A Phase IV, Single-blinded, Prospective, Randomized, Controlled, Multi-center Study to Compare the Clinical Outcomes of Genea Embryo Review Instrument Plus (GERI+) Time Lapse System With a Conventional Embryo Culture and Assessment System
Phase: PHASE4
Conditions: Infertility
Sponsor: Merck KGaA, Darmstadt, Germany

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Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018          
                               4 / 49 
  
Principal Investigator Signature 
 
Trial Title: A phase IV, single-blinded, prospective, randomized, controlled, 
multi-center study to compare the clinical outcomes of GERI+ time lapse system with 
a conventional embryo culture and assessment system (TICON-Day 3)   
Trial Number: MS200497_0006 
Protocol Version/Date: Version 3.0 / Jan 31, 2018 
Center Number:16 
Principal Investigator:  
 
I, the undersigned, am responsible for the conduct of the trial at this site and affirm 
that: 
 I understand and will conduct the trial according to the clinical trial protocol, 
any approved protocol amendments, International Standard ISO14155 
(Clinical investigation of medical devices for human subjects – Good Clinical 
Practice) and all applicable Health Authority requirements and national laws 
 I will not deviate from the clinical trial protocol without prior written 
permission from the Sponsor and prior review and written approval from the 
Institutional Review Board or Independent Ethics Committee, except where 
necessary to prevent immediate danger to the subject. 
 
 
 
 
 
Signature 
 
Date of Signature 
 
 
 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018         
                               5 / 49 
  
Table of Contents 
SIGNATURE PAGE ...................................................................................................... 2 
LIST OF ABBREVIATIONS ........................................................................................ 8 
1. 
SYNOPSIS ........................................................................................................... 10 
2. 
SPONSOR, INVESTIGATOR AND ADMINISTRATIVE STRUCTURE ........ 13 
3. 
BACKGROUND INFORMATION ..................................................................... 13 
4. 
BENEFIT-RISK ASSESSMENT ......................................................................... 15 
4.1 
Risks Related to the GERI+ system .......................................................... 16 
4.2 
Benefits of the GERI+ system ................................................................... 17 
5. 
STUDY OBJECTIVES AND ENDPOINTS ....................................................... 17 
5.1 
Objectives .................................................................................................. 17 
5.2 
Endpoints ................................................................................................... 18 
5.2.1 
Primary Endpoint ............................................................................ 18 
5.2.2 
Secondary Endpoints ...................................................................... 18 
6. 
INVESTIGATIONAL PLAN .............................................................................. 19 
6.1 
Overall Study Design and Plan .................................................................. 19 
6.2 
Discussion of the Study Design ................................................................. 20 
6.3 
Inclusion of Special Populations ............................................................... 20 
6.4 
Enrollment of Trial Population .................................................................. 20 
6.4.1 
Inclusion Criteria ............................................................................ 20 
6.4.2 
Exclusion Criteria ........................................................................... 21 
6.5 
Recruitment of Participants ....................................................................... 21 
6.6 
Method of Blinding ................................................................................... 21 
6.7 
Randomization and Allocation of Subjects ............................................... 21 
6.8 
Description of Treatment and Definition of Exposure to Trial Medication .. 
.................................................................................................................. 22 
6.9 
Criteria for Subject Withdrawal ................................................................. 24 
6.10 Definition of Completion of the Study ...................................................... 24 
6.11 Potential Confounding Factors .................................................................. 25 
6.12 Estimated Trial Calendar ........................................................................... 25 
7. 
STUDY PROCEDURES, ASSESSMENTS AND DATA COLLECTION ......... 25 
7.1 
Baseline Data Collection ........................................................................... 25 
7.2 
Data Collection on Day of Ovulation Triggering ...................................... 26 
7.3 
Data Collection on Day 0-3 of Embryo Culture ........................................ 26 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018         
                               6 / 49 
  
7.4 
Data Collection on Day of hCG Test ......................................................... 27 
7.5 
Data Collection for Clinical Pregnancy Ultrasound Test .......................... 27 
7.6 
Data Collection for Ongoing Pregnancy Ultrasound Test ......................... 28 
7.7 
Adverse Events and Assessment of Safety ................................................ 28 
7.7.1 
Definitions ...................................................................................... 28 
7.7.2 
Reporting period for safety surveillance ........................................ 30 
7.7.3 
Safety assessment of embryological data ....................................... 30 
7.7.4 
Device Deficiency .......................................................................... 31 
7.7.5 
Reporting after defined reporting period for safety surveillance ... 31 
8. 
STATISTICS ........................................................................................................ 32 
8.1 
Sample Size ............................................................................................... 32 
8.2 
Randomization ........................................................................................... 32 
8.3 
Analysis Sets.............................................................................................. 32 
8.4 
Description of Statistical Analyses ............................................................ 33 
8.4.1 
General Consideration .................................................................... 33 
8.4.2 
Analysis of Primary Endpoint ........................................................ 33 
8.4.3 
Analysis of Secondary Endpoints ................................................... 33 
8.4.4 
Interim Analysis .............................................................................. 34 
9. 
ETHICAL AND REGULATORY ASPECTS ...................................................... 34 
9.1 
Responsibilities of the Investigator ........................................................... 34 
9.2 
Subject Information and Informed Consents ............................................. 35 
9.3 
Subject Identification and Privacy ............................................................. 37 
9.4 
Emergency Medical Support and Subject Card ......................................... 37 
9.5 
Clinical Trial Insurance and Compensation to Subjects ............................ 37 
9.6 
Independent Ethics Committee .................................................................. 38 
9.7 
Health Authorities ...................................................................................... 38 
10. STUDY MANAGEMENT .................................................................................. 38 
10.1 Data collection and Electronic Case Report Form Handling .................... 39 
10.2 Source Data and Subject Files ................................................................... 40 
10.3 Investigator Site File and Archiving .......................................................... 40 
10.4 Monitoring, Quality Assurance and Inspection by Health Authorities ...... 41 
10.5 Protocol Deviations ................................................................................... 41 
10.6 Changes to the Clinical Trial Protocol ....................................................... 42 
10.7 Assessment of Clinical Investigators and Sites ......................................... 42 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018         
                               7 / 49 
  
10.8 Trial Training ............................................................................................. 42 
10.9 Required Trial Equipment ......................................................................... 43 
10.10 Site Activation and Supply of Trial Materials ........................................... 43 
10.11 Clinical Trial Report and Publication Policy ............................................. 44 
10.12 Intellectual Property .................................................................................. 46 
10.13 Trial or Site Discontinuation ..................................................................... 46 
10.14 Trial Closure .............................................................................................. 47 
11. REFERENCES .................................................................................................... 47 
 
 
 
 
 
 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018          
                               8 / 49 
  
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
AFC 
Antral Follicle Count  
AMH 
Anti-Müllerian Hormone 
ART 
Assisted Reproductive Technologies 
ASADE 
Anticipated Serious Adverse Device Effect 
CAE 
Clinical Applications Engineer 
CE 
European Conformity 
COS 
Controlled Ovarian Stimulation 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
EDC 
Electronic Data Capture 
EEVA  
Early Embryo Viability Assessment 
ET 
Embryo Transfer 
EU 
European Union 
E2 
Estradiol 
FA 
Full Analysis 
FHB 
Fetal Heart Beat 
FPI 
First Patient In 
FSH 
Follicle Stimulation Hormone 
GERI+ 
Genea Embryo Review Instrument Plus 
hCG 
Human Chorionic Gonadotropin 
ICF 
Informed Consent Form 
ICSI 
Intracytoplasmic Sperm Injection 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IVF 
In Vitro Fertilization 
LPI 
Last Patient In 
LPO 
Last Patient Off study 
NCA 
National Competent Authorities 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018          
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PN 
Pronuclear stage 
PP 
Per Protocol 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SA 
Subgroup Analysis 
SAP 
Statistical Analysis Plan  
SD 
Standard Deviation 
TL 
Time-lapse 
TMF 
Trial Master File 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 
 
 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018         
                               10 / 49 
  
1. SYNOPSIS 
 
Trial title 
A 
phase 
IV, 
single-blinded, 
prospective, 
randomized, controlled, multi-center study to 
compare the clinical outcomes of GERI+ time 
lapse system with a conventional embryo culture 
and assessment system  
Trial number 
MS200497_0006 
Sponsor 
Merck KGaA, Frankfurter Str. 250, 64293 
Darmstadt, Germany 
Trial type 
Phase IV company sponsored trial 
Coordinating Investigator 
TBC 
Trial center(s)/country(ies) 
16 Centers in 7 Countries: 
Italy, Spain, Portugal, France, Denmark, Norway, 
Canada 
Study duration 
21 months 
recruitment 
time + 3 months 
observation time = 24 months from FPI (First 
Patient In) until LPO (Last Patient Off study) 
Trial objectives 
The main objective of this trial is to evaluate the 
overall clinical value of GERI+ as an integrated 
embryo culture and assessment system, providing 
an undisturbed culture environment, continuous 
monitoring of embryo development and automated 
scoring using a predictive algorithm. 
 
Trial design and plan 
Single-blinded, 
prospective, 
randomized, 
controlled, multicenter trial with two treatment 
arms.   
No interim analysis is planned. 
Planned number of subjects 
1,386  
Study population 
IVF/ICSI patients 
Main inclusion and exclusion 
criteria 
Inclusion:  
1. Couples with ≤ two failed fresh IVF/ICSI 
embryo transfer cycles. 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018         
                               11 / 49 
  
2. Age ≥ 18 and ≤ 40 years 
3. BMI: 18-30 kg/m2 
4. Normal uterine cavity under ultrasound. 
5. Subject and her husband/partner must have 
read and signed the Informed Consent form. 
6. At least four normally fertilized oocytes (2PN) 
in the current cycle.  
Exclusion: 
1. Male with non-ejaculated sperm 
2. Subjects 
with 
abnormal, 
undiagnosed 
gynecological bleeding or with genitourinary 
malformations. 
3. Subjects with any contraindication to COS for 
ART or to gonadotropins. 
4. Planned “freeze all” cycle (oocytes or 
embryos). 
5. Planned PGS or PGD cycle. 
6. Concurrent participation in another clinical 
study. 
Investigational Medicine 
Product 
Not applicable. 
Investigational Medical 
Device 
GERI+ incubator equipped with EEVA and GERI 
Assess software. 
Planned duration of 
observation for each subject 
10-12 weeks.  
Primary endpoint(s) 
Clinical pregnancy with positive fetal heart beat in 
gestational week 6-8 after fresh embryo transfer on 
Day 3. 
Secondary endpoint(s) 
1. Number of utilizable embryos  
2. Number of good quality embryos 
3. Number of non-viable embryos 
4. Implantation with positive fetal heart beat  
5. Biochemical pregnancy 
6. Ongoing pregnancy  

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018          
                               12 / 49 
  
7. Multiple pregnancy  
8. Ectopic pregnancy  
9. Spontaneous miscarriage  
Estimated Trial calendar 
FPI: April 2018 
LPI: December 2019 
LPO: March 2020 
Trial Report Date: October 2020 
 
 
 
 
 
 
 
 
 

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Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018          
                              14 / 49 
  
 
A recent single-center RCT showed that embryos cultured in EmbryoScope (Vitrolife, 
Sweden), a box TL incubator, showed no benefit in clinical outcomes over those 
cultured in conventional box incubators (Park et al., 2015). This might be explained by 
the fact that culturing of embryos of multiple patients in one big chamber may 
inevitably lead to lid openings disturbing the culture conditions. In contrast, TL 
incubators such as GERI (Genea Embryo Review Instrument, Genea Biomedx, 
Australia) and GERI+ (Genea Biomedx, Australia) are equipped with both 
microscopes/cameras and independent incubation chamber for each individual patient, 
providing undisturbed homeostatic conditions throughout the culture period. 
High-level evidence is needed to confirm whether undisturbed culture conditions, as 
provided by GERI or GERI+ incubators, may contribute to the optimal growth of 
embryos. 
 
B. The continuous monitoring of embryos 
The conventional method for embryo assessment developed in 1980s is based on daily 
observations of embryos under regular epi-light microscopy (Fisch et al., 2001; Scott, 
2003). This system relies on the static images of embryos analyzing the cell numbers, 
symmetry of the blastomeres, multinucleation, fragmentation, vacuoles, and etc. 
(Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group 
Embryology, 2011). Due to the limited number of images examined, the predictive 
value of such embryo assessment system is very limited, as elaborated in detail below: 
 
1) The status of embryo fragmentation and multinucleation are usually highly 
dynamic (Bromer and Seli, 2008).  
2) Irregular divisions such as direct cleavage (i.e. division from one cell to three cells) 
(Athayde Wirka et al., 2014) and reverse cleavage (fusion of two cells) (Liu et al., 
2014) are hallmarks of embryos of poor quality but cannot be captured by 
conventional microscopic observation.  
3) Studies showed that cell number and morphology of approximately 50% of the 
embryos may change within 4 hours from 38 to 42 h post insemination, resulting in 
alternations in their assessment (Bromer and Seli, 2008; Montag et al., 2011).  
4) Embryo assessment only by Day 3 morphology does not necessarily reflect the 
viability and developmental potential of the embryo (Milki et al., 2002; Rijnders 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018          
                               15 / 49 
  
and Jansen, 1998). 
 
The GERI Assess software embedded in the GERI+ system facilitates the 
identification of the irregular divisions and recording of the developmental timing and 
cell numbers at different developmental stages by continuous TL imaging. Again, 
evidence is needed to prove whether such objective and continuous assessment of 
embryos will lead to better clinical outcomes. 
 
EEVA (Early Embryo Viability Assessment) is an automated embryo prognostic 
software. It analyzes the dark-field images obtained through a GERI+ incubator and 
assesses the embryo quality automatically based on morphokinetic parameters and 
morphology (VerMilyea et al., 2014; Wong et al., 2010). There is also another embryo 
assessment model based on morphokinetic parameters (Rubio et al., 2014). However, a 
well-accepted universal empirical algorithm is currently unavailable. The benefit of 
embryo assessment based on morphokinetics is still in debate and contradicting results 
have been reported in several single-center RCTs using different algorithms (Adamson 
et al., 2016; Armstrong et al., 2015b; Basile et al., 2015; Goodman et al., 2016).  
 
In this multi-centric, single-blinded, randomized and controlled trial we will 
investigate whether embryos cultured under the undisturbed conditions and assessed 
with continuous monitoring of morphological and morphokinetic parameters may lead 
to better clinical outcomes as compared to embryos cultured in conventional 
incubators and assessed by bench-top microscopy. The main aim of this trial is to 
evaluate the overall clinical value of GERI+ as an integrated embryo culture and 
assessment system, providing an undisturbed culture environment, continuous 
monitoring of embryo development and automated scoring using a predictive 
algorithm.   
 
4. BENEFIT-RISK ASSESSMENT 
The GERI+ system is composed of the following two components: 
1) GERI+ embryo incubator, a CE marked Class IIA medical device. 
2) EEVA automated embryo prognosticsoftware, a CE marked Class IIA/B medical 
device. 
 

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morphological assessment, and no risk is expected for clinical use of EEVA in embryo 
assessment. 
 
4.2 
Benefits of the GERI+ system  
The GERI+ system provides undisturbed and comparable embryo culture conditions 
to the conventional embryo culture system.  
 
Adjunctive use of the EEVA prognostic test (early version with 2 EEVA categories, 
High and Low) has been shown to significantly improve the ability to identify 
embryos that would reach the usable blastocyst stage, with a specificity of 84.7% (52% 
for morphology alone) and a positive predictive value (PPV) of 54.7% (34.5% for 
morphology alone) (Conaghan et al., 2013). Specificity (or true negative rate) is the 
percentage of embryos that have a negative “test” result (“EEVA Low”) and a 
negative outcome (non-usable blastocyst). The EEVA test also reduced 
inter-embryologist specificity variability in embryo assessment (Conaghan et al., 
2013). The value of EEVA in predicting blastocyst formation and improving 
consistency of embryo assessment was later reconfirmed in a prospective multicenter 
study (Diamond et al 2015). Quite recently, Adamson et al (2016), in a prospective 
concurrent controlled trial comparing adjunctive use of EEVA (version 2.0, with 2 
EEVA categories, High, and Low) against conventional morphology alone, showed 
significantly higher Day 3 implantation (30.2% vs 19.0%) and clinical pregnancy 
rates (46.0 vs 32.1%) in the 2 groups respectively (Adamson et al., 2016). They 
conclude that this non-invasive test adds valuable information to conventional 
morphological assessment (Adamson et al., 2016; Diamond et al., 2015). 
 
An additional benefit is that the GERI+ system generates consistent and objective 
data that help embryologists to standardize embryo assessment between 
embryologists and IVF clinics (Adamson et al., 2016; Diamond et al., 2015). The 
subjects included in this trial may also benefit from the GERI+ system by getting 
more viable embryos with high implantation potential for transfer.  
 
5. STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
The main aim of this trial is to evaluate the overall clinical value of GERI+ as an 

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integrated embryo culture and assessment system, providing an undisturbed culture 
environment, continuous monitoring of embryo development and automated scoring 
using a predictive algorithm  
 
5.2 
Endpoints 
5.2.1 Primary Endpoint 
The primary end point is clinical pregnancy with fetal heartbeat. It is defined as the 
pregnancy diagnosed by ultra-sonographic or clinical documentation of at least one 
fetus with heart beat in gestational week 6 to 8. It includes ectopic pregnancy 
(Zegers-Hochschild et al., 2009).  
. 
5.2.2 Secondary Endpoints 
• 
The number of Utilizable Embryos: defined as the number of embryos that are 
transferred and/or cryopreserved per subject. 
• 
The number of Good Quality Embryos: defined as the number of embryos with 7 
or more blastomeres, <25% fragmentation, size and symmetry of blastomeres 
appropriate to the cell number, and no evidence of multinucleation, based on the 
morphology on Day 3 of embryo culture per subject (modified from Alpha 
Scientists in Reproductive Medicine and ESHRE Special Interest Group 
Embryology, 2011).  
• 
The number of Non-viable Embryos: defined as the number of embryos in which 
development has been arrested for at least 24 h or in which all the cells have 
degenerated or lysed (Alpha Scientists in Reproductive Medicine and ESHRE 
Special Interest Group Embryology, 2011). 
• 
Implantation with positive fetal heart beat: Implantation refers to the attachment 
and subsequent penetration by the zona-free blastocyst (usually in the 
endometrium) that starts 5 to 7 days after fertilization (Zegers-Hochschild et al., 
2009). A successful implantation is defined as the presence of one gestational sac 
with fetal heart beat under ultrasonography at gestational weeks 6-8. 
• 
Biochemical Pregnancy: defined as a pregnancy diagnosed only by the detection 
of hCG in serum or urine and that does not develop into a clinical pregnancy 
(Zegers-Hochschild et al., 2009). 
• 
Ongoing Pregnancy: defined as the presence of viable fetuses identified by 
ultrasonography at gestational weeks 10-12 (Rubio et al., 2014). 

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• 
Multiple Pregnancy: defined as a pregnancy with more than one fetus. It is 
identified by ultrasonography at gestational weeks 10-12 (Zegers-Hochschild et 
al., 2009).  
• 
Ectopic Pregnancy: defined as a pregnancy in which implantation takes place 
outside the uterine cavity.  It is identified by ultrasonography at weeks 6-8 
(Zegers-Hochschild et al., 2009).  
• 
Spontaneous Miscarriage: the spontaneous loss of a clinical pregnancy before 20 
completed 
weeks 
of 
gestational 
age 
(18 
weeks 
after 
fertilization) 
(Zegers-Hochschild et al., 2009). In this study, the spontaneous miscarriage is 
tracked up to 10-12 weeks of gestational age.  
 
6. INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan 
 
This is an interventional, multi-center, single-blinded (the subjects are blinded while 
the clinicians and the embryologists are not blinded), randomized, controlled clinical 
trial and will include 16 investigational sites. Each site will conduct the trial using the 
same clinical protocol. Recruitment of subjects at each site, with subjects who 
voluntarily consent to participate, is expected to continue for up to 21 months. 
Competitive enrollment is applied to maximize subject recruitment. Additional 
follow-up after embryo transfer will take place up to 12-18 days to verify hCG 
positivity, at 6-8 gestational weeks to verify implantation and clinical pregnancy, and 
10-12 gestational weeks to verify ongoing pregnancy. Total duration of the trial, 
including start up (First patient in, FPI) and close out activities (Last patient off study, 
LPO), is approximately 24 months. 

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6.2 
Discussion of the Study Design  
The design selected for this trial is defined based on the need to locally validate the 
value of GERI+ system to improve clinical outcomes by collecting real life clinical 
data. It will be the first multi-centric RCT to be implemented in Europe testing the 
potential benefit brought about by the GERI+ integrated embryo culture and EEVA 
assessment system over conventional embryo culture and microscopy-based static 
morphological assessment method. Considering the large sample size, it will also be a 
landmark for the future application of this integrated continuous monitoring and 
undisturbed embryo culture and assessment system worldwide. 
 
The rate of clinical pregnancy with positive fetal heart beat (CPR with positive FHB) 
will be studied in this trial as the primary endpoint. CPR with positive FHB provides 
strong evidence for continued viability of embryos, following culture and assessment.  
 
This trial is single-blinded for subjects and is open to embryologists who will process, 
culture and grade the embryos, and to clinicians/nurses who will perform the embryo 
transfer and pregnancy tests and scans. Considering the volume of IVF and ICSI 
patients in these 16 sites participating in this trial, recruitment of subjects should be 
completed within 21 months. 
 
6.3 
Inclusion of Special Populations  
Not applicable. 
 
6.4 
Enrollment of Trial Population  
All subjects must meet all the inclusion criteria and must not meet any of the 
exclusion criteria.  
 
6.4.1 Inclusion Criteria  
1) Couples with ≤ two failed fresh IVF/ICSI embryo transfer cycles. 
2) Age ≥ 18 and ≤ 40 years. 
3) BMI: 18-30 kg/m2. 
4) Normal uterine cavity under ultrasound. 
5) Subject and her husband/partner must have read and signed the Informed 

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Consents form. 
6) At least four normally fertilized oocytes (2PN) in the current cycle. 
 
6.4.2 Exclusion Criteria 
1) Male with non-ejaculated sperm. 
2) Subjects with abnormal, undiagnosed gynecological bleeding or with 
genitourinary malformations. 
3) Subjects with any contraindication to COS for ART or to gonadotropins. 
4) Planned “freeze all” cycle (oocytes or embryos). 
5) Planned PGS or PGD cycle. 
6) Concurrent participation in another clinical study. 
 
6.5 
Recruitment of Participants 
Subjects will be recruited from patients undergoing IVF or ICSI treatment cycles at 
the investigators’ clinics. Subjects will be assessed according the Inclusion/ Exclusion 
criteria to determine their eligibility. 
 
6.6 
Method of Blinding 
• 
Blinding: The trial is blinded to the subjects. The trial is not blinded to the 
embryologists handling the embryos or the clinicians/nurses conducting embryo 
transfer and pregnancy tests/scans. 
• 
Emergency Un-blinding: in case of a medical emergency, the subject will be 
informed by her trial doctor or embryologist which incubator and embryo grading 
method are used for her embryos.  
 
6.7 
Randomization and Allocation of Subjects 
After signing the informed consent form, all eligible subjects will be randomized and 
allocated to either of the two treatment groups immediately after fertilization check on 
Day 1 of embryo culture.  
 
A stratified block randomization with fixed block length and allocation ratio 1:1 will 
be used. The stratification will be based on site and the age of subject (age group 
18-35 vs. 36-40). Randomization will be accomplished using the Interactive Web 
Response Services (IWRS) system. An independent statistician will generate the 

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randomization schedule and upload to the IWRS system. All randomization codes will 
not be reused and subjects who discontinue the study early will not be replaced. 
 
A subject can be considered as a drop-out during the study if she is randomized but 
primary endpoint data is not available for this subject, for whatever reason. Reasons 
for study discontinuation will be recorded in the Trial Exit eCRF.  
 
6.8 
Description of Treatment and Definition of Exposure to Trial Medication 
Treatment is defined as the process of embryo culture and assessment, whereas no 
trial medication is applied in this trial. 
 
In the experimental treatment arm:  
• 
On Day 1 of embryo culture, all 2PN zygotes are transferred by embryologists 
into the GERI dishes which have been pre-equilibrated. The GERI dishes are then 
placed in the GERI+ incubator for both bright-field and dark-field time lapse 
monitoring until Day 3. Pre-mixed Gas with 6% CO2 (or whichever CO2 
concentration is required to meet manufacturers requirements for optimal pH of 
their culture media) and 5% O2 is recommended. 
. If a different gas composition is used, this must be the same for both test and control 
arms.  
 
• 
On Day 3 of embryo culture, all embryos are reviewed firstly by GERI Assess 
software, using bright-field imaging. Five parameters, including cell number, 
abnormal divisions (reverse cleavage and direct cleavage), multinucleation, 
fragmentation and symmetry of blastomeres are annotated in the GERI Assess 
system.  
• 
It is recommended that Day 3 cell count is assessed at 68±1 hours 
post-insemination across all sites, for generation of final EEVA score (Alpha 
Scientists in Reproductive Medicine and ESHRE Special Interest Group 
Embryology, 2011).  
• 
The prognostic EEVA information, used adjunctively with morphology 
assessment will assist embryologists to further identify, for transfer, the embryo(s) 
with optimal potential to form a blastocyst.  
• 
Finally, the embryo(s) with the highest EEVA grade are transferred. Note: 

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− Cell number should be entered via the EEVA system, to generate a final 
EEVA test result (based on the dark-field imaging). A second review of 
embryo videos should be carried out to confirm P2 and P3 parameters, and 
when required, a manual update should be carried out. 
− EEVA results should be applied only to those embryos of overall good and 
fair quality i.e. > 6 cells with < 25% fragmentation and without severe 
asymmetry. EEVA test results are not recommended for adjunctive use with 
poor quality embryos i.e. < 5 cells or 6 cells with > 25% fragmentation and 
with severe asymmetry.  
− Priority should be given to transfer embryos without direct cleavage or 
reverse cleavage.   
− If the EEVA result shows “NR” (No Result) or there are only poor-quality 
embryos, the embryologist will grade the embryos with morphology (Alpha 
Scientists in Reproductive Medicine and ESHRE Special Interest Group 
Embryology, 2011) and apply the decision grid used in the control group.   
 
− If two or more embryos have the same EEVA score, preference should be 
given to the embryos with better morphology and subject to the 
embryologist’s decision grid used in the control group. 
• 
National/regional regulations and procedures will be followed to manage the 
remaining embryos, provided that in each case the provisions of the Germany 
Embryo Protection Act are observed.  
 
In the control treatment arm:  
• 
On Day 1 of embryo culture, all 2PN zygotes are transferred by embryologists 
into the GERI dishes which have been pre-equilibrated with embryo culture 
medium routinely used in their laboratory. The GERI dishes are then placed in a 
conventional incubator for culture until Day 3. Gas with 6% CO2 (or whichever 
CO2 concentration is required to meet manufacturers requirements for optimal pH 
of their culture media) and 5% O2 is recommended. If a different gas composition 
is used, this must be the same for both test and control arms. 
• 
On Day 2 of embryo culture, the embryos may or may not be taken out of the 
incubators for observation using bench-top microscopy, to follow the routine 
protocols of the laboratory. 

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• 
On Day 3 of embryo culture, all embryos are assessed using a bench-top 
microscope by embryologists, at a recommended time of 68±1 hours post 
insemination. (Alpha Scientists in Reproductive Medicine and ESHRE Special 
Interest Group Embryology, 2011). The embryo(s) with optimal cell stage and 
grade will be transferred. National/regional regulations and procedures will be 
followed to manage the remaining embryos, provided that in each case the 
provisions of the Germany Embryo Protection Act are observed. 
 
Please be advised that there is no restriction on the number of embryos to be 
transferred but we recommend a single embryo transfer in this study. 
 
6.9 
Criteria for Subject Withdrawal  
Subjects will be informed that they have the right to withdraw from the trial at any 
time between randomization and completion of the study, 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, including the reason for 
withdrawal.  
 
Subject data will be included in the analyses up to the time that consent is withdrawn. 
The trial exit electronic case report form should be completed at the time a subject is 
withdrawn from the trial and will included the reason for withdrawal.  
 
6.10 
Definition of Completion of the Study 
Completion of the study is achieved when all subjects finish the test for ongoing 
pregnancy.  
 
The subject may complete and exit from this trial at the following time points: 
• 
Test for hCG 12-18 days post embryo transfer: a subject will exit from the trial if 
the blood or urinary test result for hCG is negative. Otherwise subject waits until 
the test for clinical pregnancy. 
• 
Test for clinical pregnancy at gestational weeks 6-8: a subject will exit from the 
trial if the ultrasound test result for clinical pregnancy is negative. Otherwise the 
subject waits until the test for ongoing pregnancy. 
• 
Test for ongoing pregnancy at gestational weeks 10-12: a subject will finish the 

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trial at this time point, regardless of whether the ultrasound result for ongoing 
pregnancy is positive or negative. 
• 
Miscarriage: a subject will exit from the trial upon spontaneous or therapeutic 
miscarriage. 
 
6.11 
Potential Confounding Factors 
Smoking status, age, gestational history, COS strategy, embryo culture media, luteal 
phase support, number of embryos transferred and site locations are potential 
confounding factors in this study. Multivariate logistic analysis will be performed 
with these factors in the model as covariates when testing the primary endpoint.  
 
6.12 
Estimated Trial Calendar 
Trial will begin enrollment in April 2018 and will continue until 1,386 subjects are 
enrolled. Last patient off study is expected to be accomplished by March 2020 and 
close-out activities and clinical trial report will follow within 7 months after. 
7. STUDY PROCEDURES, ASSESSMENTS AND DATA 
COLLECTION 
Embryos will be observed until they are transferred and then the clinical outcome of 
all subjects will be recorded until the ongoing pregnancy is verified (up to 10-12 
weeks of gestation).  
 
Subjects will be followed up until lost to follow-up, meeting the withdrawal or 
premature discontinuation criteria (as defined in Sections 6.9 and 10.13), or exiting 
from the trial (as defined in Section 6.10), whichever comes first. 
 
7.1 
Baseline Data Collection 
Before controlled ovarian stimulation (COS), potential subjects in the trial will 
undergo pre-ICSI/IVF preparations per the standard protocol currently in force at each 
site. Collection of trial-related information may take place only after the potential 
subject and her partner have given voluntary, documented, informed consents (ICFs). 
 
The following information is recorded in the Screening and Baseline eCRF: 
• Date of Informed Consents to be signed by potential subjects and their partners; 
• Demographics, pregnancy history, cause of infertility, hormone levels (FSH, LH, 

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E2 and AMH) and antral follicle count (AFC) of the potential subject, as well as 
the date of data collection. 
 
7.2 
Data Collection on Day of Ovulation Triggering 
The following data on COS and ovulation triggering is recorded in the COS and 
Ovulation Triggering eCRF: 
• 
Downregulation and COS regimen, total dose of gonadotropin, type of 
gonadotropin, the date of the first dose of gonadotropin and the duration of COS;  
• 
The date, time and method of ovulation triggering, and the pre-trigger hormonal 
and ultra-sonographic data. 
 
7.3 
Data Collection on Day 0-3 of Embryo Culture 
Oocyte retrieval and ICSI/IVF will follow the local protocols/practice in place at each 
trial site. All oocytes/zygotes are cultured in routine culture dishes in conventional 
incubators for both treatment groups until fertilization check on Day 1 of embryo 
culture. Immediately after confirming the number of 2PN zygotes, the last step of 
subject screening is accomplished and randomization is conducted. 
 
The following information is captured in the OPU (Oocyte pick-up) and 
Insemination eCRF: 
• 
Date and time of oocyte retrieval, the number of oocytes retrieved and the 
maturation status: GV, MI, MII, and degenerated; 
• 
Date, time and method(s) of insemination: (i) ICSI (ii) IVF (iii) both; 
• 
Date and time of fertilization check and the number of 2PN zygotes. 
• 
Randomization and allocation of subjects. 
 
After randomization and allocation, the 2PN zygotes are transferred to GERI dishes 
with pre-equilibrated culture media and are relocated to either GERI+ incubators or 
conventional incubators. The embryo culture, assessment and transfer are described in 
detail in Section 6.8 Description to Treatment. 
 
The following data is collected in the Embryo Culture, Assessment and Transfer 
eCRF: 
• 
Embryo culture conditions (including humidification, gas phase, brand of oil and 

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media); 
• 
Date and time of embryo assessment; 
• 
Status and fate of each individual embryo; 
• 
Date and time of embryo transfer; 
• 
The number of embryos(s) transferred; 
• 
The procedure of embryo transfer: with ultrasound guidance or not, and difficulty. 
 
7.4 
Data Collection on Day of hCG Test 
A standard urine or blood serum hCG test is performed 12-18 days after embryo 
transfer, following the routine practices at the trial site. The following information is 
recorded in the LPS (Luteal Phase Support) and Clinical Outcome eCRF: 
• Strategy of LPS; 
• Date of the hCG test; 
• Method of hCG test and the result; 
• Quantitative β-hCG, as applicable. 
 
If the result of the hCG test is negative, the subject will have completed the trial and 
be exited at that time (complete Trial Exit eCRF). 
 
7.5 
Data Collection for Clinical Pregnancy Ultrasound Test 
The ultrasound test to verify clinical pregnancy is carried out between gestational 
weeks 6 and 8. The following information is recorded in the LPS and Clinical 
Outcome eCRF: 
• 
Date of the last ultrasound test for clinical pregnancy; 
• 
Result 
− Number of intrauterine gestational sacs 
− Number of fetal heartbeats 
− Ectopic pregnancy (Yes or No) 
− Biochemical pregnancy (Yes or No) 
− Other 
 
If the result of the ultrasound test 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 eCRF). 

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7.6 
Data Collection for Ongoing Pregnancy Ultrasound Test 
The ultrasound test to verify ongoing pregnancy is done between gestational weeks 10 
and 12 for subjects who are confirmed as being pregnant at ultrasound scan during 
gestational weeks 6 to 8. The following information is recorded in the LPS and 
Clinical Outcome eCRF:  
• 
Date of the last ultrasound test for ongoing pregnancy; 
• 
Result 
− Number of intrauterine viable fetus; 
− Spontaneous Miscarriage (miscarriage after the initial confirmation of 
clinical pregnancy). 
 
Conclusion of the clinical outcome (ongoing pregnancy or miscarriage) is recorded on 
the Trial Exit eCRF as well. 
 
7.7 
Adverse Events and Assessment of Safety 
An adverse event or a serious adverse event, whether or not related to the 
investigational medical device, in subjects participating in the study, is not applicable. 
In addition, according to European Guidelines for post-marketing device studies 
(MEDDEV 2.12/2 rev2, dated January 2012), reporting of serious adverse events to 
Health Authorities is not applicable. 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 Section 7.7.1 
Definitions).  
 
Safety of GERI+ system will be evaluated by the assessment of routine embryological 
data collected in the eCRF (See Section 7.7.3), and by reporting of device deficiencies 
(See Section 7.7.4).  
 
7.7.1 Definitions 
As per the European Guidelines on medical devices (MEDDEV 2.7/3 REV 3), dated 
May 2015:  
 
Investigational medical device 

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Medical device being assessed for safety or performance in a clinical investigation 
NOTE: This includes medical devices already on the market that are being evaluated 
for new intended uses, new populations, new materials or design changes. 
 
Adverse Event (AE) 
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. 
NOTE 1: This definition includes events related to the investigational device or the 
comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices.  
 
Serious Adverse Event (SAE) 
Adverse event that: 
a) led to a death, injury or permanent impairment to a body structure or a body 
function. 
b) led to a serious deterioration in health of the subject, that either resulted in: 
- a life-threatening illness or injury, or 
- a permanent impairment of a body structure or a body function, or 
- in-patient hospitalization or prolongation of existing hospitalization, or 
- in medical or surgical intervention to prevent life threatening illness 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect. 
NOTE 1: Planned hospitalization for pre-existing condition, or a procedure required by 
the Clinical Investigation Plan, without a serious deterioration in health, is not 
considered a serious adverse event.  
 
Device deficiency 
Inadequacy of an investigational medical device related to its identity, quality, 
durability, reliability, safety or performance. This may include malfunctions, use error, 
or inadequacy in the information supplied by the manufacturer. 
 
Adverse Device Effect (ADE) 

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Adverse event related to the use of an investigational medical device. 
NOTE 1- This includes any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, the implantation, the 
installation, the operation, or any malfunction of the investigational medical device. 
NOTE 2- This includes any event that is a result of a use error or intentional abnormal 
use of the investigational medical device. 
 
Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has 
not been identified in the current version of the risk analysis report. 
NOTE: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity 
or outcome has been previously identified in the risk analysis report. 
   
7.7.2 Reporting period for safety surveillance 
The reporting period for safety surveillance begins when the subject is included into the 
trial (date of randomization) and continues after embryo transfer until achievement of 
ongoing pregnancy. There is no live birth follow-up planned in the frame of this study. 
 
7.7.3 Safety assessment of embryological data 
To comprehensively evaluate the safety of GERI+ embryo culture system, as provided 
by 
the 
GERI+ 
incubator, 
we 
will 
monitor 
the 
following 
secondary 
endpoints/parameters which are closely related to the quality and viability of embryos 
and report to Merck Global Drug Safety after the completion of this trial: 
• 
The number and percentage of Good Quality Embryos per subject, in both arms 
of study: Good Quality Embryos are embryos with 7 or more blastomeres, <25% 
fragmentation, size and symmetry of blastomeres appropriate to the cell number, 
and no evidence of multinucleation, based on the Day 3 morphology (modified 
from Alpha Scientists in Reproductive Medicine and ESHRE Special Interest 
Group Embryology, 2011)  
• 
The number and percentage of Non-viable Embryos per subject, in both arms of 

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study: Non-viable Embryos are embryos in which development has been arrested 
for at least 24 h or in which all the cells have degenerated or lysed (Alpha 
Scientists in Reproductive Medicine and ESHRE Special Interest Group 
Embryology, 2011). 
 
7.7.4 Device Deficiency 
Methods of recording Device Deficiencies 
Investigators must inform, via the established customer complaint process, their local 
Merck KGaA contact, usually the Clinical Applications Engineer (CAE) in case of 
any device related complaint and/or deficiency. Feedback may consist of any alleged 
deficiency related to the physical characteristics, identity, quality, durability, reliability, 
effectiveness or performance of GERI+ system.  
 
Genea Biomedx, the legal manufacturer of GERI+ system, will investigate device 
malfunctions/deficiencies and perform an evaluation to determine and document the 
root cause of any device deficiency. A final list of all device deficiencies occurring at 
the study sites during the course of the study will be attached to the clinical study 
report. 
 
Reporting of Device Deficiencies 
Investigators are responsible for reporting to Merck KGaA device deficiencies that 
may affect the culture and assessment process of the embryos during the course of 
embryo culture through trial completion. An assessment of the device deficiency by 
the investigator is not mandatory. 
 
Genea Biomedx is responsible for reporting of device deficiencies to NCA (National 
Competent Authorities) according to applicable legal post-marketing reporting 
obligations for medical devices (e.g. Directive 93/42/EEC). 
 
7.7.5 Reporting after defined reporting period for safety surveillance 
Beyond the defined reporting period of this study, it is the responsibility of the 
investigators to inform any serious abnormal pregnancy outcome in subjects who 
participated in this study, including of any congenital anomalies in the offspring of 
these subjects, to spontaneously report the serious adverse events either directly to the 

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marketing authorization holder Genea Biomedx or to their local regulatory health 
authorities, if necessary, as required by the local reporting guidelines. 
 
8. STATISTICS  
8.1 
Sample Size 
Based on an expected clinical pregnancy rate of 30% (Adamson et al., 2016) in the 
control group and a 25% relative increase of clinical pregnancy rate in the 
experimental group, a two-sided test with an alpha level of 0.05 needs 623 subjects 
per group to reach a power of 80%. With a drop-out rate of 10%, 1,386 subjects (693 
per group) need to be randomized. A subject can be considered as a drop-out during 
the study if she is randomized but primary endpoint data is not available for this 
subject, for whatever reason. 
 
The calculation of sample sizes was performed using nQuery Advisor® version 7.0. 
 
8.2 
Randomization 
A stratified permutated block randomization with fixed block size and allocation ratio 
1:1 will be used. Randomization will be accomplished using Interactive Web 
Response Services (IWRS) system. The stratification will be based on site and age of 
the subject (18-35 versus 36-40). This guarantees, at any time, a similar number of 
subjects between experimental and control groups at each site. 
 
8.3 
Analysis Sets 
Three analysis sets will be used: the Full Analysis dataset, the Per Protocol dataset 
and the Subgroup Analysis dataset. 
• Full Analysis (FA-) dataset includes all randomized subjects. Subjects will be 
presented as randomized. 
• Per Protocol (PP) dataset includes all subjects who have been treated according to 
the Clinical Trial Protocol and have received Day 3 fresh embryo transfer, with 
no major Clinical Trial Protocol violation in respect of factors likely to affect the 
efficacy of treatment. 
• Subgroup Analysis dataset (SA):Subjects who had embryos transferred which 
were either good or fair (i.e. not poor quality)  
•  

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• . 
 
The FA population is the primary analysis population. PP population is used for 
sensitivity analysis. SA population is used for supportive analysis. 
 
8.4 
Description of Statistical Analyses  
8.4.1 General Consideration 
Descriptive Statistics  
For continuous variables, the following parameters will be presented: Number (N) of 
subjects, mean, standard deviation (SD), median, first quartile (q1), third quartile (q3), 
minimum, and maximum. For categorical variables, the total number (‘N’) of subjects 
and proportions will be presented. Graphical methods will be used as appropriate. 
Number of subjects with missing values (‘Missing’) will be listed for the analyses 
based on observed case data. 
 
Method of handling missing data 
Missing data will not be imputed.  
 
8.4.2 Analysis of Primary Endpoint 
The FHB positive clinical pregnancy rate (the number of subjects with FHB positive 
clinical pregnancy divided by the number of subjects with embryo transfer) for either 
of the two treatment groups will be computed. 
 
Primary hypothesis will be tested between the treatment groups based on a 
Cochrane-Mantel-Haenzel CMH test adjusting for stratification factors providing the 
derived Odds Ratio and its 95% confidence interval. As sensitivity analysis, a logistic 
regression model with confounding factors and stratification factors as covariates will 
be performed. Details regarding the model and analysis will be specified in the SAP. 
 
8.4.3 Analysis of Secondary Endpoints 
• Utilization Rate: the number of transferred and cryopreserved embryos divided 
by the number of 2PN zygotes per subject. 
• Good Quality Embryo Rate: the number of good quality embryos divided by the 
number of 2PN zygotes per subject. 

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• Non-viable Embryo Rate: the number of non-viable embryos divided by the 
number of 2PN zygotes per subject.  
• FHB positive implantation rate is calculated per embryo transferred (IR) and per 
subject randomized (IR*):  
a. 
IR: the number of gestational sacs with positive FHB under ultrasound scan 
at gestational weeks 6-8 divided by the total number of embryos transferred.  
b. IR*: IRw is calculated for each subject and not aggregated per group of 
patients. In the scenario where maximally two or maximally three embryos 
are transferred at once, the IRw can only have two (0 and 1.0), three (0, 0.5 
and 1.0) and four (0, 0.33, 0.66 and 1.0) states, respectively. As such, IRw is 
an ordinally scaled categorical event. Then the overall IR* for each treatment 
group= (1/n)* Σw=1,n IRw. 
• Biochemical Pregnancy Rate: the number of subjects with biochemical pregnancy 
divided by the number of subjects with embryo transfer. 
• Ongoing Pregnancy Rate: the number of subjects with ongoing pregnancy 
divided by the number of subjects with embryo transfer.  
• Multiple Pregnancy Rate: the number of subjects with multiple pregnancy 
divided by the number of subjects with ongoing pregnancy.  
• Ectopic Pregnancy Rate: the number of subjects with ectopic pregnancy divided 
by the number of subjects with embryo transfer. 
• Spontaneous Miscarriage Rate: the number of subjects with spontaneous 
miscarriage divided by the number of subjects with clinical pregnancy. 
 
Descriptive statistics for all of the secondary endpoints will be provided. Detailed 
statistical analysis methods will be specified in the SAP. 
 
8.4.4 Interim Analysis 
Not applicable. 
 
9. ETHICAL AND REGULATORY ASPECTS  
9.1 
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 

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Protocol Version: 3.0 / Jan 31, 2018          
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as with the International Standard ISO14155 (Clinical Investigation of medical 
devices for human subjects – Good Clinical Practice) and applicable regulatory 
requirements as well as the provisions of German Embryo Protection Act. In 
particular, the Investigator must ensure that only subjects who have given their 
informed consent are included into the trial. 
 
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 7.7. 
 
The investigator shall submit a progress report and end of trial notification according 
to the requirements of the reviewing Ethics Committee, if applicable. 
 
9.2 
Subject Information and Informed Consents 
An unconditional prerequisite for a subject’s participation in the trial is the written 
informed consents of the subject and her partner. Informed consents should be signed 
before oocyte retrieval. 
 
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. The confidentiality provisions within all 
applicable laws and regulations will apply throughout. Obtaining informed consents 
in accordance with the policy of the EC, this clinical protocol, and applicable 
regulations is mandatory for subject participation. Merck KGaA 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 and her 
partner read and understand. All subjects and their partners must provide voluntary, 
written informed consents prior to the start of any trial-related activities.   
 
Adequate information must therefore be given to the subject by the Investigator 

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Protocol Version: 3.0 / Jan 31, 2018          
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before informed consents are 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 Merck KGaA for the purpose of obtaining 
informed consents. 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 
partner and sign the Informed Consent Form. 
 
The Informed Consent Form must be signed and personally dated by the subject, her 
partner 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 and partner prior to participation. 
 
Whenever important new information becomes available that may be relevant to the 
subject and partner’s consent, the written subject information sheet and any other 
written information provided to subjects will be revised by Merck KGaA and be 
submitted again to the EC for review and favorable opinion. The agreed, revised 
information will be forwarded to each subject and partner 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 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 and partners may be 
required to re-consent, as determined by the reviewing EC.    

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Protocol Version: 3.0 / Jan 31, 2018         
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9.3 
Subject Identification and Privacy 
A unique subject number will be assigned to each subject at inclusion, immediately 
after informed consents are obtained and the randomization is triggered. 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 Merck KGaA, 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 Merck KGaA, 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 Merck KGaA, 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 Merck KGaA 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 and partners consent on data handling 
procedures in accordance with national regulations. 
 
9.4 
Emergency Medical Support and Subject Card  
Not applicable. 
 
9.5 
Clinical Trial Insurance and Compensation to Subjects  
Insurance covers all the subjects who are included in the study. After signing the ICF, 

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appropriate insurance should be conducted according to requirements of local 
legislation, GCP guidelines and relevant provisions of hospitals in the study. No 
compensation is planned for subjects participating in this trial. 
 
9.6 
Independent Ethics Committee 
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 for its favorable opinion/approval. The written favorable 
opinion/approval of the IEC will be filed in the Investigator Site File, and a copy will 
be filed in the Trial Master File (TMF) at Merck KGaA. 
 
The trial must not start at a site before Merck KGaA has obtained written 
confirmation of favorable opinion/approval from the concerned IEC. The IEC will be 
asked to provide documentation of the date of the meeting at which the favorable 
opinion/approval is 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 to Merck KGaA by the 
investigator. Where possible, copies of the meeting minutes should be obtained and 
provided to Merck KGaA by the investigator. 
 
Amendments to the clinical trial will also be submitted to the concerned IEC, before 
implementation in case of substantial changes (see Section 10.6). Relevant safety 
information will be submitted to the IEC during the course of the trial in accordance 
with national regulations and requirements. 
  
9.7 
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. 
 
10. STUDY MANAGEMENT 
The whole process of the study will be monitored remotely by the CRO. The 
Electronic Data Capture (EDC) system will be jointly managed by the CRO and 

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PPD

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
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Protocol Version: 3.0 / Jan 31, 2018          
                               41 / 49 
  
research institute, or practice) for the longest possible time permitted by the 
applicable local regulations, and/or as per applicable GCP guidelines, whichever is 
longer. In any case, the Investigator should ensure that no destruction of medical 
records is performed without the written approval of Merck KGaA. 
 
10.4 
Monitoring, Quality Assurance and Inspection by Health Authorities  
Study monitoring, quality assurance and regulatory audits will be conducted in 
accordance with GCP principles, ISO14155 and site-level regulations. 
 
This trial will be monitored in accordance with the International Standard ISO14155.  
 
Representatives of Merck KGaA and/or the CRO will monitor the registry.  
Monitoring, data management, data cleaning and auditing procedures developed by 
the CRO will be followed. These procedures are in compliance with ISO 14155 GCP 
guidelines and ensure the acceptability of the data. The Investigator must make 
available all medical records and regulatory documentation at every monitoring visit 
onsite or remotely. The CRO will evaluate the EDC data for completeness and clarity, 
and for verification of the data with source documents in accordance with an agreed 
Data Management Plan and Monitoring Plan. Any discrepancies found are to be 
clarified by the Investigator or the CRO. Appropriate considerations for medical 
confidentiality and data protection will be maintained at every visit onsite or remotely. 
 
10.5 
Protocol Deviations 
A protocol/GCP deviation occurs when an 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 and specific requirements of IEC.  
 
If Merck KGaA finds that an investigator is not complying with the executed clinical 
research agreements, the clinical protocol, applicable legal regulations, or specific 
requirements of IEC prompt, action will be taken to secure compliance. In addition, 
the participation of an investigator may be terminated. 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018         
                              42 / 49 
  
 
10.6 
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 relevant IEC 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 Merck KGaA and at the site. They will be submitted to the relevant IEC 
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. 
 
10.7 
Assessment of Clinical Investigators and Sites 
Investigators will be responsible for fulfilling the clinical trial requirements as 
specified in this clinical protocol. The site must have the necessary resources to 
comply with the requirements. The following criteria will be used to select 
investigators in the clinical trial: 
• Investigator is qualified by training and expertise in IVF/ICSI science and 
methods use. 
• Investigator and clinical research staff have experience with IVF/ICSI clinical 
studies and have the time to conduct the trial in accordance with the clinical 
protocol. 
• Agreement to comply with clinical protocol and regulatory requirements. 
• Adequate volume of potential subjects. 
• Appropriate facilities, resources, and equipment. 
• An expressed desire to participate in the trial. 
• Willing to undergo required trial training. 
• Have completed training on the GERI+ system. 
 
10.8 
Trial Training 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018         
                               43 / 49 
  
All investigators will sign the appropriate trial-related agreements before they are 
added to the clinical trial. Training of trial personnel will be documented on the 
appropriate training record form and maintained with the site and Merck KGaA. 
Clinical research staff will be supplied with the clinical protocol, instructions for use, 
case report form instructions, and other supporting materials. 
 
Topics to be covered at the training may include the following, as appropriate: 
• 
Clinical protocol overview and trial timeframes 
• 
Subject screening and eligibility criteria 
• 
Informed consent procedure 
• 
GERI+ incubator instructions for use 
• 
Informed consent procedure 
• 
GERI dish preparation 
• EEVA software instructions for use 
• GERI Assess/EEVA decision tree for embryo assessment 
• 
GERI+ and EEVA system malfunctions 
• 
EDC system, eCRF completion instructions and corrections 
• 
Monitoring procedures 
• 
EC policies and procedures 
• 
Regulatory requirements and compliance 
 
Merck KGaA scientific and technical personnel and Monitors from CRO may be 
present during this trial to provide support. Also, an investigators’ meeting may be 
considered prior to the start of the trial for the purpose of trial-related training. 
 
10.9 
Required Trial Equipment 
A GERI+ incubator and a server installed with GERI Connect & Assess and an EEVA 
server and monitor will have been previously installed at each site for clinical use.  
 
10.10 Site Activation and Supply of Trial Materials 
Before the first subject 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 the CRO) that the site can start. In addition, the following documentation must be 
on file at Merck KGaA: 

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PPD

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018          
                               45 / 49 
  
Institution and/or Investigator, as the case may be, in writing of any information 
contained therein which is Confidential Information (other than Study Data) or which 
may impair the availability of patent protection for Inventions. Sponsor shall have the 
right to require Institution and/or Investigator, as applicable, to remove specifically 
identified Confidential Information (other than Study Data) and/or to delay the 
proposed publication or presentation for an additional sixty (60) days to enable 
Sponsor to seek patent protection for Inventions. 
 
Institution and Investigator shall not, without the Sponsor’s prior written consent, 
independently publish, present or otherwise disclose any results of or information 
pertaining to Site’s own activities conducted for this trial until a multi-center 
publication is published. In the event the Sponsor coordinates the multi-center 
publication, the participation of the Investigator as a named author shall be 
determined in accordance with Sponsor’s policies, requirements of the publisher and 
generally accepted standards of authorship. If a multi-center publication is not 
published within eighteen (18) months after completion of the Study and lock of the 
database at all research sites or any earlier termination or abandonment of the Study, 
Institution and Investigator shall have the right to publish and present the Site Study 
results following from Site’s own activities conducted for this trial, including Study 
Data, solely consistent with scientific standards and the submission requirements as 
outlined in this section.  
 
Institution and Investigator acknowledges and agrees that Study Data that is not 
published, presented or otherwise disclosed (“Unpublished Data”) shall be subject to 
the provisions on Confidential Information according to Section 10.12 of this protocol, 
and Institution and Investigator shall not, and shall require their personnel not to, 
disclose Unpublished Data to any other site participating in this trial or any third party 
or disclose any Study Data to any other site participating in this trial or any third party 
in greater detail than the same may be disclosed in any publications, presentations or 
disclosures made in accordance with this section. 
 
Merck KGaA will not suppress or veto publications, but maintains the right to delay 
publication in order to protect intellectual property rights. 
 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018         
                              46 / 49 
  
10.12 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, provided in each case the party requested to 
make such disclosure will timely inform Merck KGaA and use all reasonable 
efforts to limit the disclosure and maintain the confidentiality of such confidential 
information to the extent possible. In addition, the disclosing party will permit 
Merck KGaA to attempt to limit such disclosure by appropriate legal means. 
• Further, during the term of this protocol and thereafter, the Institution, its 
employees, agents, subcontractors or affiliates will not use the confidential 
information for any purpose other than that indicated in this protocol and the 
clinical research agreement without Merck KGaA's prior written approval. 
• Institution, its employees, agents, subcontractors or affiliates will not disclose to 
Merck KGaA any information which is confidential or proprietary to a third party 
unless Institution has first obtained the prior written approval of both such third 
party and Merck KGaA. 
 
10.13 Trial or Site Discontinuation 

Study Number: MS200497_0006                          Short title: TICON-Day 3 clinical 
trial 
Protocol Version: 3.0 / Jan 31, 2018          
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• At any time of the study, due to adverse events, or risks outweighing the benefit 
as determined by the investigators; 
• Merck KGaA may temporarily or permanently discontinue the trial at a single site 
or at all sites for ethical, compliance or other reasons. If this is necessary, Merck 
KGaA will endeavor to provide advance notification to the site. If the site or trial 
is suspended or discontinued, the Investigator will be responsible for ensuring 
prompt notification to the EC. Where required by local regulations, Merck KGaA 
will be responsible for informing the EC of trial or site discontinuation.   
 
10.14 Trial Closure 
Upon completion (when all subjects enrolled have completed the ongoing pregnancy 
ultrasound test or have previously exited the trial, and the eCRFs and queries have 
been completed) or termination of the trial, Merck KGaA will notify the sites.  
  
Close-out activities will be performed. The GERI+ system and any unused trial 
material will be collected and returned to Merck KGaA and/or the CRO. The monitors 
(CRO) will ensure that the investigator’s regulatory files are up to date and complete, 
that printed CRFs are provided as PDF files to the sites, and that any outstanding 
issues from previous visits have been resolved. Other issues that may be reviewed 
with the investigator include: discussing record retention requirements (refer to the 
Section on Investigator Records), publication policy, and notifying the EC of trial 
closure, etc. 
 
11. REFERENCES 
1. 
Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group Embryology 
(2011). Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. 
Reproductive biomedicine online 22, 632-646. 
2. 
Adamson, G.D., Abusief, M.E., Palao, L., Witmer, J., Palao, L.M., and Gvakharia, M. (2016). 
Improved implantation rates of day 3 embryo transfers with the use of an automated 
time-lapse-enabled test to aid in embryo selection. Fertility and sterility 105, 369-375 e366. 
3. 
Armstrong, S., Arroll, N., Cree, L.M., Jordan, V., and Farquhar, C. (2015a). Time-lapse systems 
for embryo incubation and assessment in assisted reproduction. The Cochrane database of 
systematic reviews 2, CD011320. 
4. 
Armstrong, S., Vail, A., Mastenbroek, S., Jordan, V., and Farquhar, C. (2015b). Time-lapse in the 

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trial 
Protocol Version: 3.0 / Jan 31, 2018         
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IVF-lab: how should we assess potential benefit? Hum Reprod 30, 3-8. 
5. 
Athayde Wirka, K., Chen, A.A., Conaghan, J., Ivani, K., Gvakharia, M., Behr, B., Suraj, V., Tan, 
L., and Shen, S. (2014). Atypical embryo phenotypes identified by time-lapse microscopy: high 
prevalence and association with embryo development. Fertility and sterility 101, 1637-1648 
e1631-1635. 
6. 
Basile, N., Barriere, P., Meseguer, M., and Freour, T. (2015). Time-lapse in the IVF lab: how 
should we assess potential benefit? Hum Reprod 30, 1276. 
7. 
Bromer, J.G., and Seli, E. (2008). Assessment of embryo viability in assisted reproductive 
technology: shortcomings of current approaches and the emerging role of metabolomics. Current 
opinion in obstetrics & gynecology 20, 234-241. 
8. 
Conaghan, J., Chen, A.A., Willman, S.P., Ivani, K., Chenette, P.E., Boostanfar, R., Baker, V.L., 
Adamson, G.D., Abusief, M.E., Gvakharia, M., et al. (2013). Improving embryo selection using a 
computer-automated time-lapse image analysis test plus day 3 morphology: results from a 
prospective multicenter trial. Fertility and sterility 100, 412-419 e415. 
9. 
Diamond, M.P., Suraj, V., Behnke, E.J., Yang, X., Angle, M.J., Lambe-Steinmiller, J.C., Watterson, 
R., Athayde Wirka, K., Chen, A.A., and Shen, S. (2015). Using the Eeva Test adjunctively to 
traditional day 3 morphology is informative for consistent embryo assessment within a panel of 
embryologists with diverse experience. Journal of assisted reproduction and genetics 32, 61-68. 
10. Fisch, J.D., Rodriguez, H., Ross, R., Overby, G., and Sher, G. (2001). The Graduated Embryo 
Score (GES) predicts blastocyst formation and pregnancy rate from cleavage-stage embryos. Hum 
Reprod 16, 1970-1975. 
11. Goodman, L.R., Goldberg, J., Falcone, T., Austin, C., and Desai, N. (2016). Does the addition of 
time-lapse morphokinetics in the selection of embryos for transfer improve pregnancy rates? A 
randomized controlled trial. Fertility and sterility 105, 275-285 e210. 
12. Liu, Y., Chapple, V., Roberts, P., and Matson, P. (2014). Prevalence, consequence, and 
significance of reverse cleavage by human embryos viewed with the use of the Embryoscope 
time-lapse video system. Fertility and sterility 102, 1295-1300 e1292. 
13. Milki, A.A., Hinckley, M.D., Gebhardt, J., Dasig, D., Westphal, L.M., and Behr, B. (2002). 
Accuracy of day 3 criteria for selecting the best embryos. Fertility and sterility 77, 1191-1195. 
14. Montag, M., Liebenthron, J., and Koster, M. (2011). Which morphological scoring system is 
relevant in human embryo development? Placenta 32 Suppl 3, S252-256. 
15. Park, H., Bergh, C., Selleskog, U., Thurin-Kjellberg, A., and Lundin, K. (2015). No benefit of 
culturing embryos in a closed system compared with a conventional incubator in terms of number 
of good quality embryos: results from an RCT. Hum Reprod 30, 268-275. 

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trial 
Protocol Version: 3.0 / Jan 31, 2018         
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16. Rijnders, P.M., and Jansen, C.A. (1998). The predictive value of day 3 embryo morphology 
regarding blastocyst formation, pregnancy and implantation rate after day 5 transfer following 
in-vitro fertilization or intracytoplasmic sperm injection. Hum Reprod 13, 2869-2873. 
17. Rubio, I., Galan, A., Larreategui, Z., Ayerdi, F., Bellver, J., Herrero, J., and Meseguer, M. (2014). 
Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, 
controlled trial of the EmbryoScope. Fertility and sterility 102, 1287-1294 e1285. 
18. Scott, L. (2003). Pronuclear scoring as a predictor of embryo development. Reproductive 
biomedicine online 6, 201-214. 
19. VerMilyea, M.D., Tan, L., Anthony, J.T., Conaghan, J., Ivani, K., Gvakharia, M., Boostanfar, R., 
Baker, V.L., Suraj, V., Chen, A.A., et al. (2014). Computer-automated time-lapse analysis results 
correlate with embryo implantation and clinical pregnancy: a blinded, multi-centre study. 
Reproductive biomedicine online 29, 729-736. 
20. Wong, C.C., Loewke, K.E., Bossert, N.L., Behr, B., De Jonge, C.J., Baer, T.M., and Reijo Pera, 
R.A. (2010). Non-invasive imaging of human embryos before embryonic genome activation 
predicts development to the blastocyst stage. Nature biotechnology 28, 1115-1121. 
21. Zegers-Hochschild, F., Adamson, G.D., de Mouzon, J., Ishihara, O., Mansour, R., Nygren, K., 
Sullivan, E., and Vanderpoel, S. (2009). International Committee for Monitoring Assisted 
Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary 
of ART terminology, 2009. Fertility and sterility 92, 1520-1524. 
22. Zhang, J.Q., Li, X.L., Peng, Y., Guo, X., Heng, B.C., and Tong, G.Q. (2010). Reduction in 
exposure of human embryos outside the incubator enhances embryo quality and blastulation rate. 
Reproductive biomedicine online 20, 510-515.