they are used.  During storage, the batteries should 
remain in the Manager.  See the User Manual for details regarding OmniPod pump use and storage.9 
Provera® should be stored according to the commercial pack.  
The investigator or designee will dispense the medication only to the identified subjects of this 
study, following the procedures described in this study protocol and documented in the subject 
dispensing log.  Drug inventory/dispensing will be documented in the source documents for each 
subject and the drug accountability binder.  Subjects will be given a diary card on Treatment Day 1 
to document time of replacing pods every 4th day.  The investigator is responsible for all drug 
supplies.  Written documentation is mandatory.  After completion of the study, all unused 
investigational Medicinal product and Non-investigational medicinal product will be returned to the 
sponsor. 
5.4 
Blinding / Unblinding 
5.4.1 
Blinding 
To ensure blinding, subjects assigned to placebo will be randomized to 1 of 3 placebo “dose” 
groups – 10 g, 15 g, or 20 g according to a computer-generated randomization list prepared for 
all trial sites.  Study personnel involved in the conduct of the study will be blinded to the assigned 
drug product (active or placebo) regardless of dose.  The OmniPod Manager will display the dose 
once it has been programmed for a subject, regardless of active or placebo assignment. 
All eligible subjects will be randomly assigned at least 5 days before Treatment Day 1 (7 days for 
sites in Canada), based on the computer-generated randomization list.  The first 15 eligible subjects 
will be randomly assigned to 1 of 3 treatment arms: LutrePulse OmniPod SC 10 g, LutrePulse 
OmniPod SC 20 μg, or OmniPod SC placebo in a 1:1:1 ratio.  The subsequent 25 eligible subjects 
will be randomly assigned to LutrePulse OmniPod SC 10 g, LutrePulse OmniPod SC 15 g, 
LutrePulse OmniPod SC 20 μg, or OmniPod SC placebo in a 1:2:1:1 ratio.  The rest of the eligible 
subjects will be randomly assigned to LutrePulse OmniPod SC 10 g, LutrePulse OmniPod SC 15 
g, LutrePulse OmniPod SC 20 μg, or OmniPod SC placebo in a 1:1:1:1 ratio.  To maintain 
blinding for subjects and the unblinded coordinator to the assigned drug product, the placebo 
subjects will be randomly assigned to the equivalent dosing setting in the Manager for 10 g /pulse 
or 20 μg /pulse for the first 15 eligible subjects and 10 g /pulse, 15 g /pulse, or 20 μg /pulse for 


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the other randomization schemes.  The randomization dose assignment (dose only) will be available 
to the OmniPod Manager programmer (unblinded coordinator), but not to any other site personnel 
involved in the conduct and evaluation of the study until the study database is declared clean and is 
released to the statistician.   
Prior to the start of the study, the investigator will assign a coordinator to act as the unblinded 
coordinator.  This person will be the only person unblinded to the subject’s study drug dose and will 
be responsible for the set-up of the Manager, distribution and accountability of the drug.  Although 
the unblinded coordinator will be aware of the dose assigned, the unblinded coordinator will not be 
aware of whether the subject is receiving active drug or placebo.  The unblinded coordinator will 
instruct each subject as to the proper administration and the timing of administration of the study 
drug.  This person will be available to answer the subject’s questions regarding study drug and its 
administration. 
The integrity of the blind will be further preserved by requiring each subject and the unblinded 
coordinator to sign a nondisclosure affidavit form (Appendix I) instructing subjects and the 
unblinded coordinator not to disclose the study drug dosage. 
5.4.2 
Unblinding of Individual Subject Treatment 
An emergency decoding possibility (either a code envelope or another system) will be available to 
the investigator and designated persons at Ferring.  Breaking of the blind for individual subjects in 
emergency situations is only permitted in case of an important adverse event where the knowledge 
of the IMP in question is required for therapeutic decisions for the management of the subject. 
As far as the emergency permits, the need to break the blind will be agreed by the investigator and 
Ferring.  The person who opens a code envelope must record on it the reason and the date of 
opening, and then sign and date the opened envelope if a code envelope is prepared.  If the 
randomization is done via an electronic system, the system will record the access for this 
unblinding. It should be recorded in the eCRF that the code is broken, why, when, and by whom.  
The investigator must record the event of unblinding in the subject’s medical record, including the 
reason for unblinding, but not the treatment allocation if this can be avoided. 
In case of accidental unblinding to the dose (e.g., the subject tells the investigator), the same 
documentation as for emergency unblinding must be obtained, i.e., why, when and by whom must 
be noted in the eCRF, and the event must also be recorded in the subject’s medical record. 


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It may be necessary to unblind an individual subject’s treatment for the purposes of expedited 
reporting to the authorities and/or IECs/IRBs.  In that situation, every effort will be made to 
maintain blinding of sponsor personnel involved in data analysis and interpretation.  
Pharmacovigilance/Safety personnel may be unblinded for purposes of reporting suspected 
unexpected serious adverse reactions (SUSARs).  Regulatory Affairs personnel submit SUSARs to 
the FDA.  A US Regulatory Affairs person not involved with the conduct of the study will be 
designated to submit SUSARs to the IND. 
Information on whether the blind has been broken for any subjects must be collected before the 
database is declared clean and is released to the statistician. 
5.5 
Selection of Doses in the Study 
The selected GnRH dose per pulse will be either 10 μg, 15 g, or 20 μg delivered at 90-minute 
intervals.   
The SC GnRH doses proposed in this study are based on existing Ferring data and previously 
published research. The 20 μg dose has been used successfully in clinical studies in the US and 
Europe.3   
In a pharmacokinetic study conducted in a small group of women with hypothalamic amenorrhea, 
SC GnRH administration resulted in pulsatile plasma GnRH and gonadotropin responses 
resembling those seen after IV GnRH.15  No significant differences were found between peak LH 
responses to 10 µg/pulse of IV and SC doses of GnRH administered at 90-minute intervals.   
In Ferring Study 2005-06, the SC route was associated with a slightly lower rise to peak and a 
slower disappearance of GnRH from the circulation; however, SC and IV dosing produced similar 
peak concentrations and total exposures (area under the concentration-time curve, AUC).5  The 
study showed 25% bioavailability with SC compared to IV administration of GnRH.  Thus, if the 
most commonly used initiating dose of the IV route is 5 µg /pulse, the SC dose needed to achieve 
approximately the same blood concentration GnRH levels is expected to be 4-fold higher, namely, 
20 µg /pulse. 
Ferring Study 000010 demonstrated favorable GnRH and LH profiles following SC administration 
of 20 µg/pulse doses every 90 minutes of LutrePulse with the OmniPod device.7  Martin (1990) 
reported that 10 to 20 µg of GnRH per bolus yielded satisfactory ovulatory rates.16 
The frequency of GnRH administration is best based on the GnRH pulse frequency in normal 
women.  The literature to date supports a follicular-phase pulse frequency of 90 minutes or less to 
achieve maximum spontaneous ovulation rates. 


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Taken together, these results confirm the suitability of the SC route and the selected 10, 15, and 
20 µg doses in a study with fixed 90-minute interpulse frequency for GnRH ovulation induction 
therapy. 
5.6 
Treatment Compliance 
5.6.1 
Dispensing and Accountability 
The IMP will be dispensed only to subjects who meet the eligibility criteria.  A drug-dispensing log 
will be maintained at the site detailing the date and quantity of IMP administered to each subject, as 
well as the batch number.  The monitor will verify drug accountability during the study.  The drug 
accountability binder will be managed by the study coordinator or designee.  Subject Diary Cards 
(Appendix II) documenting date and time of replacement pods will also be monitored. Any unused 
investigational product and Non-Investigational Medicinal products will be accounted for and 
returned to the sponsor.  The used vials, pumps, and Managers must be returned to the trial site by 
the subject and will be destroyed at the site and/or returned to the sponsor. 
5.6.2 
Assessment of Compliance 
The OmniPod will be applied at the study site on Treatment Day 1, Treatment Day 10, and 
Treatment Day 25 (if applicable).  All other OmniPods can be applied by the subject either at home 
or at the study site.  Subjects will be provided training and an instruction manual.   
On Day 1 and at each study visit during treatment, the subjects will be monitored closely by the 
unblinded coordinator to ensure the medication is being delivered and the pump is functioning 
properly.  The Manager records drug delivery data that may also be analyzed.  The data in the 
Manager may be collected and recorded by the unblinded coordinator when the subject returns the 
Manager to the site. 
5.7 
Auxiliary Supplies 
All subject auxiliary items and devices are described in Section 5.1.1 and Section 5.1.2.  These will 
be provided by the sponsor and packaged into blinded subject kits.  These kits will be distributed to 
the sites together with the IMP for Treatment Days 1, 10, and 25 (if applicable).   
5.8 
Return and Destruction of Medicinal Products and Auxiliary Supplies 
All unused IMP and NIMP will be returned to the sponsor, as instructed by Ferring IMP 
Department, after the drug accountability has been finalized, verified by the monitor, and signed off 
by the investigator or designee. 
The used vials, pumps, and Managers must be returned to the trial site by the subject and will be 
destroyed at the site and/or returned to the sponsor.  Used syringes and needles must be discarded in 
the sharps container and returned to the site.  


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The trial medication delegate at the site should ensure that the destruction of used medicinal 
products is done in accordance with local legislation/national requirements after the drug 
accountability has been finalized, verified by the monitor, and signed off by the investigator or 
designee. 


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6 
STUDY FLOW CHART AND STUDY PROCEDURES 
6.1 
Schedule of Activities 
The schedule of activities for the study is presented in Table 1. 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Table 1 
Schedule of Activities 
Procedure 
Screening 
(Day -60 
to Day -1) 
Treatment 
Day 1 
Treatment 
Day 10 
Follicle 
≥ 18 mm and 
LH surge 
Days 19, 21, 23, 25 and 27 
14 (+4) days post 
LH surge and 
3 days later 
2 to 4 weeks from 
2nd positive serum 
ß-hCG test 
End-of-
Study 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
Medical/gynecologic 
history 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
X 
Gynecological exam 
X 
 
 
 
 
 
 
X 
Vital signs 
X 
 
 
 
 
 
 
X 
Safety laboratory tests 
X 
 
 
 
 
 
 
X 
Hepatitis B, C, & HIV 
screen 
X 
 
 
 
 
 
 
 
Hormones: PRL, TSH 
X 
 
 
 
 
 
 
 
TVUS 
X 
 
X   –   Xa 
 
 
Xb 
 
Semen analysis 
X 
 
 
 
 
 
 
 
Progestin challenge testc 
X 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
 
X 
 
 
 
 
 
Xd 
Blood samples for E2 
X 
X 
Xa 
Xa 
 
 
 
 
Hormones: LH, FSH 
X 
Xe 
Xe 
 
 
 
 
 


Date: 06 Dec 2017 
E-Protocol Amendment-21975;1.0 
Supersedes: None 
Page 41 of 82 
 
 
 
 
Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Procedure 
Screening 
(Day -60 
to Day -1) 
Treatment 
Day 1 
Treatment 
Day 10 
Follicle 
≥ 18 mm and 
LH surge 
Days 19, 21, 23, 25 and 27 
14 (+4) days post 
LH surge and 
3 days later 
2 to 4 weeks from 
2nd positive serum 
ß-hCG test 
End-of-
Study 
Visit 
Blood samples for P4 
X 
X 
 
 
X 
 
 
Xf 
Randomization 
 
Xg 
 
 
 
 
 
 
OmniPod applicationh 
 
X 
 
 
 
 
 
 
Clearblue testingi 
 
 
 
X 
 
 
 
 
 
Begin sexual intercoursej 
 
 
 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Follow-up phone callk 
 
 
 
 
 
 
 
X 
a. 
Follicular size will be monitored every other day (minimum of 3 times) starting at Day 10 until a follicle ≥ 18 mm or LH surge is detected.  E2 samples will be taken each time a TVUS is performed. 
b. 
If fetal heartbeat is not documented, the subject may return within 7 days for another TVUS. 
c. 
Subjects with uterine bleeding within 5 days of the last dose of medroxyprogesterone acetate will be considered screen failures.  Rescreening for the progestin challenge test is not allowed. 
d. 
A urine pregnancy test should be performed at the End-of-Study visit for all except those with documented fetal heart movement. 
e. 
On Day 1 (pre-treatment baseline) and Day 10 (post-treatment), LH and FSH samples will be collected at 0 hour (first sample taken prior to dosing) and 5, 15, 30, 60, and 90 minutes after the first dose is 
administered.   
f. 
Only for subjects who have discontinued the study early and ended treatment on or after Day 14 
g. 
Randomization will occur at least 5 days before Treatment Day 1 (7 days for sites in Canada). 
h. 
The first OmniPod applied will remain on the subject until Day 4, when the second OmniPod will be applied at approximately the same time (±1 hour); each OmniPod will be worn for 3 full days. 
i. 
When follicles ≥ 14 mm are detected on TVUS, Clearblue tests are dispensed to the subject to be administered each day at approximately the same time between 8 AM and 11 AM until a positive test result occurs.  
j. 
Intercourse to begin at confirmed Clearblue LH surge.  
k. 
For subjects who achieve biochemical pregnancy – collect ongoing pregnancy rate and birth data. 


Date: 06 Dec 2017 
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Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
6.2 
Study Procedures 
6.2.1 
Screening/Pre-treatment 
Screening procedures are to be performed between Days -60 and -1.  Note: The diagnosis of 
primary amenorrhea with HH should be known by the investigator. 
Screening (Days -60 to -1) 
At the Screening Visit, the subject should receive a detailed explanation of the study and, after 
having sufficient time to consider her participation in the study, sign the Informed Consent Form.  
After the subject has signed the Informed Consent Form, the following will be collected/performed: 
• Inclusion/exclusion criteria 
• Medical/gynecologic history and demographic data 
• Physical examination, including height and weight  
• Vital signs (blood pressure, heart rate, and oral temperature) 
• Clinical safety laboratory assessment:  chemistry, hematology, urinalysis 
• Other laboratory assessment: hepatitis B, hepatitis C, HIV screen 
• Hormone assessments:  E2, P4, FSH, LH, prolactin, and TSH 
• Serum pregnancy test  
• Gynecological examination (including breast exam) and Pap smear (unless Pap smear 
results within the past 24 months are provided) 
• TVUS 
• Documentation of normal semen analysis within past year for male partners 
• Prior/concomitant medication use up to 14 days prior to the Screening Visit 
• Progestin Challenge Test during Screening: 
▪ Medroxyprogesterone acetate 10 mg oral tablet once daily for 10 days 


Date: 06 Dec 2017 
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Page 43 of 82 
 
 
 
 
Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
▪ If uterine bleeding occurs within 5 days of the last dose of progestin, the subject is 
considered a screen failure and ineligible for study participation. Rescreening for the 
progestin challenge test is not allowed.  Per investigator’s discretion, occasional spotting 
is not considered withdrawal bleeding. 
▪ If uterine bleeding does not occur 5 days after the last dose of progestin, the subject will 
return to the study site for initiation of treatment. 
6.2.2 
Treatment Day 1 through Day 10 
Randomization is to occur at least 5 days before Treatment Day 1 (7 days for sites in Canada). 
Treatment Day 1 
• Urine pregnancy test 
• Blood samples for baseline E2 and P4 collected prior to first dose.  Blood samples for 
baseline LH and FSH collected prior to first dose and 5, 15, 30, 60, and 90 minutes after the 
first dose is administered.   
• Instruction and application of OmniPod 
• Distribution of LutrePulse subject study kit and Subject Diary Card  
• Concomitant medication use  
• Adverse event and unanticipated adverse device effect (UADE) assessment post treatment 
• 12-lead electrocardiogram (ECG) (for subjects who report chest pain or are symptomatic of 
chest pain)   
Treatment Day 10 
Subjects will return to the study site at approximately the same time as Day 1 for pharmacodynamic 
(PD) assessments and monitoring of follicular development and endometrial thickness.  They will 
remove their current pod and apply their Day 10 pod at the study site.   
• Concomitant medication use  
• A single blood sample for E2  
• Blood samples for LH and FSH collected at the same time as Day 1 first sample (± 1 hour), 
before the first dose is administered by the Day 10 pod and 5, 15, 30, 60, and 90 minutes 
after the dose is administered.   


Date: 06 Dec 2017 
E-Protocol Amendment-21975;1.0 
Supersedes: None 
Page 44 of 82 
 
 
 
 
Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• TVUS to monitor size and number of follicles and endometrial thickness 
• Adverse event and unanticipated adverse device effect assessment  
• 12-lead ECG (for subjects who report chest pain or are symptomatic of chest pain) 
OmniPod Application Days 
Subjects remove the OmniPod and apply a new OmniPod at approximately the same time as the 
first OmniPod was applied (±1 hour) every fourth day.  This occurs on Treatment Days 4, 7, 10, 13, 
16, 19, and onwards if deemed necessary by the investigator. 
After confirmed LH surge, treatment will continue for approximately another 2 weeks to maintain 
corpus luteum function (continue until confirmatory serum pregnancy test).   
6.2.3 
Treatment Day 11 until LH Surge 
Subjects will return to the study site every other day (or at the investigator’s discretion [minimum of 
3 times]) to monitor follicular development and endometrial thickness, until a dominant follicle of ≥ 
18 mm mean diameter and LH surge are confirmed.  If LH surge is not detected after 21 full 
treatment days, the subject will be discontinued.  However, the treatment may be continued for a 
maximum of 39 days at the discretion of the investigator if the patient has growing follicle(s). 
• 
TVUS 
• 
Blood collection for E2 (each time TVUS is performed) 
• 
When follicles ≥ 14 mm are detected on TVUS, Clearblue tests will be dispensed to subject 
to begin testing 
o Clearblue digital urine ovulation test is to be performed every day at approximately 
the same time between 8 and 11 AM   
o When a positive test result occurs, the subject should notify the site immediately to 
schedule a visit within 72 hours for confirmatory TVUS and will be advised to 
engage in sexual intercourse on the day of LH surge, the day following LH surge, 
and per investigator’s discretion thereafter   
o Subjects should document the date of their first Clearblue test and the date of their 
first positive test result on the subject diary card (Appendix II) 
o  The subject should also document the date(s) of sexual intercourse on the subject 
diary card. 


Date: 06 Dec 2017 
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Supersedes: None 
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Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• Concomitant medication use  
• Adverse event and unanticipated adverse device effect assessment 
• 12-lead ECG (for subjects who report chest pain or are symptomatic of chest pain) 
Up to 72 hours after LH surge 
• Confirmatory TVUS  
• Concomitant medication use  
• Adverse event and unanticipated adverse device effect assessment 
• 12-lead ECG (for subjects who report chest pain or are symptomatic of chest pain) 
6.2.4 
Progesterone and Pregnancy Monitoring 
Treatment Days 19, 21, 23, 25, and 27 
• Blood collection for P4  
• Concomitant medication use 
• Adverse event and unanticipated adverse device effect assessment 
• 12-lead ECG (for subjects who report chest pain or are symptomatic of chest pain) 
• LutrePulse Omnipod treatment continues for luteal phase support for subjects with 
confirmed LH surge 
Interview and study drug return 
Non-pregnant subjects will visit the site to return used and unused study drug product, their subject 
diary card and the OmniPod delivery system and report the day menstruation began and duration of 
menses, if applicable.  Gonadotropins for one treatment cycle as well as compensation toward a 
future IVF cycle could be offered to all non-pregnant subjects who participated in and completed 
the study (had at least 14 days of study medication) and completed an End-of-Study visit.  No 
study-related follow-up will be conducted regarding such cycles. 


Date: 06 Dec 2017 
E-Protocol Amendment-21975;1.0 
Supersedes: None 
Page 46 of 82 
 
 
 
 
Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
14 (+ 4) days after LH surge and 3 days thereafter 
Two positive serum pregnancy tests are required to confirm biochemical pregnancy 14 (+ 4) days 
after LH surge and 3 days thereafter.  If only one of the 2 tests is positive, the subject will return 
within 5 days (unscheduled visit) to confirm pregnancy with another serum pregnancy test.  
Subjects with 2 negative pregnancy tests will complete an End-of-Study Visit on the day of the 
second negative pregnancy test. 
• Serum pregnancy test 
• Concomitant medication use  
• Adverse event and unanticipated adverse device effect assessment 
• 12-lead ECG (for subjects who report chest pain or are symptomatic of chest pain) 
2 to 4 weeks after second positive serum pregnancy test 
• TVUS to detect gestational sac and fetal heartbeat 
• If fetal heartbeat is not documented, the subject may return within 7 days for another TVUS 
• Concomitant medication use  
• Adverse event and unanticipated adverse device effect assessment 
• 12-lead ECG (for subjects who report chest pain or are symptomatic of chest pain) 
End-of-Study Visit 
The End-of-Study Visit is performed in conjunction with the final TVUS visit 2 to 4 weeks after the 
second positive serum pregnancy test or on the day of the second negative serum pregnancy test for 
subjects who do not become pregnant (2 negative serum pregnancy tests). 
• Gynecological examination, including breast exam 
• Physical examination, including weight  
• Vital signs (blood pressure, heart rate, and oral temperature) 
• 12-lead ECG (for subjects who report chest pain or are symptomatic of chest pain)   
• Clinical safety laboratory assessment: chemistry, hematology, urinalysis 


Date: 06 Dec 2017 
E-Protocol Amendment-21975;1.0 
Supersedes: None 
Page 47 of 82 
 
 
 
 
Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• Urine pregnancy test (for all except those with documented fetal heart movement) 
• Blood collection for P4 (only for subjects who have discontinued the study and ended 
treatment on or after Day 14) 
• Concomitant medication use  
• Adverse event and unanticipated adverse device effect assessment 
After the End-of-Study Visit, the site will be asked to provide follow-up information on subjects 
with a biochemical pregnancy regarding ongoing pregnancy rate and birth data.  The follow up will 
be conducted via telephone or mail.  The site will also document miscarriage/pregnancy loss 
(spontaneous and/or induced), date of live birth, number of deliveries, fetal anomalies, and birth 
defects.   
 


Date: 06 Dec 2017 
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Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7 
STUDY ASSESSMENTS 
7.1 
Pharmacodynamic Assessments 
Hormone assays will be performed by a central laboratory service.  LH will be measured by 
automated LH two-site sandwich immunoassay using direct chemiluminometric technology 
(ICMA).  Estradiol, progesterone and FSH will also be assayed by a central laboratory service. 
A blood sample for E2, LH and FSH will be taken on Day 1 (pre-treatment baseline) prior to dosing.  
Additional blood samples for LH and FSH will be taken 5, 15, 30, 60, and 90 minutes after the first 
dose is administered.  The trial site should prepare the subject for at least a 2 to 3-hour office visit. 
A blood sample for E2, LH and FSH will be taken on Day 10 at the same time as the Day 1 first 
sample (± 1 hour) before the first dose is administered by the Day 10 pod.   Additional blood 
samples for LH and FSH will be taken 5, 15, 30, 60, and 90 minutes after the first dose is 
administered.  Samples for measurement of E2 will also be obtained each time the subject has a 
TVUS to monitor follicular development and endometrial thickness. 
PD blood samples of 10 mL (for LH, FSH, and E2 levels) will be collected. 
Serum samples will be obtained following centrifugation of clotted samples.  All serum samples 
should be clearly labeled before freezing to ensure label adherence to the container and to avoid 
sample mix up. 
All samples will be kept frozen at -20C and shipped on dry ice.  No more than 45 minutes is to 
elapse between collecting the blood and freezing the serum sample.  The subject’s number and 
initials, actual 24-hour clock and date time of each sample collection, sample identification number, 
and other appropriate information will be recorded on the label and in the eCRF.  Any deviations 
either from the scheduled time of sample collection or from the instructions for handling and 
processing of samples should be documented in the study records. 
Specific instructions for blood collection will be provided in a laboratory manual to the study 
center. 
7.2 
Transvaginal Ultrasound 
A transvaginal ultrasound, including ovaries, uterus, endometrium, and adnexa, will be performed 
at Screening (to determine eligibility) and beginning at Day 10 of treatment to monitor number and 
size of follicles and endometrial thickness.  Subjects will return every other day (or based on 
investigator judgment) for additional TVUS (at least 3 TVUS are to be performed). For subjects that 
become pregnant, a TVUS will be performed 2 to 4 weeks after the 2nd positive serum pregnancy 
test. 


Date: 06 Dec 2017 
E-Protocol Amendment-21975;1.0 
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Page 49 of 82 
 
 
 
 
Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7.3 
Detection of LH Surge 
When follicles ≥ 14 mm in mean diameter are detected on TVUS, subjects will begin monitoring 
LH surge using a Clearblue test.  The test will be administered each morning at approximately the 
same time between 8 and 11 AM.  When a positive test result occurs, subjects are to notify the site 
and will be advised to engage in sexual intercourse on the day of LH surge, the day following LH 
surge, and per investigator’s discretion thereafter. 
7.4 
Progesterone Evaluations 
Blood samples (10 mL) for measurement of progesterone levels will be obtained by venipuncture 
on Days 19, 21, 23, 25, and 27.  A blood sample will also be obtained at the End-of-Study visit for 
any subject that discontinues the study early and ends treatment on or after Day 14.  A P4 level ≥ 6 
ng/mL as measured by a central laboratory indicates ovulation. 
7.5 
Pregnancy Assessments 
7.5.1 
Serum Pregnancy Tests 
Serum pregnancy tests (-hCG) will be performed at Screening, and negative pregnancy test results 
are required for study admission and/or administration of pulsatile GnRH (urine pregnancy tests are 
performed prior to initial study drug administration for all subjects and at the End-of-Study visit for 
all subjects except those with documented fetal heart movement).  To confirm biochemical 
pregnancy, a serum pregnancy test will be performed 14 days (+ 4 days) after LH surge and 3 days 
thereafter.  Two positive serum pregnancy tests are required to confirm biochemical pregnancy.  If 
only one of the 2 tests is positive, the subject will return within 5 days (unscheduled visit) to 
confirm pregnancy with another test.  Subjects who have 2 negative serum pregnancy test results 
will complete their End-of-Study Visit on the day of the second negative serum pregnancy test. 
7.5.2 
Pregnancy and Pregnancy Outcome 
Subjects who achieve pregnancy (2 positive serum pregnancy tests) will be followed up for clinical 
pregnancy (gestational sac and fetal heart movement) and will complete their final visit (End-of-
Study Visit) on the day of documented fetal heart movement on TVUS (2 to 4 weeks after second 
positive serum pregnancy test). 
7.6 
Safety Assessments 
7.6.1 
Medical History 
A complete medical/gynecologic history will be obtained at Screening and will include a review of 
prior medical history and female reproductive status.  Documentation of the diagnosis of primary 
amenorrhea with HH should be provided, including normal or unchanged CT scan or MRI scan of 
the hypothalamic pituitary region on file and blood samples indicating FSH < 5 IU/L and LH 
< 5 IU/L.  Medical history findings will be recorded in the eCRF. 


Date: 06 Dec 2017 
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Page 50 of 82 
 
 
 
 
Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7.6.2 
Physical and Gynecological Examination 
A complete physical examination including height, weight and BMI calculation will be performed 
at Screening.  A gynecological exam including pelvic and breast exam will be performed at 
Screening.  In addition, a Pap smear (or other cervical cancer screening) will also be performed at 
Screening if not done in the previous 24 months (PAP smear can be performed at Screening, per 
investigator discretion, even if results within 24 months are available).  If done in the previous 
24 months, a copy of the report is needed and must be filed in the subject’s chart.  At the End-of-
Study Visit (or at the time of early termination), another physical and gynecological examination 
including vital signs will be performed.  Any clinically significant deterioration from baseline will 
be recorded as an adverse event. 
7.6.3 
Vital Signs 
At Screening and the End-of-Study Visit, blood pressure, heart rate, and oral body temperature will 
be measured under resting conditions.  All blood pressure measurements should be made using the 
same arm and prior to any scheduled blood draws.      
7.6.4 
ECG Evaluation 
Subjects who report chest pain or are symptomatic of chest pain should have an ECG evaluation 
any time during the study when chest pain or symptoms occur. 
7.6.5 
Clinical Laboratory Tests 
7.6.5.1 
Hematology, Serum Chemistry, and Urinalysis 
A standard panel, as well as the following safety laboratory tests, will be performed at Screening 
and at the End-of-Study Visit (or at the time of early termination).  A 10 hour overnight fast is 
required prior to collecting the blood samples.  The total amount of blood required for safety 
assessments is approximately 80 mL. 
Hematology: red blood cell count, white blood cell count, hematocrit, hemoglobin, platelet count, 
and differential count. 
Serum Chemistry: fasting glucose, blood urea nitrogen, creatinine, potassium, sodium, chloride, 
calcium, total protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, and gamma glutamyl transferase. 
Urinalysis: leukocyte esterase, blood, pH, specific gravity, protein, glucose, urobilinogen, and 
microscopic if positive for blood or protein. 
7.6.5.2 
Serological Testing 
Serological testing for hepatitis B, hepatitis C, and HIV I and II will be performed at Screening. 


Date: 06 Dec 2017 
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Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7.6.5.3 
Hormone Testing 
Prolactin (PRL) and TSH will be measured only at Screening.  P4 levels will be measured at 
Screening and Treatment Days 19, 21, 23, 25, and 27.  P4 levels will also be measured at the End-
of-Study visit for any subject that discontinues the study early and ends treatment on or after Day 
14.  E2 levels will be measured at Screening, Treatment Days 1 and 10, and each time a TVUS is 
performed.  LH and FSH levels will be measured at Screening and again on Treatment Days 1 and 
10 (prior to first dose and 5, 15, 30, 60, and 90 minutes after first dose is administered).  


Date: 06 Dec 2017 
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Page 52 of 82 
 
 
 
 
Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7.6.6 
Ovarian Hyperstimulation Syndrome Monitoring 
In women undergoing controlled ovarian hyperstimulation, an excessive response to follicular 
stimulating agents may lead to the development of ovarian hyperstimulation syndrome (OHSS).  
OHSS represents a spectrum that can be categorized as mild, moderate or severe.   
The following table will be used in assessing and classifying the severity of OHSS. 
Table 2 
Classification of Mild, Moderate and Severe OHSS17 
Mild OHSS 
     Grade 1 
Abdominal distension and discomfort  
     Grade 2  
Features of grade 1 plus nausea/vomiting and/or diarrhea. Ovaries enlarged to 
5-12 cm.a) 
Moderate OHSS 
     Grade 3  
Features of mild OHSS plus ultrasonic evidence of ascites.b) 
Severe OHSS 
     Grade 4  
Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax 
(or breathing difficulties). Paracentesis due to OHSS symptoms. c) 
     Grade 5  
All of the above plus change in blood volume, increased blood viscosity due to 
hemoconcentration, coagulation abnormalities, and diminished renal perfusion and 
function.d)  Hospitalization due to OHSS symptoms. 
a) For each ovary, the size will be the average of the greatest diameter and its greatest perpendicular diameter. Ovarian 
enlargement will be based on the average size of the right and left ovaries. The sizes of both ovaries should be 
recorded.  
b) For subjects with transvaginal evidence of ascites, the size of the fluid pockets in the pelvis (Douglas pouch, vesico-
uterine pouch, etc.) should be estimated by measuring the greatest diameter and its greatest perpendicular diameter, 
and multiplying these two numbers (the unit will be cm2). Peritoneal fluid is the total size of all fluid pockets in the 
pelvis.  
c) In case of paracentesis, the volume of fluid drained should be measured. 
d) Hemoconcentration is defined as hematocrit >45 %. Electrolyte disturbances is defined as hyponatremia (sodium 
<135 mEq/L) and/or hyperkalemia (potassium >5.0 mEq/L). Coagulation abnormalities are defined as presence of 
thromboembolic events, abnormal prothrombin time or abnormal activated partial thrombin time. Diminished renal 
perfusion is defined as creatinine >1.2 mg/dl. Oliguria is defined as urine output less than 500 mL / 24 hours. Anuria 
is defined as failure to produce urine. If applicable, actual volume of urine output will be recorded. 
 
All cases of OHSS will be considered adverse events and will be recorded in the source documents 
for that subject and on the Adverse Event page in the eCRF.  Severe OHSS that requires medical or 
surgical intervention (i.e., paracentesis, hospitalization, dopamine administration) is considered a 
serious adverse event (see Section 8.3). 


Date: 06 Dec 2017 
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Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7.7 
Concomitant Medications 
At each study visit, subjects will be queried for use of any medication other than the study drug 
since the last visit.  Any use of prior medication or concomitant medication, including vitamin or 
dietary supplements or oral herbal preparations, will be recorded in the source documents and the 
eCRF and include the following information: name of medication, total daily dose, route of 
administration, start and stop dates, and reason for use.  If the reason for the use of concomitant 
medication meets the definition of an adverse event, the adverse event should be recorded in the 
source documents for that subject and on the Adverse Event page of the eCRF. 


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Gonadorelin Acetate, FE 
999037, FE 999903 
Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
8 
ADVERSE EVENTS AND UNANTICIPATED ADVERSE DEVICE EFFECTS 
8.1 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial.  It 
includes: 
• 
Any unfavorable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP. 
• 
Adverse events commonly observed and adverse events 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: findings from 
assessments and examinations done during screening are not adverse events, 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. 
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. 
The sources of adverse events 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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Trial Code: 000070  
No Specified Dosage Form and Strength 
Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
8.2.2 
Recording of Adverse Events 
The investigator must record all adverse events in the Adverse Event Log provided in each subject’s 
eCRF with information about: 
• 
Adverse event 
• 
Date and time of onset (time can be omitted, if applicable) 
• 
Intensity 
• 
Causal relationship to IMP 
• 
Action taken to IMP 
• 
Other action taken 
• 
Date and time of outcome (time can be omitted, if applicable) 
• 
Outcome 
• 
Seriousness (see 8.3.1 for definition) 
• 
Each of the items in the Adverse Event Log is described in detail in the following sections. 
Adverse Event 
Adverse events 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 adverse event more than once and the subject recovers in between 
the events, the adverse events should be recorded separately.  If an adverse event 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.a 
                                              
a  
Exception: if an adverse event with onset before the first IMP administration (i.e., a pre-treatment adverse 
event) changes in intensity, this must be recorded as two separate events.  The initial adverse event should be 
recorded with outcome “not yet recovered” and the date and time of outcome is when the intensity changed.  
The second adverse event should be recorded with date and time of onset when the intensity changed.   


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Note the following: A procedure is not an adverse event; the reason for conducting the procedure is.  
Hospitalization is not an adverse event; the reason for hospitalization is.  Death is not an adverse 
event, but the cause of death is (an exception is sudden death of unknown cause, which is an 
adverse event). 
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 adverse 
event 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 adverse event 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). 
Causal Relationship to IMP 
The possibility of whether the IMP caused the adverse event 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 adverse event.  The adverse event may occur as part of the pharmacological action of 
the IMP or may be unpredictable in its occurrence. 
Examples:  
• 
adverse events that are uncommon but are known to be strongly associated with IMP 
exposure. 
• 
adverse events 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 re-challenge. 
No reasonable possibility: 
  There is no reasonable evidence or argument to suggest a causal 
relationship between the IMP and the adverse event. 
Examples: 
• 
known consequences of the underlying disease or condition under investigation. 


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• 
adverse events common in the trial population, which are also anticipated to occur with 
some frequency during the course of the trial, regardless of IMP exposure. 
Action Taken to IMP 
The action taken to the IMP in response to an adverse event must be classified as one of the 
following: 
• 
No change (medication schedule maintained or no action taken) 
• 
Withdrawn 
• 
Dose Interrupted 
Other Action Taken 
Adverse events 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 adverse event, 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 adverse event 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 
• 
Not yet recovered 
• 
Fatal 


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8.3 
Serious Adverse Events 
8.3.1 
Serious Adverse Event Definition 
An event is defined a serious 
adverse event 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.  Overnight stay for observation, stay at emergency room 
or treatment on an outpatient basis do not constitute a 
hospitalization.  However, medical judgment 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 an SAE.  Hospital admissions and/or 
surgical operations planned before trial inclusion are not 
considered adverse events, 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.  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. 


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An event is defined a serious 
adverse event if it: 
Guidance 
is an important medical 
event 
Important medical events are events that may not be 
immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above.  
Examples of important medical events include AEs that suggest 
a significant hazard, contraindication or precaution, occurrence 
of malignancy or development of drug dependency or drug 
abuse.  Medical and scientific judgement should be exercised in 
deciding whether events qualify as medically important. 
Important medical events include any suspected transmission of 
an infectious agent via a medicinal product.  Any organism 
virus or infectious particle (e.g., prion protein transmitting 
Transmissible Spongiform Encephalopathy), pathogenic or non-
pathogenic, is considered an infectious agent.  A transmission of 
an infectious agent may be suspected from clinical symptoms or 
laboratory findings indicating an infection in a subject exposed 
to a medicinal product. 


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8.3.2 
Collection, Recording and Reporting of Serious Adverse Events 
SAE Reporting by the Investigator 
An SAE must be reported immediately to Ferring Pharmaceuticals as soon as it becomes known to 
the investigator and not later than within 24 hours of the investigator’s knowledge of the occurrence 
of an SAE. 
The investigator is responsible for submitting the completed SAE Report Form with the fullest 
possible details to the local safety officer at Ferring Pharmaceuticals, Inc. by fax within 24 hours of 
his/her knowledge of the SAE and submit all related follow-up information no later than 
3 calendar days using the contact details below: 
Safety Fax: 
 
Safety E-mail: 
 
For questions contact: Medical Monitor, 
 
E-mail: 
 
Contact Number: 
 
 
Completion of the Demographics, Adverse Events Log, Medical History Log and Concomitant 
Medication Log is mandatory for initial reports and for follow-up reports if any changes have been 
made since the initial report. 
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, such 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 IEC/IRB with any additional requested information 
such as results of post-mortem examinations and hospital records. 
Expedited Reporting by Ferring 
Ferring will report all adverse events that are serious, unexpected and with a reasonable possible 
causality to the IMP as judged by either the investigator or Ferring to the relevant parties within 
the stipulated timelines. 


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The expectedness is assessed by Ferring according to the Investigator’s Brochure.14  
SAEs will be considered reportable regardless of whether or not the IMP was used in accordance 
with the provisions in the protocol, Investigator’s Brochure and labelling. 
8.4 
Follow-up of Adverse Events and Serious Adverse Events  
8.4.1 
Follow-up of Adverse Events with Onset during the Trial 
During the trial, the investigator must follow-up on each adverse event until it is resolved or until 
the medical condition of the subject is stable. 
After the subject’s last visit, the investigator must follow-up on any adverse event 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. 
8.4.2 
Collection of Serious Adverse Events with Onset after Last Visit 
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. 
8.5 
Unanticipated Adverse Device Effects 
The definition of an Unanticipated Adverse Device Effect per FDA regulations is as follows: 
Unanticipated adverse device effect is any serious adverse effect on health or safety, any life-
threatening problem or death caused by or associated with a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the application; or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. Adverse device effects should be collected and assessed as for adverse events 
above. 
The investigator should collect, record, and assess any UADE similar to the directions for adverse 
events above.  The investigator must report the adverse device effect to Ferring as described in 
Section 8.3.2 above on the device report form.  In the circumstance that a serious adverse event and 
an UADE occur together, the SAE form should be completed and the device information also 
included. 


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9 
STATISTICAL METHODS  
Details of the statistical methodology will be provided in a separate Statistical Analysis Plan.   
9.1 
Determination of Sample Size 
The sample size was determined based on the original fixed parallel group study design. The true 
ovulation rate for LutrePulse OmniPod SC 20 μg, 15 μg, 10 μg, and placebo was assumed to be 
70%, 65%, 60%, and 1%, respectively.  Under these assumptions, a sample size of 14 subjects per 
group (total 56 subjects) will provide at least 80% power to detect differences between LutrePulse 
OmniPod SC 20 μg and placebo, 15 μg and placebo, and 10 μg and placebo in ovulation rate 
separately using the stratified one-sided Fisher’s exact tests 19 at an overall one-sided significance 
level of 0.025 with the closed testing procedure (Kong et al., 2005)18 to be used for the primary 
efficacy analysis.   
Approximately 60 subjects will be randomized, assuming up to 4 subjects may be ineligible for the 
full analysis set (FAS). 
9.2 
Subject Disposition 
The number and percentage of randomized subjects treated with IMP, prematurely discontinued, 
and completing the study will be summarized.  All post-baseline discontinuations will be 
summarized by reason for discontinuation.  The number of subjects screened and not randomized 
will be presented. 
9.3 
Protocol Deviations 
The criteria for protocol deviations considered major with the implication of data exclusions from 
the per-protocol analysis set will be determined before database lock. 
9.4 
Analysis Sets 
9.4.1 
Intent-to-Treat (ITT) Analysis Set  
All randomized subjects will be included in the ITT analysis set. 
9.4.2 
Full Analysis Set (FAS) 
All randomized subjects who are included in the ITT analysis set and received at least 14 days of 
study drug for pituitary priming will be included in the FAS. 
9.4.3 
Modified Intent-to-Treat (mITT) Analysis Set 
All randomized subjects who received at least one (1) pulsatile injection delivery of study drug will 
be included in the mITT Population. 


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9.4.4 
Per Protocol Set (PPS) 
All subjects who are included in the FAS and did not have major protocol deviations will be 
included in the PPS. 
9.4.5 
Safety Population 
All subjects who received at least one (1) pulsatile injection delivery of study drug will be included 
in the Safety Population. 
9.5 
Trial Population 
9.5.1 
Demographic and Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for the 
subjects in the FAS by treatment group. 
9.5.2 
Medical History and Concomitant Medications 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Prior and concomitant medications will be summarized by anatomical-therapeutic-chemical (ATC) 
classification 1st level (alphabetically) and ATC classification 2nd level (in decreasing order of 
frequency). 
9.6 
Efficacy Endpoint Assessments 
9.6.1 
General Considerations 
A Bayesian adaptive design is adopted to address the following objectives: 
1. Demonstrate superiority of the pooled middle and high doses over placebo in the 
ovulation rate 
2. Evaluate the dose-response relationship 
The adaptive design includes two interim analyses, conducted after approximately 9 and 12 patients 
per arm enrolling in the study, respectively. The interim analysis provides an opportunity for 
stopping the trial early due to efficacy success utilizing the group sequential strategy or due to 
efficacy futility through Bayesian predictive probability of success. Furthermore, it allows the low 
dose to be dropped following the interim look if it shows a much lower response rate compared 
with the middle and high doses.  
Each interim analysis will result in one of the following possible outcomes: 
1. Continue the trial with all arms 
2. Continue the trial without the low dose 
3. Declare early success, but continue the trial without placebo 
4. Declare early success and stop the trial (both placebo and low dose dropped) 
5. Stop the trial for futility 


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When the primary efficacy analysis is not successful at the interim analysis, and if the ovulation rate 
in the low-dose arm is sufficiently low, satisfying 
                                           Rlow < (Rhigh +middle) – 0.2,                                                      (1) 
then the trial will continue without the low dose, resulting in outcome #2 listed above. Note that 
Rlow and Rhigh +middle in inequality (1) are the observed ovulation rates in the low dose arm and the 
combined middle- and high-dose arms, respectively. However, if inequality (1) is not satisfied, then 
the trial will continue with all arms (outcome #1 listed above).  
Conversely, when success on the primary efficacy analysis is declared at an interim analysis, if the 
response rate in the low-dose arm meets the condition in inequality (1), then the trial is completed at 
this point (outcome #4 listed above) with dose selection performed using the ED80 rule (see below).   
In the case the primary efficacy analysis is successful, but the response rate in the low-dose arm is 
within 20% from the combined low- and high-dose success rate, the trial is not stopped 
immediately. Rather, the trial will continue to enroll additional patients into the low-, middle- and 
high-dose arms to further assess dose responses.  
Finally, the trial may terminate (outcome #5 listed above) as a result of a low predictive probability 
of success (<0.05) given the data collected at the interim analysis.  
At the end of the study, for a trial that achieves efficacy success, the dose to be selected as the 
lowest effective dose is the ED80 dose, defined as the lowest dose that retains at least 80% of the 
largest treatment effect, i.e.  
                                  (RED80 – Rplacebo) ≥ (Rmaximum – Rplacebo) ×0.8,                                   (2) 
where Rmaximum is the observed ovulation rate in the most effective dose arm, Rplacebo is the observed 
ovulation rate in the placebo arm, and RED80 is the observed ovulation rate in the selected dose arm. 
9.6.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the ovulation rate calculated as the proportion of subjects who had 
at least one post-baseline P4 level ≥ 6 ng/mL or pregnancy confirmed by a positive serum β-hCG 
(i.e., 2 positive results) or presence of a gestational sac documented by transvaginal ultrasound 
(TVUS). The denominator will be based on all subjects in the FAS. Subjects who do not have a 
confirmed pregnancy or at least one P4 level ≥ 6 ng/mL due to the P4 levels never reaching this 
threshold, missing data, early withdrawal, or any other reason will be counted as not having 
ovulation (treatment failure). 
The primary efficacy analysis will compare the pooled ovulation rate of LutrePulse OmniPod SC 20 
g and 15 g to placebo. Let Phigh+middle and Pplacebo be the underlying ovulation rates in the 
combined middle- and high-dose arms and the placebo arm, respectively. The hypotheses for the 
one-sided statistical testing are: 
 


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𝐻0: 𝑃ℎ𝑖𝑔ℎ+𝑚𝑖𝑑𝑑𝑙𝑒≤ 𝑃𝑝𝑙𝑎𝑐𝑒𝑏𝑜, 
vs. 
𝐻0:𝑃ℎ𝑖𝑔ℎ+𝑚𝑖𝑑𝑑𝑙𝑒> 𝑃𝑝𝑙𝑎𝑐𝑒𝑏𝑜. 
The hypotheses are tested using a stratified one-sided Fisher’s exact test (Jung et al., 2014) in the 
FAS including the randomization scheme as the stratification factor. The SAS PROC FREQ with 
permutation-based Cochran-Mantel-Haenszel test with exact p-value derived from all possible 
permutations will be employed for the calculation of p-value for the stratified Fisher’s exact test. 
Jung has shown that the stratified Fisher’s exact test is equivalent to the exact stratified Mantel-
Haenszel test when exact p-value is derived from all possible permutations. 
To account for the multiplicities introduced by early success interim analyses, Pocock boundaries 
are used. Thus, the success threshold at each analysis corresponds to a nominal p-value < 0.0131 to 
maintain an overall one-sided type I error rate of 0.025.  
Further details on the Bayesian adaptive method, including simulation studies assessing design 
operating characteristics, will be provided in the Statistical Analysis Plan (SAP). 
9.6.2.1 
Sensitivity Analyses  
The primary comparison between the pooled middle- and high-dose arms vs. the placebo arm for 
the primary variable will be conducted on the following analysis sets as sensitivity analyses:   
- 
PPS 
- 
mITT 
9.6.3 
Secondary Efficacy Endpoints 
Clinical and biochemical pregnancy rates, as well as rates of LH surge, will be compared between 
the pooled middle- and high-dose arms vs. the placebo arm using the same method to be applied to 
the primary efficacy analysis. 
Numbers of follicles with a mean diameter ≥ 14 mm and dominant follicles with a mean diameter 
≥ 18 mm in LutrePulse OmniPod SC 20 μg, 15 μg, and 10 μg groups will be compared to those in 
the placebo group using Wilcoxon’s rank sum test by stratifying based on the randomization 
scheme. 
The maximum P4 level and the mean P4 level from Days 19, 21, 23, 25, and 27 values in LutrePulse 
OmniPod SC 20 μg, 15 μg, and 10 μg groups will be compared to those in placebo group using an 
analysis of covariance (ANCOVA) model including the treatment group and randomization scheme 
as factors and mean baseline value as covariate. 
The proportion of subjects with at least one (1) post-baseline P4 level ≥ 10 ng/mL will be compared 
to placebo using the same statistical method to be applied to the primary efficacy analysis. 


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The mean FSH and LH on Day 10 calculated from all time points on a day as well as the change 
from baseline in LutrePulse OmniPod SC 20 μg, 15 μg, and 10 μg groups will be compared to those 
in the placebo group using an ANCOVA model including the treatment group and randomization 
scheme as factors and mean baseline value as covariate.  The E2 levels on Day 10 as well as the 
change from baseline in LutrePulse OmniPod SC 20 μg, 15 μg, and 10 μg groups will be compared 
to those in the placebo group using a similar ANCOVA model.  The change in the maximum value 
of FSH, LH, and E2 levels on Day 1 and Day 10 from the first value taken on Day 1 and Day 10, 
respectively, will be presented with descriptive statistics by treatment group.  The FSH, LH, and E2 
levels on Day 1 and Day 10 will be presented graphically by treatment group. 
9.7 
Extent of Exposure 
The total study treatment exposure, measured by total duration (calculated by treatment start and 
stop dates/times), will be summarized and listed for the Safety Population by treatment group. 
9.8 
Safety Analysis 
9.8.1 
General Considerations 
Complete listings and summary tables for all safety information, including adverse events, clinical 
laboratory safety data, physical examination, and vital signs, will be presented for subjects who are 
included in the Safety Population.  No formal statistical analysis will be performed. 
9.8.2 
Adverse Events 
Treatment-emergent adverse events (TEAEs) will be tabulated by System Organ Class (SOC) and 
Preferred Term (PT) using MedDRA for each treatment group.  The total number of subjects 
reporting a TEAE, the percentage of subjects (%) with a TEAE, and the number of TEAEs reported 
will be presented.  A TEAE will be any adverse event occurring after the start of IMP and within 
2 days after the last dose, or a pre-treatment adverse event or pre-existing medical condition that 
worsens in intensity after the start of IMP and within 2 days after the last dose.  All adverse events 
occurring after 2 days from the last dose will be categorized as post-treatment adverse events. 
In addition, TEAEs will be presented by causality (relationship to the study medication) and 
intensity (severity).  Deaths, serious adverse events, and adverse events leading to discontinuation 
will be listed. 
9.8.3 
Clinical Laboratory Variables 
Baseline and end-of-study laboratory values for each subject will be listed by test, and all values 
outside the normal range will be identified.  Mean changes from baseline to the end of study will be 
summarized by treatment group using descriptive statistics. 


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9.9 
Interim Analyses 
Two interim analyses are planned after approximately 9 and 12 patients per arm complete the study. 
The details of the interim analysis strategy are described in Section 9.6 and SAP.  
An independent data monitoring committee consisting of two unblinded clinicians and one 
unblinded statistician will be set up to review the interim analysis study results and make 
recommendations for the direction of the study, in accordance with the adaptive design decision-
making rules specified in Section 9.6. In addition, an independent statistician and programmer will 
be identified to generate the data analysis output. Individuals involved in the first and second 
interim analysis of the study will not be involved in the conduct of the study afterwards; individual 
patient identification will not be released to anyone who is directly involved in the conduct of the 
study. 
The interim analysis process, the measures used to protect the blind and the integrity of the study, 
the communication plan, and the confidentiality agreement will be described in a separate 
document. 


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10 DATA HANDLING  
10.1 
Source Data and Source Documents 
Source Data – 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 
For each subject allocated to treatment, the investigator will indicate in the hospital/medical source 
records that the subject participates in this trial and the date of obtaining the informed consent. The 
records should document data on the condition of the subject at the time the subject is enrolled in 
the trial to enable verification of eligibility.  Signed and dated Informed Consent Forms will be 
stored and archived according to local requirements.  In addition, the following information, at the 
minimum, will also be recorded in the hospital/medical source records for each subject: 
• Documentation of signed and dated informed consent 
• Subject’s name and date of birth 
• Screening/randomization number 
• Trial identification 
• Eligibility of participation in the trial (inclusion/exclusion) 
• Body weight and height 
• Dosing of IMP/NIMP–date of first and last dose 
• Occurrence of any AEs/SAEs (including description and duration) 


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• Medical history 
• Date of each visit 
• Any assessment performed 
• Any concomitant therapy 
• Status of the subject at the end of trial 
• Reason for discontinuation/withdrawal, if applicable 
The following documents collected during the trial should be stored and archived together with the 
subject’s hospital/medical records or in the Investigator File as agreed upon prior to the trial start at 
each trial site: 
• Laboratory print-outs from central and local laboratory – evaluated, signed, and dated by the 
investigator or a delegated sub-investigator 
• Patient dispensing logs of IMP 
• Evaluations of physical examinations 
• Collection of laboratory samples 
• Demographics 
• Known substance abuse 
10.2 
eCRF 
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. 
Data should be entered into the system within 5 working days after the subject has attended a visit 
or after the data become available, as applicable. 
The investigator will approve/authorize the eCRF entries for each subject with an electronic 
signature that is equivalent to a handwritten signature.   


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CONFIDENTIAL 
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 on a CD and will be provided to the 
investigator before access to the eCRF is revoked. 
Errors occurring in the eCRF will be corrected electronically.  Such corrections/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. 
For each subject enrolled, an eCRF will be completed and signed by the investigator. 
10.3 
Data Management 
A data management plan will be created under the responsibility of the Biometrics department.  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 describe captured methods, who is authorized to enter the data, 
decisions about ownership of data, source data storage, which data will be transferred (including 
timing of transfers), the origin and destination of the data, and who will have access to the data at 
all times. 
10.4 
Provision of Additional Information 
On request, the investigator will provide the Sponsor with additional data relating to the study, or 
copies of relevant source records, duly anonymized and protected in accordance with applicable 
requirements. 


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Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
11 MONITORING PROCEDURES 
11.1 
Periodic Monitoring 
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference of Harmonisation-Good Clinical Practice (ICH-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 to 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 randomized at the trial site, a 
monitoring visit will take place shortly afterwards.  For this trial, the frequency of the interim 
monitoring visits will be determined by the enrollment rate and will be detailed in the Monitoring 
Plan.   
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 IECs/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 IECs/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/randomization number will appear on these copies. 
The investigator should notify Ferring without any delay of any inspection by a regulatory authority 
or IEC/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 that consists of an assigned number in the trial.  Documents 
that are not for 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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Ferring Pharmaceuticals 
CONFIDENTIAL 
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 IEC(s)/IRB(s) 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 IEC(s)/IRB(s) approval/favorable opinion. 
12.2 
Deviations from the Protocol 
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 
answer to a query in the eCRF, in a protocol deviation report or a combination of both.  A log of 
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 2 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 IECs/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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CONFIDENTIAL 
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.  The final report may be used for the further development of the investigational product 
as considered necessary by Ferring.   
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 
Pharmaceuticals, Inc. 
13.3 
Publications and Public Disclosure 
13.3.1 
Publication Policy 
Submission of data for journal publication and/or presentation of data to scientific audiences may be 
considered by Ferring Pharmaceuticals Inc. and the investigator(s).  Submission of a manuscript for 
publication will be considered based on the merits of the study results.  The details of specific 
journal authorship will be discussed by the investigator(s) and the sponsor, with the final decision at 
the discretion of the sponsor.  The investigator(s) agrees the sponsor will have the opportunity to 
review (at least 30 days) all manuscripts and abstracts related to this study prior to any submission 
for presentation or publication.  Likewise, if the sponsor prepares a publication based on the results 
of this study, a copy of the manuscript will be provided to the investigator(s) prior to publication. 
Any external contract research organization or laboratory involved in the conduct of this study has 
no publication rights regarding this study. 
13.3.2 
Public Disclosure Policy  
The International Committee of Medical Journal Editors member journals have adopted a trials-
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) that is sponsored by the National 
Institutes of Health. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
14 ETHICAL AND REGULATORY ASPECTS 
14.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
An IEC/IRB will review the protocol and any amendments and advertisements used for recruitment.  
The IEC/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 IECs/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 Authorities 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 trial will end on the date of the last visit of the last subject (LSLV) ongoing in the trial.   
For public disclosure purposes, FDA uses the ‘primary completion date’ as a baseline point in time 
from which disclosure reporting of results is required.  The primary completion date is defined as 
the date of the final data collection specifically regarding the Primary Outcome Measure of a trial.  
(This could be the date the last subject was examined [e.g., LSLV] or the date the subject received 
intervention for the purpose of the final collection of data for the primary outcome). 
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, anticipated 
benefits, potential hazards, and any other aspects of the trial which 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 who has provided information to the subject regarding the trial 
before the subject is exposed to any trial-related procedure, including screening tests for eligibility. 


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CONFIDENTIAL 
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 IEC(s)/IRB(s) (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/IEC 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. 
For subjects not qualified to give their legal consent, the written informed consent must be obtained 
from the legal parent or guardian in accordance with national/local regulations.  If such subjects can 
understand the risks and benefits of the trial, they should also be informed and provide their written 
assent. 
14.6 
Compliance Reference Documents 
The Helsinki Declaration, the consolidated ICH-GCP, and other national laws in the countries 
where the trial takes place shall constitute the main reference guidelines for ethical and regulatory 
conduct. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
15 LIABILITIES AND INSURANCE 
15.1 
ICH-GCP Responsibilities 
The responsibilities of Ferring, the monitor and the investigator will be as defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place.  The investigator is responsible for adhering to the ICH-GCP responsibilities of investigators, 
for dispensing 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 
In case of any damage or injury occurring to a subject in association with the IMP or the 
participation in the trial, Ferring has contracted an insurance that covers the liability of Ferring, the 
investigator and other persons involved in the trial in compliance with the laws in the countries 
involved. 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
16 ARCHIVING 
16.1 
Investigator File 
The investigator is responsible for maintaining all the records that 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 (or longer if so 
required by local law) 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 that provides the sole link between named subject source records and 
anonymous CRF 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 (or longer if so 
required by local law) 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.  Documents may be transferred to Ferring 
Global Quality Assurance, for example, if the investigator retires and the documents no longer can 
be archived by the site. 
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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Ferring Pharmaceuticals 
CONFIDENTIAL 
17 REFERENCES 
1. 
Martin KA, Hall J, Adams J, Crowley Jr. WF.  Pulsatile GnRH in hypogonadotropic 
hypogonadism.  In: Filicori M, Flamigni C, eds.  Ovulation Induction: Basic Science and 
Clinical Advances.  Elsevier Science B.V., 1994:255-66. 
2. 
Filicori M, Flamigni C, Dellai P, Cognigni L, Michelacci L, Arnone R, et al.  Treatment of 
anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical 
results in 600 cycles.  J Clin Endocrinol Metab.  1994;79:1215-20. 
3. 
Christin-Maitre S, de Crécy M, pour le groupe Français des pompes à GnRH.  Pregnancy 
outcomes following pulsatile GnRH treatment: results of a large multicenter retrospective 
study.  Reçu le 18 août 2006 ; avis du comité de lecture le 23 octobre 2006; définitivement 
accepté le 7 décembre 2006.   
4. 
Handlesman DJ, Jansen RPS, Boylan LM, Spaliviero JA, Turtle JR.  Pharmacokinetics of 
gonadotropin-releasing hormone: comparison of subcutaneous and intravenous routes.  J 
Clin Endocrinol Metab.  1984;59:739-746. 
5. 
Ferring Study 2005-06: A Single-Center, Randomized, Open-Label, Pharmacokinetic Study 
of a Pulsatile GnRH Iontophoretic Patch Compared to Pulsatile GnRH Delivered via 
Intravenous (IV) and Subcutaneous (SC) Pump in Healthy Pre-menopausal Female Subjects.  
12 September 2005. 
6. 
Ferring Study 2005-09: A Single-Center, Randomized, Open-Label, Pharmacokinetic Study 
of a Pulsatile GnRH Iontophoretic Patch Compared to Pulsatile GnRH Delivered via 
Subcutaneous (SC) Pump in Healthy Pre-menopausal Female Subjects.  5 November 2007. 
7. 
Ferring Study 000010: A Randomized, Open-Label, 2-Way Crossover Pilot Study 
Evaluating Pharmacokinetics of Pulsatile GnRH Administered Subcutaneously (via 
OmniPod Pump) or Intravenously (via Zyklomat Pump) in Healthy Female Subjects.  
22 October 2012. 
8. 
Santoro N, Wierman ME, Filicori M, Waldstreicher J, Crowley WF Jr.  Intravenous 
administration of pulsatile gonadotropin-releasing hormone in hypothalamic amenorrhea: 
effects of dosage.  J Clin Endocrinol Metab.  1986;62:109-116. 
9. 
LutrePulse™ User Guide for OmniPod Pump.  Insulet Corporation, and Ferring, Inc., 2013. 
10. 
Provera® (medroxyprogesterone acetate) package insert.  Pharmacia & UpJohn Company, 
Division of Pfizer, September 2007. 
11. 
LutrePulse™ Healthcare Professional (HCP) Quick Reference Guide (Clinical), Ferring 
Inc., 2013. 


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Clinical Trial Protocol - Amendment 7 
Ferring Pharmaceuticals 
CONFIDENTIAL 
12. 
LutrePulse™ Guide for the Patient (Clinical), Ferring Inc., 2013. 
13. 
Clearblue®.  SPD Swiss Precision Diagnostics GmbH; distributed by Procter & Gamble, 
2009.   
14. 
Investigator’s Brochure.  LutrePulse OmniPod.  Ferring Pharmaceuticals, 2013. 
15. 
Hurley DM, Clarke IJ, Shelton R, Burger HG.  Subcutaneous administration of 
gonadotropin-releasing hormone: absorption kinetics and gonadotropin responses.  J Clin 
Endocrinol Metab.  1987 Jul;65(1):46-52. 
16. 
Martin K, Santoro N, Hall J, Filicori M, Wierman M, Crowley WF Jr.  Clinical Review 15: 
Management of ovulatory disorders with pulsatile gonadotropin-releasing hormone.  J Clin 
Endocrinol Metab.  1990;71:1081A-1081G. 
17. 
Golan A, Ron-El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian Hyperstimulation 
Syndrome: An Update Review. Obstetrical and Gynecological Survey. 1989;44:6:430-440. 
18. 
Kong, L, Koch, G, Liu, T, Wang, H.  Performance of some multiple testing procedures to 
compare three doses of a test drug and placebo. Pharmaceutical Statistics.  2005;4,25-35. 
19. 
Jung, S.-H. Stratified Fisher’s exact test and its sample size calculation. Biometrical J. 
2014;56. doi: 10.1002/bimj.201300048. 
 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
18 APPENDICES 
Appendix I – Subject’s Confidential Non-Disclosure Affidavit 
 
CONFIDENTIAL NON-DISCLOSURE AFFIDAVIT 
 
 
I, ____________________________________, agree to keep confidential my study medication 
assignment provided to me by: _______________________, Study Coordinator. 
 
On this date: _________________________, I agree not to discuss or to disclose the dose of my 
study medication assigned to me with the study doctor and anyone other than the above Study 
Coordinator in order to protect the integrity of the data being collected for this clinical research 
study. I understand that the study doctor will not know my study medication assignment and will 
not be allowed to ask me questions about my study medication assignment. If I have questions 
concerning my study medication assignment, I agree to use the following contact information.   
 
Study Contact: _________________________________________ 
 
Study Contact Number:  __________________________________ 
 
SIGNATURES 
I have read this affidavit and understand the above information. The content and meaning of this 
information has been explained to me.   
 
 
_________ 
 
_____________________ 
 
___________________________ 
Date/Time 
 
Print Subject Name       
    
Subject Signature 
   
 
 
________ 
 
_____________________ 
 
___________________________ 
Date/Time 
 
Name of Person conducting       
Signature of Person conducting    
 
 
 
Discussion 
 
 
       
Discussion 
 
 
Copy of signed/dated confidential non-disclosure affidavit given to subject on (date) __________ 
by ___________ (initials) 
 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Appendix II – Subject Diary Card 
 
Front of card 
 
                                  Site Number:  ____  ____  ____      
                            Subject Initials:  ____  ____  ____ 
                   Subject Number:  ____  ____  ____  ____   
If you have any questions regarding your 
appointment, please contact the study site. 
Coordinator: _________________________________ 
Phone:  _____________________________________ 
BRING THIS CARD WITH YOU TO ALL OF YOUR APPOINTMENTS AT THE STUDY SITE. 
Start completing this diary card on your first day of treatment. 
• Your OmniPod will be applied at the site on Treatment Days 1 and 10. 
• Change your OmniPod every 4th day at the same time of day +/- one (1) hour. 
• Record each Omnipod change on this card on the corresponding day even if the change is unscheduled. 
• Record any unscheduled changes, pod malfunctions, application errors or other issues/concerns in the 
Notes/Comments field.  There is also a field for Additional Notes.  
Day 
Date 
Time of OmniPod Application 
Notes/Comments 
Day 1 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________    
          hr                 min        
    AM 
    PM 
 
 
 
 
Day 4 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________    
          hr                 min        
    AM 
    PM 
 
 
 
 
Day 7 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________    
          hr                 min        
    AM 
    PM 
 
 
 
 
Day 10 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________    
          hr                 min        
    AM 
    PM 
 
Were you instructed to start LH testing?  If so, 
don’t forget to enter your testing information on 
the back of the card!  
Day 13 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________    
          hr                 min        
    AM 
    PM 
 
Were you instructed to start LH testing?  If so, 
don’t forget to enter your testing information on 
the back of the card!  
Day 16 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________    
          hr                 min        
    AM 
    PM 
 
Were you instructed to start LH testing?  If so, 
don’t forget to enter your testing information on 
the back of the card!  
Day 19 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________    
          hr                 min        
    AM 
    PM 
 
Were you instructed to start LH testing?  If so, 
don’t forget to enter your testing information on 
the back of the card!  
ADDITIONAL NOTES: 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Back of card 
 
 
• Bring this card with you to all of your appointments. 
• Change your OmniPod every 4th day at the same time of day +/- one (1) hour. 
• Record each Omnipod change on this card on the corresponding day even if the change is unscheduled. 
• Record any unscheduled changes, pod malfunctions, application errors or other issues/concerns in the 
Notes/Comments field.  There is also a field for Additional Notes. 
Day 
Date 
Time of OmniPod Application 
Notes/Comments 
Day 22 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________      
          hr                 min          
    AM 
    PM 
 
Day 25 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________      
          hr                 min          
    AM 
    PM 
 
Day 28 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________      
          hr                 min          
    AM 
    PM 
 
Day 31 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________      
          hr                 min          
    AM 
    PM 
 
Day 34 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________      
          hr                 min          
    AM 
    PM 
 
Day 37 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________      
          hr                 min          
    AM 
    PM 
 
 
Day 37 can be included if applicable. 
Day 
______ 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________      
          hr                 min          
    AM 
    PM 
 
This is an unspecified day.  It can be included if 
applicable. 
Day 
______ 
________/_______/________ 
    mm              dd             yyyy 
 _________:_________      
          hr                 min          
    AM 
    PM 
 
This is an unspecified day.  It can be included if 
applicable. 
LH Surge Testing 
and Detection 
with Clearblue® 
Ovulation Kit 
Date Clearblue testing began:         _________ /________ /__________ 
                                                                               mm             dd                yyyy 
Date Clearblue testing is positive:  _________ /________ /__________  
 
 
 
                                mm             dd                yyyy 
Sexual Intercourse:   You must engage in sexual intercourse on the day that your Clearblue test is positive, on 
the day following your positive test, and per your doctor’s instruction after that.  Enter the date(s) of sexual 
intercourse below for each day that applies. 
Day 
Date 
Did you have sexual intercourse on this day? 
Day of positive Clearblue test 
______ /______ / ______ 
     mm            dd             yyyy 
 Yes          No 
1 day after positive Clearblue test 
______ /______ / ______ 
     mm            dd             yyyy 
 Yes          No 
2 days after positive Clearblue test 
______ /______ / ______ 
     mm            dd             yyyy 
 Yes          No 
3 days after positive Clearblue test 
______ /______ / ______ 
     mm            dd             yyyy 
 Yes          No 
ADDITIONAL NOTES:  ___________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 
___________________________________________________________________________________________ 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
Title of trial:  
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating Three Doses of Subcutaneous Pulsatile GnRH Administered via 
OmniPod Pump for Ovulation Induction in Female Subjects with Primary 
Amenorrhea with Hypogonadotropic Hypogonadism  
NCT number: 
NCT01976728 
Sponsor trial code: 
000070 
Date:  
07 Dec 2017 
 
 
 
 
 


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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Evaluating Three 
Doses of Subcutaneous Pulsatile GnRH Administered via OmniPod Pump for Ovulation 
Induction in Female Subjects with Primary Amenorrhea with Hypogonadotropic 
Hypogonadism 
 
 
Trial Code 000070 
 
 
Investigational Product: 
LutrePulse OmniPod 
 
Indication: 
Primary Hypothalamic Amenorrhea 
 
Phase: 
III 
 
Author: 
 
 
Date of issue: 
December 7, 2017 
 
Version: 
Amendment 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
Change log 
 
Version 
No. 
 
Effective 
Date 
 
Reason for the Change / Revision 
 
Supersedes 
V1.0 
Jul 11, 2017 
SAP based on Protocol Amendment 6 
dated June 30, 2017. 
 
Amend
ment 1 
Dec 7, 2017 
1. Per protocol amendment 7, the 
definition for the primary efficacy 
endpoint of ovulation is changed. 
Subjects who had a confirmed 
positive serum β-hCG (i.e., 2 positive 
results) or presence of a gestational 
sac documented by transvaginal 
ultrasound (TVUS) is considered as 
ovulatory, even if the subject did not 
have any post-baseline P4 ≥6 ng/mL. 
2. The positive LH surge rate is added as 
a secondary efficacy endpoint. 
V1.0 


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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
  
TABLE OF CONTENTS 
 
TABLE OF CONTENTS .............................................................................................................. 3 
1 
Introduction ....................................................................................................................... 6 
1.1 
Definitions/ Abbreviations.......................................................................................... 6 
1.1.1 
Definition of Terms ..................................................................................... 6 
1.1.2 
Abbreviations ............................................................................................. 6 
2 
Trial Objectives and Endpoints ........................................................................................... 8 
2.1 
Primary Objective ..................................................................................................... 8 
2.2 
Secondary Objectives ................................................................................................ 8 
2.3 
Primary Endpoint ...................................................................................................... 8 
2.4 
Secondary Endpoints ................................................................................................. 8 
2.4.1 
Progesterone Level...................................................................................... 8 
2.4.2 
Pregnancy .................................................................................................. 8 
2.4.3 
Ovarian Follicular Development.................................................................... 8 
2.4.4 
Luteal Phase Support ................................................................................... 9 
2.4.5 
Pharmacodynamic (PD) Endpoints ................................................................ 9 
2.4.6 
Safety Endpoints ......................................................................................... 9 
3 
Trial design .......................................................................................................................10 
3.1 
General Design Considerations ..................................................................................10 
3.2 
Determination of Sample Size ....................................................................................10 
3.3 
Randomization, Blinding, and Replacement of Subjects .................................................11 
4 
Subject Disposition ............................................................................................................13 
5 
Protocol Deviations ............................................................................................................14 
6 
Analysis sets ......................................................................................................................15 
6.1 
Intent-To-Treat Analysis Set ......................................................................................15 
6.2 
Full-Analysis Set .....................................................................................................15 
6.3 
Modified Intent-To-Treat Analysis Set ........................................................................15 
6.4 
Per Protocol Analysis Set ..........................................................................................15 
6.5 
Safety Analysis Set ..................................................................................................15 
7 
Trial population ................................................................................................................16 
7.1 
Demographics and Other Baseline Characteristics .........................................................16 
7.1.1 
Demographics ...........................................................................................16 
7.1.2 
Vital Signs at Baseline ................................................................................16 
7.1.3 
Laboratory Efficacy/Pharmacodynamic Parameters at Baseline .........................16 
7.2 
Medical History .......................................................................................................16 
7.3 
Prior and Concomitant Medication..............................................................................16 
7.4 
Physical Examination ...............................................................................................17 
8 
Exposure and Treatment Compliance .................................................................................18 
8.1.1 
Extent of Exposure .....................................................................................18 
8.1.2 
Treatment Compliance ................................................................................18 
9 
Efficacy.............................................................................................................................19 


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Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
9.1 
General Considerations .............................................................................................20 
9.2 
Primary Endpoint(s) .................................................................................................20 
9.2.1 
Primary Variable Analysis...........................................................................20 
9.2.1.1 
Bayesian Adaptive Design Rules................................................21 
9.2.1.2 
Sensitivity Analyses.................................................................23 
9.3 
Secondary Endpoint(s) ..............................................................................................23 
9.3.1 
Progesterone Level.....................................................................................23 
9.3.2 
Pregnancy .................................................................................................23 
9.3.3 
Ovarian Follicular Development...................................................................23 
9.3.4 
Luteal Phase Support ..................................................................................23 
9.4 
Pharmacodynamic Parameters....................................................................................24 
10 
Safety ...............................................................................................................................25 
10.1 
General Considerations .............................................................................................25 
10.2 
Adverse Events........................................................................................................25 
10.2.1 
Partial/Missing Dates for Adverse Events ......................................................25 
10.2.2 
Overview of Treatment-Emergent Adverse Events ..........................................26 
10.2.3 
Incidence of Adverse Events ........................................................................26 
10.3 
Safety Laboratory Variables ......................................................................................27 
10.3.1 
Summary Statistics.....................................................................................27 
10.3.2 
Laboratory Variable Changes Relative to Normal Range ..................................27 
10.3.3 
Markedly Abnormal Changes.......................................................................28 
10.3.4 
Data Listings .............................................................................................28 
10.3.5 
Urinalysis .................................................................................................28 
10.4 
Vital Signs and ECGs ...............................................................................................28 
10.4.1 
Vital Signs ................................................................................................28 
10.4.1.1 
Summary Statistics ..................................................................28 
10.4.1.2 
Markedly Abnormal Changes ....................................................28 
10.4.1.3 
Data Listings ..........................................................................28 
10.4.2 
ECGs .......................................................................................................28 
10.5 
Other Safety Variables ..............................................................................................29 
10.5.1 
Pregnancy Test ..........................................................................................29 
10.5.2 
Serological Test .........................................................................................29 
10.5.3 
Ovarian Hyperstimulation Syndrome (OHSS) ................................................29 
11 
Interim analyses ................................................................................................................30 
12 
Deviations from protocol analysis .......................................................................................31 
13 
References.........................................................................................................................32 
14 
Tables, Listings and Figures ...............................................................................................33 
15 
Appendix ..........................................................................................................................33 
15.1 
Schedule of Events ...................................................................................................33 
15.2 
More on the Bayesian Adaptive Design .......................................................................35 
15.2.1 
Design Flow Diagram .................................................................................35 
15.2.2 
Example Trials ..........................................................................................36 
15.2.3 
Simulation Studies .....................................................................................40 
15.2.4 
Control of Type I Error ...............................................................................54 
15.2.5 
Computational Details ................................................................................55 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
15.3 
Additional Missing Data Handling Procedures..............................................................55 
15.4 
Analysis Visit Windows ............................................................................................56 
15.5 
Markedly Abnormal Laboratory Safety Values and Vital Signs .......................................57 
 
 


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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
1 
Introduction 
This document describes the data analysis specifications for Ferring Pharmaceuticals protocol 
LutrePulse OmniPod titled: “A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating Three Doses of Subcutaneous Pulsatile GnRH Administered via OmniPod Pump for 
Ovulation Induction in Female Subjects with Primary Amenorrhea with Hypogonadotropic 
Hypogonadism”. This version of the statistical analysis plan dated December 7, 2017 was prepared 
in accordance with the protocol LutrePulse OmniPod, Trial ID 000070, Amendment 7, dated 
December 6, 2017. Other related documents are the electronic case report form (eCRF), data 
definition fields and data set definitions. 
 
The purpose of this Statistical Analysis Plan (SAP) is to provide greater and more technical details 
of the pre-planned statistical analyses described in the statistical section of the Clinical Trial 
Protocol. It aims to answer the protocol objectives in a statistically rigorous fashion using methods 
identified prior to database lock. Any deviations from these methods must be documented in the 
final clinical study report. Specifications of tables, figures, and data listings are contained in a 
separate document (Table shells). 
1.1 
Definitions/ Abbreviations 
1.1.1 
Definition of Terms 
Terms 
Definitions 
Randomised 
Subject randomised to trial treatment 
Screened 
Subject who enters the screening phase 
OmniPod 
A disposable delivery pump for drug delivery with a handheld 
wireless controller (the Manager) for SC drug delivery 
OmniPod Manager 
A wireless, handheld device that programs the OmniPod with the 
subject’s LutrePulse delivery instructions and wirelessly monitors 
the OmniPod’s operation  
Unblinded Coordinator 
Assigned by the investigator prior to the start of the study and 
will be unblinded to the subject’s study drug assignment (dose 
only) and will be responsible for the set-up of the OmniPod 
Manager, distribution and accountability of the drug.  
 
 
1.1.2 
Abbreviations 
Abbreviations 
Meaning of abbreviations in document 
AE 
Adverse Event 
ANCOVA 
ATC 
GLM 
ITT 
FAS 
Analysis of Covariance  
Anatomical-Therapeutic-Chemical 
General Linear Model 
Intent-to-Treat 
Full Analysis Set 
PPS 
SAS 
NPAR1WAY 
IMP 
Per-Protocol Set 
Statistical Analysis System 
Non-Parametric One-Way Analysis of Variance 
Investigational Medicinal Product 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Abbreviations 
Meaning of abbreviations in document 
HH 
LH 
eCRF 
FSH 
ECG 
E2 
P4 
PRL 
TSH 
TVUS 
FHM 
GnRH 
CT 
MedDRA 
MRI 
mITT 
-hCG 
Hypogonadotropic Hypogonadism 
Luteinizing Hormone 
Electronic Case Report Form 
Follicle-Stimulating Hormone 
Electrocardiography 
Estradiol 
Progesterone 
Prolactin 
Thyroid-Stimulating Hormone 
Transvaginal Ultrasound 
Fetal Heart Movement 
Gonadotropin-Releasing Hormone 
Computed Tomography 
Medical Dictionary for Regulatory Activities 
Magnetic Resonance Imaging 
Modified Intent-to-Treat 
Beta human Chorionic Gonadotropin  


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
2 
Trial Objectives and Endpoints 
2.1 
Primary Objective 
• To compare the ovulation rate in women with primary amenorrhea with hypogonadotropic 
hypogonadism (HH) following each of 3 doses (10 g, 15 g, and 20 g per pulse) of 
subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) administered with the 
LutrePulse OmniPod Pump versus placebo  
2.2 
Secondary Objectives 
• To evaluate clinical pregnancy rate  
• To evaluate biochemical pregnancy rate  
• To evaluate positive LH surge rate 
• To evaluate ovarian follicular development  
• To evaluate luteal phase support with GnRH 
• To evaluate pharmacodynamic parameters  
• To evaluate the safety of LutrePulse OmniPod SC 
2.3 
Primary Endpoint 
• Ovulation rate, calculated as a proportion of subjects with at least 1 post-baseline 
progesterone (P4) level ≥ 6 ng/mL as measured by a central laboratory a confirmed positive 
serum β-hCG (i.e., 2 positive results) or presence of a gestational sac documented by 
transvaginal ultrasound (TVUS). 
2.4 
Secondary Endpoints 
2.4.1 
Progesterone Level 
• Proportion of subjects with at least 1 post-baseline progesterone (P4) level ≥ 10 ng/mL 
2.4.2 
Pregnancy 
Clinical pregnancy rate 
• 
Proportion of subjects with presence of gestational sac and fetal heart movement (FHM) 
on transvaginal ultrasound (TVUS) at approximately 2 to 4 weeks after second positive 
serum beta human chorionic gonadotropin (-hCG) test 
Biochemical pregnancy rate 
• 
Proportion of subjects with a confirmed positive (i.e., 2 positive results) serum beta 
human chorionic gonadotropin (-hCG) test 14 + 4 days post LH surge  
2.4.3 
LH surge detection 
• Proportion of subjects with a positive detection of LH surge on their Clearblue tests 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
2.4.4 
Ovarian Follicular Development 
• Number  of follicles with a mean diameter ≥ 14 mm  
• Number of dominant follicles with a mean diameter ≥ 18 mm  
2.4.5 
Luteal Phase Support 
• Maximum P4 levels from Days 19, 21, 23, 25, and 27 
• Mean P4 levels from Days 19, 21, 23, 25, and 27 
2.4.6 
Pharmacodynamic (PD) Endpoints 
• FSH and LH change from baseline in relation to the first GnRH pulse on Day 1 and Day 10  
• Mean serum FSH and LH levels on Day 1 and Day 10 
• Estradiol (E2) serum levels on Day 1 and Day 10 
2.4.7 
Safety Endpoints 
• Adverse events (type, frequency, causality, intensity and seriousness) 
• Clinical chemistry, haematology, urinalysis 
• Frequency and severity of ovarian hyperstimulation syndrome (OHSS) 
 
 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
3 
Trial design 
This multicenter, randomized, double-blind, placebo-controlled study will be performed in women 
with primary amenorrhea with HH who desire pregnancy. Subjects with primary amenorrhea with 
HH will be treated with 1 of 3 doses of pulsatile GnRH or placebo, administered SC via the 
OmniPod pump manufactured by Insulet. The treatment duration with LutrePulse OmniPod SC or 
placebo can be approximately 5 weeks. It is expected that the response to treatment will occur 
within 2 to 3 weeks after therapy initiation. When LH surge is detected by urine kit, therapy should 
be continued for approximately another 2 weeks to maintain corpus luteum (continue until 
confirmatory serum pregnancy test). Subjects will discontinue treatment either at the onset of 
menses or negative or positive confirmatory serum pregnancy test. Subjects will be required to 
return to the study site for pharmacodynamic blood draws, TVUS, serum pregnancy tests, and 
safety follow-up assessments. 
The study will consist of 3 periods: Screening (includes progestin challenge test), Treatment 
(includes pituitary priming and treatment phase), and Follow-up. 
3.1 
General Design Considerations 
Approximately 60 subjects will be randomly assigned to 1 of 4 treatment arms:  
 
• LutrePulse OmniPod SC 10 g  (Test Product) 
• LutrePulse OmniPod SC 15 g  (Test Product) 
• LutrePulse OmniPod SC 20 g  (Test Product) 
• Placebo (10, 15, or 20 g /pulse as a fixed “dose”)         
 
Subjects will receive consecutive pulses of GnRH or placebo, each delivered at 90-minute intervals, 
for up to 37 days of treatment. Each OmniPod will be worn for 3 full days (Days 1-3, 4-6, 7-9, etc. 
up to Day 37) and will be replaced every 4th day (i.e., Day 4, Day 7, Day 10, etc.). New OmniPod 
pumps should be applied at approximately the same time as the first pump. Randomized fixed doses 
of either 10 g, 15 g, or 20 g will be programed into the OmniPod Manager and subcutaneously 
delivered to the subject. For every 10 g, 15 g, or 20 g dose the subject will receive 10 μL, 15 
μL, or 20 μL amount of volume with the same concentration of drug per pulsatile injection. Placebo 
doses will receive the same amount of volume respectively as the Lutrepulse OmniPod dose 
without active drug substance. 
3.2 
Determination of Sample Size 
The sample size was determined based on the original fixed parallel group study design. The true 
ovulation rate for LutrePulse OmniPod SC 20μg, 15μg, 10μg, and placebo was assumed to be 70%, 
65%, 60%, and 1%, respectively. Under these assumptions, a sample size of 14 subjects per group 
(total 56 subjects) will provide at least 80% power to detect differences between LutrePulse 
OmniPod SC 20μg and placebo, 15μg and placebo, and 10μg and placebo in ovulation rate 
separately with the stratified one-sided Fisher’s exact tests at an overall significance level of 0.025 
with the closed testing procedure (Kong et al., 2005). Approximately 60 subjects will be 
randomized by assuming up to 4 subjects may be ineligible to the Full Analysis Set. 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
3.3 
Randomization, Blinding, and Replacement of Subjects 
All eligible subjects will be randomly assigned at least 3 days before Treatment Day 1, based on the 
computer-generated randomization list provided by the designated unblinded statistician.  Any 
relevant information pertaining to the generation of the randomization list including the block size 
will only be communicated from the sponsor to the unblinded statistician. 
 
The first 15 eligible subjects will be randomly assigned to 1 of 3 treatment arms: LutrePulse 
OmniPod SC 10 g, LutrePulse OmniPod SC 20 g, or OmniPod SC placebo in a 1:1:1 ratio.  The 
subsequent 25 eligible subjects will be randomly assigned to LutrePulse OmniPod SC 10 g, 
LutrePulse OmniPod SC 15 g, LutrePulse OmniPod SC 20 g, or OmniPod SC placebo in a 
1:2:1:1 ratio.  The rest of the eligible subjects will be randomly assigned to LutrePulse OmniPod 
SC 10 g, LutrePulse OmniPod SC 15 g, LutrePulse OmniPod SC 20 g, or OmniPod SC placebo 
in a 1:1:1:1 ratio.   
To maintain the blind, the placebo subjects will be randomized to the equivalent dosing setting in 
the Manager for 10 g /pulse or 20 g /pulse for the first 15 eligible subjects and 10 g /pulse, 
15 g /pulse, or 20 g /pulse for the subsequent randomization schemes.   
Table 1 displays the estimated number of subjects randomized to each treatment arm. The three 
placebo groups with different dose settings will be pooled as a single placebo group for all data 
summaries and analyses. The LutrePulse 20 g will be compared to (Placebo I + Placebo II + 
Placebo III), LutrePulse 15 g will be compared to (Placebo I + Placebo II + Placebo III), and 
LutrePulse 10 g will be compared to (Placebo I + Placebo II + Placebo III). 
 
The randomization assignment will be available to the OmniPod Manager programmer (Unblinded 
Coordinator) with respect to dose only (but will remain blinded to assigned study drug, whether 
active or placebo). The randomization assignment will not be available to any other site personnel 
involved in the conduct and evaluation of the study until the study database is declared clean and is 
released to the statistician.   
 
Subjects who discontinue early from the study for any reason will not be replaced. 
Table 1 
Treatment arms 
Treatment Arm 
Treatment 
Estimated # 
of Patients 
Entering 
Treatment 
Formulation and 
Dose of Study Drug 
Frequency 
Admin. Route 
LutrePulse 
OmniPod SC 20 
g 
LutrePulse 
20 g / pulse 
15 
20 g dose in white 
powder reconstituted 
in 20 L saline with 
0.9% sodium 
chloride 
90-minute 
intervals daily 
SC pulsatile 
injection 
Via OmniPod pump 
LutrePulse 
OmniPod SC 15 
g 
LutrePulse 
15 g / pulse 
15 
15 g dose in white 
powder reconstituted 
in 15 L saline with 
0.9% sodium 
chloride 
90-minute 
intervals daily 
SC pulsatile 
injection 
Via OmniPod pump 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
LutrePulse 
OmniPod SC 10 
g 
LutrePulse 
10 g / pulse 
15 
10 g dose in white 
powder reconstituted 
in 10 L saline with 
0.9% sodium 
chloride 
90-minute 
intervals daily 
SC pulsatile 
injection 
Via OmniPod pump 
OmniPod SC 
Placebo I 
Placebo 20 
g / pulse 
5 
20 L saline with 
0.9% sodium 
chloride 
90-minute 
intervals daily 
SC pulsatile 
injection 
Via OmniPod pump 
OmniPod SC 
Placebo II 
Placebo 15 
g / pulse  
5 
15 L saline with 
0.9% sodium 
chloride 
90-minute 
intervals daily 
SC pulsatile 
injection 
Via OmniPod pump 
OmniPod SC 
Placebo III 
Placebo 10 
g / pulse  
5 
10 L saline with 
0.9% sodium 
chloride 
90-minute 
intervals daily 
SC pulsatile 
injection 
Via OmniPod pump 
 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
4 
Subject Disposition 
The number and percentage of randomized subjects treated with Investigational Medicinal Product 
(IMP), prematurely discontinued, and completing the study will be summarized.  
A subject who has an increased risk of developing multiple gestation/OHSS (4 or more follicles 
with a mean diameter ≥ 15 mm by TVUS and E2 levels ≥ 1200 pg/mL) will be immediately 
discontinued from treatment. In addition, any clinically important adverse physical or symptomatic 
findings/events and/or abnormal laboratory findings that are above the pre-specified critical values 
defined in the laboratory manual will be grounds for discontinuation from the study. Subjects who 
fail to respond to study treatments (no LH surge) and withdraw from study treatments with less than 
14 days of study treatment exposure will be considered as an early discontinuation. For subjects 
with at least 14 days of study treatment exposure, the end of study visit is required for the subject to 
be considered as a completer.  
All post-baseline discontinuations will be summarized by reason for early termination. Subjects 
screened but not randomized/allocated to treatment will be presented with the reason(s) for screen 
failure in a data listing. All withdrawals from trial will be summarised with frequency and 
percentage for each category of withdrawal reason. 


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Statistical Analysis Plan 
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CONFIDENTIAL 
5 
Protocol Deviations 
The criteria for protocol deviations considered major with the implication of data exclusions from 
the per-protocol analysis set will be identified and documented by Ferring clinical team/project 
management based on a review of data listings prior to database lock.  
Major protocol deviations may include major violations of the inclusion/exclusion criteria, missing 
randomization, errors in treatment assignment, significant noncompliance to the dosing 
administration, or other serious violations. 
Number and percentage of subjects with any major and minor deviations will be tabulated for each 
category of protocol deviation for descriptive purposes by treatment group. 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
6 
Analysis sets 
6.1 
Intent-To-Treat Analysis Set 
All randomized (as planned) subjects will be included in the ITT analysis set. 
6.2 
Full-Analysis Set 
All randomized subjects who are included in the ITT analysis set and received at least 14 days of 
study drug for pituitary priming will be included in the FAS. 
6.3 
Modified Intent-To-Treat Analysis Set 
All randomized subjects who received at least one pulsatile injection delivery of study drug will be 
included in the mITT Population. 
6.4 
Per Protocol Analysis Set 
All subjects who are included in the FAS and did not have exclusionary major protocol deviations 
will be included in the PPS. 
6.5 
Safety Analysis Set 
All subjects who received at least one pulsatile injection delivery of study drug will be included in 
the Safety Population. Subjects are analysed according to the actual treatment received.   
 
Table 2 
Treatment group variables vs. analysis set 
Analysis Set 
Analysis Set 
Population Flag 
Treatment Variable Used in Analysis 
Variable Label 
Variable Name 
(Character) 
Variable Name 
(Numeric) 
Intent-To-Treat 
Analysis Set 
ITTFL 
Planned Treatment 
TRTP 
TRTPN 
Full-Analysis Set 
FASFL 
Planned Treatment 
TRTP 
TRTPN 
Modified Intent-To-
Treat Analysis Set 
mITTFL 
Planned Treatment 
TRTP 
TRTPN 
Per Protocol 
Analysis Set 
PPROTFL 
Planned Treatment 
TRTP 
TRTPN 
Safety Analysis Set 
SAFFL 
Actual Treatment 
TRTA 
TRTAN 
 
 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7 
Trial population 
7.1 
Demographics and Other Baseline Characteristics 
A summary of demographics and other baseline characteristics will be presented for the subjects in 
the FAS by treatment group. No statistical testing for baseline differences will be performed. 
 
Categorical (discrete) data will be summarized using numbers and percentages. The percentages 
will be 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. 
7.1.1 
Demographics 
Descriptive statistics of baseline demographics variables (e.g., age, race and ethnic origin, height, 
weight and BMI) will be summarized for the subjects in the FAS by treatment group. 
7.1.2 
Vital Signs at Baseline 
Baseline vital signs will be summarised in the FAS by treatment group. 
7.1.3 
Laboratory Efficacy/Pharmacodynamic Parameters at Baseline 
Baseline assessments of safety laboratory tests (haematology, chemistry and urinalysis) and other 
laboratory tests (urine pregnancy, LH, FSH, E2, P4) will be summarized for the subjects in the FAS 
by treatment group. The baseline values for all laboratory/pharmacodynamics parameters will be 
the values obtained at the last assessment prior to the first dose of IMP. 
7.2 
Medical History 
Medical and gynecologic history recorded at screening visit will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) at the latest version available at the time of interim 
or final analysis, and will be listed and summarized by system organ class (SOC) and preferred 
term (PT). 
7.3 
Prior and Concomitant Medication 
Prior and concomitant medication will be coded using World Health Organisation Drug 
(WHODrug) Dictionary version September 1, 2013 and summarised by anatomical-therapeutic-
chemical (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 (i.e. with stop date 
before date of first IMP administration); 
2) Concomitant medication, i.e. medication taken during the treatment period (i.e. medication 
that was not stopped before date of first IMP-administration). 
 
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. Concomitant medication 


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will be subdivided into ongoing (started before first IMP administration) and treatment-emergent 
(starting after first IMP administration) concomitant medication. 
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 
8.1.1 
Extent of Exposure  
The total duration of study treatment exposure defined as 
Date of last OmniPod application – Date of first OmniPod application  +3 
will be summarized descriptively and listed for the Safety Population by treatment group. 
8.1.2 
Treatment Compliance  
Summary (descriptive) statistics will be presented for the number of OmniPods applied by each 
patient and the treatment compliance during the patient’s actual treatment period, defined as the 
actual days of treatment exposure divided by the patient’s total treatment exposure duration. The 
actual days of treatment exposure is the sum of the durations of individual applications. For each 
OmniPod applicatiom, the duration is calculated as: date of next application – date of current 
application, or 3, whichever is smaller.  For the last application, it is equal to 3. 
. 


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9 
Efficacy 
A Bayesian adaptive design is adopted to address the following objectives: 
1. Demonstrate superiority of the pooled middle and high doses over placebo 
2. Evaluate the dose-response relationship 
The adaptive design includes two interim analyses, conducted after approximately 9 and 12 patients 
per arm enrolling in the study, respectively. Each interim analysis provides opportunities for 
stopping the trial early due to efficacy success utilizing the group sequential strategy or due to 
efficacy futility through Bayesian predictive probability of success. Furthermore, it allows the low 
dose to be dropped following the interim look if it shows a much lower response rate compared 
with the middle and high doses.  
Each interim analysis will result in one of the following outcomes: 
1. Continue the trial with all arms 
2. Continue the trial without the low dose 
3. Declare early success, but continue the trial without placebo 
4. Declare early success and stop the trial (both placebo and low dose dropped) 
5. Stop the trial for futility 
When the primary efficacy analysis is not successful at the interim analysis, and if the ovulation 
rate in the low-dose arm is sufficiently low, satisfying 
                                           Rlow < (Rhigh +middle) – 0.2,                                                      (1) 
then the trial will continue without the low dose, resulting in outcome #2 above. Note that Rlow and 
Rhigh +middle in the inequality (1) above are the observed ovulation rates in the low dose arm and the 
combined middle- and high-dose arms, respectively. However, if inequality (1) is not satisfied, then 
the trial will continue with all arms (outcome #1).  
Conversely, when success on the primary efficacy analysis is declared at an interim analysis, if the 
response rate in the low-dose arm meets the condition in inequality (1), then the trial is completed 
at this point (outcome #4) with dose selection performed using the ED80 rule (see below).   
In the case the primary efficacy analysis is successful, but the response rate in the low-dose arm is 
within 20% from the combined low- and high-dose success rate, the trial is not stopped 
immediately. Rather, the trial will continue to enroll additional patients into the low-, middle- and 
high-dose arms to further assess dose responses (outcome #3).  
Finally, the trial may terminate (outcome #5) as a result of a low predictive probability of success 
(<0.05) given the data collected at the interim analysis.  
At the end of the study, for a trial that achieves efficacy success, the dose to be selected is the ED80 
dose, defined as the lowest dose that retains at least 80% of the largest treatment effect, i.e.  
                                  (RED80 – Rplacebo) ≥ (Rmaximum – Rplacebo) ×0.8,                                   (2) 
where Rmaximum is the observed ovulation rate in the most effective dose arm, Rplacebo is the observed 
ovulation rate in the placebo arm, and RED80 is the observed ovulation rate in the selected dose arm. 
A flow diagram is presented in Figure 1 of Section 15.2.1 to illustrate the decision tree for the two-
interim adaptive design. Further details, such as the criteria for efficacy success using the group 
sequential method, the Bayesian predictive probability of future success to determine futility, the 


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rationales behind the 20% threshold to drop low dose, the ED80 dose-selection rule and dose-
response evaluations are described in Section 9.2.1.1. Simulation results to assess operating 
characteristics of the design are given in Section 15.2. 
9.1 
General Considerations 
Sites from all countries/regions (US, Canada) will be pooled for all analyses.  No stratification by 
site will be made in the analysis. 
Unless otherwise noted, data will be summarized in tabular format by treatment group using 
summary tables and data listings. All study data documented on the eCRFs will be included in the 
study data listings.  
All efficacy analyses will be conducted for the FAS. The three placebo groups with different dose 
settings will be pooled as a single placebo group for all efficacy summaries and analyses. 
Continuous variables will be described with the number of non-missing values, mean, standard 
deviation (SD), median, and minimum/maximum values. Categorical variables will be described 
with the number and percentage of subjects with each level. Missing values will not be included in 
the calculation of percentages. All individual subject data will be listed. 
The software used for all summary statistics and statistical analyses will be SAS Version 9.2 or 
later. 
9.2 
Primary Endpoint(s) 
9.2.1 
Primary Variable Analysis 
The primary efficacy endpoint is the ovulation rate calculated as the proportion of subjects who had 
at least one post-baseline P4 level ≥ 6 ng/mL or pregnancy confirmed by at least 2 positive  serum 
-hCG tests or detection of gestational sac on transvaginal ultrasound (TVUS). The denominator 
will be based on all subjects in the FAS. Subjects who do not have a confirmed pregnancy, or at 
least one P4 level ≥ 6 ng/mL due to the P4 levels never reaching this threshold, missing data, early 
withdrawal, or any other reason will be counted as not having ovulation (treatment failure). 
The primary efficacy analysis will compare the pooled ovulation rate of LutrePulse OmniPod SC 
20 g and 15 g to placebo. Let Phigh+middle and Pplacebo be the underlying ovulation rates in the 
combined middle- and high-dose arms and the placebo arm, respectively. The hypotheses for the 
one-sided statistical testing are: 
𝐻0:𝑃ℎ𝑖𝑔ℎ+𝑚𝑖𝑑𝑑𝑙𝑒≤ 𝑃𝑝𝑙𝑎𝑐𝑒𝑏𝑜, 
vs. 
𝐻0:𝑃ℎ𝑖𝑔ℎ+𝑚𝑖𝑑𝑑𝑙𝑒> 𝑃𝑝𝑙𝑎𝑐𝑒𝑏𝑜. 
The hypotheses are tested using a stratified one-sided Fisher’s exact test (Jung et al., 2014) in the 
FAS including the randomization scheme as the stratification factor. The SAS PROC FREQ with 
permutation-based Cochran-Mantel-Haenszel test with exact p-value derived from all possible 
permutations will be employed for the calculation of p-value for the stratified Fisher’s exact test. 


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Jung has shown that the stratified Fisher’s exact test is equivalent to the exact stratified Mantel-
Haenszel test when exact p-value is derived from all possible permutations.  
9.2.1.1 
Bayesian Adaptive Design Rules 
This section provides details for the decision rules to be implemented in the Bayesian adaptive 
study design.  
Success criterion using group sequential strategy 
To account for the multiplicities introduced by early success interim analyses, Pocock boundaries 
are used. Thus, the success threshold at each analysis corresponds to a nominal p-value < 0.0131 to 
maintain an overall one-sided type I error rate of 0.025.  
The simulation results in Figure 13 for Scenario 7 in Section 15.2.3, as well as the justification 
provided in Section 15.2.4, show that the type I error is well controlled under the null hypothesis 
using the success boundary. 
Futility criterion  
Given the data collected at each interim time point, we compute the Bayesian predictive probability 
that the primary analysis will meet the success threshold once all arms have n = 15 subjects. If the 
predictive probability is less than 0.05, then the trial will be declared as a failure and terminate at 
this point due to futility. 
The Bayesian predictive probability is calculated in the following fashion. First, for each arm d, we 
determine the number of future subjects required to complete the study, 𝑚𝑑. Then, the number of 
future responders occurring in arm d, 𝑍𝑑, is generated from a Beta-Binomial distribution:  
(𝑍𝑑|𝑛𝑑,𝑥𝑑) ~ 𝐵𝑒𝑡𝑎𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙 (𝑚𝑑,𝑎+ 𝑥𝑑,𝑏+ 𝑛𝑑−𝑥𝑑), 
where 𝑛𝑑,𝑥𝑑 are the numbers of subjects and responders in arm d observed at interim analysis, and 
a non-informative prior Beta distribution with parameters a = 0.5 and b = 0.5 is used independently 
for each arm.  
A large number of predicted values are sampled from the Beta-Binomial distribution for each arm, 
resulting in 1000 “complete” datasets. The predictive probability of eventual trial success is then 
the proportion of these complete datasets for which the primary analysis success threshold is met 
(p-value < 0.0131).  
 
Dropping the low dose 
If the observed response rate for the low dose meets the condition in inequality (2), then low dose 
will be dropped from additional enrolment, should the trial need to continue with the high dose, 
middle dose and placebo to assess the primary efficacy endpoint at the next analysis timing.  
The remaining sample size that had been planned for the low dose will be reallocated among the 
remaining arms. Thus the sample size for the placebo, middle, and high doses may either be 9, 12, 
15, 16, or 17 subjects, depending on whether early success is declared, and whether low dose is 
dropped at the first or second interim analysis. 


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The 20% threshold to drop low dose is chosen based on the ED80 dose-selection rule, as the 
maximum of the most effective treatment effect can reach 100% (with the success rate in the 
placebo group expected to be close to 0). It ensures that when the threshold is met, the low dose 
does not qualify as the ED80 dose.  Furthermore, we present in Table 3 below the Bayesian 
predictive probabilities of selecting low dose as ED80, should it proceed to a later analysis, for a 
range of borderline interim analysis observations where the 20% threshold is just met. A non-
informative prior Beta (0.5, 0.5) is used for all treatment arms and 10000 predictions were 
generated. The results show that such probabilities are small: <10% in all cases and <5% in all but 
three cases. Therefore, 20% is a justifiable choice for the threshold to drop low dose early. 
Table 3 
Bayesian Predicted Probability of Selecting Low Dose as ED80 at a Later 
Analysis when Low Dose was Dropped Early 
 N per arm 
at interim 
analysis 
N per arm 
at later 
analysis 
Observed n (%) of successes at 
interim analysis 
Diff* 
(%) 
Probability of 
selecting low dose as 
ED80 if continue 
with low dose 
High-dose 
Mid-dose 
Low-dose 
9 
12 
6 (67.8) 
4 (44.4) 
3 (33.3) 
-22.2 
0.0207 
 
 
5 (55.6) 
5 (55.6) 
3 (33.3) 
-22.2 
0.0735 
 
 
5 (55.6) 
4 (44.4) 
2 (22.2) 
-27.8 
0.0059 
 
 
5 (55.6) 
3 (33.3) 
2 (22.2) 
-22.2 
0.0062 
 
 
4 (44.4) 
4 (44.4) 
2 (22.2) 
-22.2 
0.0159 
 
15 
6 (67.8) 
4 (44.4) 
3 (33.3) 
-22.2 
0.0304 
 
 
5 (55.6) 
5 (55.6) 
3 (33.3) 
-22.2 
0.0672 
 
 
5 (55.6) 
4 (44.4) 
2 (22.2) 
-27.8 
0.0136 
 
 
5 (55.6) 
3 (33.3) 
2 (22.2) 
-22.2 
0.0201 
 
 
4 (44.4) 
4 (44.4) 
2 (22.2) 
-22.2 
0.0555 
12 
15 
8 (75.0) 
6 (50.0) 
4 (33.3) 
-25.0 
0.0015 
 
 
7 (58.3) 
6 (50.0) 
4 (33.3) 
-20.9 
0.0231 
 
 
7 (58.3) 
5 (41.7) 
3 (25.0) 
-25.0 
0.0012 
 
 
7 (58.3) 
4 (33.3) 
3 (25.0) 
-20.8 
0.0014 
 
 
6 (50.0) 
5 (41.7) 
3 (25.0) 
-20.8 
0.0211 
 
 
6 (50.0) 
4 (33.3) 
2 (16.7) 
-25.0 
0.0011 
 
 
5 (41.7) 
5 (41.7) 
2 (16.7) 
-25.0 
0.0059 
 
 
5 (41.7) 
4 (33.3) 
2 (16.7) 
-20.8 
0.0173 
Diff* is the difference in observed success rates between the low-dose group vs. the pooled high- and mid-dose groups  
Dose-response evaluation and dose-selection 
For trials that meet the primary analysis success threshold, we will subsequently select the ED80 
dose, the lowest effective dose satisfying inequality (2). The ED80 dose will be labeled as such in 
the primary efficacy analysis table. 
• As noted earlier, when the primary efficacy success is already declared at an interim 
analysis, but the success rate in the low-dose arm is not sufficiently low compared to the 
combined low- and high-dose success rate, the trial will continue to enroll more patients in 
the three dose arms only. Although no additional patients will be randomized to placebo, the 
success rate estimated from the enrolled placebo patients will be used in inequality (2) to 
determine the ED80 for the study. 


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9.2.1.2 
 Sensitivity Analyses  
The primary comparison between the pooled middle- and high-dose arms vs. the placebo arm for 
the primary variable will be conducted on the following analysis sets as sensitivity analyses:   
- 
PPS 
- 
mITT 
- 
ITT 
9.3 
Secondary Endpoint(s)  
9.3.1 
Progesterone Level 
The proportion of subjects with at least 1 post-baseline progesterone (P4) level ≥10 ng/mL will be 
compared between the pooled middle- and high-dose arms vs. the placebo arm using the same 
method to be applied to the primary variable analysis in Section 9.2.1.  
9.3.2 
Pregnancy 
Clinical and biochemical pregnancy rates in LutrePulse OmniPod SC 20μg and 15μggroups will be 
compared between the pooled middle- and high-dose arms vs. the placebo arm using the same 
method to be applied to the primary variable analysis in Section 9.2.1. 
9.3.3 
LH surge detection 
The positive LH surge rate in LutrePulse OmniPod SC 20μg and 15μg groups will be compared 
between the pooled middle- and high-dose arms vs. the placebo arm using the same method to be 
applied to the primary variable analysis in Section 9.2.1. 
9.3.4 
Ovarian Follicular Development 
Number of follicles with a mean diameter ≥ 14 mm and number of dominant follicles with a mean 
diameter ≥ 18 mm, collected from Days 10, 11, until LH surge or Day 21, in LutrePulse OmniPod 
SC 20μg, 15μg, and 10μg groups will be compared to those in the placebo group at each time point 
(analysis visit windows defined in Section 15.4) using Wilcoxon’s rank sum test stratified on the 
randomization scheme (van Elteren, 1960). SAS PROC FREQ with modified ridit score 
(MODRIDIT option) will be used for the stratified Wilcoxon rank sum test. Summary statistics 
including median will be presented. 
9.3.5 
Luteal Phase Support 
The maximum P4 level and the mean P4 level from Days 19, 21, 23, 25, and 27 values in 
LutrePulse OmniPod SC 20μg, 15μg, and 10μg groups will be compared to those in the placebo 
group using an analysis of covariance (ANCOVA) model including the randomization scheme and 
treatment group as factors and baseline value as covariate.  
 
Whenever the ANCOVA is performed, the least squares mean difference of the treatment groups, 
and 95% confidence intervals and p-values for the LutrePulse OmniPod SC 20μg, 15μg, and 10μg 
groups versus the placebo group based on the fitted linear model will be reported. Type III sum-of-
squares for the least-squares means will be used for the statistical comparisons. PROC GLM will be 
used for ANCOVA in SAS.   
The baseline is the value obtained at the last assessment prior to the first dose of IMP. 


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9.4 
Pharmacodynamic Parameters 
The mean FSH and LH on Day 10 calculated from all post-dose time points (i.e. 5, 15, 30, 60, and 
90 minutes after the first dose), as well as the mean change from Day 10 pre-treatment (prior to first 
dose) in LutrePulse OmniPod SC 20μg, 15μg, and 10μg groups will be compared to those in the 
placebo group using an ANCOVA model including the randomization scheme and treatment group 
as factors and Day 10 pre-treatment value as covariate. 
 
The E2 level on Day 10 (measured only at pre-treatment) as well as the change from baseline (Day 
1 pre-treatment) in LutrePulse OmniPod SC 20μg, 15μg, and 10μg groups will be compared to 
those in the placebo group using an ANCOVA model including the randomization scheme and 
treatment group as factors and baseline value as covariate.  
 
The change in the maximum post-treatment value of FSH and LH on Day 1 and Day 10 from the 
pre-treatment value taken on Day 1 and Day 10, respectively, will be presented with descriptive 
statistics by treatment group.  
 
The FSH and LH levels on Day 1 and Day 10 will be presented graphically by treatment group (i.e. 
scatter plots over all time points: Baseline, 5, 15, 30, 60, and 90 minutes after the first dose). 


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10 
Safety 
10.1 
General Considerations 
Safety parameters will be evaluated for the Safety Analysis data set. 
The three placebo groups with different dose settings will be pooled as a single placebo group for 
all safety summaries and analyses. 
 
10.2 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
 
All Adverse Events (AEs) and unanticipated adverse device effects will be listed, documenting all 
information as on the eCRF. Verbatim terms of AEs will be coded to the MedDRA preferred terms 
(PT) and related system organ classes (SOC) using the Medical Dictionary for Regulatory 
Activities (MedDRA). The latest MedDRA version available at the time of interim analysis or final 
analysis will be applied.  
 
A treatment emergent adverse event (TEAE) will be any adverse event occurring after start of IMP 
and within 5 days after the last application, or a pre-treatment adverse event or pre-existing medical 
condition that worsens in intensity after start of IMP and within 5 days after the last application. All 
adverse events occurring after 5 days from the last application will be categorized as post-treatment 
adverse events. 
Note: Collection of AEs on the eCRF will begin after the informed consent form (ICF) is obtained 
from the patient. Any AE prior to the signed ICF will be recorded in the medical history. 
Written narratives will be issued for all serious AEs (including deaths) and AEs leading to 
withdrawal. 
10.2.1 
Partial/Missing Dates for Adverse Events 
For any adverse event that has a missing or incomplete start date, a query will be issued to capture 
the full date. If only a partial date is reported for the start of an AE, a complete date will be 
estimated using the following algorithm: 
 
• Only the year is reported (i.e., missing the month and day): The date of the first dose of 
investigation product will be used as the start of the AE. 
 
• The year and month are reported (i.e., missing the day): The first day of the month will be 
imputed or the date of the first dose, whichever is later. 
 
The month and day are reported (i.e., missing the year): Only situations where the year is self-
evident will be allowed. 


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No imputation will be applied to the incomplete AE end date. The rationale is that one should have 
a start date for all subject AEs but may not have end dates for AEs that resolve after subject is off 
study or AEs that are continuing. 
10.2.2 
Overview of Treatment-Emergent Adverse Events 
An AE overview summary table will be prepared including the number of subjects reporting an AE, 
the percentage of subjects (%) with an AE, and the number of events (E) reported, for the following 
categories:  
• Treatment-emergent adverse events 
• Deaths  
• Serious adverse events  
• Adverse events leading to withdrawal  
• Severe adverse events  
• Adverse drug reactions 
10.2.3 
Incidence of Adverse Events 
Treatment-emergent adverse events will be summarised in a Table by SOC and PT for MedDRA. 
The Table will display the total number of subjects reporting an AE, the Treatment-emergent 
adverse events (TEAEs) will be tabulated by MedDRA SOC and PT by treatment group. The total 
number of subjects reporting a TEAE, the percentage of subjects (%) with a TEAE, and the number 
of TEAEs reported will be presented. The order of SOCs presented in tables will be in alphabetic 
order of SOCs according to MedDRA. Within each SOC, the preferred terms will be shown in 
decreasing frequency of occurrence. 
Summary tables will be prepared for: 
• All adverse events 
• Adverse events by causality (related/unrelated) 
• Adverse events leading to death 
• Adverse events by intensity 
• Serious adverse events  
• Adverse events leading to withdrawal 
Note: Patients who have multiple events in the same SOC and/or preferred term will be counted 
only once at each level of summation (overall, by SOC, and by preferred term) in the tables. For 
summaries of AEs by severity, only the highest severity of AE will be counted at each level of 
summation (overall, by SOC, and by preferred term) in the tables. For summaries of related AEs, 
patients with more than one related AE will be counted only once at each level of summation 
(overall, by SOC, and by preferred term) in the tables. Treatment-related means ‘Reasonable 
possibility’ of relationship to investigational product according to investigator. If a subject has an 
AE with unknown intensity, then the subject is counted in the category of ‘Severe’. If a subject has 


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an AE with unknown relationship to IMP then the subject is counted in the category of ‘Reasonable 
possibility’. 
Supporting data listings will be provided for: 
• All adverse events sorted by centre and subject no. 
• All adverse events sorted by MedDRA Preferred Term 
• Serious adverse events  
• Adverse events leading to death 
• Adverse events leading to withdrawal 
10.3 
Safety Laboratory Variables 
Baseline for all laboratory analyses will be the values obtained at the last assessment prior to the 
first dose of the investigational medicinal product (IMP). 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 “Haematology”, “Clinical Chemistry” or “Urinalysis” 
10.3.1 
Summary Statistics 
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. 
All laboratory parameters, values, units, normal ranges, flags collected (normal/abnormal) in the 
clinical database will be included in by-patient listings for further medical review. 
10.3.2 
Laboratory Variable Changes Relative to Normal Range 
Changes relative to normal ranges are presented with shift tables with total number of subjects, and 
number and % of subjects who experienced a shift by treatment period. 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. 
• Absent:  
No value for measured variable (for urinalysis only) 
• Present:  
Any value obtained for measured variable (for urinalysis only) 
For all haematology and clinical chemistry variables, shift tables will be prepared to compare 
baseline values to the worst in-treatment value. More specifically, for haematology and clinical 
chemistry, tables presenting the changes from Low or Normal to High and from High or Normal to 


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Low will be provided. For urinalysis variables, shift tables will summarise the number (%) of 
subjects who had “absent” values at baseline and “present” values during the treatment period.  
10.3.3 
Markedly Abnormal Changes 
A summary table will be prepared that displays for each laboratory variable the number and 
percentage of subjects in each treatment group with normal baseline values who had at least one 
pre-specified markedly abnormal value anytime during the treatment period. Pre-specified 
markedly abnormal criteria for laboratory tests are given in Section 15.5.   
10.3.4 
Data Listings 
Data listings will be prepared by treatment group and centre for all subjects with any abnormal 
laboratory value at any time-point (including screening, baseline).  
10.3.5 
Urinalysis 
Incidence of changes in urinalysis will be summarised by treatment group. A summary table with 
number of subjects with change from Absent at baseline to Present during trial will be summarised.  
10.4 
Vital Signs and ECGs 
10.4.1 
Vital Signs 
Baseline for all vital signs analyses will be the values obtained at the last assessment prior to the 
first dose of IMP. Treatment-emergent vital signs data will include tests completed after the first 
dose of IMP through the time of residual drug effect. End of trial will include the last post-baseline 
observation during the trial. 
10.4.1.1 
Summary Statistics 
Mean change and mean percentage (%) change from baseline at 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.  
10.4.1.2 
Markedly Abnormal Changes 
Summary tables will be prepared displaying the number and percentage of subjects with normal 
baselines who had one or more pre-specified markedly abnormal treatment-emergent values, 
according to the definition in Section 15.5. 
10.4.1.3 
Data Listings 
Data listings will be prepared by treatment group and centre for all subjects with any abnormal vital 
signs value at any time-point (including screening, baseline). 
10.4.2 
ECGs 
12-lead ECG will be collected for subjects who report chest pain or are symptomatic of chest pain 
any time during the study (unscheduled visit).  
 


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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Treatment-emergent ECG data will include evaluations completed after the first dose of IMP 
through the time of residual drug effect.  
Data listings will be prepared by treatment group and centre for all subjects with 12-lead ECG 
value at any time-points during the study. 
10.5 
Other Safety Variables 
10.5.1 
Pregnancy Test 
Pregnancy Test results will be presented in by-patient listings for further medical review. Any 
positive test results for pregnancy reported during study will be noted in the clinical study report.  
10.5.2 
Serological Test 
Serological test results for hepatitis B, hepatitis C, and HIV I and II will be presented in by-patient 
listings.  
10.5.3 
Ovarian Hyperstimulation Syndrome (OHSS) 
The frequency and severity of ovarian hyperstimulation syndrome will be presented in by-patient 
listings and summary tables as for AEs. 


Date: 07 Dec 2017 
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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
11 
Interim analyses 
Two interim analyses are planned after approximately 9 and 12 patients per arm complete the study. 
The details of the interim analysis strategy are described in Section 9.2.  
An independent data monitoring committee consisting of two unblinded clinicians and one 
unblinded statistician will be set up to review the interim analysis study results and make 
recommendations for the direction of the study, in accordance with the adaptive design decision-
making rules specified in Section 9.2.1. In addition, independent statistician and programmer will 
be identified to generate the data analysis output. Individuals involved in the first and second 
interim analysis of the study will not be involved in the conduct of the study afterwards; individual 
patient identification will not be released to anyone who is directly involved in the conduct of the 
study. 
The interim analysis process, the measures used to protect the blind and the integrity of the study, 
the communication plan, and the confidentiality agreement will be described in a separate 
document. 
 


Date: 07 Dec 2017 
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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
12 
Deviations from protocol analysis 
 


Date: 07 Dec 2017 
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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
13 
References 
[1] International Federation of Pharmaceutical Manufacturers and Associations. Medical Dictionary 
for Regulatory Activities (MedDRA). Version 10.1. Reston, Virginia, USA; 2008. 
 
[2] WHO Collaborating Center for International Drug Monitoring. WHO Drug Dictionary. July 
2008 edition. Uppsala, Sweden; 2008. 
 
[3] SAS Institute Inc. SAS Version 9.1. Cary, NC, USA; 2002-2003. 
 
[4] Kong, L, Koch, G, Liu, T, Wang, H.  Performance of some multiple testing procedures to 
compare three doses of a test drug and placebo. Pharmaceutical Statistics.  2005;4,25-35. 
 
[5] Jung, S.H. Stratified Fisher’s exact test and its sample size calculation. Biometrical J. 2014;56. 
doi: 10.1002/bimj.201300048. 
 
[6] van Elteren, P. H. (1960). "On the combination of independent two-sample tests of Wilcoxon," 
Bulletin of the International Statistical Institute, 37, 351-361. 


Date: 07 Dec 2017 
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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
14 
Tables, Listings and Figures 
The document with tables, figures and listings (TLF) shells will be presented in a separate 
document.  
15 
Appendix  
 
15.1 
Schedule of Events 
Procedure 
Screening 
(Day -60 
to Day -3) 
Treat
ment 
Day 1 
Treatm
ent Day 
10 
Follicle 
≥ 18 m
m and 
LH 
surge 
Days 19, 
21, 23, 
25, and 
27 
14 (+4 days) 
post LH 
surge and 
3 days later 
2 to 4 weeks 
from 2nd 
positive 
serum ß-
hCG test 
End-
of-
Study 
Visita 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
Medical/gynecologic 
history 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
X 
Gynecological exam 
X 
 
 
 
 
 
 
X 
Vital signs 
X 
 
 
 
 
 
 
X 
Safety laboratory tests 
X 
 
 
 
 
 
 
X 
Hepatitis B, C, & HIV 
screen 
X 
 
 
 
 
 
 
 
Hormones: PRL, TSH 
X 
 
 
 
 
 
 
 
TVUS 
X 
 
X   –   Xb 
 
 
Xc 
 
Semen analysis 
X 
 
 
 
 
 
 
 
Progestin challenge 
testd 
X 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
X 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
 
X 
 
 
 
 
Xe 
Blood samples for E2 
X 
X 
X 
X 
 
 
 
 
Hormones: LH, FSH 
X 
Xf 
Xf 
 
 
 
 
 
Blood samples for P4 
X 
X 
 
 
X 
 
 
 
Randomization 
 
Xg 
 
 
 
 
 
 
OmniPod applicationh 
 
X 
 
 
 
 
 
 
Clearblue testingi 
 
 
 
     X 
 
 
 
 
Begin sex intercoursej 
 
 
 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Follow up phone callk 
 
 
 
 
 
 
 
X 
a. 
The end-of study visit will be performed for all subjects who discontinue early or the day of 2nd negative serum 
pregnancy test or documented fetal heart movement for subjects with clinical pregnancy.  
b. Follicular size monitoring 
c. 
If fetal heartbeat is not documented, the subject may return in 7 days for another TVUS. 
d. Subjects with uterine bleeding within 5 days of the last dose of medroxyprogesterone acetate will be considered 
screen failures. 
e. 
A urine pregnancy test should be performed at the End-of-Study visit for those who discontinue the study early and 
have no positive pregnancy results during the study. 


Date: 07 Dec 2017 
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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
f. 
On Day 1 (pre-treatment baseline) and Day 10 (post-treatment) LH and FSH samples will be collected at 0 hour 
(first sample taken prior to dosing) and 5, 15, 30, 60, and 90 minutes after the first dose is administered.   
g. Randomization will occur 3 days before Treatment Day 1. 
h. The first OmniPod applied will remain on the subject until Day 4, when the second OmniPod will be applied at 
approximately the same time that the first was applied; each OmniPod will be worn for 3 full days. 
i. 
When follicles ≥ 14 mm are detected on TVUS, Clearblue tests are dispensed to the subject to be administered at 
home each day at approximately the same time between 8 AM and 11 AM until a positive test result occurs. 
j. 
Intercourse to begin at confirmed Clearblue LH surge  
k.    For subjects who achieve biochemical pregnancy – collect ongoing pregnancy rate and birth data 
 
 
 
 


Date: 07 Dec 2017 
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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
15.2 
More on the Bayesian Adaptive Design 
15.2.1 
Design Flow Diagram 
Figure 1 illustrates the possible decisions that may be made at each interim analysis. There are 15 
possible pathways to reach a trial decision, annotated by the circled numbers on the plot. 
For example, the paths numbered 1, 3, 4, 6, 8, 9, 10, 12, and 14 represent paths ending in success, 
and are shaded by green. Of those, paths numbered 1, 3, 4, 6, 8, and 9 declare early success at an 
interim, with paths 8 and 9 continuing enrolment to the final analysis to assess dose response. 
Paths numbered 2, 5, and 7 result in early futility at an interim analysis and paths 11, 13, and 15 fail 
at the final analysis. All of these are shaded in pink. 
The boxes shaded blue indicate trials for which the low dose is dropped at an interim analysis, but 
enrolment continues on the placebo, middle, and high dose arms. Orange boxes indicate that 
enrolment continues with all arms. 
 
Figure 1 
Flowchart of possible trial outcomes 
 
 


Date: 07 Dec 2017 
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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
15.2.2 
Example Trials 
Example Trial 1 
A schematic of the first example trial is shown in Figure 2. The trial pathway is indicated by the 
colored boxes, with the observed data shown below. 
The first interim occurs after 9 subjects per arm have outcomes. In this example, there were 0 
responders on the placebo arm and 10 responders pooled across the middle and high doses. The p-
value for the pooled arms versus placebo is 0.0052, which crosses the early success threshold. 
Furthermore, there was only 1 responder on the low dose, so that the difference in observed 
response rates is 0.667 (ͲǤ͹͹ͺ െͲǤͳͳͳ). Since this difference is larger than 0.20, the low dose is 
determined not to be the best arm and is dropped from the study. 
Since both the placebo and the low dose have been dropped, the trial stops accrual. The high dose 
has the highest response rate, and is also the ED80 (shaded in blue in the data table) since the 
middle dose does not achieve at least 80% of the effect seen on the high dose. 
 
 
Figure 2 
Simulation results from Example Trial 1 
 
 
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Date: 07 Dec 2017 
E-Statistical Analysis Plan-21977;Ver.1.0 
Supersedes: None 
Page 37 of 59 
 
 
 
Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Example Trial 2 
The second example trial is shown in Figure 3. At the first interim, this trial is similar to the first, 
except on the low dose. In this trial, early success is declared, but since the low dose response rate 
is equal to the pooled response rate, the low dose will not be dropped. Thus, since superiority to 
control has been demonstrated, the placebo arm is dropped, but accrual continues on the 
investigational arms. 
The second interim occurs when each remaining arm has ݊ൌͳʹ subjects. Since no additional 
subjects have been recruited to the placebo arm, this row is greyed out in the data table. Again, the 
low dose performs similarly to the pooled middle and high dose arms. Thus, the trial continues to 
the final analysis with the low, middle, and high dose arms. 
At the final analysis, the high dose has the highest observed response rate with 11 responders out of 
15 subjects (73.3%). The low dose, with 9 responders (60.0%) is selected as the ED80. 
 
 
Figure 3 
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Date: 07 Dec 2017 
E-Statistical Analysis Plan-21977;Ver.1.0 
Supersedes: None 
Page 38 of 59 
 
 
 
Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Example Trial 3 
In the third example (Figure 4), the pooled response rate at the first interim is 44.4% (8 total 
responders, with 3 on the middle dose and 5 on the high dose) versus 0% on placebo. The p-value is 
0.0197 which does not meet the early success threshold. The predictive probability of eventual trial 
success is 86.1%, so the trial does not stop for futility. The low dose response rate is only 22.2%, 
which is more than 20% lower than the pooled response rate. Thus, the low dose is dropped, and 
accrual continues on the placebo, middle, and high dose arms. 
The second interim occurs when the remaining arms each have 12 subjects. Since the last interim, 
there is one new responder on the high dose, and no new responders on the placebo or middle dose 
arms. The p-value for the pooled versus placebo is 0.0139, which is not sufficient to declare early 
success. The predictive probability is still above the futility threshold, so the trial continues to the 
final analysis. 
Since the low dose was dropped at the first interim with only 9 subjects, the remaining 6 slots that 
would have been allocated to the low dose have been redistributed to the remaining arms. Thus, 
each arm at the final analysis has ݊ൌͳ͹ subjects rather than ݊ൌͳͷ. The p-value for the Fisher 
Exact test is 0.0011, so the trial meets success at the final analysis. The high dose is selected as the 
ED80. 
 
 
Figure 4 
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Date: 07 Dec 2017 
E-Statistical Analysis Plan-21977;Ver.1.0 
Supersedes: None 
Page 39 of 59 
 
 
 
Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Example Trial 4 
At the first interim of example trial 4 (Figure 5), the response rate is a modest 20-30% on the 
investigational arms. No responses were observed on the placebo. The trial does not declare early 
success, but has high enough predictive probability to continue. Additionally, the low dose is not 
sufficiently lower than the pooled arms to be dropped. Thus, the trial continues enrolling subjects to 
all arms. 
At the second interim, there are ݊ൌͳʹ subjects allocated to each arm. No additional responses 
were observed on the low dose, which had only 2 responders (16.7%). The response rate for the 
pooled middle and high doses is now 41.7%. Neither the early success nor futility criteria were met. 
However, the low dose response rate is no longer within 20% of the pooled, so it will be dropped. 
The 3 remaining slots for the low dose are redistributed so that each remaining arm will receive one 
additional subject. 
The final analysis occurs with ݊ൌͳ͸ subjects each on the placebo, middle, and high dose arms. 
The p-value for the primary analysis is 0.0205, resulting in trial failure. 
 
 
Figure 5 
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Date: 07 Dec 2017 
E-Statistical Analysis Plan-21977;Ver.1.0 
Supersedes: None 
Page 40 of 59 
 
 
 
Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Example Trial 5 
Figure 6 shows the fifth example trial. In this example, only 3 responses combined were observed 
on the middle and high dose arms, for a rate of 16.7%. The predictive probability of eventual trial 
success is 0.015, resulting in early futility. 
 
Figure 6 
Simulation results from Example Trial 5 
 
15.2.3 
Simulation Studies 
The operating characteristics of this trial were determined through trial simulation. We 
hypothesized several scenarios for the underlying performance of the control and investigational 
arms, and simulated the entire trial multiple times under each scenario. In each virtual trial, the 
interim analyses were conducted according to the pre-specified rules, and results were tracked for 
each trial, including whether the trial was successful, whether the low dose was dropped, the 
sample size per arm, etc. This section describes the algorithm and the parameters that were used to 
simulate subject-level data for the virtual trials. These assumptions are used only in the generation 
of virtual subjects for the simulations, and are not part of the analysis of subject data (virtual or 
real). 
We simulate individual subject responses from a Bernoulli distribution where the true response 
rates per arm are given in the following table for different scenarios. We assume that the placebo 
rate is 1% in all scenarios. We consider a null scenario in which all arms are equal to placebo, and 
scenarios that vary the treatment effect. In some scenarios, the low dose is similar to the middle and 
high doses while in other scenarios, it is considerably lower. 
 
 
 
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Date: 07 Dec 2017 
E-Statistical Analysis Plan-21977;Ver.1.0 
Supersedes: None 
Page 41 of 59 
 
 
 
Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Table 4 
Response rate profiles 
 
Placebo Low Middle High 
3 
0.01 
0.01 
0.01 
0.01 
4 
0.01 
0.10 
0.20 
0.40 
5 
0.01 
0.10 
0.40 
0.40 
6 
0.01 
0.10 
0.40 
0.50 
7 
0.01 
0.20 
0.60 
0.60 
8 
0.01 
0.50 
0.65 
0.75 
9 
0.01 
0.60 
0.65 
0.70 
Operating Characteristics 
Operating characteristics of the design are presented graphically so that all possible trial pathways 
may be represented. Additional summaries presented in tabular form include: 
• The proportion of trials with the following outcomes: 
• Success (either at an interim or final analysis). For non-null scenarios, this number is the 
power of the trial 
• Early success (all trials that met the early success criterion, regardless of whether enrolment 
continued without the placebo arm in order to address dose response) 
• Early futility 
• The average sample size per arm and overall 
• The proportion of trials for which each arm was selected as the ED80 (note: no arm is 
selected for unsuccessful trials) 
For all operating characteristics in this section, the results are based on 10000 virtual trials per 
scenario. 
Scenario 1: 0.01, 0.60, 0.65, 0.70 
In this scenario, all doses are highly effective. The power of the trial exceeds 99%, with most trials 
declaring early success at an interim. Of the 10000 simulated trials, 9332 trials (93.3%) declared 
early success at the first interim. Of those, 2782 trials also dropped the low dose at the same time 
(ending the trial), and 6550 dropped the placebo and continued with only the investigational arms. 
Of those trials, 570 trials dropped the low dose at the second interim, while the remaining 5980 
trials continued to the final analysis with all investigational arms. The average sample size reflects 
the tendency of trials to declare early success, with the placebo arm having, on average, 9.2 subjects 
(smaller than the investigational arms). In truth, the low dose is quite effective, so it is rarely 
dropped, and it is selected as the ED80 in 45.6% of trials. 
 


Date: 07 Dec 2017 
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Statistical Analysis Plan 
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CONFIDENTIAL 
 
Figure 7 
Operating Characteristics for Scenario 1: 0.01, 0.60, 0.65, 0.70 
 
 
 


Date: 07 Dec 2017 
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Scenario 2: 0.01, 0.50, 0.65, 0.75 
In this scenario, there is a larger range between the low dose and high dose response rates. The low 
dose response rate is exactly 20% lower than the combined middle and high doses. 
This scenario also has quite high power, and is more likely to stop the trial early due to declaring 
early success and dropping the low dose. Roughly half of the trials (50.5%) ended at the first 
interim, with an additional 45% declaring early success at the first interim, but continuing the trial 
(without the placebo arm). The average sample size tends to be smaller in this scenario, since more 
trials end early. The middle dose is most likely to be selected as the ED80. 


Date: 07 Dec 2017 
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Statistical Analysis Plan 
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CONFIDENTIAL 
 
 
Figure 8 
Operating Characteristics for Scenario 2: 0.01, 0.50, 0.65, 0.75 
 
 
 


Date: 07 Dec 2017 
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Statistical Analysis Plan 
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CONFIDENTIAL 
Scenario 3: 0.01, 0.20, 0.60, 0.60 
In this scenario, the middle and high doses are equivalent, each having a 60% response rate (less 
effective than previous scenarios, but still highly effective relative to placebo). The low dose 
response rate is 40% lower than the combined middle and high doses, so we expect it to be dropped 
in a large percentage of trials. 
In fact, since the pooled middle and high doses are effective and the low dose is inferior to pooled, 
most trials are able to declare early success and stop the trial early: 76.5% of trials declare success 
and stop at the first interim, and an additional 14.7% (353+235+885 trials) ended with success at 
the second interim. There were 459 trials that declared early success at an interim, but continued 
enrolling the low dose to the final analysis. The middle dose was selected as the ED80 in 72% of 
trials. 


Date: 07 Dec 2017 
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Trial Code: 000070  
Statistical Analysis Plan 
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CONFIDENTIAL 
 
Figure 9 
Operating Characteristics for Scenario 3: 0.01, 0.20, 0.60, 0.60 
 
 
 


Date: 07 Dec 2017 
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Statistical Analysis Plan 
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Scenario 4: 0.01, 0.10, 0.40, 0.50 
In this scenario, the pooled response rate for the middle and high doses is 45%. This smaller effect 
is reflected in lower power relative to the previous scenarios. 
The trial stopped for futility 4.7% of the time (240 trials at the first interim and 232 trials at the 
second interim). Since the low dose is much lower than the middle and high doses, and since the 
efficacy of the middle and high doses is lower than previous scenarios, we see more trials here that 
drop the low dose and continue the trial with only the placebo, middle dose, and high dose. There 
were 4620 trials that dropped the low dose at the first interim. Of those, 2319 trials met early 
success at the next interim (thus ending the trial), while 122 of the trials stopped for futility at the 
next interim and 2179 continued to the final analysis. Thus, for these 2179 trials, the final sample 
size for the low dose was 9 subjects, while the middle and high doses each had a final sample size 
of 17 subjects (each arm receiving two extra subjects because of the low dose dropping at the first 
interim). Additionally, there were 323 trials that continued all arms at the first interim, then dropped 
the low dose at the second interim. In these trials, the final sample size for the low dose was 12 
subjects while the middle and high doses each received one extra subject for a total of 16 subjects at 
the final analysis. 


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Gonadorelin Acetate, FE 999037, FE 999903 
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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
Figure 10 
Operating Characteristics for Scenario 4: 0.01, 0.10, 0.40, 0.50 
 
 
 


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Statistical Analysis Plan 
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Scenario 5: 0.01, 0.10, 0.40, 0.40 
In this scenario, the middle and high doses are equivalent with a 40% response rate. The low dose is 
30% lower than the middle and high doses. 
Roughly half of the simulated trials (5185 trials, or 51.9%) dropped the low dose at the first interim, 
but continued enrolling the other arms. An additional 482 trials (4.8%) dropped the low dose at the 
second interim. With the high probability of dropping the low dose, the average sample size for the 
low dose is 9.9 while the middle and high doses tend to have larger sample sizes, since they receive 
re-allocated subjects from the dropped low dose. The power for this scenario is 80.7%. The 
probability of early futility is 10.6% (5.5% at the first interim and 5.1% at the second interim). 
 
 


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Gonadorelin Acetate, FE 999037, FE 999903 
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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
Figure 11 
Operating Characteristics for Scenario 5: 0.01, 0.10, 0.40, 0.40 
 
 


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Gonadorelin Acetate, FE 999037, FE 999903 
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Statistical Analysis Plan 
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CONFIDENTIAL 
Scenario 6: 0.01, 0.10, 0.20, 0.40 
This scenario is similar to the last, except that the middle dose response rate has been lowered to 
20%. Given the lower effect on the middle dose, the power of the trial drops to 42.8%. A larger 
percentage of trials (37.5%) stop for early futility. 
 
 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
Figure 12 
Operating Characteristics for Scenario 6: 0.01, 0.10, 0.20, 0.40 
 
 


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Gonadorelin Acetate, FE 999037, FE 999903 
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Statistical Analysis Plan 
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CONFIDENTIAL 
Scenario 7: 0.01, 0.01, 0.01, 0.01 
This is a null scenario in which all arms are equivalent to placebo. In the simulated trials, 100% of 
trials stopped for futility, and in fact, stopped at the first interim analysis. 
 
Figure 13 
Operating Characteristics for Scenario 7: 0.01, 0.01, 0.01, 0.01 
 
 


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Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
15.2.4 
Control of Type I Error 
To understand the type I error, we begin by examining the type I error rate of a fixed trial. That is, 
we consider a trial with 𝑛= 15 subjects on the placebo arm and 𝑛= 30 subjects on the pooled 
middle and high doses. There are no interims for early stopping, and no adjustments to sample size 
for dropping the low dose arm. 
There are 496 possible combinations of outcomes: there may be between 0 and 15 responders on 
the placebo arm (16 possible outcomes) and between 0 and 30 responders on the pooled 
investigational arms (31 possible outcomes). We compute the probability of each combination 
using Binomial distributions. Then we analyze each combination with Fisher's Exact test. The type 
I error rate is then simply the sum over all successful combinations (p-value < 0.025, since there are 
no interims in this example), weighted by the probability of each of those combinations. 
This computation yields a type I error rate of 1.018 × 10−11. This is an exact calculation, not 
simulation-based. 
Fisher's Exact Test is known to be conservative, so it is not surprising that the type I error rate is 
below the nominal 0.025 for the fixed trial. To further understand the small type I error rate, we 
examine the types of outcomes that would lead to a successful trial. Figure 7 illustrates all possible 
outcomes for the pooled arms (y-axis) versus all possible outcomes for the placebo (x-axis). Thus 
each dot on the graph represents a possible combination. The dots shaded in green indicate the 
combinations leading to success. Out of the 496 possible outcomes, only 118 result in a successful 
trial. Furthermore, these combinations are unlikely to occur under the null hypothesis of a 1% 
responder rate in all arms. For example, the probability of observing 9 or more responders out of 30 
subjects, assuming a true responder rate of 1% is 1.184 × 10−11. 
Given the extremely low type I error rate for the fixed design, combined with the Pocock 
boundaries for the adaptive design, the addition of early success interims does not inflate the type I 
error above the nominal 0.025. In fact, in simulations of 100000 trials under the null hypothesis, no 
instances of trial success were observed. 
In the execution of the trial, there may be slight deviations from the assumptions used in this report. 
For example, the sample size may not be exactly equal to the planned 9 subjects in each arm at the 
first interim analysis (e.g. due to blocking). Such small deviations do not pose a threat for type I 
error inflation since the type I error rate is so far below the nominal value. 
 
 


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Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
(Green = success, Grey = failure) 
Figure 14 
All possible response outcomes for a fixed trial 
15.2.5 
Computational Details 
The simulations were run using custom code written in the R software package. The stopping 
boundaries for the group sequential design were obtained from the gsDesign package. R was also 
used to summarize the simulation output and to create graphics and tables for this report. 
15.3 
Additional Missing Data Handling Procedures 
Unless otherwise noted in previous sections, in general, data will be analysed as received from the 
clinical database. Hence, missing values including those caused by dropouts will not be imputed. 
Missing or partially missing date of the following situations will be imputed for purposes of 
analysis. It is anticipated that all study-related visit and procedure dates entered into the clinical 
study database will be complete (i.e. day, month, year are all recorded) and accurate. Any missing 
or partially missing date of this type will be queried before statistical analyses are performed. If the 
day, month, and/or year are still unknown, then the dates will be imputed as follows for purposes of 
analysis: 
•  If the day of the visit or procedure date is missing, then take the previous visit and add the 
number of days to the next visit according to the visit schedule.  
•  If the month of the visit or procedure date is missing then take the previous visit and add 
the number of months to the next visit according to the visit schedule. 
•  If the year of the visit or procedure date is missing, then the year will be queried. If the year 
is unknown, no imputation of year will take place.  
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Number of Placebo Responders
Number of Pooled (Mid + High) Responders


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Gonadorelin Acetate, FE 999037, FE 999903 
Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Only collected dates will be noted in the patient data listings. 
15.4 
Analysis Visit Windows 
For the analysis of follicular development by visit from study day 10 to study day 21, visit windows 
are allowed for certain visits per the schedule of assessments. Subject data will not be excluded 
from analyses due to the subject’s failure to comply with the visit schedule.  
The following rules as shown in Table 5 will be applied to assign analysis visit to study visits. The 
analysis visit is determined by the number of days between the date of first study treatment 
application and the corresponding visit dates for TVUS (for monitoring follicular development). 
In the case of multiple assessments at a specific visit, the observation which is closest to the target 
date will be used. If the observations have the same distance to the target date, the latest one will be 
used.  If baseline assessments are not performed, the last non-missing measurement taken before 
the first dose will be used as baseline. 
The visit windows described in the following table will be applied to the analyses of efficacy 
endpoints. 
 
Table 5 
Analysis visit windows 
Study Visit 
Target Day 
Analysis Visit Window 
4*  
10 
2Day10 
5* 
12 
11Day13 
6* 
15 
14Day16 
7* 
18 
17Day19 
8* 
21 
20Day22 
 
Target day is calculated as the study day relative to the first day of IMP administration: date of 
visit – date of first IMP administration + 1. 
 


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Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
15.5 
Markedly Abnormal Laboratory Safety Values and Vital Signs  
When applying the markedly abnormal criteria defined below, the low/high thresholds will be 
compared to the laboratory normal reference low/high limits. If the normal reference low limit is 
smaller than the low threshold, then the normal reference low limit would be used; On the other 
hand, if the normal reference high limit is larger than the high threshold, then the normal reference 
high limit would be used. 


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Trial Code: 000070  
Statistical Analysis Plan 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Table 6: Markedly abnormal Criteria for Laboratory Tests 
 
 
Markedly abnormal Criteria 
Variable 
Units 
Low 
High 
Haematology 
Haemoglobin 
g/L 
 115 
Not applicable 
Haematocrit 
Ratio 
 0.37 
 0.56 
Total WBC 
109/L 
 2.8 
 16.0 
Eosinophils 
% 
Not applicable 
 10 
Neutrophils 
% 
 15 
 90 
Lymphocytes 
% 
 10 
 80 
Monocytes 
% 
Not applicable 
 20 
Basophils 
% 
Not applicable 
 5 
Bands 
% 
Not applicable 
 20 
Platelets 
109/L 
 75 
 700 
Total RBC 
1012/L 
 3.5 
Not applicable 
Clinical Chemistry 
AST  
IU/L 
Not applicable 
> 3xULN 
ALT  
IU/L 
Not applicable 
> 3xULN 
Alkaline 
phosphatase 
IU/L 
Not applicable 
> 3xULN and 25% increase from 
baseline 
GGT 
IU/L 
Not applicable 
> 3xULN 
LDH 
IU/L 
Not applicable 
> 3xULN 
Total bilirubin 
μmol/L 
Not applicable 
 1.5xULN 
Urea nitrogen 
mmol/L 
Not applicable 
 10.7 
Creatinine 
μmol/L 
Not applicable 
 177 
Total protein 
g/L 
 45 
 90 
Albumin 
g/L 
 25 
 65 
Sodium 
mmol/L 
 130 
 155 
Potassium 
mmol/L 
 3.0 
 5.8 
Chloride 
mmol/L 
 90 
 115 
Phosphorus 
mmol/L 
 0.5 
 1.9 
Calcium 
mmol/L 
1.8 
 3.9 
Uric acid 
mmol/L 
Not applicable 
 0.62 
Glucose 
mmol/L 
 2.8 
 10 
Total cholesterol 
mmol/L 
Not applicable 
 8.0 
Urinalysis: Quantitative 


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Statistical Analysis Plan 
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CONFIDENTIAL 
pH 
None 
 4 
Not applicable 
Specific gravity 
None 
 1.005 
Not applicable 
Urinalysis: Dipstick Chemistries 
Glucose 
0 - 4+ 
Not applicable 
Increase of 2 or more units from baseline 
Casts 
 
Not applicable 
Increase of 2 or more units from baseline 
Protein 
0 - 4+ 
Not applicable 
Increase of 2 or more units from baseline 
Ketones 
0 - 4+ 
Not applicable 
Increase of 2 or more units from baseline 
Blood (Hgb) 
0 - 4+ 
Not applicable 
Increase of 2 or more units from baseline 
Urinalysis: Microscopic Variables 
RBC 
no./hpf 
Not applicable 
 10 
WBC 
no./hpf 
Not applicable 
 20 
Casts 
no./hpf 
Not applicable 
Neg at baseline to positive on-treatment 
Bacteria 
no./hpf 
Not applicable 
Neg at baseline to positive on-treatment 
Cells 
no./hpf 
Not applicable 
Neg at baseline to positive on-treatment 
Crystals 
no./hpf 
Not applicable 
Neg at baseline to positive on-treatment 
 
Table 7: Markedly abnormal 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 
Increase to  39.4C 
* To be identified as markedly abnormal, a treatment value must meet the criterion value and also the 
specified change from baseline.