Clinical trial NCT03858049
Conditions: Infertility
Keywords: Frozen-thawed embryo transfer Infertility Crinone Duphaston Chinese population
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2019-05-31; Completion date: 2021-10-27
Enrollment: 172 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study to compare to the efficacy and safety of Crinone versus combination medication in infertile women receive frozen-thawed embryo transfer (FET) in artificial cycles (AC).

Detailed description:

Arms: arm 1: Participants received Crinone 8% (90 milligrams \[mg\] an intravaginal progesterone gel contained in a single use, one piece applicator) once daily in morning from the day of endometrial transformation (Day -5) until ongoing pregnancy was confirmed up to Day 63. arm 2: Participants received Crinone 8% (90 mg an intravaginal progesterone gel contained in a single use, one piece applicator) once daily in morning followed by 10 mg of Duphaston tablet orally twice a day from the day of endometrial transformation (Day -5) until ongoing pregnancy was confirmed up to Day 63.
Interventions: intervention 1: Crinone intervention 2: Duphaston
Intervention descriptions: intervention 1: Participants received Crinone 8% (90 milligrams \[mg\] an intravaginal progesterone gel contained in a single use, one piece applicator) once daily in morning from the day of endometrial transformation (Day -5) until ongoing pregnancy was confirmed up to Day 63. intervention 2: Participants received 10 mg of Duphaston tablet orally twice a day from the day of endometrial transformation (Day -5) until ongoign pregnancy was confirmed up to Day 63.

Protocol documents:
Prot_000.pdf: 
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Comparison of Crinone® versus combination medication for luteal phase support on the 
ongoing pregnancy rate of frozen-thawed cycle in Chinese population a randomized, 
interventional, open-label, Phase IV, single center, pilot study 
 


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Protocol Version 1.1-CHN (15-Jan-2020) 
Overall Rationale for Amendment 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 1.2 
Schema, 4.1 
Overall Design, 
and 4.2 Scientific 
Rationale for 
Study Design 
Study duration increased from 15 to 25 months 
Study duration lengthened due to 
recruitment status and to accommodate 
protocol amendment finalization time 
1.2 Schema, 4.1 
Overall Design, 
Appendix 4 Visit 
Procedures 
Remove visit 2 – estradiol valerate initiation 
Inclusion/Exclusion (I/E) criteria checking at 
visit 2 and 3 as well 
Eligible patients for the study may have 
already started on estradiol valerate so by 
removing the estradiol valerate initiation 
procedure, it may improve patient 
enrollment 
1.3 Schedule of 
Actitvities and 
Appendix 4 
Removed visit 2 – estradiol valerate initiation 
and its administration and shifted all 
subsequent visits from 3 to 2 etc. 
Checking of I/E criteria added to visit 2 and 3 
as well 
Eligible patients for the study may have 
already started on estradiol valerate so by 
removing estradiol valerate initiation may 
improve patient enrollment 
1.3 Schedule of 
Actitvities 
Note for Duphaston® revised from dispensed to 
prescribed 
The drug is prescribed by the Investigator 
and purchased by the patients themselves 
4.1 Overall 
Design 
Study period changed from 95 to 75 days  
Duration of study changed after removing 
estradiol valerate initiation 
5.1 Inclusion 
Criteria 
Day of embryo now also includes Day 6 
embryos 
The outcomes are similar with Day 5 
embryos transfer. 
6.4 Study 
Intervention 
Compliance 
Compliance is at a minimun of 80%  not 80-
85%. 
This should not be a range.  
6.5.1 Rescue 
Medicine 
Definition for rescue medicine provided 
Rescue medicine section was not clear 
enough and Investigators may confuse 
this with prohibited medicines. Therefore, 
a definition is now provided. 
6.5.3 Prohibited 
Medicines 
Clarified prohibited medicines.  
Participants are allowed to remain on study if 
both the Sponsor and the Investigator agrees 
with it. 
Rescue medicines are not considered 
prohibited medicines 
Progestogens are usually used as rescue 
medicines. 
6.5.4 Other 
Interventions 
Procedure for estradiol valerate use now 
follows local practice. Original details 
removed. 
Following local practice is easier to 
implement for Investigators 


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Section # and 
Name 
Description of Change 
Brief Rationale 
8.3.1 8.3.1 Time 
Period and 
Frequency for 
Collecting 
Adverse Event 
and Serious 
Adverse Event 
Information 
The AE reporting period for safety surveillance 
begins upon endometrial transformation 
instead of estradiol valerate initation. 
Change due to removal of estradiol 
valerate initiation 
8.4 Study 
intervention 
Overdose 
Rescue medicines that are administered are not 
considered overdosing. 
Routine clinical practice. Prevent protocol 
deviations. 
Appendix 3 
Paper serious adverse event (SAE) reporting 
methods revised 
Currently, all SAEs and overdose must be 
recorded on the SAE report form as the 
primary reporting method, rather than the 
back-up method 
Appendix 4 Visit 
Procedures 
 
Visit 1 (baseline 
evaluation) 
Medical history prior to informed consent form 
(ICF) signing may also be accepted per the 
Investigator’s discretion for the following: 
 
-clinical and gynecological exam 
 
-ultrasound 
 
-serum human chorionic gonadotrophin 
(β-hCG) levels 
Patients will have clinical and 
gynecological exams at their first visit in 
the clinic; exams will not repeat 
afterwards according to local practice.  
The patients’ ultrasounds are usually 
performed at the clinic shortly prior to the 
signing of the ICF according to local 
practice. Therefore, there is no need to 
repeat the ultrasound after ICF signing.  
Serum β-hCG levels will be performed at 
the patient’s first visit to the clinic; exams 
will not repeated afterwards according to 
local practice. 
Appendix 4 Visit 
Procedures 
 
Visit 2 
(endometrial 
transformation 
day) 
Irrelevant wording for estradiol valerate 
removed and that related to its dose adjustment 
to reach appropriate endometrial thickness 
Added data to be collected for estradiol 
valerate including date of initiation, initial 
dose, details of dose adjustment, and duration 
and total dose. 
Endometrial thickness may be measured by 
ultrasound or if ultrasound was performed on 
the endometrial transformation day prior to 
signing the ICF, a new ultrasound is not 
required. 
Due to changes in the study procedure, 
estradiol valerate is no longer considered 
an intervention; therefore all estradiol 
valerate-associated procedures have been 
removed. 
Due to the change in study procedure, 
data for estradiol valerate including date 
of initiation, initial dose, details of dose 
adjustment, and duration and total dose, 
will be collected at visit 2. 
 
Appendix 4 Visit 
Procedures 
 
Visit 3 (embryo 
transfer day) 
Days for assisted secretory transformation of 
the endometrium changed to 4-6 instead of just 
4. 
Embryo allowed to be transferred include D5 
and D6 instead of just D6 
Embryo transfer may occur on the fifth, sixth, 
or seventh day instead of just the fifth.  
Ultrasound to assess the endometrium removed 
Procedural changes described now follow 
that of local practice and does not affect 
the outcome of the study. 
 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and document formatting 
revisions 
Minor, therefore, have not been 
summarized 
Protocol Version 1.2-CHN (1-Jul-2020) 
Overall Rationale for Amendment 
Section # and 
Name 
Description of Change 
Brief Rationale 
5.2 Exclusion 
Criteria  
To add one more exclusion critieria: 
Participants with potential risk (The 
participants/parterner are  from high risk region 
which can be tracked by health barcode) or 
symptoms of COVID-19 (eg. fever, cough etc).  
To exclude subjects with potential 
COVID-19 risks 
Protocol Version 2.0-CHN (19-Jan-2021) 
Overall Rationale for Amendment 
Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion 
Criteria 
Day of embryo now includes Day 5 embryos 
only. 
According to the quality control data of all 
the FET blastocyst transfer (n = 110), there 
is a difference between CPR of D5 embryo 
transfer and D6 embryo transfer (61.8% 
vs. 43.3%). Only D5 embryo is allowed to 
be transferred is to reduce the bias 
produced by the day of transfer.  
Appendix 4 Visit 
Procedures 
 
Visit 3 (embryo 
transfer day) 
Only D5 embryo allowed to be transferred 
instead of both D5 and D6 embryo allowed to 
be transferred. 
To reduce the bias produced by the day of 
transfer.  
- Confidential – 
This document is the property of Merck Healthcare KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express permission of Merck 
Healthcare KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2018 by Merck Healthcare KGaA, Darmstadt, Germany, 
or its subsidiary. All rights reserved. 
 


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Table of Contents 
Title Page 
 ..............................................................................................................2 
Table of Contents  ..............................................................................................................7 
1 
Protocol Summary ..............................................................................10 
1.1 
Synopsis ..............................................................................................10 
1.2 
Schema ................................................................................................12 
1.3 
Schedule of Activities .........................................................................13 
2 
Introduction .........................................................................................15 
2.1 
Study Rationale ...................................................................................15 
2.2 
Background .........................................................................................15 
2.3 
Benefit/Risk Assessment ....................................................................16 
3 
Objectives and Endpoints ...................................................................17 
4 
Study Design .......................................................................................18 
4.1 
Overall Design ....................................................................................18 
4.2 
Scientific Rationale for Study Design ................................................18 
4.3 
Justification for Dose ..........................................................................19 
4.4 
End of Study Definition ......................................................................19 
5 
Study Population .................................................................................20 
5.1 
Inclusion Criteria ................................................................................20 
5.2 
Exclusion Criteria ...............................................................................20 
5.3 
Lifestyle Considerations .....................................................................21 
5.4 
Screen Failures ....................................................................................21 
6 
Study Interventions .............................................................................22 
6.1 
Study Interventions Administration ....................................................22 
6.2 
Study Interventions Preparation, Handling, Storage, and 
Accountability .....................................................................................22 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................23 
6.3.1 
Study Intervention Assignment ..........................................................23 
6.3.2 
Blinding ..............................................................................................24 
6.4 
Study Intervention Compliance ..........................................................24 
6.5 
Concomitant Therapy .........................................................................24 


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6.5.1 
Rescue Medicine .................................................................................24 
6.5.2 
Permitted Medicines ...........................................................................24 
6.5.3 
Prohibited Medicines ..........................................................................25 
6.5.4 
Other Interventions .............................................................................25 
6.6 
Dose Selection and Modification ........................................................25 
6.7 
Study Intervention after the End of the Study ....................................25 
6.8 
Special Precautions .............................................................................25 
6.9 
Management of Adverse Events of Interest ........................................25 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................26 
7.1 
Discontinuation of Study Intervention ................................................26 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................26 
7.3 
Lost to Follow-Up ...............................................................................26 
8 
Study Assessments and Procedures ....................................................28 
8.1 
Efficacy Assessments .........................................................................28 
8.1.1 
Primary endpoints ...............................................................................28 
8.1.2 
Secondary endpoints: ..........................................................................28 
8.2 
Safety Assessments and Procedures ...................................................28 
8.2.1 
Physical Examinations ........................................................................28 
8.2.2 
Vital Signs ..........................................................................................29 
8.3 
Adverse Events and Serious Adverse Events .....................................29 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ....................................................29 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ...29 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events ...............29 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .....30 
8.3.5 
Pregnancy ...........................................................................................30 
8.4 
Study intervention  Overdose .............................................................30 
8.5 
Pharmacokinetics ................................................................................31 
8.6 
Pharmacodynamics .............................................................................31 
8.7 
Pharmacogenetics ...............................................................................31 
8.8 
Biomarkers ..........................................................................................31 


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1.2 
Schema 
This is a local, single center, open label, pilot, randomized controlled clinical study to compare the 
efficacy and safety of Crinone® versus combination medication. The study participants are those 
who will receive frozen-thawed embryo transfer (FET) in artificial cycles (ACs). This study plans 
on including 334 participants from a single reproductive center over 25 months. 
 
The participants will sign an ICF; the participants are free to withdraw at any time without 
prejudice to their medical care, and they are not obliged to state their reasons for withdrawal. 
Participants will be randomized on the day of embryo transfer (ET). Upon site initiation, the 
Investigator site will enroll the eligible participants who meet the inclusion and none of the 
exclusion criteria in a consecutive manner until the enrollment target is reached. Relevant data 
according to study requirements will be recorded in a standard case report forms (CRF). When the 
study starts, this reproductive center will include participants who enter the cycle. The information 
of the qualified yet excluded participants who have signed ICFs will be recorded, and the reason 
for their exclusion will also be recorded in the CRF. If a participant has entered the study and later 
discontinue their study intervention, the reason for discontinuing the study intervention will be 
recorded in the CRF.  
Participant follow-up will occur until her ongoing pregnancy is confirmed and/or until End of 
Study (defined in Section 4.4)


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1.3 
Schedule of Activities 
 
Visit 
Screening/ 
Baseline 
Endometrial 
Transformation 
Day 
Embryo 
Transfer (ET) 
Day (see 
Appendix 4 
Visit 3) 
β -hCG Test 
Clinical 
Pregnancy 
Assessment 
Ongoing 
Pregnancy 
Assessment 
 
 
Notes 
Study Day 
 
Day -5 
Day 1 
Day 14 
Day 35 
Day 63 
Ongoing pregnancy assessment occurs 
between 10-12 weeks of pregnancy (8-10 
weeks after ET). The middle number of 9 
weeks (Day 63) after ET is used to define 
the study day with a window of 10 days on 
each side as leeway 
Window (day) 
 
±1 
0 
±1 
±7 
±10 
 
Visit number 
1 
2 
3 
4 
5 
6 
 
Signed ICF 
× 
 
 
 
 
 
 
Randomization 
 
 
× 
 
 
 
 
Demography 
× 
 
 
 
 
 
 
Medical history 
× 
 
 
 
 
 
 
Inclusion and 
exclusion criteria  
× 
× 
× 
 
 
 
 
Physical 
examination and 
vital signs 
× 
 
 
 
 
 
 
Weight and 
height 
× 
 
 
 
 
 
 
Clinical and 
gynecological 
examination 
× 
 
 
 
 
 
 
Ultrasound 
× (see 
Appendix 4 
Visit 1) 
× (see Appendix 4 
Visit 2) 
 
 
 
 
Visit 2:  If the ultrasound was performed 
on the endometrial transformation day 
prior to signing the ICF, a new ultrasound 
is not required. 
Serum β-hCG 
levels  
× 
 
 
× 
 
 
 
Administration of 
Crinone® 
 
< --------------------------------------------------------------------------------------------------------- > 
Crinone® will be dispensed at each 
scheduled 
visit 
starting 
from 
the 
endometrial transformation day. Crinone® 


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should be dispensed with enough amount 
for self-administration until the next 
scheduled visit. 
Administration of  
Duphaston® 
(combination 
medication 
group) 
 
 
< ------------------------------------------------------------------------------ > 
Duphaston® will be prescribed at each 
scheduled visit starting from the ET day. 
Duphaston® should be dispensed with 
enough amount for self-administration 
until the next scheduled visit. 
ET  
 
 
× 
 
 
 
 
Clinical 
pregnancy as 
assessed by 
ultrasound scan  
 
 
 
 
× 
 
 
Ongoing 
pregnancy 
assessment  
 
 
 
 
 
× 
 
AEs 
 
× 
× 
× 
× 
× 
 
Bleeding 
assessment 
 
 
 
× 
× 
× 
Bleeding assessment on Visit 5 will 
include luteal phase bleeding; the ones on 
Visits 6 will include vaginal bleeding. 
 
Concomitant 
medication  
× 
× 
× 
× 
× 
× 
 




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hormone replacement during FET cycles – this is also favored by an increasing number of 
clinicians as it is simple to apply, and it reduces both the monitoring frequency and cycle 
cancellation rate. The corpus luteum does not form endogenously in FET cycles due to the 
absence of ovulation; therefore, secretory transformation of the endometrium – prior to ET 
and maintenance of normal embryonic development after ET – is dependent on exogenous 
progesterone supplementation (15–20). 
Progesterone plays an important role in endometrial-embryo synchrony and the maintenance 
of early pregnancy (21) There are currently three routes of progesterone administration in 
China: oral, intramuscular and vaginal. Intramuscular progesterone administration is 
frequently used in the clinic as it is inexpensive and both a high serum level and a stable 
clinical pregnancy rate can be achieved. However, intramuscular progesterone administration 
is painful, requires daily injections, and may be inconvenient as commute is required of the 
participant to and from the hospital. Furthermore, intramuscular administration may lead to 
inflammation at the site of injection, widely resulting in symptoms such as allergic reactions 
or local panniculitis, which may progress to abscesses (22). Oral medication is convenient, 
but bioavailability is low due to hepatic first-pass effect. The vaginal route of progesterone 
administration is convenient, and it achieves a stable endometrial concentration with low 
serum levels, which reduces the risks of systemic adverse effects. According to the United 
States Food and Drug Administration, application of vaginal progesterone gel is the only 
accepted study intervention option for replacement of progesterone in FET cycles (23,24)   
No consensus has yet been reached worldwide as to whether the route or dosage of 
progesterone administration affects clinical outcomes of FET cycles. Chinese clinicians prefer 
to give a dose of progesterone that is higher than physiological needs for luteal phase support 
in all protocols. Currently, oral progesterone combined with vaginal progesterone is the 
preferred regimen for luteal phase support in FET cycles in China. Wang Y et al. reported that 
the clinical pregnancy rate of combined medication in FET-AC cycle was 40% in a Chinese 
population(1). In addition, a few Chinese retrospective studies supported the daily use of 90 
mg of Crinone® during FET cycles (2–6). The Chinese consensus also supports the use of 
Crinone® with 20 mg of Duphaston® for FET luteal support (25).This prompts the question 
as to whether the small dose of oral progesterone is needed. A well-designed randomized and 
controlled trial is yet to be conducted to compare the clinical outcomes of FET cycles when 
administering Crinone® on its own versus combination administration. Therefore, in this pilot 
study, Crinone® on its own will be compared with combination medication (Crinone® plus 
Duphaston®) for luteal phase support in FET cycles by assessing their effects on the ongoing 
pregnancy rate. This study will provide preliminary evidence that differentiates the two 
protocols. 
2.3 
Benefit/Risk Assessment 
Crinone® and Duphaston® are both currently on the market and have already been evidenced 
to be well tolerated. 
 
 




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5 
Study Population 
The criteria in Sections 5.1 (Inclusion Criteria) and 5.2 (Exclusion Criteria) are designed to 
enroll only participants, who are appropriate for the study; thereby, ensuring the study fulfills 
its objectives. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a participant is suitable for this study. 
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, are not permitted. 
Before performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will confirm that the participant or the participant’s legal representative 
has provided written informed consent, as indicated in Appendix 2 (Study Governance). 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Are 20 through 38 years old women who will receive artificial FET cycle study 
interventions 
2. No more than two Day 5 embryos are planned to be transferred (follow the clinical 
practice of the study site)  
3. Have received estradiol valerate for no more than 20 days  
4. Have a transitional-endometrium of ≥ 8 mm 
5. Have normal uterine cavity 
6. Can give signed informed consent, as indicated in Appendix 2 (Study Governance), 
which includes compliance with the requirements and restrictions listed in the ICF and 
this protocol. 
7. Are willing to follow the study protocol and able to complete the study 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. ≥3 previously failed cycles of ET 
2. Participants with diseases that cannot tolerate pregnancy 
3. Hydrosalpinx 
4. Severe endometriosis (Endometriosis American Society for Reproductive Medicine 
(ASRM) criteria from 1996) 


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5. Known hypersensitivity to progesterone, the excipients of Crinone® and Duphaston® 
6. Vaginal bleeding of unknown origin  
7. History of recurrent miscarriages 
8. Vaginitis 
9. Thromboembolic diseases (thrombophlebitis, thromboembolic disorder, or cerebral 
apoplexy) or patients with an history of these conditions 
10. Known or suspected progestogen-dependent neoplasm 
11. Participation in another clinical trial within the past 30 days 
12. Contraindications of both Crinone® and Duphaston® 
13. Participants with potential risk (The participants/parterner are  from high risk region 
which can be tracked by health barcode) or symptoms of COVID-19 (eg. fever, cough 
etc). 
5.3 
Lifestyle Considerations 
Not applicable 
5.4 
Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 
 
 


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6 
Study Interventions 
Study intervention is any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant per the study protocol. 
6.1 
Study Interventions Administration 
Study Intervention 
Name: 
Crinone® 
Duphaston® 
Dose Formulation: 
Progesterone gel 8% (90 mg) Tablet 
Unit Dose 
Strength(s)/Dosage 
Level(s): 
90 mg 
10 mg/tablet 
Route of 
Administration: 
Intravaginal 
Oral 
Dosing Instructions: 
1 gel, q.d. in the morning 
1 tablet, b.i.d 
Supplier/Manufacturer: 
Merck will provide Crinone® 
for free 
Prescribed for participants in 
the clinic by Investigators 
Packaging and Labeling 
 every box contains 15 
applicators 
 The validity period is 36 
months  
 Each applicator will be 
packaged and labeled per 
all applicable regulatory 
requirements and Good 
Manufacturing Practice 
Guidelines. 
 According to the package 
labelling as prescribed by 
the Investigator 
6.2 
Study Interventions Preparation, Handling, Storage, and 
Accountability 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
 Upon receipt of the study intervention(s), the Investigator or designee must confirm 
appropriate temperature conditions have been maintained during transit and any 
discrepancies are reported and resolved before use. Also, the responsible person will 
check for accurate delivery and acknowledge receipt by signing or initialing and dating 
the appropriate document and returning it to the location specified. A copy will be 
archived for the Investigator Site File. 


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 Only participants enrolled in the study may receive study intervention(s) and only 
authorized site staff may supply it. All study intervention(s) must be stored in a secure, 
environmentally-controlled, and monitored (manual or automated) area, in accordance 
with the labeled storage conditions, and with access limited to the Investigator and 
authorized site staff. 
 Dispensing will be recorded on the appropriate accountability forms so that accurate 
records will be available for verification at each monitoring visit. 
 Study intervention(s) accountability records at the study site will include the following: 
o Confirmation of receipt, in good condition and in the defined temperature range. 
o The inventory provided for the clinical study and prepared at the site. 
o The dose(s) each participant used during the study. 
o The disposition (including return, if applicable) of any unused study 
intervention(s). 
o Dates, quantities, batch numbers, expiry dates, and the participant numbers. 
 The Investigator site will maintain records, which adequately documents that 
participants were provided the doses specified in this protocol, and all study 
intervention(s) provided were fully reconciled. 
 Unused study intervention(s) must not be discarded or used for any purpose other than 
the present study. No study intervention that is dispensed to a participant may be re-
dispensed to a different participant. 
 A Study Monitor will periodically collect the study intervention(s) accountability 
forms. 
 Further guidance and information for the final disposition of unused study 
intervention(s) are provided in the Study Reference Manual. 
6.3 
Measures 
to 
Minimize 
Bias: 
Study 
Intervention 
Assignment and Blinding 
6.3.1 
Study Intervention Assignment 
Participants will be randomized in a 1:1 ratio to receive either Crinone® or the combination 
medication group on the day of ET.  
The trial is designed as a single center trial, and randomization will be conducted on the ET 
day by using the block permutation method and stratified by age group (ages 20 to 35 years, 
or ages 35 years and over), which will guarantee that a balanced number of participants will 
be obtained between Crinone® and the combination medication groups inside each age 
stratum. If an error occurs (for example if the wrong list is used), the participant should 
continue with their assigned study intervention, and the next participant should still be 
assigned the next available number and study intervention of the correct list. The site must 
not attempt to “correct” for the error (i.e., if a participant is on the Crinone® list instead of the 


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combination medication group list, the site must not try to assign the Crinone® participant to 
the combination medication group list to offset this). Since ACCESS is an open-labeled 
observational study, baseline characteristic analysis will be presented to show whether the 
participants were well-stratified by age between the two study intervention groups. 
6.3.2 
Blinding 
Not applicable 
6.4 
Study Intervention Compliance 
See Section 6.2 for dispensing and accountability of the study interventions.  
Crinone® will be provided for free and Duphaston® will be prescribed by the physicians and 
will be bought by the participants themselves. Study intervention administration must be 
recorded in the CRF as applicable. 
The acceptable compliance for this study is at a minimum of 80%. 
6.5 
Concomitant Therapy 
Record in the CRF all concomitant therapies (e.g., medicines or nondrug interventions) used 
from the time the participant signs the informed consent until completion of the study, 
including any changes. For prescription and over-the-counter medicines, vaccines, vitamins, 
and herbal supplements, record the name, reason for use, dates administered, and dosing 
information. 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
6.5.1 
Rescue Medicine 
Rescue medications may be administered to address ineffective study intervention, anticipated 
adverse reactions or anticipated emergency situations. 
Rescue medicine will be defined as the drug changed or dosage changed when the patient 
experiences threatened abortion. Rescue medicines will not be considered as prohibited 
medicines. Participants who use rescue medicines will be allowed to remain in the study. 
6.5.2 
Permitted Medicines 
Medications that are considered necessary to protect the participant’s welfare and will not 
interfere with the trial medication may be given at the Investigator’s discretion.  
Any medicines that are considered necessary to protect the participant’s welfare in 
emergencies may be given at the Investigator’s discretion, regardless if it results in a protocol 
deviation. 


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6.5.3 
Prohibited Medicines 
Other types of progesterone used one month before and during this study such as Utrogestan, 
intramuscular injections of progesterone; other ongoing vaginal medications. If any prohibited 
medicines are used, study participants will be allowed to remain on study provided that the 
Sponsor and the Investigator agrees. Rescue medicines are not considered prohibited 
medicines.  
6.5.4 
Other Interventions 
Estradiol valerate will be administered according to local practice.  
All participants will receive oral estradiol valerate continuously and the dose of estradiol 
valerate will be adjusted according to local practices. 
6.6 
Dose Selection and Modification 
Not applicable. 
6.7 
Study Intervention after the End of the Study 
The Sponsor will not provide any additional care to participants after they leave the study. 
6.8 
Special Precautions 
Not applicable. 
6.9 
Management of Adverse Events of Interest 
Refer to the package inserts for possible adverse drug reactions to Crinone® and Duphaston®. 
The management of adverse drug reactions should be based on the Investigator's judgment 
according to the medical condition of the participant.  
 
 


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7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1 
Discontinuation of Study Intervention 
See Section 7.2. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study intervention and the study if any one or more of 
the below criteria are met: 
 Adverse event (AE)/SAE, according to the discretion of the Investigator 
 Participant is lost to follow up 
 Withdraw consent 
Participants will be informed that they have the right to withdraw from the trial at 
any time without prejudice to their medical care, and that they are not obligated to 
state their reasons for withdrawal. Participant data will be included in the analyses 
up until consent is withdrawn. 
The trial exit electronic CRF will be completed when a participant is withdrawn from the trial. 
All withdrawals must be fully documented in the source documents. 
A participant is considered having completed the observation period (i.e., not withdrawn from 
study intervention or study) when 
 The participant achieves ongoing pregnancy 
Or 
 FET cycle may be considered finished when any one of the following applies:  
o β-hCG is negative (on the 13-15th day after ET）  
o Clinical pregnancy is negative (between the 4-6th week post-transfer） 
o Fetal heart beat stops before 10-12 weeks of pregnancy (8-10 weeks after ET). 
7.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain if the participant wants to or should continue in the study. 


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 Before a participant is deemed “lost to follow-up”, the Investigator or designee must 
make every effort to regain contact with the participant: 1) where possible, make 3 
telephone calls; 2) if necessary, send a certified letter (or an equivalent local method) 
to the participant’s last known mailing address, and 3) if a participant has given the 
appropriate consent, contact the participant’s general practitioner for information. 
These contact attempts should be documented in the participant’s medical record. 
 Should the participant continue to be unreachable, she will be considered to have 
withdrawn from the study. 
 
 


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8 
Study Assessments and Procedures 
The visit procedures are described in the Schedule of Activities (Section 1.3) and Appendix 4. 
8.1 
Efficacy Assessments 
8.1.1 
Primary endpoints 
Ongoing pregnancy (at 10-12 weeks of pregnancy [8-10 weeks after ET]). Ongoing pregnancy 
is defined in Section 9.4.1.1. 
8.1.2 
Secondary endpoints:  
 β-hCG positive 
 Implantation 
 Clinical pregnancy 
 Early abortion 
 Bleeding (luteal phase, vaginal)  
 The safety profile of the study intervention will be assessed according to Section 8.2. 
The definitions are provided in Section 9.4.1.2. 
8.2 
Safety Assessments and Procedures 
The safety profile of the study intervention will be assessed through the recording, reporting 
and analysis of baseline medical conditions, AEs, physical examination findings and 
laboratory tests. 
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1 (Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information). 
8.2.1 
Physical Examinations 
 A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 


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8.2.2 
Vital Signs 
 Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse  
8.3 
Adverse Events and Serious Adverse Events 
The definitions of an AE and a SAE are in Appendix 3. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information 
The AE reporting period for safety surveillance begins upon endometrial transformation (Visit 
2) and continues until the End of Study Visit. 
Any SAE assessed as related to study intervention must be recorded and reported, as indicated 
in Appendix 3, whenever it occurs, irrespective of the time elapsed since the last 
administration of study intervention. 
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and 
the procedures for completing and transmitting SAE reports are in Appendix 3. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
At each study visit, the participant will be queried on changes in his or her condition. During 
the reporting period, any unfavorable changes in the participant’s condition will be recorded 
as AEs, regardless if reported by the participant or observed by the Investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the 
reporting period (defined below) will be reported on an ongoing basis in the appropriate 
section of the CRF. All SAEs must be additionally documented and reported using the 
appropriate Report Form as specified in Appendix 3. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
AEs are recorded and assessed continuously throughout the study, as specified in 
Section 8.3.1 (Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information) and are assessed for their outcome at the End of Study Visit. All SAEs 
ongoing at the End of Study Visit must be monitored and followed up by the Investigator until 
stabilization or until the outcome is known, unless the participant is documented as “lost to 
follow-up”. Reasonable attempts to obtain this information must be made and documented. It 
is also the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. Further information on follow-up 
procedures is given in Appendix 3 (Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reports). 


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8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
The Sponsor will send appropriate safety notifications to Health Authorities in accordance 
with applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the Independent Ethics 
Committee (IEC)/ Institutional Review Board (IRB) that approved the study. 
In accordance with International Council for Harmonization (ICH) Good Clinical Practice 
(GCP), the Sponsor/designee will inform the Investigator of findings that could adversely 
affect the safety of participants, impact the conduct of the study or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the study. In line with respective regulations, the 
Sponsor/designee will inform the Investigator of AEs that are both serious and unexpected 
and considered to be related to the administered product (“suspected unexpected serious 
adverse reactions” or SUSARs). The Investigator should place copies of Safety Reports in the 
Investigator Site File. National regulations regarding Safety Report notifications to 
Investigators will be considered. 
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records 
of these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety Reports provided by the Sponsor/designee and of filing copies of all 
related correspondence in the Investigator Site File. 
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related Detailed Guidance documents. 
8.3.5 
Pregnancy 
Not applicable since ongoing pregnancy is the primary endpoint of the study. 
8.4 
Study intervention  Overdose 
For this study, any dose of Crinone® greater than 90 mg/p.v./q.d in the single treatment 
group, or Crinone® at 90 mg/p.v./q.d  and Duphaston® at 10 mg/p.o./b.i.d in the combination 
treatment group will be considered an overdose. The schedule can be seen in Section 1.3. In 
case of an overdose, the participant will be assessed by Investigators as to whether they will 
continue participating in the study or not. Rescue medicines that are administered are not 
considered overdosing. 


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Even if it not associated with an AE or a SAE, any overdose is recorded in the CRF and 
reported to drug safety in an expedited manner. Overdoses are reported on a SAE Report 
Form, following the procedure in Appendix 3, section on Reporting Serious Adverse Events. 
8.5 
Pharmacokinetics 
Not applicable. 
8.6 
Pharmacodynamics 
Not applicable. 
8.7 
Pharmacogenetics 
Not applicable. 
8.8 
Biomarkers 
Not applicable. 
8.9 
Immunogenicity Assessments 
Not applicable 
 
 


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9.4.1.2 
Secondary Endpoints 
 β-hCG positive  
Definition: A pregnancy diagnosed by the detection of β-hCG in serum 
 Implantation: 
Definition: The number of gestational sacs observed by ultrasound scan 
 Clinical pregnancy 
Definition: A pregnancy diagnosed by ultrasound of one or more gestational sacs or 
definitive clinical signs of pregnancy. It includes ectopic pregnancy. Note: Multiple 
gestational sacs are counted as one clinical pregnancy. 
 Early abortion 
Definition: The spontaneous loss of an intra-uterine pregnancy prior to 12 completed 
weeks of gestational age. 
 Bleeding (luteal phase, vaginal) 
Definition: The bleeding data will be collected in a CRF after each visit by Investigators 
according to original medical documents. 
- 
Luteal phase bleeding: defined as the onset of any bleeding after ET and prior to 
the pregnancy test. The luteal phase bleeding rate will be assessed in each group 
and analysed according to the pregnancy outcomes. 
- 
Vaginal bleeding is defined as any bleeding recorded in the CRF after a pregnancy 
test via serum β-hCG and is considered as an AE. The vaginal bleeding rate will 
be assessed and compared in both groups at each visit. 
9.4.1.3 
Safety Endpoint(s) 
Safety parameters will include the incidence and severity of all AEs. 
9.4.2 
General Considerations 
Descriptive Statistics 
For the continuous parameters, the following statistics will be presented: Number (N) of 
participants, mean, standard deviation (SD), median, first quartile (q1), third quartile (q3), 
minimum, and maximum. The number of participants with missing values (‘Missing’) will be 
presented based on observed case data if necessary. An overall column will also be added 
where appropriate.  
For categorical parameters, the total number (‘N’) of participants and percentages will be 
presented. The number of participants with missing values (‘Missing’) will be presented based 
on observed case data if necessary. An overall column will also be added where appropriate. 
Method for handling missing data 


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Normally, missing data will not be imputed. If the participant does not have the required 
evidence for ovulation, follicular development, or pregnancy, then the participant will be 
counted as a failure for that particular endpoint. 
Should a specific endpoint need another method to handle missing data, this will be specified 
in the Statistical Analysis Plan. 
9.4.3 
Analysis of Endpoints 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The analysis of the primary endpoint in this pilot study is essential 
for further planning of formal clinical trials. The analysis for the 
primary endpoint will estimate the ongoing pregnancy rate and its 
corresponding 95% CI for each group, and difference in ongoing 
pregnancy rate between combination medication and Crinone® and 
its corresponding 90% CI.  The CIs for each treatment group will be 
calculated with the Clopper-Pearson method. The CI for the 
difference between the two treatment groups will be calculated with 
the Pearson chi-square test 
Ongoing pregnancy rate: the number of ongoing pregnancies 
expressed per 100 ET cycles (from the start date of first ET to the End 
of Study). 
Since the number of embryos transferred is medically known to have 
an impact on the chance of achieving an ongoing pregnancy rate, the 
rate of participants with only 1 embryo transferred within each arm 
will be examined. If the data suggest a possible imbalance between 
the two arms, pertinent subgroup analyses of the primary endpoint in 
participants with only 1 embryo transferred and in participants with 
2 embryos transferred may be performed. Details will be specified in 
the Statistical Analysis Plan. 
Secondary 
The analyses of secondary endpoints will take the similar manner as 
primary endpoint.  
Implantation rate: The number of gestational sacs observed divided 
by the number of embryos transferred (usually expressed as a 
percentage, %). 
-hCG positive rate: the number of -hCG positive participants 
expressed per 100 ET cycles. 
Clinical pregnancy rate: the number of clinical pregnancies expressed 
per 100 ET cycles.  


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Endpoint 
Statistical Analysis Methods 
Luteal phase bleeding rate：the number of the participants with luteal 
phase bleeding expressed per 100 embryos transferred cycles. 
Vaginal bleeding rate: the number of the participants with vaginal 
bleeding expressed per 100 embryos transferred cycles. 
 
9.4.4 
Safety Analyses 
Safety Analyses will be performed using the Safety population. 
Data on AEs will be collected on scheduled and unscheduled visits, based on information 
spontaneously provided by the participant and/or by questioning the participant. The most 
current version of Medical Dictionary for Regulatory Activities (MedDRA) and the World 
Health Organization Drug Dictionary (WHODRUG) coding dictionaries will be used for AEs, 
medical conditions, and concomitant medications. Number and percentage of patients with 
AEs or SAEs will be presented according to System Organ Class and the preferred term from 
the MedDRA dictionary.  
9.4.5 
Sequence of Analyses 
No formal interim analyses are planned. 
 
 


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10 
References  
1.  
Wang Y, He Y, Zhao X, Ji X, Hong Y, Wang Y, et al. Crinone® gel for luteal phase 
support in frozen-thawed embryo transfer cycles: A prospective randomized clinical 
trial in the Chinese population. PLoS One. 2015;10:e0133027.  
2.  
He JY, Zou LB, Cheng Z. Comparison of two protocols of luteal phase support on the 
frozen embryo transfer cycle. Matern Child Healthc China. 2015;30(35):6296–8.  
3.  
Leng YF, Sun XL, Mou LL, Liang JY, Hu SM. Comparison of different luteal phase 
support protocol in fresh cycle and frozen embryo transfer cycle. Chinese J Clin 
(Electronic Ed. 2015;9:2436–9.  
4.  
Zhen L, Yang JJ, Zhang M, Lou H, Qiao HW, Wang YF, et al. Compare two protocols 
of luteal phase support after frozen-thawed embryo transfer. Matern Child Healthc 
China. 2015;30:4504–6.  
5.  
Hou XH, Huang YG, Zhang HN, Xiao Y, Huang CX, Lu JQ. Evaluation of two 
protocols of luteal phase support in the IVF / ICSI cycle and HRT cycle. J Pract Obstet 
Gynecol. 2013;29(3):152–4.  
6.  
He B, Chi Y, Huang L, Wang SK. 3 protocols of luteal phase support for HRT cycle. 
Guangxi Med J. 2013;35(9):1210–1.  
7.  
Trounson A, Mohr L. Human pregnancy following cryopreservation, thawing and 
transfer of an eight-Cell embryo. Nature. 1983;305:707–9.  
8.  
Zeilmaker GH, Alberda AT, van Gent I, Rijkmans CM, Drogendijk AC. Two 
pregnancies following transfer of intact frozen-thawed embryos. Fertil Steril. 
1984;42:293–6.  
9.  
Devroey P, Bourgain C, Macklon NS, Fauser BCJM. Reproductive biology and IVF: 
Ovarian stimulation and endometrial receptivity. Trends Endocrinol Metab. 
2004;15(2):85–90.  
10.  
Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence 
of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: 
A prospective randomized trial comparing fresh and frozen-thawed embryo transfer in 
normal responders. Fertil Steril. 2011;96:344–8.  
11.  
Roque M, Lattes K, Serra S, Solà I, Geber S, Carreras R, et al. Fresh embryo transfer 
versus frozen embryo transfer in in vitro fertilization cycles: A systematic review and 
meta-analysis. Fertil Steril. 2013;99:156–62.  
12.  
Blockeel C, Drakopoulos P, Santos-Ribeiro S, Polyzos NP, Tournaye H. A fresh look 
at the freeze-all protocol: A SWOT analysis. Hum Reprod. 2016;31:491–7.  


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13.  
Veleva Z, Orava M, Nuojua-Huttunen S, Tapanainen JS, Martikainen H. Factors 
affecting the outcome of frozen-thawed embryo transfer. Hum Reprod. 2013;28:2425–
31.  
14.  
Kupka MS, D’Hooghe T, Ferraretti AP, De Mouzon J, Erb K, Castilla JA, et al. 
Assisted reproductive technology in Europe, 2011: Results generated from European 
registers by ESHRE. Hum Reprod. 2016;31:233–48.  
15.  
Li YF, Zhu GJ, Zhang HW, Jin R, Yue J, Liu Q, et al. Comparison of three methods of 
endometrial preparation in frozen-thawed embryo transfer cycles. Reprod Contracept. 
2009;29(2):113–6.  
16.  
Chen SL, He JX, Song HD, Li SZ, Liu XN, Li H, et al. Comparison of clinical outcomes 
of four regimens using for frozen-thawed embryo transfer. J South Med Univ. 
2007;27(3):303–6.  
17.  
Liu YC, Yun X. Comparison of clinical outcomes of frozen-thawed embryo transfer 
cycles by using three regimens for endometrial preparation. Acta Univ Med Anhui. 
2009;44(5):625–7.  
18.  
Zhu HQ, Wu RR, Xu JY, Fang XW, Liao YC, Du Y. Preparation of endometrium in 
frozen-thawed embryo transfer cycles. Guangdong Med J. 2006;27(6):869–70.  
19.  
Gao H, Sun ZY, Deng CY, Yu Q, He FF. Comparison of efficacy for endometrial 
preparation in frozen-thawed embryo transfer cycles by artificial cycle versus natural 
cycle. Reprod Contracept. 2008;1(28):54–60.  
20.  
Tian H, Fu YL, Kuang YP. Study on the effect of non-GnRHa down regulation 
hormone replacement therapy and HMG ovulation stimulation on endometrial 
preparation in frozen-thawed embryo transfer cycles. Reprod Contracept. 
2006;26(6):344–6.  
21.  
Nawroth F, Ludwig M. What is the “ideal” duration of progesterone supplementation 
before the transfer of cryopreserved-thawed embryos in estrogen/progesterone 
replacement protocols? Hum Reprod. 2005;20:1127–34.  
22.  
Tavaniotou A, Smitz J, Bourgain C, Devroey P. Comparison between different routes 
of progesterone administration as luteal phase support in infertility treatments. Hum 
Reprod Update. 2000;6(2):139–48.  
23.  
Cicinelli E, De Ziegler D, Bulletti C, Matteo MG, Schonauer LM, Galantino P. Direct 
transport of progesterone from vagina to uterus. Obstet Gynecol. 2000;95:403–6.  
24.  
Yanushpolsky E, Hurwitz S, Greenberg L, Racowsky C, Hornstein M. Crinone® 
vaginal gel is equally effective and better tolerated than intramuscular progesterone for 
luteal phase support in in vitro fertilization-embryo transfer cycles: A prospective 
randomized study. Fertil Steril. 2010;94:2596–9.  


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25.  
Chen ZJ, Lin Q De, Wang XT, Tian QJ. Progesterone maintains early pregnancy and 
prevents early abortion – A consensus by Chinese experts. Chinese J Obstet Gynecol. 
2016;51(7):481–3.  
 


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11 
Appendices 
 


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Appendix 1 
Abbreviations  
AC 
Artificial cycle 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ART 
Assisted reproductive treatment 
ASRM 
American Society for Reproductive Medicine 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case report form 
CT 
Computed tomography 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ET 
Embryo transfer 
FET 
Frozen-thawed embryo transfer 
GCP 
Good clinical practice 
β-hCG 
Beta human chorionic gonadotrophin 
HIPAA 
Health Insurance Portability and Accountability Act 
I/E 
Inclusion/Exclusion 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
ITT 
Intention-to-treat 
IVF 
In vitro fertilization  
MRI 
Magnetic resonance imaging 
PP 
SAE 
Per protocol 
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse reactions 
MedDRA 
Medical Dictionary for Regulatory Activities 
WHODRUG World Health Organization Drug Dictionary 


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Appendix 2 
Study Governance 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information, as requested, for the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. This 
information is required during the study and for 1 year after completion of the study. 
Informed Consent Process 
 The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions on the 
study. 
 Participants must be informed that their participation is voluntary. 
 Participants will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50; local regulations; ICH guidelines; Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable; and the IRB/IEC or 
study center. 
 The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
 If the ICF is updated during their participation in the study, participants must be re-
consented to the most current, approved version. 
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
 The original signed and dated consent will remain at the Investigator’s site and must be 
safely archived so that it can be retrieved at any time for monitoring, auditing and 
inspection purposes. 
Data Protection 
 The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. All participant records or datasets transferred to the Sponsor will contain the 
identifier only; participant names or any identifiable information will not be transferred. 
 The Sponsor must inform participants that their personal study-related data will be used 
per local data protection and privacy laws. The level of disclosure must also be explained 
to the participant. 
 The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by 
appropriate IRB/IEC members, and by regulatory authority inspectors.  All such persons 
will strictly maintain participants’ confidentiality. 
 


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Study Administrative 
The Principal Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Coordinating Investigator will provide expert 
medical input and advice on the study design and execution and is responsible for the review 
and signoff of the clinical study report. 
The study will appear in the following clinical studies registries: clinicaltrials.gov 
Details of structures and associated procedures will be defined in a separate Study Reference 
Manual. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and the following: 
 Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
 Applicable ICH GCP Guidelines 
 Applicable laws and regulations 
The Investigator must submit the protocol, protocol amendments (if applicable), ICF, 
Investigator Brochure, and other relevant documents (e.g., advertisements) to an IRB/IEC and 
the IRB/IEC must review and approve them before the study is initiated. 
Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities. 
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures. 
 Notifying the IRB/IEC of SAEs or other significant safety findings, as required by 
IRB/IEC procedures 
 Providing oversight of the study conduct at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site. 
Emergency Medical Support 
 The Sponsor or designee will provide Emergency Medical Support cards to participants 
for use during the study. These provide the means for participants to identify themselves 
as participating in a clinical study. Also, these give health care providers access to any 
information about this participation that may be needed to determine the course of medical 


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study intervention for the participant. The information on the Emergency Medical Support 
card may include the process for emergency unblinding (if applicable). 
 The first point of contact for all emergencies will be the clinical study Investigator caring 
for the participant.  Consequently, the Investigator agrees to provide his or her emergency 
contact information on the card. If the Investigator is available when an event occurs, they 
will answer any questions. Any subsequent action (e.g., unblinding) will follow the 
standard process established for Investigators. 
Clinical Study Insurance and Compensation to Participants 
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable. 
Clinical Study Report 
After study completion, the Sponsor will write a clinical study report in consultation with the 
Principal Investigator. 
Publication 
 The first publication will include the results of the analysis of the primary endpoints and 
will include data that provided evaluable data. The Investigator will inform the Sponsor in 
advance about any plans to publish or present data from the trial. Any publications and 
presentations of the results (abstracts in journals or newspapers, oral presentations, etc.), 
either in whole or in part, by Investigators or their representatives will require review by 
the Sponsor before submission. The Sponsor will not suppress publication, but maintains 
the right to delay publication in order to protect intellectual property rights. 
 The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows Merck to protect proprietary information and to provide 
comments.  
 The Sponsor will comply with the requirements for publication of study results. Per 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by agreement. 
 Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
After completion of the trial, a clinical trial report will be written by the Sponsor in 
conjunction with the Principal Investigator following the guidance in ICH Topic E3. The 
report must fully present the study objectives, methods, results, limitations of the study, and 
the interpretation of the findings. 


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Data Quality Assurance 
 All participant study data will be recorded on printed or electronic CRFs or transmitted to 
the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are complete, accurate, legible, and timely by 
physically or electronically signing the CRF. Details for managing CRFs are in the Study 
Reference Manual. 
 The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF. 
 The Investigator must permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and 
source data. 
 Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are in the Monitoring Plan. 
 The Sponsor or designee is responsible for data management of this study, including 
quality checking of the data and maintaining a validated database. Database lock will occur 
once quality control and quality assurance procedures have been completed. PDF files of 
the CRFs will be provided to the Investigators at study completion. 
 Study monitors will perform ongoing source data verification to confirm that data in the 
CRF are accurate, complete, and verifiable; that the safety and rights of participants are 
being protected; and that the study is being conducted per the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion, unless local 
regulations, institutional policies, or the Sponsor requires a longer retention. No records 
may be destroyed during the retention period without the Sponsor’s written approval. No 
records may be transferred to another location or party without the Sponsor’s written 
notification. 
Source Documents 
 Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. 
 The Investigator must keep a paper or electronic file (medical file and original medical 
records) at the site for each study participant. The file must identify each participant, 
contain the following demographic and medical information for the participant, and should 
be as complete as possible: 
o Participant’s full name, date of birth, sex, height, and weight 
o Medical history and concomitant diseases 


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o Prior and concomitant therapies (including changes during the study) 
o Study identifier (i.e., the Sponsor’s study number) and participant’s study 
number. 
o Dates of entry into the study (i.e., signature date on the informed consent) and 
each visit to the site 
o Any medical examinations and clinical findings predefined in the protocol 
o All AEs 
o Date that the participant left the study, including any reason for early withdrawal 
from the study or study intervention, if applicable. 
 All source data must be filed (e.g., computed tomography [CT] or magnetic resonance 
imaging [MRI] scan images, electrocardiogram [ECG] recordings, and laboratory results). 
Each document must have the participant number and the procedure date; ideally, printed 
by the instrument used for the procedure. As necessary, medical evaluation of these records 
should be performed, documented, signed and dated by the Investigator.  
 Data recorded on printed or electronic CRFs that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available. 
 The study monitors will use printouts of electronic files for source data verification. These 
printouts must be signed and dated by the Investigator and kept in the study file. 
 Source documents are stored at the site for the longest possible time permitted by the 
applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. The 
Investigator ensures that no destruction of medical records is performed without the 
Sponsor’s written approval. 
 Definition of what constitutes source data is found in the source document agreement. 
Study and Site Closure 
 The Sponsor reserves the right to close the study site or terminate the study at any time and 
for any reason. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a site 
closure visit has been completed. 
 The Investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
 Reasons for the early closure of a study site by the Sponsor or Investigator may include: 
o Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
o Inadequate recruitment of participants by the Investigator 
o Discontinuation of further development of the Sponsor’s compound 


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Appendix 3 
Adverse 
Events: 
Definitions 
and 
Procedures 
for 
Recording, Evaluating, Follow-up, and Reporting 
Definitions 
Adverse Event 
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product, regardless of causal relationship with this study intervention. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, regardless 
if it is considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
The Investigator is required to grade the severity or toxicity of each AE. 
Investigators must assess the severity of AEs per the Qualitative Toxicity Scale, as follows: 
Mild: 
The participant is aware of the event or symptom, but the event or symptom 
is easily tolerated. 
Moderate: 
The participant experiences sufficient discomfort to interfere with or reduce 
his or her usual level of activity. 
Severe: 
Significant impairment of functioning: the participant is unable to carry out 
his or her usual activities. 
Investigators must also systematically assess the causal relationship of AEs to study 
intervention (including any other non-study interventions, radiation therapy, etc.) using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE 
to the study intervention include, but may not be limited to, temporal relationship between 
the AE and the study intervention, known side effects of study intervention, medical 
history, concomitant medication, course of the underlying disease, and study procedures. 
Unrelated: 
Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol. A reasonable alternative explanation 
must be available. 
Related: 
Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol.  
Abnormal Laboratory Findings and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG 
trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to study intervention discontinuation or are considered otherwise 
medically important by the Investigator. If a laboratory abnormality fulfills these criteria, 
the identified medical condition (e.g., anemia or increased alanine aminotransferase 
[ALT]) must be reported as the AE rather than the abnormal value itself. 


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Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening. Life-threatening refers to an event in which the participant is at risk of 
death at the time of the event, not an event that hypothetically might have caused death if 
it was more severe. 
 Requires inpatient hospitalization or prolongs an existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 
 Is otherwise considered to be medically important. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the participant or 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such events include allergic bronchospasm requiring intensive study 
intervention in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
In this clinical study, any spontaneous abortion, ectopic pregnancy, should be considered 
as an SAE. 
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE. 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify study intervention or procedures 
(e.g., an overnight stay to facilitate intravenous therapy) are not considered SAEs. 
However, all events leading to unplanned hospitalizations or unplanned prolongation of an 
elective hospitalization (i.e., undesirable effects of any administered study intervention) 
must be documented and reported as SAEs. 
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial study visit that do not worsen in severity or 
frequency during the study are defined as Baseline Medical Conditions, and are not to be 
considered AEs. 
Recording and Follow-Up of AE and/or SAE 
It is important that each AE report include a description of the event, its duration (onset 
and resolution dates and also onset and resolution times, when it is important to assess the 
time of AE onset relative to the recorded study intervention administration time), its 
severity, its causal relationship with the study intervention, any other potential causal 
factors, any study intervention given or other action taken, including dose modification or 
discontinuation of the study intervention, and its outcome. In addition, serious cases should 
be identified and the appropriate seriousness criteria documented. 


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Specific guidance is in the CRF Completion and Monitoring Conventions provided by the 
Sponsor. 
Reporting Serious Adverse Events  
Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform 
the Sponsor or its designee using the paper report form. Names, addresses, and telephone 
and fax numbers will be included on the paper form. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by 
telephone; in these cases, a paper SAE report form must be completed immediately 
thereafter. 
Relevant informstion may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g., 
laboratory results, hospital report, autopsy report).  
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for 
initial reports. This is necessary to ensure prompt assessment of the event by the Sponsor 
or designee and (as applicable) to allow the Sponsor to meet strict regulatory timelines 
associated with expedited safety reporting obligations. 
Requests for follow-up will usually be made via the study monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 


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Appendix 4 
Visit Procedures 
All participants’ data will be collected in anonymity. The participants are assigned to the two 
study intervention groups at the ratio of 1:1 using a permuted block randomization according 
to a randomization schedule generated by the statistician using a computer program. Each 
participant will have a unique participant number assigned to her and this will be referenced 
throughout the study as the participant’s identifier. The Investigator should keep a separate 
code identification list with all the participants’ information to be retained at the site. Details 
of randomization are in Section 6.3. 
After randomization, the participants will receive either Crinone® or Crinone® in combination 
with Duphaston® for luteal phase support in FET AC. 
The data collection time points for the two protocols are as follows: 
1. Screening/Baseline  
2. Endometrial transformation day 
3. ET day 
4. β-hCG test: Serum β-hCG test 13 to 15 days after ET 
5. Clinical Pregnancy Assessment: Ultrasound examination 4 to 6 weeks after ET 
6. Ongoing Pregnancy Assessment (presence of viable fetus at 10-12 weeks of pregnancy 
[8-10 weeks after ET]) 
All procedures described in Appendix 4 will be conducted according to the routine practices 
of the study site. 
Visit 1 (baseline evaluation): 
The participant will be informed of the study objectives and overall requirements at the initial 
study visit and written informed consent will be obtained prior to any study-specific 
assessments. Participants may have already initiated estradiol valerate use. The participant 
will then undergo a brief clinical evaluation to ensure compliance with the inclusion and 
exclusion criteria to determine eligibility (see Section 5). 
Data for all participants will come from the participants’ screening or baseline visits and the 
participants’ medical records. 
The following must be completed at Visit 1: 
 Visit date  
 Participant name will be recorded and kept confidentially in the clinic solely for the 
purposes of generating a unique participant number, which will be used to identify each 
participant in the study anonymously.  


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 Demographics include age, gender and date of birth  
 Physical exam and vital signs 
 Weight and height  
 Clinical and gynecological examination (pelvic examination will be performed); 
examinations from medical history prior to signing the ICF is also accepted per the 
Investigator’s decision 
 Gynecological history: duration of infertility, menstrual cycle, history of miscarriages, 
history of pelvic surgery, history of ovarian surgery. 
 Medical history and concomitant illness  
 Any concomitant medication taken by the participant when entering the study   
 Concomitant medications prescribed and reasons  
 Ultrasound without abnormal findings (endometrium thickness will be measured); 
examinations from medical history prior to the initiation of estradiol valerate before 
signing the ICF is also accepted per the Investigators decision 
 Serum β-hCG levels must be negative; examinations from medical history prior to signing 
the ICF is also accepted per the Investigators decision  
 Check I/E criteria 
 Date of initiation of estradiol valerate (if applicable) 
 Initial dose of estradiol valerate (if applicable) 
 Details of dose adjustments of estradiol valerate if any (if applicable) 
 Duration and total dosage of estradiol valerate (if applicable) 
 
Visit 2 (endometrial transformation day) 
The participants should come to the clinic to measure their endometrial thickness on 
endometrial transformation day. Should the endometrial thickness be ≥8 mm, Crinone® will 
be administered at a dose of 90 mg/d for 4-6 days to assist the secretory transformation of the 
endometrium. The following data will be collected:  
 Date of initiation of estradiol valerate 
 Initial dose of estradiol valerate 
 Details of dose adjustments of estradiol valerate if any  
 Duration and total dosage of estradiol valerate  
 Date of initiation of Crinone® 


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 Endometrial thickness before initiation of Crinone® (Endometrial thickness will be 
measured by ultrasound. However, if the ultrasound was performed on the endometrial 
transformation day prior to signing the ICF, a new ultrasound is not required.) 
 Check I/E criteria 
 Recording of AEs  
 Concomitant medications prescribed and reasons.  
The total duration of estradiol valerate before the endometrial transformation should be no 
more than 20 days. 
Visit 3 (embryo transfer day) 
After 4-6 days of assisted secretory transformation of the endometrium, no more than two D5 
embryos will be transferred on the fifth, sixth, or seventh day. After randomization, the luteal 
phase support study intervention will be initiated.  
 Study intervention A (Crinone® group): Randomized participants will be given 
Progesterone gel 8% (Crinone®) 90 mg/p.v./q.d from the day of endometrial 
transformation. It will be suggested that they administer the drug in the morning and 
at the same time of day throughout the trial. A β-hCG test will be done 14 days after 
ET. If serum β-hCG levels are negative, the study will be discontinued. If the result of 
the β-hCG test is positive, Crinone® administration will continue with the above 
regimen. At 35 days after ET, an ultrasound will be done to detect the number of 
gestational sacs to confirm the results of clinical pregnancy. If clinical pregnancy is 
positive, continue Crinone® administration until ongoing pregnancy assessment. 
Should a miscarriage occur at any point, Crinone® administration will be discontinued.  
 Study intervention B (Crinone® + Duphaston® group): Randomized participants will 
be given Progesterone gel 8% (Crinone®) 90 mg/p.v./q.d from the day of endometrial 
transformation, following which Duphaston® at 10 mg/p.o./bid will be administered 
from the day of ET. It will be suggested that they administer the drugs in the morning 
and at the same time of day throughout the trial. A β-hCG test will be done 14 days 
after ET. If serum β-hCG levels are negative, the study will be discontinued. If the 
result of the β-hCG test is positive, the combination medication will continue with the 
above regimen. At 35 days after ET, an ultrasound will be done to detect the number 
of gestational sacs to confirm the results of clinical pregnancy. If clinical pregnancy 
is positive, continue combination medication until ongoing pregnancy assessment. 
Should a miscarriage occur at any point, combination medication will be discontinued.  
All participants will receive oral estradiol valerate continuously and the dose of estradiol 
valerate will be adjusted according to local practices. 
The following data will be collected:  
 Duration and total dosage of estradiol valerate 


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 Date of ET 
 Number of embryo(s) transferred (no more than 2) 
 Embryo quality  
 Check I/E criteria 
 Recording of AEs  
 Concomitant medications prescribed and reasons. 
Visit 4 (β-hCG positive assessment) 
Participants treated by ART are routinely monitored for early detection of pregnancy by 
measuring serum β-hCG concentration according to the site’s routine clinical practices.  
After about 13 to 15 days of ET, early detection of pregnancy will be done by measuring β-
β-hCG levels using blood tests and the results will be recorded.  
The following data will be collected:  
 Date of pregnancy assessment  
 β-hCG test results (positive or negative) 
 Details of luteal phase bleeding, if any  
 Recording of AEs  
 Concomitant medications prescribed and reasons.  
If the result of the pregnancy assessment is negative, procedures related to End of Study visit 
will be performed. 
Visit 5 (Clinical Pregnancy Assessment) 
If the result of the β-hCG pregnancy assessment is positive, it will be further confirmed by a 
clinical pregnancy assessment (by means of an ultrasound examination) 4 to 6 weeks after 
ET.  
The following data will be collected:  
 Date of pregnancy assessment  
 Pregnancy status  
 Positive pregnancy status has to be confirmed by ultrasound examination (presence or non-
presence of gestational sac(s), gestational sacs with or without heartbeat, gestational stage 
at which ultrasound is performed is to be recorded and ectopic pregnancy).  
 Details of vaginal bleeding, if any 
 Recording of all AEs, expedited reporting of all SAEs 


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 Concomitant medications prescribed and reasons.  
 
If the result of the pregnancy assessment is negative, procedures related to End of Study 
visit will be performed. 
Visit 6 (Ongoing Pregnancy assessment) 
Ongoing pregnancy is defined as the presence of viable intra uterine fetus detected by 
ultrasound examination in 12 weeks of pregnancy. The following data will be collected:  
 End of study intervention date 
 Singleton pregnancy / multiple pregnancy 
 Status of ongoing pregnancy 
 Early miscarriage, if any 
 Details of vaginal bleeding, if any 
 Recording of AEs  
 Concomitant medications prescribed and reasons.  
If the status of ongoing pregnancy is confirmed negative, all procedures related to End of 
Study Visit will be performed. 
If the status of ongoing pregnancy is negative and if it is due to an abortion - the reason for 
abortion should be recorded. 
End of Study 
The date and the reason of the completion/withdraw from study intervention or study (see 
Section 7.2) will be collected. 
 





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Seri o us A d verse E ve nts  ...................................................................... 2 2 
1 5. 2. 3  
Blee di n g .............................................................................................. 2 2 
1 5. 3  
Cli nical La b orat o r y E val uati o n ........................................................... 2 4 
1 5. 4  
Vital Si g ns  .......................................................................................... 2 4 
1 6  
A nal yses of Ot her E n d p oi nts .............................................................. 2 4 
1 7  
Refere nces  ........................................................................................... 2 4 
1 8  
A p pe n dices ......................................................................................... 2 4 
 


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5/ 2 4 
 
 
2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms 
 
A Da M  
A nal ysis Data M o del  
A E  
A d verse e ve nt  
A T C  
A nat o mical T hera pe utic C he mical classificati o n  
CI  
C o nfi de nce I nter val  
(e) C R F 
(electr o nic) Case Re p ort F or m 
C S R  
Cli nical St u d y Re p ort  
E D C  
Electr o nic data ca pt ure  
E T  
E m br y o tra nsfer  
F E T  
Fr oze n -t ha we d e m br y o tra nsfer 
β -h C G  
Beta h u ma n c h ori o nic g o na d otr o p hi n  
I A P 
I nte grate d A nal ysis Pla n 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n 
I T T 
I nte nti o n-t o-treat 
I V R S 
I nteracti ve V oice Res p o nse S yste m 
L O C F  
Last O bser vati o n Carrie d F or war d  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
N A  
N ot A p plica ble  
P D  
Pr ot oc ol De viati o n  
P T  
Preferre d Ter m  
P P  
S A E  
Per pr ot oc ol 
Seri o us a d verse e ve nt  
S C R  
Scree ni n g a nal ysis p o p ulati o n  
S D  
Sta n dar d De viati o n  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T L F  
Ta bles, Listi n gs, a n d Fi g ures  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
 






A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8/ 2 4 
 
 
8  
Pr ot oc ol De vi ati o ns  a n d A n al ysis P o p ul ati o ns  
8. 1  
Defi niti o n of Pr ot oc ol De vi ati o ns  
I m p orta nt  pr ot oc ol  de viati o ns  are  pr ot oc ol  de viati o ns  t hat  mi g ht  si g nifica ntl y  affect  t he 
c o m plete ness,  acc u rac y,  a n d/ or  relia bilit y  of  t he  st u d y  data  or  t hat  mi g ht  si g nifica ntl y  affect  a 
s u bject's ri g hts, safet y, or well- bei n g. 
T he f oll o wi n g de viati o ns will be i de ntifie d a n d c o nfir me d pri or t o or at t he Data Re vie w Meeti n g 
at t he latest. 
I m p orta nt pr ot oc ol de viati o ns i ncl u de : 
•  De viati o ns fr o m t he i ncl usi o n a n d e xcl usi o n criteria 
•  De viati o ns p ost i ncl usi o n  
•  S u bset of t hese i m p orta nt pr ot oc ol de viati o ns are cli nicall y i m p orta nt,  if lea di n g t o t he e xcl usi o n 
of a s u bject fr o m a n a nal ysis p o p ulati o n (see secti o n 8. 2) 
All   i m p orta nt  pr ot oc ol  de viati o ns base d  o n  e C R F  data base  are d oc u me nte d  i n A Da M  datasets  
w het her i de ntifie d t hr o u g h site m o nit ori n g, me dical re vie w or pr o gra m mi n g . 
 
8. 2  
Defi niti o n of A n al ysis P o p ul ati o ns a n d S u b gr o u ps  
T he  a nal ysis  p o p ulati o ns  are  s pecifie d  bel o w.  T he  fi nal  decisi o n  t o  e xcl u de s u bjects  fr o m  a n y 
a nal ysis p o p ulati o n will be ma de d uri n g a data re vie w meeti n g pri or t o data base l oc k. 
 
A n al y si s P o p ul ati o n  
D e s cri pti o n  
I nt e nti o n-t o-Tr e at (I T T)  
P o p ul ati o n  
T h e I T T P o p ul ati o n will i n cl u d e all s u bj e ct s w h o r e c ei v e at l e a st o n e d o s e of 
r a n d o mi z e d st u d y i nt er v e nti o n aft er r a n d o mi z ati o n . S u bj e ct s will b e a n al y z e d 
a c c or di n g t o t h e st u d y i nt er v e nti o n t h e y w er e i niti all y a s si g n e d.  
P er -Pr ot o c ol ( P P)  
P o p ul ati o n  
I n cl u d e s all s u bj e ct s i n I T T p o p ul ati o n wit h o ut a n y i m p ort a nt pr ot o c ol vi ol ati o n s.  
S af et y P o p ul ati o n  
I n cl u d e all s u bj e ct s w h o h a v e r e c ei v e d at l e a st o n e d o s e of st u d y i nt er v e nti o n  aft er 
r a n d o mi z ati o n. S u bj e ct s will b e a n al y z e d a c c or di n g t o t h e a ct u al st u d y i nt er v e nti o n 
t h e y r e c ei v e d. 
T he ge neral use of t he a nal ysis p o p ulati o ns i n t he differe nt a nal yses are s u m marize d as bel o w.  
 
 
A n al y si s P o p ul ati o n  
A n al y s e s  
I nt e nt-t o-Tr e at  
P er Pr ot o c ol  
S af et y  
B a s eli n e A s s e s s m e nt s  
 
 
 
C o n c o mit a nt T h er a pi e s  
 
 
 
C o m pli a n c e a n d E x p o s ur e  
 
 
 


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9/ 2 4 
 
 
 
A n al y si s P o p ul ati o n  
A n al y s e s  
I nt e nt-t o-Tr e at  
P er Pr ot o c ol  
S af et y  
Effi c a c y: Pri m ar y  
 
 
 
Effi c a c y: S e c o n d ar y  
 
 
 
S af et y  
 
 
 
If  t he  Per  Pr ot oc ol  a nal ysis p o p ulati o n i ncl u des  at  least  9 0 %  of s u bjects  i n  t he  I T T  a nal ysis 
p o p ulati o n , a d diti o nal efficac y a nal yses o n t he Per Pr ot oc ol a nal ysis p o p ulati o n will be o mitte d as 
t he  differe nces  i n  t he  res ults  base d  u p o n  t hese  t w o  a nal ysis p o p ulati o ns are  e x pecte d  t o  be 
ne gli gi ble.  
A d diti o n al S u b gr o u p A n al ysis P o p ul ati o ns  
S u b gr o u p a nal yses  of t he pri mar y e n d p oi nt will be perf or me d o n s u b gr o u ps as defi ne d bel o w  if 
nee de d .  F or  t he  defi niti o n  of  s u b gr o u p,  data  as  d oc u me nte d  i n  t he  electr o nic  case  re p ort  f or m 
(e C R F) will be ta ke n. 
S u b gr o u ps: 
T he f oll o wi n g s u b gr o u ps will be defi ne d  if t he data s u g gest a p ossi ble i m bala nce bet wee n t he t w o 
ar ms: 
•  t he n u m ber of e m br y os tra nsferre d 
•  1 e m br y o tra nsferre d 
•  2 e m br y os tra nsferre d   
9  
Ge ner al S pecific ati o ns f or D at a A n al yses  
St u d y i nter ve nti o n gr o u ps  
St u d y  i nter ve nti o n gr o u ps  are  defi ne d  a n d  la belle d  as Cri n o ne ®   a n d c o m bi nati o n  me dicati o n 
( Cri n o ne®  pl us D u p hast o n® ). 
U nless ot her wise i n dicate d all a nal yses will be prese nte d se paratel y f or t he t w o st u d y i nter ve nti o n 
gr o u ps. 
D at a h a n dli n g after c ut - off d ate  
Data after c ut- off d o n ot u n der g o t he clea ni n g pr ocess. 
Data o btai ne d after t he c ut -off will n ot be dis pla ye d i n a n y listi n gs or use d f or s u m mar y statistics, 
e. g. la b orat or y val ues of sa m ples ta ke n after data c ut -off, A E s wit h o nset date after data c ut off, 
etc. will n ot be i ncl u de d i n a n y a nal ysis or listi n g. 
St o p dates are n ot affecte d b y t his r ule, e. g. a st o p date of A Es, w hic h starts pri or t o t he c ut -off, 
b ut st o ps after date of c ut- off, will n ot be c ha n ge d. 


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0/ 2 4 
 
 
Si g nific a nce le vel  
T here is n o f or mal statistical h y p ot h esis testi n g i n t his st u d y. F or treat me nt differe nce, t w o si de d 
9 0 % c o nfi de nce i nter vals will be calc ulate d, u nless ot her wise i n t his I A P s pecifie d. 
Prese nt ati o n of c o nti n u o us a n d q u alit ati ve v ari a bles  
C o nti n u o us varia bles will be s u m marize d usi n g descri pt i ve statistics, i.e. 
•  n u m ber of s u bjects, n u m ber of s u bjects wit h n o n- missi n g val ues, 
•  mea n, sta n dar d de viati o n, 
•  me dia n, 2 5t h Perce ntile - 7 5t h Perce ntile ( Q 1 -Q 3),  
•  mi ni m u m, a n d ma xi m u m. 
Q ualitati ve varia bles will be s u m marize d b y c o u nts  a n d perce nta ges. 
U nless ot her wise state d t he calc ulati o n of pr o p orti o ns will be base d o n t he n u m ber of s u bjects of 
t he a nal ysis p o p ulati o n of  i nterest. T heref ore, c o u nts of missi n g o bser vati o ns will be i nc l u de d i n 
t he de n o mi nat or a n d prese nte d as a se parate cate g or y. 
I n case t he a nal ysis refers o nl y t o certai n visits perce nta ges will be base d o n t he n u m ber of s u bjects 
still prese nt i n t he st u d y at t hat visit, u nless ot her wise s pecifie d . 
Defi niti o n of b aseli ne  
I n ge neral, t he last n o n-missi n g  meas ure me nt pri or t o  (≤)  ra n d o mizati o n date will ser ve as t he 
baseli ne meas ure me nt. If n o s uc h a val ue is a vaila ble, t he last meas ure me nt pri or t o (≤) t he first 
st u d y  i nter ve nti o n a d mi nistrati o n date  after ra n d o mizati o n  date will  be  use d  as  t he  baseli ne 
meas ure me nt . 
C o n versi o n f act ors 
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da ys i nt o m o nt hs or years: 1 m o nt h = 
3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys. 
H a n dli n g of missi n g d at a  
U nless ot her wise s pecifie d , missi n g data will n ot be re place d. 
I n all s u bject data listi n g s, i m p ute d val ues will be prese nte d. I n all listi n gs i m p ute d i nf or mati o n 
will be fla g ge d.  
Missi n g statistics, e. g. w he n t he y ca n n ot be calc ulate d, s h o ul d be prese nte d as “ n d ”. F or e xa m ple, 
if n = 1, t he meas ure of varia bilit y ( S D) ca n n ot be c o m p ute d a n d s h o ul d be prese nte d as “ n d”. 
Ti me wi n d o w  


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1/ 2 4 
 
 
Da y 1 is t he da y of start of st u d y i nter ve nti o n after ra n d o mizati o n , t he da y bef ore is Da y -1 ( n o 
Da y 0 is defi ne d). 
St u d y da y is defi ne d relati ve t o Da y 1. 
S oft w are(s)  
All a nal yses will be perf or me d usi n g S A S ® S oft ware versi o n 9. 4 or hi g her. 
 
1 0  
St u d y  S u bject s 
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or re p orti n g s u bject dis p ositi o n a n d st u d y 
i nter ve nti o n/st u d y disc o ntin uati o ns. A d diti o nall y , pr oce d ures f or re p orti n g pr ot oc ol de viati o ns are 
pr o vi de d. 
 
1 0. 1  
Dis p ositi o n of S u bject s a n d Disc o nti n u ati o ns 
•  T otal n u m ber of s u bjects scree ne d (i.e. s u bjects w h o ga ve i nf or me d c o nse nt) 
•  N u m ber  of s u bjects w h o  disc o nti n ue d  fr o m  t he st u d y pri or  t o  ra n d o mizati o n  o verall  a n d 
gr o u pe d b y t he mai n reas o n (e. g. t he faile d s pecific i ncl usi o n or e xcl usi o n criteria , wit h dra w of 
c o nse nt) 
•  N u m ber of r a n d o mize d s u bjects.  
•  N u m ber  of  ra n d o mize d s u bjects  w h o  recei ve d  at  least  o ne d ose of st u d y  i nter ve nti o n after 
ra n d o mizati o n 
•  N u m ber of ra n d o mize d s u bjects w h o c o m plete d st u d y after ra n d o mizati o n , gr o u pe d b y  st u d y 
i nter ve nti o n gr o u p a n d mai n reas o n. 
•  N u m ber of ra n d o mize d s u bjects w h o disc o nti n ue d t he st u d y after ra n d o mizati o n , gr o u pe d b y 
st u d y i nter ve nti o n gr o u p a n d mai n reas o n  
T he  n u m ber  a n d  perce nta ge  of s u bjects  i n  eac h  of  t he  a b o ve  dis p ositi o n  cate g ories  will  be 
prese nte d b y ra n d o mize d st u d y i nter ve nti o n gr o u p (if a p plica ble) a n d o verall. Perce nta ges will be 
prese nte d wit h res pect t o t he n u m ber of ra n d o mize d s u bjects. St u d y c o m pleti o n or disc o nti n uati o n 
a n d t heir c orres p o n di n g reas o ns will  be s u m marize d fr o m “ S t u d y Ter mi nati o n” eC R F pa ge.  
Dis p ositi o n of s u bjects b y all ocate d st u d y i nter ve nti o n gr o u p will be prese nte d i n a C O N S O R T 
Fl o w Dia gra m.  
T he res ults of t he ra n d o mizati o n al g orit h m (acc or di n g t o I V R S) will be s u m marize d as f oll o ws:  
•  N u m ber  of s u bjects by ra n d o mizati o n strat u m (I V R S)  
 


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2/ 2 4 
 
 
1 0. 2  
Pr ot oc ol De vi ati o ns  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De vi ati o ns 
T he  f oll o wi n g  s u m mar y  ta bles  a n d  listi n gs  of  i m p orta nt  pr ot oc ol  de viati o ns  will  be  pr o vi de d 
(se paratel y f or pre-/ p ost i ncl usi o n de viati o ns): 
•  Fre q ue nc y ta ble per reas o n of i m p orta nt pr ot oc ol de viati o ns 
•  Listi n g of i m p orta nt pr ot oc ol de viati o ns 
 
1 0. 2. 2  
Re as o ns  Le a di n g  t o  t he  E xcl usi o n  fr o m  a n  A n al ysis 
P o p ul ati o n  
F or s u bjects e xcl u de d fr o m t he P P, t he reas ons f or e xcl usi o n will be s u m marize d a n d liste d; 
•  Fre q ue nc y ta ble per reas o n of e xcl usi o n fr o m t he P P p o p ulati o n 
•  Listi n g of reas o ns of e xcl usi o n fr o m t he P P p o p ulati o n 
 
1 1  
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics  
If n ot state d ot her wise, s u m maries will be prese nte d o n t he I T T a nal ysis p o p ulati o n , b y ra n d o mize d 
st u d y i nter ve nti o n gr o u p a n d o verall. 
 
1 1. 1  
De m o gr a p hics  
De m o gra p hic c haracteristics will be s u m marize d usi n g t he f oll o wi n g i nf or mati o n fr o m t he “Visit 
1 ( Baseli ne  E val uati o n)” eC R F pa ges.  
•  De m o gra p hic c haracteristics  
•  A ge at freezi n g ( years) 
•  A ge  at tra nsfer  ( years) 
•   Age cate g ories  at tra nsfer : 
•  < 3 5 years  a n d ≥ 2 0 years  
•  ≥ 3 5 years 
•  Race: Asia n, ot her , n ot c ollecte d at t his site 
•  Wei g ht at Baseli ne 
•  B MI at Baseli ne  


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3/ 2 4 
 
 
S pecificati o ns f or c o m p utati o n i n E D C: 
•  A ge at tra nsfer  (years ) 
•  F or m ula: ( date of gi ve n i nf or me d c o nse nt - date of birt h) / 3 6 5. 2 5 . 
•  I n case of missi n g da y f or at least o ne date, b ut m o nt h a n d year a vaila ble f or b ot h dates: 
F or t he deri vati o n of a ge , t he da y of i nf or me d c o nse nt a n d t he da y of birt h will be set t o 1 
a n d t he f or m ula a b o ve will be use d 
•  I n case of missi n g m o nt h f or at least o ne date, b ut year a vaila ble f or b ot h dates: 
F or t he deri vati o n of a ge, t he da y a n d t he m o nt h of i nf or me d c o nse nt a n d t he da y a n d m o nt h 
of birt h will be set t o 1 a n d  t he f or m ula a b o ve will be use d 
•  B MI ( k g/ m²) = wei g ht ( k g) / [ hei g ht (c m) x hei g ht (cm) ] x 1 0 0 0 0 
 
De viati o n:  
•  A ge at freezi n g ( years)  
•  F or m ula: ( date of fr oze n e m br y o- date of birt h) / 3 6 5. 2 5.  
•  Data  S o urce: date of fr oze n e m br y o is fr o m “ E m br y o Tra nsfer” e C R F pa ge.  
•  Missi n g date i m p utati o n: sa me as t he wa y  as t he o ne f or a ge at tra nsfer.  
1 1. 2  
Me dic al Hist or y  
T he me dical hist or y will be s u m marize d fr o m t he “ Me dical Hist or y” e C R F pa ge, usi n g Me d D R A, 
c urre nt versi o n, preferre d ter m as e ve nt cate g or y a n d s yste m or ga n class ( S O C) b o d y ter m as B o d y 
S yste m cate g or y.  
Me dical hist or y will be dis pla ye d i n ter ms of fre q ue nc y ta bles: or dere d b y pri mar y S O C a n d P T 
i n al p ha betical or der. 
1 1. 3  
Ot her B aseli ne C h ar acteristics  
I nf or mati o n o n disease c haracteristics an d E T pre parati o n  c ollecte d at t he baseli ne  e val uati o n visit 
will be s u m marize d b y st u d y i nter ve nti o n gr o u p a n d o verall. S u m mar y  statistics will be prese nte d 
f or: 
Dise ase hist or y  
•  S u bjects wit h pel vic s ur ger y hist or y (“ Pel vic S ur ger y Hist or y ” e C R F pa ge) 
•  Pre vi o us pre g na ncies (‘ Yes’ or ‘ No ’) (“ O B S T E T RI C A L HI S T O R Y” e C R F pa ge) 
o  D efi niti o n: s u bjects wit h n u m ber of pre vi o us pre g na ncies > 0 will be cate g orize d t o 
be ‘ Y es’, ot her wise ‘ No’ 


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4/ 2 4 
 
 
o  If Yes, n u m ber of pre vi o us pre g na ncies  will be pr o vi de d a n d dis pla ye d b y n u m ber 
cate g or y . 
•  Li ve birt hs (‘ Yes’ or ‘ No ’) (“ O B S T E T RI C A L HI S T O R Y” e C R F pa ge) 
o  Defi niti o n : s u bjects wit h n u m ber of li ve birt hs > 0 will be cate g orize d t o be ‘ Y es’, 
ot her wise ‘ N o’ 
o  If Y, n u m ber of li ve birt hs  will be pr o vi de d a n d dis pla ye d b y n u m ber cate g or y. 
•  S p o nta ne o us a b orti o ns (“ O B S T E T RI C A L HI S T O R Y” e C R F pa ge) 
o  Defi niti o n : s u bjects wit h n u m ber of s p o nta ne o us a b orti o ns > 0  will be cate g orize d 
t o be ‘ Y’, ot her wise ‘ N’ 
o  If Y, n u m ber of sp o nta ne o us a b orti o ns  will be pr o vi de d a n d dis pla ye d b y n u m ber 
cate g or y. 
•  T hera pe utic/electi ve a b orti o ns (“ O B S T E T RI C A L HI S T O R Y” e C R F pa ge) 
o  Defi niti o n :  s u bjects  wit h  n u m ber  of  t hera pe utic/electi ve  a b orti o ns > 0 will  be 
cate g orize d t o be ‘ Y’, ot her wise ‘ N’  
o  If Y, nu m ber of t hera pe utic/electi ve a b orti o ns  will be pr o vi de d a n d dis pla ye d b y 
n u m ber cate g or y. 
•  I nfertilit y ( pri mar y or sec o n dar y) (“I nfertilit y Hist or y” e C R F pa ge) 
•  D urati o n of I nfer tilit y ( M o nt hs) (“I nfertilit y Hist or y” e C R F pa ge) 
•  T y pe of I nfertilit y (“I nfertilit y Hist or y” e C R F) 
o  C a uses of fe male i nfertilit y  
E m br y o tr a nsfer rel ate d b aseli ne c h ar acteristics  
•  E n d o metrial  t hic k ness  at  baseli ne  (“Ultras o u n d Sca n  Assess me nt -Scree ni n g ”  e C R F  pa ge  at 
visit 1 ) 
•  D urati o n of Estra di ol Valerate  pri or t o ra n d o mizati o n date ( da y) 
•  Deri vati o n: ra n d o mizati o n date  - t he date of Estra di ol Valerate  i nitiati o n + 1  
•  Data s o urce:  
o  T he date of Estra di ol Valerate i nitiati o n: t he first d ose date i n “A d mi nistrati o n o f 
Estra di ol Valerate ” e C R F pa ge  
o  Ra n d o mizati o n  date:  ra n d o mizati o n  date  i n  t he  “ Ra n d o mizati o n”  e C R F  pa ge  at 
visit 4  
•  E n d o metrial t hic k ness pri or t o i nitiati o n of Cri n o ne  (“Ultras o u n d Sca n Assess me nt - 1” e C R F 
pa ge at visit 3)  
•  E n d o metrial t hic k n ess at tra nsfer da y  (“Ultras o u n d Sca n Assess me nt - 2” e C R F pa ge  at visit 4) 
•  N u m ber of D 5 e m br y os tra nsferre d  ( dis pla ye d b y n u m ber cate g or y)  (“E m br y o Tra nsfer ” e C R F 
pa ge)  


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5/ 2 4 
 
 
•  D urati o n of e m br y o fr oze n ( m o nt hs) 
•  F or m ula: =e m br y o tra nsfer date – t he date of fr oze n e m br y o + 1  
•  Data s o urce: “ E m br y o Tr a nsfer ” e C R F pa ge  
•  G o o d q ualit y e m br y o 
•  Deri vati o n: f or eac h s u bject, it is t he n u m ber of e m br y os gra de d i n A A , A B, B A or B B  (i n ner 
cell mass is n ot e q ual t o  ' C' a n d tr o p hect o der m is n ot e q ual t o  ' C') acc or di n g t o t he Gar d ner 
E m br y o Gra di n g S yste m. 
•  Data s o urce: “ E m br y o Tr a nsfer ” e C R F pa ge  
1 2  
C o nc o mit a nt Me dic ati o ns/ P r oce d ures  
C o nc o mit a nt tre at me nts  are me dicati o ns, ot her t ha n st u d y i nter ve nti o ns  a n d estra di ol valerate , 
w hic h are ta ke n b y s u bjects a n y ti me o n-st u d y ( o n or after t he first da y of st u d y i nter ve nti o n after 
ra n d o mizati o n f or eac h s u bject) or pri or t o  last d ose of trial dr u g. 
C o nc o mita nt treat me nt  will be s u m marize d fr o m t he “ C o nc o mita nt M e dicati o n” e C R F  pa ge. A T C-
2 n d  le vel  a n d  preferre d  ter m will  be  ta b ulate d  as  gi ve n  fr o m  t he  W H O - D D dicti o nar y  c urre nt 
versi o n. I n case m ulti ple A T C’s are assi g ne d t o a dr u g, all A T C- 2n d le vel will be use d f or re p orti n g. 
I n  case  t he  date  val ues  will  n ot  all o w  t o  u ne q ui v ocall y all ocate a  me dicati o n  t o  c o nc o mita nt  
me dicati o n , t he me dicati o n will be c o nsi dere d as c o nc o mita nt me dicati o n. 
All C o nc o mit a nt pr oce d ures ,  w hic h  were  u n derta ke n  a n y  ti me  o n st u d y,  will  be  s u m marize d 
acc or di n g t o t he eC R F pa ge “ C o nc o mita nt Pr oce d ures”. C o nc o mita nt pr oce d ures will be classifie d  
b y me dical re vie w.  
N u m ber of s u bjects wit h c o nc o mita nt pr oce d ures ( o n or after t he first da y of st u d y i nter ve nti o n  
after ra n d o mizati o n  or pri or t o  last d ose of st u d y i nter ve nti o n) will be prese nte d b y  o verall a n d b y 
t y pe of pr oce d ure (as classifie d b y me dical re vie w) 
1 3  
St u d y i nter ve nti o n  C o m pli a nce a n d E x p os ure  
All  d osi n g  calc ulati o ns  a n d  s u m maries  will  be  base d  o n  “ A d mi nistrati o n  of Cri n o ne”  a n d 
“ A d mi nistrati o n  of D u p hast o n” e C R Fs pa ges.  
Cri n o ne will be a d mi nistere d  pri or t o ra n d o mizati o n , b ut first d ose date after ra n d o mizati o n will 
be use d as start date i n t he f oll o wi n g calc ulati o n. 
A n al ysis P o p ul ati o n to be use d f or s u m m aries:  
•  Safet y p o p ulati o n 
C o m pli a nce  
•  C o m plia nce ( %) = 1 0 0 * act ual d ose / pla nne d d ose f or st u d y i nter ve nti o n d urati o n. 
o  Cri n o ne Pla n ne d D ose : 9 0 m g / gel, q. d 
o  D u p hast o n Pla n ne d D ose : 1 0 m g/ta blet, b.i. d 


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 6/ 2 4 
 
 
1 4  
Effic ac y A n al yses  
1 4. 1  
Pri m ar y E n d p oi nt: O n g oi n g Pre g n a nc y  








A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 0/ 2 4 
 
 
1 5  
S afet y A n al yses  
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or s u m marizi n g safet y e n d p oi nts t hat are 
c o m m o n acr oss cli nical st u dies s uc h as a d verse e ve nts, la b orat or y tests a n d vital si g ns. 
Safet y  a nal yses  will  be  d o ne  o n  t he  safet y  a nal ysis p o p ulati o n a n d  acc or di n g  t o  t he  as -treate d 
pri nci ple.  
 
1 5. 1  
A d verse E ve nts  
U nless ot her wise state d A E will be assesse d via s u m mar y statistics.  
Defi niti o ns  
Tre at me nt -e mer ge nt a d verse e ve nts  ( T E A Es): t h ose e ve nts wit h o nset dates occ urri n g wit hi n 
t he treat me nt peri o ds. T he tre at me nt peri o d is defi ne d fr o m t he first da y of st u d y i nter ve nti o n 
after ra n d o mizati o n u ntil last d ose of st u d y i nter ve nti o n date or t he cli nical c ut -off date, w hate ver 
occ urs earlier.  
All a nal yses descri be d i n Secti o n 1 5. 1 will be base d o n T E A Es if n ot ot her wise s pecif ie d. 
A d verse e ve nts rel ate d t o st u d y i nter ve nti o n  are t h ose e ve nts wit h relati o ns hi p missi n g, u n k n o w n 
or yes. 
Missi n g d at a h a n dli n g  
I nc o m plete A E-relate d dates will be ha n dle d as f oll o ws: 
•  I n case t he o nset date is missi n g c o m pletel y or missi n g partiall y b ut t he o nset m o nt h a n d year, 
or t he o nset year are e q ual t o t he start of st u d y i nter ve nti o n t he n t he o nset date will be re place d 
b y t he mi ni m u m of start of st u d y i nter ve nti o n a n d A E res ol uti o n date. 
•  I n all ot her cases, t he missi n g o nset da y or missi n g o nset m o nt h will be re place d b y 1. 
•  I nc o m plete st o p dates will be re place d b y t he last da y of t he m o nt h (if da y is missi n g o nl y), if 
n ot res ulti n g i n a date later t ha n t he date of s u bject's deat h. I n t he latter case, t he date of deat h 
will be use d t o i m p ute t he i nc o m plete st o p date. 
•  I n all ot her cases, t he i nc o m plete st o p date will n ot be i m p ute d. If St o p date of A E is after date 
of c ut- off o utc o me of A E is o n g oi n g at c ut- off.  
•  F urt her i nf or mati o n after c ut -off (li ke fatal o utc o me) mi g ht be ta ke n fr o m Safet y data base a n d 
i ncl u de d se paratel y i nt o CS R.  
 


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 1/ 2 4 
 
 
1 5. 1. 1  
All A d verse E ve nts  
U nless ot her wise state d, a d verse e ve nts will be dis pla ye d i n ter ms of fre q ue nc y ta bles: b y  pri mar y 
s yste m or ga n class ( S O C) i n al p ha betical or der a n d preferre d ter m (P T ) i n i nci de nce desce n di n g 
or der. 
If a n a d verse e ve nt is re p orte d f or a gi ve n s u bject m ore t ha n o nce d uri n g st u d y i nter ve nti o n, t he 
w orst se verit y a n d t he w orst relati o ns hi p t o st u d y i nter ve nti o n will be ta b ulate d.  
I n a d diti o n, t he f oll o wi n g o verall fre q ue nc y ta ble will be pre pare d  b y pri mar y S O C i n al p ha betical 
or der a n d P T  i n i nci de nce desce n di n g or der: 
•  A n y T E A E  
o  A n y  eit her trial dr u g relate d T EA Es  
o  A n y Cri n o ne o nl y relate d T E A Es  
o  A n y D u p hast o n o nl y relate d T E A Es  
o  A n y T E A Es relate d t o b ot h dr u gs 
•  A n y seri o us T E A Es  
o  A n y eit her trial dr u g relate d seri o us T EA Es  
o  A n y Cri n o ne o nl y relate d seri o us T EA Es  
o  A n y D u p hast o n o nl y relate d seri o us T E A Es  
o  A n y seri o us T E A Es relate d t o b ot h dr u gs 
•  A n y A E b y w orst se verit y 
o  A n y eit her trial dr u g relate d T EA Es  b y w orst se verit y 
o  A n y Cri n o ne o nl y relate d T E A Es  b y w orst se verit y  
o  A n y D u p hast o n o nl y relate d T E A Es  b y w orst se verit y  
o  A n y T E A Es relate d t o b ot h dr u gs b y w orst se verit y  
•  A Es  lea di n g t o deat h ( A Es wit h Gra de 5 or o utc o me “fatal” if gra de 5 n ot a p plica ble) 
o  A n y  eit her trial dr u g relate d T EA Es  lea di n g t o deat h ( A Es wit h Gra de 5 or o utc o me 
“fatal” if gra de 5 n ot a p plica ble ) 
o  A n y Cri n o ne o nl y relate d T E A Es  lea di n g t o deat h ( A Es wit h Gra de 5 or o utc o me 
“fatal” if gra de 5 n ot a p plica ble)  
o  A n y D u p hast o n o nl y relate d T E A E s lea di n g t o deat h ( A Es wit h Gra de 5 or o utc o me 
“fatal” if gra de 5 n ot a p plica ble ) 
o  A n y T E A Es relate d t o b ot h dr u gs  lea di n g t o deat h ( A Es wit h Gra de 5 or o utc o me 
“fatal” if gra de 5 n ot a p plica ble)  
 


A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2/ 2 4 
 
 
1 5. 1. 2  
A d verse  
E ve nts  
Le a di n g  
t o  
St u d y  
I nter ve nti o n 
Disc o nti n u ati o n  
T he  f oll o wi n g o verall fre q ue nc y ta bles will be pre pare d f or t he a d verse e ve nt acti o ns f or t he first 
st u d y i nter ve nti o n b y P T a n d pri mar y S O C i n al p ha betical or der.   
•  A Es ca usi n g disc o nti n uati o n of at least o ne st u d y i nter ve nti o n (eit her Cri n o ne or D u p hast o n) 
•  A Es ca usi n g disc o nti n uati o n of Cri n o ne 
o  Cri n o ne o nl y relate d A Es  ca usi n g disc o nti n uati o n of Cri n o ne 
•  A Es ca usi n g disc o nti n uati o n of D u p hast o n 
o  D u p hast o n o nl y relate d A Es ca usi n g disc o nti n uati o n of D u p hast o n 
 
1 5. 2  
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts  
1 5. 2. 1  
De at hs  
If t here is deat h re p orti n g i n t his st u d y, all deat hs will be ta b ulate d base d o n i nf or mati o n fr o m t he 
“ St u d y Ter mi nati o n ” eC R F  pa ge. 
•  N u m ber of Deat hs 
I n a d diti o n, date a n d ca use of deat h will be pr o vi de d i n i n di vi d ual s u bject data listi n g  t o get her wit h 
selecte d d osi n g i nf or mati o n ( date of first / last a d mi nistrati o n after ra n d o mizati o n) if a p plica ble 
•  S u bject listi n g of deat hs 
•  Incl u de c ol u m ns f or : 
o  A Es wit h fatal o utc o me (list preferre d ter ms of A Es wit h o utc o me = fatal) 
 
1 5. 2. 2  
Seri o us A d verse E ve nts  
Please refer t o Secti o n 1 5. 1. 1 . F or t hese A Es, s u bject listi n gs will be pr o vi de d i n a d diti o n. 
 
1 5. 2. 3  
Blee di n g




A C C E S S  
M S 2 0 0 1 1 3 _ 0 0 0 5  Versi o n 1 . 0
1 . 0  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4/ 2 4 
 
 
1 5. 3  
Cli nic al L a b or at or y E v al u ati o n  
β- h C G c o nce ntrati o n listi n g will be pr o vi de d. 
1 5. 4  
Vit al Si g ns  
Baseli ne c haracteristics wit h res pect t o vital si g ns will be part of Secti o n 1 1. 1  (De m o gra p hics ). 
T here is n o p ost -baseli ne vital si g ns data c ollecti o n.  
A n a d diti o nal s u bject data listi n g will prese nt all rec or ds. 
 
1 6  
A n al yses of Ot her E n d p oi nts  
N A  
1 7  
R efere nces  
Mietti ne n O, N ur mi ne n M. C o m parati ve a nal ysis of t w o rates. Stat Me d 1 9 8 5; 4( 2): 2 1 3- 2 6  
 
1 8  
A p pe n dices  
N A