A Phase IV, Prospective, Randomized, Exploratory, Multicenter, Eeva™ Trial (Time Lapse Eeva - TiLE)
Phase: PHASE4
Conditions: Fertility
Sponsor: Merck KGaA, Darmstadt, Germany

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Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
5/38 
 
Table of Contents 
Introduction…………………………………………………………………………… ......1 
Principal Investigator Signature ...........................................................................................4 
Table of Contents………….. ...............................................................................................5 
List of Abbreviations ...........................................................................................................8 
1 
Synopsis ..............................................................................................10 
2 
Sponsor, Investigators and Trial Administrative Structure ................13 
3 
Background Information and Trial Rationale .....................................13 
3.1 
Benefit-risk assessment ......................................................................15 
3.1.1 
Risks Related to Eeva .........................................................................15 
3.1.2 
Benefits of Eeva ..................................................................................15 
4 
Trial Objectives ..................................................................................15 
4.1 
Primary ...............................................................................................15 
4.2 
Secondary ...........................................................................................16 
5 
Investigational Plan ............................................................................16 
5.1 
Overall Trial Design and Plan ............................................................16 
5.2 
Discussion of Trial Design .................................................................16 
5.3 
Selection of Trial Population ..............................................................16 
5.3.1 
Inclusion Criteria ................................................................................16 
5.3.2 
Exclusion Criteria ...............................................................................17 
5.4 
Recruitment of Participants ................................................................17 
5.5 
Criteria for Randomization .................................................................17 
5.6 
Description of Treatment and Definition of Exposure to trial 
medication ...........................................................................................17 
5.7 
Criteria for Subject Withdrawal ..........................................................18 
6 
Trial Endpoints and Assessment Procedures ......................................18 
6.1 
Endpoints ............................................................................................18 
6.2 
Potential Confounding Factors ...........................................................18 
6.3 
Frequency of Assessments ..................................................................19 
6.3.1 
Baseline Information and hCG Trigger Day ......................................19 
6.3.2 
Oocyte Retrieval, Insemination, and Day 1 Fertilization Check ........19 
6.3.3 
Embryo Day 3 .....................................................................................19 

Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
6/38 
 
6.3.4 
Embryo Transfer .................................................................................20 
6.3.5 
Embryo Day 5-6 .................................................................................20 
6.3.6 
Post Oocyte Retrieval or Post Transfer Day 12-18 ............................20 
6.3.7 
Gestational Age Week 5-8 ..................................................................21 
6.3.8 
Post-Pregnancy follow-up ..................................................................21 
6.3.9 
Additional Ultrasound > 8 weeks (Optional) .....................................21 
6.4 
Assessment of Safety ..........................................................................21 
6.4.1 
Definitions ..........................................................................................22 
6.4.2 
Device Deficiency ..............................................................................23 
6.5 
Reporting after the defined reporting period for safety surveillance ..23 
7 
Data Analysis and Statistics ................................................................24 
7.1 
Predetermination of Sample Size ........................................................24 
7.2 
Sample Size ........................................................................................24 
7.3 
Randomization ....................................................................................24 
7.4 
Endpoints ............................................................................................25 
7.4.1 
Primary Endpoint(s) ............................................................................25 
7.4.2 
Secondary Endpoint(s) ........................................................................25 
7.5 
Analysis Sets .......................................................................................25 
7.6 
Description of Statistical Analyses .....................................................26 
7.6.1 
General Considerations .......................................................................26 
7.6.2 
Analysis of Primary Endpoint(s) ........................................................26 
7.6.3 
Analysis of Secondary Endpoint(s) ....................................................26 
7.7 
Interim Analysis ..................................................................................26 
7.8 
Ethical and Regulatory Aspects ..........................................................27 
7.9 
Estimated Trial Calendar ....................................................................27 
7.10 
Protocol Deviations ............................................................................27 
7.11 
Protocol Modifications .......................................................................27 
7.12 
Source of Information .........................................................................27 
7.13 
Data Collection ...................................................................................28 
7.14 
Data Monitoring Committee ...............................................................29 
8 
Ethical and Regulatory Aspects ..........................................................29 
8.1 
Responsibilities of the Investigator ....................................................29 
8.2 
Subject Information and Informed Consent .......................................30 

Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
7/38 
 
8.3 
Subject Identification and Privacy ......................................................31 
8.4 
Independent Ethics Committee or Institutional Review Board ..........31 
8.5 
Health Authorities ...............................................................................32 
9 
Trial Management ...............................................................................32 
9.1 
Electronic Case Report Form Handling ..............................................32 
9.2 
Source Data and Subject Files ............................................................32 
9.3 
Investigator Site File and Archiving ...................................................33 
9.4 
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................33 
9.5 
Assessment of Clinical Investigators and Sites ..................................33 
9.6 
Trial Training ......................................................................................34 
9.7 
Required Trial Equipment ..................................................................34 
9.8 
Site Activation and Supply of Trial Materials ....................................35 
9.9 
Changes to the Clinical Trial Protocol ................................................35 
9.9.1 
Clinical Trial Report ...........................................................................35 
9.10 
Publication ..........................................................................................36 
10 
Intellectual Property ............................................................................36 
11 
Trial or site Discontinuation ...............................................................37 
12 
Trial Closure .......................................................................................37 
13 
References ...........................................................................................37 
 
 

Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
8/38 
 
List of Abbreviations 
 
 
 
AE 
Adverse Event 
AFC 
Antral Follicular Count  
AMH 
Antimullerian Hormone 
ART 
Assisted Reproductive Technologies 
B 
Blastocyst 
CE 
European Community 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSL 
Clinical Science Liaison 
EB 
Early Blastocyst 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
EDC 
Electronic Data Capture 
EEVA 
H/M/L 
Eeva Predicted High, M: Medium, L: Low 
ET 
Embryo Transfer 
EU 
European Union 
 
 
GP 
General Practitioner 
hCG 
Human Chorionic Gonadotropin 
HFEA 
Human Fertilisation and Embryology Authority – UK 
ICF 
Informed Consent Form 
ICH 
International Committee on Harmonisation 
ICSI 
Intracytoplasmatic Sperm Injection 
IEC 
Independent Ethics Committee 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 

Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/38 
 
ITT 
Intention to Treat 
IVF 
In Vitro Fertilization 
NCA 
National Competent Authorities 
PN 
Pronuclei stage 
SAP 
Statistical Analysis Plan  
SPC 
Summary of Product Characteristics 
USA 
 
United States of America 

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Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
11/38 
 
Diagnosis and main inclusion 
and exclusion criteria 
All IVF/ICSI patients according to the eligibility 
criteria: 
For inclusion in the trial, all of the following 
inclusion criteria must be fulfilled: 
1. All infertile patients treated with 
IVF/ICSI. 
2. Patient age ≤ 40 years. 
3. ≤ 3 failed IVF/ICSI cycles. 
4. At least 4 normally fertilized eggs 
(2PN) in current cycle.  
5. Normal uterine cavity. 
6. Fertilization using only ejaculated 
sperm (fresh or frozen).  
7. Subject must have read and signed 
the Informed Consent form. 
Subjects are not eligible for this trial if they 
fulfill any of the following exclusion criteria: 
1. Have clinically significant systemic 
disease. 
2. Have abnormal, undiagnosed 
gynecological bleeding. 
3. Have any contraindication to 
Controlled Ovarian Stimulation 
(COS) for ART and to 
gonadotropins to be used in ART. 
4. Egg donor cycle. 
5. Planned “freeze all” cycle (oocytes 
or embryos). 
6. Concurrent participation in another 
clinical trial. 
 
 

Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
12/38 
 
 
Investigational Medicine 
Product 
Not applicable. 
 
Investigational Medical Device 
EEVA, a type-II medical device that received the 
CE marking in a de novo process as a diagnostic 
device 
Planned duration of 
observation for each subject 
Embryos of consented subjects will be assessed 
with EEVA System and morphological 
assessment and after ET will be follow-up until 
achievement of implantation and confirmation of 
pregnancy. 
Primary endpoint(s) 
Implantation rate from embryos transferred on 
day 3 or 5. 
Secondary endpoint(s) 
Utilization rate, Clinical pregnancy, Ongoing 
pregnancy, Multiple pregnancy and Miscarriage. 
Estimated  Trial calendar 
FPI: 29-JUN-2015 
LPI: 31-OCT-2016 
LPLV: 31-DEC-2016 
Trial Report Date: 30-APR-2017 

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PPD
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PPD
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     Short title : TiLE Clinical Trial 
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blastocyst stage. The user has the ability to export image data, embryo reports, and movies. The 
images are acquired while embryos are developing inside standard incubators. In case of any 
Eeva malfunction the subsequent development of the embryos will not be affected in any way 
and the only missing piece will be the automatic recommendation by the computer. 
The optimal goal of IVF/ICSI should be the delivery of a healthy singleton baby.3-5 The clinical 
dilemma, is how to reduce the number of embryos for transfer to prevent multiple births while at 
the same time maintaining or improving IVF/ICSI success rates.  
Currently, embryos are being selected based on traditional morphology scores developed in the 
early 1980s, which are based on multiple observations of embryos under regular light 
microscopes.6-9  However, it is  that traditional morphology grading, which only captures static 
images at a few time points, is of very limited predictive value.  It was reported that only 51% of 
embryos transferred on Day 5 were pre-selected for transfer on Day 3.10  In a controlled  Trial, 
embryologists were asked to choose 2 embryos with optimal potential for blastocyst 
development using traditional morphology grading criteria.  Results showed that morphology 
criteria assessed on Day 3 did not accurately predict blastocyst formation.  In 39% of cycles 
neither choice resulted in blastocyst formation, and in 38% of cycles 1 assessment resulted in a 
blastocyst transferred.  Embryologists were able to pick the best 2 embryos in just 23% of 
cycles.11   
Recently, researchers from Stanford University reported results that correlated time-lapse image 
analysis with gene expression profiling of pre-implantation human embryo development.12   It 
was discovered that success in development to the human blastocyst stage can be predicted 
accurately from dynamic, non-invasive imaging parameters that are observed prior to embryonic 
genome activation (on Day 3).  These parameters can be reliably measured by way of automated 
image analysis, confirming that successful development follows a set of carefully orchestrated 
and predictable events.  Moreover, image phenotypes reflected underlying molecular programs 
of the embryo and individual blastomeres. This was the first trial to report that dynamic 
morphology parameters of embryo development reflect underlying molecular program status and 
provide a promising platform for early assessment of embryo viability.12    
Eeva was developed to translate the significant findings from the research trial to the clinical 
setting.12 The benefit demonstrated during the clinical investigation of the Eeva System Trial was 
that Eeva may assist the embryologist in improving embryo assessment accuracy by predicting 
blastocyst formation at cleavage stage with a specificity of 85%.13 That is, out of all Non-
Blastocyst (arrested) embryos, Eeva was able to identify 85% of them.  The main limitation in 
traditional morphology is its high sensitivity and low specificity.  Currently, any embryo with 
good morphology is considered to be “viable.”  However, clinical results have shown that many 
embryos selected by good Day 3 morphology criteria are false positives.7,8  Embryologists are in 
need of a test which can discriminate – particularly among the embryos with good morphology – 
those which are truly viable and will form blastocysts.  The high specificity of Eeva system’s 
determines which good morphology embryos will actually arrest.  Therefore, Eeva is a useful 
complement to aid the embryologist in identifying the most viable embryos for transfer. 

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3.1 
Benefit-risk assessment 
 The analysis of the risks and benefits demonstrated that, the Eeva System met its safety and 
performance requirements and the device fulfilled its intended use as claimed by Merck KGaA 
Fertility Technologies. Following is a description of potential (expected) risks and benefits that 
may be associated with use of Eeva technology. Eeva received the CE marking in a de novo 
process as a diagnostic device.   
 
3.1.1 
Risks Related to Eeva 
Indeed, there are no risks related with Eeva utilization that could potentially affect embryos 
survival or quality due to the fact that any malfunction on the Eeva system will only affect its 
ability to take pictures of the embryos in culture but will not affect in any way the temperature, 
gas environment and/or culture media conditions to which the embryos will be exposed during 
the incubation process. In Eeva clinical investigation studies, the average blastocyst formation 
rate in subjects who had embryo transfers at the blastocyst stage was 47.4%.  This demonstrated 
that embryos imaged by Eeva did not have their development to blastocyst stage altered given 
the average rate reported in the literature for blastocyst formation is approximately 45.4%.17 
3.1.2 
Benefits of Eeva 
The benefit demonstrated during the first clinical investigation was that the Eeva System can 
assist the embryologist in improving embryo assessment accuracy by predicting blastocyst 
formation at cleavage stage with a specificity of 85%.  That is, out of all arrested embryos, Eeva 
was able to identify 85% of them.13    
An additional benefit is that the Eeva System generates consistent and objective data which help 
embryologists to be more standardized while performing embryo assessments.  Furthermore, the 
Eeva System provides a tool that is fully automated, real-time, and can be easily implemented in 
the IVF/ICSI laboratory and fit into the work flow.  
4 
Trial Objectives 
The aim of this trial is to use Eeva per the approved, CE mark labeling and gather additional data 
to evaluate the efficacy to predict embryo implantation potential when combined with 
morphological assessments.   
4.1 
Primary 
The primary objective of the trial is to compare the rate of implantation for Day 3/5 embryo 
transfers using Eeva scores plus morphology grading versus Day 3/5 embryo transfers using 
morphology grading only. Implantation rates are calculated by dividing the number of 
gestational sacs with fetal heart beat identified by ultrasonography at weeks 5 to 8 by the number 
of embryos transferred on Days 3 or 5.  

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4.2 
Secondary 
The secondary objective is to compare the following outcomes from the combined Eeva + 
morphology results vs. the control (morphology only) group: Utilization Rate (number of 
transferred and frozen embryos divided by number of normally fertilized oocytes x100), Clinical 
Pregnancy (assessed by ultrasonography at weeks 5 to 8), Ongoing pregnancy rate (assessed by 
ultrasonography at weeks 10 to12), Multiple pregnancy rate (assessed by ultrasonography at 
weeks 5 to 8) and spontaneous miscarriage. 
5 
Investigational Plan 
5.1 
Overall Trial Design and Plan 
In general, the Eeva EU/Canadian trial will include 22 investigational sites.  Each site will 
conduct the trial using the same clinical protocol.   
Recruitment of patients at each site, with subjects who voluntarily consent to participate, is 
expected to continue for up to 9 months.  Additional follow-up after embryo transfer will take 
place up to Day 12-18 days to verify biochemical pregnancy and at 5-8 gestational weeks to 
verify clinical pregnancy. Additionally, pregnancy outcomes will be collected via eCRF for 
subjects who were pregnant at the 5-8 week gestational follow-up visit (or subsequent ultrasound 
results).  Total duration of the trial, including start up and close out activities, is approximately 
19 months. Desired follow-up endpoints and additional collection of outcomes like spontaneous 
miscarriage is not being considered in the timeline for completion.  
5.2 
Discussion of Trial Design 
The prospective, randomized, exploratory design selected for this trial was defined based on the 
need to test new diagnostic technologies, like Eeva, to assess embryo viability by collecting real 
life clinical data and compare it with a control. Implantation rate of individual embryos using the 
technology will be explored to define realistic confidence intervals utilized for the generation of 
strong hypothesis to be validated in future RCT. 
5.3 
 Selection of Trial Population 
Subjects for this trial are IVF/ICSI patients to be enrolled according to the eligibility criteria. 
5.3.1 
Inclusion Criteria 
For inclusion in the trial, all of the following inclusion criteria must be fulfilled: 
1. All infertile patients treated with IVF/ICSI. 
2. Patient age ≤ 40 years. 
3. ≤ 3 failed IVF/ICSI cycles. 
4. At least 4 normally fertilized eggs (2PN) in current cycle.  
5. Normal uterine cavity. 
6. Fertilization using only ejaculated sperm (fresh or frozen).  
7. Subject must have read and signed the Informed Consent form. 

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5.3.2 
Exclusion Criteria 
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria: 
1. Have clinically significant systemic disease. 
2. Have abnormal, undiagnosed gynecological bleeding. 
3. Have any contraindication to Controlled Ovarian Stimulation (COS) for ART and 
to gonadotropins to be used in ART. 
4. Egg donor cycle. 
5. Planned “freeze all” cycle (oocytes or embryos). 
6. Concurrent participation in another clinical trial. 
5.4 
Recruitment of Participants 
Subjects will be recruited from patients undergoing IVF/ICSI treatment cycles at the 
investigators’ clinics. Patients will be assessed according the Inclusion/ Exclusion criteria to 
determine their eligibility for participation. 
5.5 
Criteria for Randomization 
All eligible subjects will be assigned to the group of subjects with embryo transfers using Eeva 
scores plus morphology grading and to group of subjects with embryo transfers using 
morphology grading only by randomization. A permuted block randomization with fixed block 
size and allocation ratio of 2:1 will be used. Further details of the procedure will be described in 
the EDC related manuals. 
An allocation ratio of 2:1 is used since this is an explorative trial. The main objective is to collect 
data of first experience with the EEVA Time Lapse system. To generate hypotheses in 
comparison to the ‘morphology grading only’ group comparable data of the morphology grading 
only need to be collected.  
 
5.6 
Description of Treatment and Definition of Exposure to trial 
medication  
Not applicable as there will be no use of any trial medication. Subjects’ embryos will be 
observed using morphological assessments as standard of practice at the IVF laboratories and a 
part of the trial patients in an allocation ratio of 2:1 will be assigned to have EEVA Time Lapse 
system embryos observation and assessments added to their standard assessment. Culture 
conditions and elements will be the same for all embryos in the laboratory regardless of their 
allocation at randomization. 

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5.7 
Criteria for Subject Withdrawal 
Subjects 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.  Any 
withdrawal must be fully documented in the source documents 
 Subject data will be included in the analyses up to the time that consent was withdrawn. The 
trial exit electronic case report form should be completed at the time a subject is exited from the 
trial.   
The sponsor reserves the right to discontinue this trial at any time. 
6 
Trial Endpoints and Assessment Procedures 
Embryos will be observed until they are transferred and then subjects’ outcomes information will 
be collected for all subjects until implantation and pregnancy are verified (up to 8 weeks after 
embryo transfer). Additional follow up to determine final pregnancy outcome may be included if 
available. 
Subjects will be followed up until loss to follow-up, occurrence of an exclusion criterion, or the 
end of the data collection period, whichever comes first. 
6.1 
Endpoints 
Primary Endpoint: Implantation rate from embryo transfers performed on day 3 or day 5. 
Secondary Endpoints: Utilization rate, Clinical pregnancy rate, Ongoing pregnancy rate, 
Multiple pregnancy rate, Spontaneous miscarriage rate.  
Endpoints are defined as follows : 
• Implantation rate (number of sacs with fetal heart beat/ total number of embryos 
transferred) 
• Utilization rate (transferred + frozen/ fertilized eggs) X100. 
• Clinical pregnancy rate (at approximately 5-8 weeks gestational age) 
• Multiple pregnancy rate defined as a clinical pregnancy with ≥ 2 fetal sacs.  
• Spontaneous miscarriage rate as a desired follow-up endpoint. 
6.2 
Potential Confounding Factors 
There are no expected major confounding factors that would contribute to determine the 
outcomes on either one of the arms related to the main variables, that is, use or not of Eeva 
technology for embryo assessment in addition to standard morphological assessment. Such 
standard scoring and grading conventions will be provided to sites to capture accordingly in the 
eCRFs. 

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6.3 
Frequency of Assessments 
6.3.1 
Baseline Information and hCG Trigger Day 
Enrolled subjects in the trial will undergo pre-IVF/ICSI preparations per the standard protocol 
currently in force for each site.  Collection of trial-related information may take place only after 
the subject and partner, if applicable, has given voluntary, documented, informed consent and 
will include the following information, which will be recorded on the baseline electronic case 
report form including: 
• Demographics 
• Pregnancy history  
• Prior ART  
• Cycle Day 3 hormones  (FSH, AMH, Estrogens, LH, etc) 
• Cause of Infertility 
• Protocol of Stimulation 
• Time of hCG trigger to oocyte retrieval 
Data pertaining to the stimulation protocol, stimulation medications, and an evaluation of the 
endometrium for each subject will be recorded retrospectively on the ART Treatment eCRF 
form.  
6.3.2 
Oocyte Retrieval, Insemination, and Day 1 Fertilization 
Check 
Oocyte retrieval and insemination will follow the standard protocol in place at each trial site.   
Data will be recorded on the Oocyte Retrieval and Insemination/Fertilization eCRF including: 
• Date and time of oocyte retrieval 
• Number of oocytes retrieved 
• Andrology information  
• Insemination method 
• Total number of normally fertilized eggs (2PN) 
• Culture conditions (including gas phase, media, and protein, etc.) 
• Embryo morphological grading may be assessed on Day 2 as per local laboratory 
standard practice in those subjects randomized to the Morphology group only.  
6.3.3 
Embryo Day 3 
Day 3 embryo morphological grading will be performed according to standard protocol and 
laboratory procedure manual.  Eeva results will be printed and used per the Instructions for Use. 
Data collected will be recorded on the Day 3 Laboratory Data eCRF including: 
• Date and time of evaluation 
• Type of Eeva Petri Dish (number of micro-wells) 

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• Eeva micro-well identification 
• Cell stage and Morphology grading 
• Eeva results  
• Number of cells after 42 hours, up to the morning of day 3 
• Fate of each embryo (Transferred, Cryopreserved, Discarded or extended culture to 
Day 5/6) 
• Eeva Petri Dish and Scope information 
• Culture conditions 
6.3.4 
Embryo Transfer 
Embryo transfer will follow the standard protocol in place at each clinical trial site. Data 
pertaining to the Day 3 or Day 5/6 embryo transfer procedure will be recorded on the Transfer 
and Treatment Outcome eCRF for all patients (Eeva and non-Eeva ones) including: 
• Date and day of transfer 
• Luteal phase support 
• Use of ultrasound 
• Final number of embryos transferred  
6.3.5 
Embryo Day 5-6 
If any embryos are cultured to Day 5 or Day 6, data will be recorded on the Day 5-6 Laboratory 
Data eCRF including: 
• Date and time of evaluation 
• Type of Eeva Petri Dish (number of micro-wells) 
• Eeva micro-well identification 
• Development stage and Morphology grading 
• Fate of the embryo (Transferred, Cryopreserved, Discarded or extended culture to 
Day 5/6) 
• Eeva Petri Dish and Scope  information 
• Culture conditions 
6.3.6 
Post Oocyte Retrieval or Post Transfer Day 12-18 
The institution’s standard urine or blood serum pregnancy testing results (biochemical pregnancy 
assessed between days 12 and 18) will be recorded on the Transfer and Treatment Outcome 
eCRF including: 
• Date of the biochemical pregnancy test 
• Pregnancy test results 
• Quantitative hCG, as applicable 

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If the result of the pregnancy test is negative, the subject will have completed the trial and be 
exited at that time (complete Trial Exit electronic case report form).  
6.3.7 
Gestational Age Week 5-8 
The first ultrasound to verify clinical pregnancy will be recorded on the Transfer and 
Treatment Outcome eCRF including: 
• Date of ultrasound 
• Result of initial pregnancy ultrasound 
o Number of intrauterine gestational sacs 
o Number of fetal heartbeats 
If the result of the ultrasound is negative, that is, if no fetal heartbeat is detected, then the subject 
will have completed the trial and be exited at that time (complete Trial Exit electronic case 
report form).  
6.3.8 
Post-Pregnancy follow-up  
Pregnancy outcome will be obtained via clinic visit, telephone contact or from HFEA database 
review for subjects who were pregnant as of their most recent vaginal ultrasound (5-8 gestational 
weeks or additional ultrasound if post-5-8 gestational weeks), and a Post-Pregnancy Follow-up 
eCRF. 
6.3.9 
Additional Ultrasound > 8 weeks (Optional) 
Any additional vaginal ultrasounds performed after 8 weeks may be recorded on an Additional 
Ultrasound eCRF.  The collection of this data is optional, however encouraged.  
Data will include the following: 
• Date of ultrasound 
• Result of initial pregnancy ultrasound 
o Number of fetal sacs and number of fetal heartbeats 
6.4 
Assessment of Safety 
Safety of Eeva will be evaluated by assessment of device deficiency only.  
An adverse event or a serious adverse event, whether or not related to the investigational medical 
device Eeva, in subjects participating to the study is not applicable. In addition, given the design 
of this study and the reporting period for safety surveillance, assessment of  serious adverse 
device effects in offspring of subjects participating in the trial is not applicable (see definitions).  

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6.4.1 
Definitions 
6.4.1.1 
Specific Definitions  
As per the European Guidelines on medical devices (MEDDEV 2.7/3), dated December 2010.                       
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or 
any untoward clinical signs (including an abnormal laboratory finding) in subjects, users or other 
persons whether or not related to the investigational medical device. 
A device deficiency is an “Inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance, such as malfunction, misuse or use error and 
inadequate labeling. 
Device Malfunction:  A failure of a device to perform in accordance with its intended purpose 
when used in accordance with the manufacturer’s instructions. 
Use Error:   Act or omission of an act that has a different result to that intended by the 
manufacturer or expected by the operator. 
A Serious Adverse Device Effect is “an adverse device effects that has resulted in any of the 
consequences characteristics of a serious adverse event”. 
A Serious Adverse Event (SAE) is an adverse event that: 
(In the consented subjects)  
a) Led to a death, 
b) Led to a serious deterioration in health that either:  
1) Resulted in a life-threatening illness or injury, or 
2) Resulted in a permanent of a body structure or a body function, or 
3) Required in-patient hospitalization or prolongation of existing hospitalization, or 
4) Resulted in medical or surgical intervention to prevent life threatening illness or 
injury or permanent impairment to a body structure or a body function. 
            In the offspring of consented subjects: 

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PPD

Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
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7 
Data Analysis and Statistics 
7.1 
Predetermination of Sample Size 
7.2 
Sample Size 
This is an exploratory trial to generate hypotheses for future confirmatory clinical trials.  
It is planned to enroll 1000 subjects in the group of subjects with embryo transfers using Eeva 
scores plus morphology grading and 500 subjects into the control group of subjects with embryo 
transfers using morphology grading only. Enrollment is non-competitive, each center selected to 
participate in the study is expected to enroll a minimum number of patients to be defined at site 
start-up.   
Based on this number of subject’s precise estimates of the primary endpoint, the rate of 
implantation for Day 3/5 embryo transfers, is possible. 
The following table shows for different implantation rates the distance from the rate (proportion) 
to the limit of a 95% confidence interval.  
 
Implantation rate 
 Distance to limit  of 95% CI 
 
500 subjects 
1000 subjects 
25% 
3.8 
2.7 
30% 
4.0 
2.8 
35% 
4.2 
3.0 
40% 
4.3 
3.0 
45% 
4.4 
3.1 
 
7.3 
Randomization 
Subjects will be assigned to the group of subjects with embryo transfers using Eeva scores plus 
morphology grading and to group of subjects with embryo transfers using morphology grading 
only by randomization. A permuted block randomization with fixed block size and allocation 
ratio of 2:1 will be used. Further details of the procedure will be described in the EDC related 
Manuals. 
An allocation ratio of 2:1 is used since this is an explorative trial. The main objective is to collect 
data of first experience with the EEVA Time Lapse system. To generate hypotheses in 

Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
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comparison to the ‘morphology grading only’ group comparable data of the morphology grading 
only need to be collected.  
 
7.4 
Endpoints 
7.4.1 
Primary Endpoint(s) 
The primary endpoint is the Implantation Rate from embryo transfers performed on day 3 or 5. 
The crude estimate of the implantation for each embryo assessment method (Eeva scores plus 
morphology grading, morphology grading only) will be calculated as the ratio of the total fetal 
sacs identified by ultrasonography at weeks 5 to 8 and the  number of embryos transferred. 
7.4.2 
Secondary Endpoint(s) 
The secondary endpoints are: 
• Clinical Pregnancy (assessed by ultrasonography at weeks 5 to 8) 
• Ongoing pregnancy rate (assessed by ultrasonography at weeks 10 to12) 
• Multiple pregnancy rate (assessed by ultrasonography at weeks 5 to 8) 
• Utilization Rate ([number of transferred and frozen embryos divided by number of 
normally fertilized oocytes] x100) 
• Spontaneous miscarriage (communicated during medical appointment or by telephone 
contact). 
7.5 
Analysis Sets 
The following sets of subjects will be considered in the analysis: 
Intention-to-treat (Full Analysis Set) 
The intention-to-treat population includes all randomized subjects. Due to the fact that this is an 
exploratory trial in contrast to usual definitions of ITT (‘presented as randomized’) subjects will 
be presented based on the method used (Eeva scores plus morphology grading, morphology 
grading only).   
Subgroups of Eeva scores plus morphology grading group 
The EEVA Time Lapse system assists the embryologist in improving embryo assessment 
accuracy. Whether the embryologist follows the recommendation made by the system is the 
decision of the embryologist. Therefore two subgroups will be considered: 

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• Subjects form Eeva scores plus morphology grading group for whom the embryologist has 
followed 
the 
recommendation 
of 
the 
Eeva 
system.  
As the principle selection algorithm for the test arm of the study the selection of embryos 
for transfer is based on the recommendations made by the EEVA system.    
• Subjects form Eeva scores plus morphology grading group for whom the embryologist has 
NOT followed the recommendation of the Eeva system. Every effort at the site will be 
made to keep this case to a minimum of cases as investigators are encouraged to use their 
technical expertise and follow the EEVA system recommendations.  However, on 
investigators’ discretion and patients’ best interests it may be decided to exceptionally 
disregard the system recommendation when such recommendation contradicts the 
morphological pre-assessment of the embryos. 
7.6 
Description of Statistical Analyses 
7.6.1 
General Considerations 
 
Descriptive statistics for continuous variables will be calculated which will include measures of 
central tendency, dispersion, summary statistics, and a count of the number of missing values.  
Categorical variables will be summarized with counts and proportions.  Graphical methods will 
be used as appropriate.  No data imputations will be performed. Further details will be specified 
in the Statistical Analysis Plan (SAP). 
7.6.2 
Analysis of Primary Endpoint(s) 
The crude estimate of the implantation for each embryo assessment method will be calculated as 
the ratio of the total fetal sacs identified by ultrasonography at weeks 5 to 8 and number of 
embryos transferred.  The approximate 95 % confidence interval of implantation for each 
embryo assessment method will be calculated. The difference between the methods will be 
analyzed in an exploratory way using a Poisson regression model.  Details regarding the model 
and analysis approach will be specified in the SAP. 
7.6.3 
Analysis of Secondary Endpoint(s) 
Descriptive statistics for each and all of the secondary endpoints will be provided.  The specific 
exploratory analyses used to assess the endpoints, for example, to examine whether there is a 
difference in a specific endpoint associated with an embryo assessment method or other relevant 
assessments will be specified in the SAP. 
7.7 
Interim Analysis 
When half of the patients have completed the study (pregnancy/implantation yes/no) an interim 
analysis will be done. Primary and secondary endpoints will be analyzed in an explorative way 
similar as planned for the final analysis. Further details will be specified in the SAP. 

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7.8 
Ethical and Regulatory Aspects 
7.9 
Estimated Trial Calendar 
 Trial will begin enrollment on April 2015 and will continue until 1500 subjects will be enrolled 
or January 31, 2016, whichever comes first. Last patient observation will be recorded by March 
31, 2016 and close-out activities and trial final report will follow within 3 months after. 
7.10 
Protocol Deviations 
A protocol/GCP deviation occurs when a clinical investigator and/or trial site personnel do not 
conduct the trial according to the clinical protocol/GCP.   
Investigators must maintain accurate, complete, and current records related to the trial.  This 
includes source documents showing the dates and reasons for each deviation from the clinical 
protocol/GCP.  Depending upon the nature of the protocol deviation, expedited reporting to the 
reviewing EC according to the reporting requirements of that EC, and prior approval from Merck 
KGaA may be required.   
If Merck KGaA finds that an investigator is not complying with the executed clinical research 
agreements, the clinical protocol, applicable regulations, or the requirements of the reviewing 
EC, prompt action will be taken to secure compliance.  In addition, the participation of an 
investigator may be terminated.   
7.11 
Protocol Modifications 
The sponsor will lead all protocol modifications and will provide the final version of the 
modified protocol to the principal investigator at each investigational site.  If applicable, the 
sponsor will secure any EC or regulatory approvals required.  
7.12 
Source of Information 
Investigators must maintain information in the trial subject’s medical records to corroborate data 
collected on the eCRFs.  The following types of information should be maintained and made 
available as required by Merck KGaA and/or its designees.  Shadow charts are not appropriate or 
adequate source documentation.  Medical (clinical and hospital) records may include the 
following documentation.   
 
• Medical history/physical condition of the patient before involvement in the trial. 
• Signed notes in the subject’s medical record on the enrollment day that identify and 
include:  the subject’s date of enrollment, the trial sponsor (Merck KGaA), the subject-
assigned identification number, and documentation and confirmation that the appropriate 
informed consent was obtained. 
• Description of the IVF/ICSI procedure. 
• Dated and signed notes for each subject’s trial visit. 

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It is the responsibility of the investigators and the trial staff to complete the eCRFs accurately 
and in a timely fashion.  The principal or designated trial investigator will sign and date each 
eCRF to verify that the data has been reviewed by him/her.   
This trial will not have blinding procedures as subject cohorts will be assigned to each arm 
according to the procedure described. 
 
7.14 
Data Monitoring Committee 
The trial will not utilize a data monitoring committee, a safety monitoring committee or an 
adjudication committee. 
8 
Ethical and Regulatory Aspects 
8.1 
Responsibilities of the Investigator 
The Investigator is responsible for the conduct of the trial at his/her site. He/she will ensure that 
the trial is performed in accordance with the clinical trial protocol and with the ethical principles 
that have their origin in the Declaration of Helsinki, as well as with the International Standard 
ISO14155 (Clinical Investigation of medical devices for human subjects – Good Clinical 
Practice) and applicable regulatory requirements. In particular, the Investigator must ensure that 
only subjects who have given their informed consent are included into the trial. 
In addition, Merck KGaA, Inc. confirms that the Eeva System complies with the Essential 
Requirements of the European directives 93/42/EEC (Medical Device Directive) and that of the 
Canadian regulation on medical device (SOR/98-282).   
The Investigator is responsible for the conduct of the trial at his/her site. He/She will ensure that 
the trial is performed in accordance with the protocol and will ensure the quality and integrity of 
data, following the applicable international and national guidelines. 
This trial will not interfere with treatment prescription by Investigators. Accordingly, the 
Investigator will decide in advance the best therapeutic strategy for each patient according to 
current practice, regardless of the potential participation of this patient in the trial.  
The Investigator is responsible for device malfunction recording and reporting, as specified in 
Section 6.4.2. 
The investigator shall submit a progress report and end of trial notification according to the 
requirements of the reviewing EC, if applicable. 
 

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8.2 
Subject Information and Informed Consent 
An unconditional prerequisite for a subject’s participation in the trial is his/her written informed 
consent.  
To protect the rights and welfare of trial subjects, the trial will be conducted in conformance with 
the Declaration of Helsinki and elements of good clinical practices as may be applied to medical 
devices.1,2 The confidentiality provisions within all applicable laws and regulations will apply 
throughout.  Obtaining informed consent in accordance with the policy of the EC, this clinical 
protocol, and applicable regulations is mandatory for subject participation.  The sponsor will 
avoid improper influence on or inducement of the subject for participating in the trial. The 
subject informed consent document(s) must be provided in a language that the patient reads and 
understands.  All subjects must provide voluntary, written informed consent prior to the start of 
any trial-related activities.  This includes subjects who are the partners of the subjects, if 
applicable.  
Informed consent should be signed prior to the day of oocyte pick up, preferably on the day of 
the last ultrasonography for assessment of number of follicles available. On day 1 after oocyte 
pick up and following assessment of the number of 2PNs available, subjects will either be 
enrolled in the trial or not included in the trial. 
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained (a person designated by the Investigator may give the information, if 
permitted by local regulations). A subject information sheet in the local language will be 
provided by the Sponsor for the purpose of obtaining informed consent. In addition to providing 
this written information to a potential subject, the Investigator or his/her designee will inform the 
subject verbally of all pertinent aspects of the trial (the language used in doing so must be chosen 
so that the information can be fully and readily understood by laypersons). Depending on 
national regulations, a person other than the Investigator may inform the subject and sign the 
Informed Consent Form. 
The Informed Consent Form must be signed and personally dated by the subject and the 
Investigator. The signed and dated declaration of informed consent will remain at the 
Investigator’s site, and must be safely archived by the Investigator. A copy of the signed and 
dated information and consent form should be provided to the subject prior to participation. 
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor and be submitted again to the IEC/IRB for review and 
favorable opinion. The agreed, revised information will be forwarded to each subject in the trial. 
The Investigator will explain the changes to the previous version. 
Merck KGaA and the EC must review and approve the informed consent documentation and any 
modifications to the consent materials prior to use. The approved informed consent 
documentation should have a version number or version date.  The informed consent process 
(including time and date of discussion), should be documented in the subject’s medical record 
and signed/dated by the individual (investigator or designee) who recorded it.  The original 

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signed consent form should be filed in the subject’s medical record and a copy of the signed 
informed consent documentation given to the subject.   
In the event of a consent form revision, enrolled subjects may be required to re-consent, as 
determined by the reviewing EC.    
 
8.3 
Subject Identification and Privacy 
A unique subject number will be assigned to each subject at inclusion, immediately after 
informed consent has been obtained. This number will serve as the subject’s identifier in the trial 
as well as in the clinical trial database. 
The Investigator must ensure that the subjects’ anonymity is maintained. On the CRFs or other 
documents submitted to the Sponsor, subjects should not be identified by their names, but by 
their assigned identification numbers. If subject names are included on copies of documents 
submitted to the Sponsor, the names must be obliterated and the assigned subject numbers added 
to the documents. 
The Investigator should keep a separate log of subjects’ identification numbers, names, 
addresses, telephone numbers and hospital numbers (if applicable). Documents not for 
submission to the Sponsor, such as signed Informed Consent Forms, should be maintained in 
strict confidence by the Investigator. 
Only authorized persons will have access to identifiable personal details, if required for data 
verification. The subject’s original medical data that are reviewed at the site during source data 
verification by the Monitor, audits, and Health Authority inspections will be kept strictly 
confidential. The Investigator agrees to provide direct access to these documents to the Sponsor 
and to Health Authority representatives. The Investigator is responsible for retrieving 
information from personal medical records. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data and embryo images. Subjects will be informed accordingly, and will be 
requested to give their consent on data handling procedures in accordance with national 
regulations. 
 
8.4 
Independent Ethics Committee or Institutional Review 
Board 
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with its associated documents including informed consent forms to the responsible 
IEC/IRB for its favorable opinion/approval. The written favorable opinion/approval of the 
IEC/IRB will be filed in the Investigator Site File, and a copy will be filed in the Trial Master 
File (TMF) at Merck KGaA. 

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The trial must not start at a site before the Sponsor has obtained written confirmation of 
favorable opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and Informed Consent Form version reviewed should be provided. Where possible, 
copies of the meeting minutes should be obtained. 
Amendments to the clinical trial will also be submitted to the concerned IEC/IRB, before 
implementation in case of substantial changes (see Section 10.5). Relevant safety information 
will be submitted to the IEC/IRB during the course of the trial in accordance with national 
regulations and requirements. 
  
8.5 
Health Authorities 
The clinical trial protocol and any applicable documentation (e.g. Subject Information and 
Informed Consent Form) will be submitted or notified to the Health Authorities in accordance 
with the regulations of the countries involved in the trial. 
9 
Trial Management 
9.1 
Electronic Case Report Form Handling 
 The main purpose of the eCRF is to obtain those data required by the clinical trial protocol in a 
complete, accurate, legible and timely fashion. The data in the eCRF should be consistent with 
the relevant source documents. . 
 The Investigator or designee will be responsible for entering trial data in the eCRF provided by 
the Sponsor. It is the Investigator’s responsibility to ensure the accuracy of the data entered in 
the eCRFs. 
The data will be entered into a validated database. Merck KGaA will be responsible for data 
processing, in accordance with the Sponsor’s data management procedures. Database lock will 
occur once quality control procedure, and quality assurance procedures (if applicable) have been 
completed. PDF files of the eCRFs will be provided to the Investigators at the completion of the 
trial. 
9.2 
Source Data and Subject Files 
The Investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the trial. This file will contain the available 
demographic and medical information for the subject, and should be as complete as possible.  

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Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
35/38 
 
9.8 
Site Activation and Supply of Trial Materials 
Before a patient is enrolled at a trial site, the investigator must have been initiated and be in 
receipt of written confirmation (email or letter) from Merck KGaA (or designee) that the site can 
start.  In addition, the following documentation must be on file at Merck KGaA: 
  
• EC favorable opinion/approval letter for the clinical protocol and informed consent 
documentation (including any subject recruitment materials) 
• EC membership list or voting list 
• Fully executed Clinical Research Agreement  
• Executed Non-Disclosure Agreement (or Clinical Research Agreement) 
• Curriculum Vitae (investigator, sub-investigators, research coordinator) – current within 2 
years, signed and dated 
• Current laboratory certifications, if applicable 
Merck KGaA will provide the electronic data capture system.  Investigators will be provided 
with the clinical protocol, training, informed consent information and templates, electronic case 
report form instructions, and other supportive documents required for the trial. 
9.9 
Changes to the Clinical Trial Protocol 
Changes to the clinical trial protocol will be documented in written protocol amendments. Major 
(substantial, significant) amendments will usually require submission to the Health Authorities 
and to the relevant IEC/IRB for approval or favorable opinion. In such cases, the amendment 
will be implemented only after approval or favorable opinion has been obtained. 
Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health 
Authorities only where requested by pertinent regulations. 
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the subject’s informed consent prior to implementation Clinical Trial Report and 
Publication Policy 
9.9.1 
Clinical Trial Report 
After completion of the trial, a clinical trial report according to ICH Topic E3 will be written by 
the Sponsor in consultation with Merck KGaA responsible, the Coordinating Investigator and 
assigned Medical Writer. An initial report will be generated based on the data that is 
accumulated when 50% of the subjects have completed the trial with implantation results.  
Additionally, an interim report will be generated based on the accumulated trial data.  The data 
cutoff date for each report will be pre-specified in its SAP. 

Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
36/38 
 
The completed trial will be summarized in a final report that accurately and completely presents 
the trial objectives, methods, results, limitations of the trial, and interpretation of the findings. 
9.10 
Publication 
If the institution or investigator prepares any presentation or publication relating to the trial, the 
institution or investigator will provide Merck KGaA with a draft of the same for Merck KGaA’s 
review and comment, of which comments the institution or investigator will give due consideration.  
Merck KGaA will return comments to the institution or investigator within thirty (30) days after 
receipt of the draft from the institution or investigator.  In the event that the institution or the 
investigator and Merck KGaA differ in their opinion or interpretation of data in the publication, the 
parties will resolve such differences in good faith through appropriate scientific debate.  In addition, 
the institution or investigator will delay any proposed publication/presentation an additional sixty 
(60) days, in the event Merck KGaA so requests, to enable Merck KGaA to secure patent or other 
proprietary protection. 
The first publication will be a publication of the results of the analysis of the primary endpoint(s) 
that will include data from all trial sites. 
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 pre-submission review by the Sponsor. 
The Sponsor will not suppress or veto publications, but maintains the right to delay publication 
in order to protect intellectual property rights. 
10 
Intellectual Property 
During the term of this trial and thereafter, Institution, its employees, agents, subcontractors or 
affiliates will not disclose confidential information (other than to Merck KGaA or Merck 
KGaA-designated parties) without Merck KGaA's prior written consent.  “Confidential 
information” will include the protocol, eCRFs, and all materials and information concerning Merck 
KGaA and the trial disclosed to the Institution or Investigator by Merck KGaA or developed as a 
result of conducting the trial, except any portion thereof which: 
 
• Is known to Institution, its employees, agents, subcontractors or affiliates before receipt thereof 
under this protocol, as evidenced by its written records; 
• Is disclosed to Institution, its employees, agents, subcontractors or affiliates after acceptance of 
this protocol by a third party who has a right to make such disclosure in a non-confidential 
manner; or 
• Is or becomes part of the public domain through no fault of the Institution, its employees, 
agents, subcontractors or affiliates.  
• Nothing in this trial will be construed to restrict the Institution or Investigator from disclosing 
confidential information as required by law or court order or other regulatory order or request, 

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Study EMR700623_545 
 
     Short title : TiLE Clinical Trial 
 Protocol Version  5.0  Final 21 March 2016  
C O N F I D E N T I A L 
I N F O R M A T I O N 
38/38 
 
3. Adamson D, Baker V. Multiple births from assisted reproductive technologies: a challenge 
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before embryonic genome activation predicts development to the blastocyst stage.  Nat 
Biotechnol. 2010;28:1115-21. 
13. Eeva System  Trial unpublished data.  Merck KGaA, Inc, 2012. 
14. Racowsky C, Vernon M, Mayer J, et al.  Standardization of grading embryo morphology.  
Fertil Steril. 2010;94:1152-3. 
15. GHTF – SG2 N54R8:2006.  Medical devices:  Postmarket surveillance:  Global guidance 
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2010.       
17. Blake D, Farquhar C, Johnson N, Proctor M. Cleavage stage versus blastocyst stage 
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