Evaluation of a Mobile Preconception Lifestyle Programme in Couples Undergoing in Vitro Fertilisation: a Multicentre Randomized Controlled Trial (PreLiFe-RCT)
Phase: NA
Conditions: Infertility
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
 
Page 1 of 19 
 
 
 
 
Protocol Full Title interventional trial: 
The PreLiFe study: Effectiveness of a mobile preconception lifestyle programme in couples undergoing 
fertility treatment: a multicentre randomized controlled trial 
Protocol Acronym/short title: 
PreLiFe-study: A mobile Preconception Lifestyle programme in couples undergoing Fertility treatment 
 
Version and date of final protocol: 
Version 1: 18/06/2018  
Trial identifiers 
NCT (clinicaltrials.gov): Application after EC approval 
 
Sponsor: 
Name:  
UZ Leuven with funding by FWO-TBM 
Address: 
Herestraat 49, 3000 Leuven, Belgium 
Principal Investigator: 
Name:   
Dr. Sharon Lie Fong 
Address:  
UZ Leuven, Leuven University Fertility Centre, Herestraat 49, 3000 Leuven 
Telephone:  
+3216344975  
 
 
E-mail:   
sharon.liefong@uzleuven.be  
 
Sub investigators: 
PhD Student KU Leuven:  
Name:   
Tessy Boedt 
Address:  
KU Leuven, Chronic Diseases Metabolism and Aging, Herestraat 49, 3000 Leuven 
Telephone:  
+3216329946  
 
 
E-mail:   
tessy.boedt@kuleuven.be 
Sub investigators UZ Leuven / KU Leuven:  
Name:  
Myriam Welkenhuysen 
Address: 
UZ Leuven, Leuven University Fertility Centre, Herestraat 49, 3000 Leuven 
Telephone: 
+3216343544  
 
E-mail:  
myriam.welkenhuysen@uzleuven.be 
Name:  
Dr. Eline Dancet 
Address: 
KU Leuven, Organ Systems, Herestraat 49, 3000 Leuven 
Telephone: 
+3216343651  
 
 
E-mail:  
eline.dancet@kuleuven.be   

 
 
Page 2 of 19 
 
 
Name:  
Prof. Dr. Carl Spiessens 
Address: 
UZ Leuven, Leuven University Fertility Centre, Herestraat 49, 3000 Leuven 
Telephone: 
+3216341312  
 
 
E-mail:  
carl.spiessens@uzleuven.be 
 
Name:  
Prof. Dr. Ir. Christophe Matthys  
Address: 
KU Leuven, Chronic Diseases Metabolism and Aging, Herestraat 49, 3000 Leuven 
Telephone: 
+3216342655  
 
 
E-mail:  
christophe.matthys@uzleuven.be  
 
Name:  
Prof. Dr.  Jan Seghers  
Address: 
KU Leuven, Physical Activity, Sports and Health, Tervuursevest 101, 3001 Leuven 
Telephone: 
 +3216329048   
 
 
E-mail:  
jan.seghers@kuleuven.be  
Name:  
Dr.  Katleen Van Der Gucht  
Address: 
KU Leuven,  Psychology & Educational Sciences, Tiensestraat 102, 3000 Leuven  
Telephone: 
 +3216373183  
 
 
E-mail:  
katleen.vandergucht@kuleuven.be 
 
Sub investigators UZ Antwerpen / U Antwerpen:  
Name:  
Prof. Dr. Diane De Neubourg 
Address: 
UZA, Centre for Reproductive Medicine, Wilrijkstraat 10, 2650 Edegem 
Telephone: 
+3238213684  
 
 
E-mail:  
diane.deneubourg@uza.be  
Sub investigators AZ Diest / UZ Leuven: 
Name:  
Prof. Dr. Karen Peeraer 
Address: 
AZ Diest / UZ Leuven, Leuven University Fertility Centre, Herestraat 49, 3000 Leuven 
Telephone: 
+3216343651  
 
 
E-mail:  
karen.peeraer@uzleuven.be  
Sub investigators AZ Sint Jan Brugge-Oostende: 
Name:  
Dr. Arne Van De Vijver 
Address: 
AZ Sint Jan, Department of Gynaecology, Ruddershove 10, 8000 Brugge 
Telephone: 
+3250452769  
 
 
E-mail:  
Arne.VanDeVijver@azsintjan.be  
Sub investigators Imeldaziekenhuis Bonheiden: 
Name:  
Dr. Sofie Pelckmans 
Address: 
Imeldaziekenhuis Bonheiden, Department of Gynaecology, Imeldalaan 9, 2820 Bonheiden 
Telephone: 
+3215412434  
 
 
E-mail:  
sofie.pelckmans@imelda.be   
 
 
 
 
 
 
 
 
 
 
Date:18/06/2018 

 
 
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Contents 
1. 
Study synopsis ........................................................................................................................................ 4 
2. 
Background and rationale ...................................................................................................................... 5 
3. 
Study objectives and design ................................................................................................................... 6 
3.1 
Study objectives ....................................................................................................................................6 
3.2 
Primary endpoints ................................................................................................................................6 
3.3 
Secondary endpoints ............................................................................................................................6 
3.4 
Study Design and setting ......................................................................................................................6 
4. 
Methods ................................................................................................................................................. 7 
4.1 
Study population and sample size ........................................................................................................7 
4.2 
Interventions (treatment of participants) ............................................................................................8 
4.3 
Study procedures ............................................................................................................................... 10 
Participant timeline ................................................................................................................................... 10 
Selection and recruitment of participants ................................................................................................. 11 
Study intake & baseline measurements (T0)............................................................................................. 11 
Randomisation procedure, blinding and treatment allocation ................................................................. 11 
Follow-up measurements of participants (T1-T4) ..................................................................................... 11 
End of study ............................................................................................................................................... 11 
Withdrawal of participants ........................................................................................................................ 11 
4.4 
Data collection and data management ............................................................................................. 12 
Data collection ........................................................................................................................................... 12 
Data management ..................................................................................................................................... 13 
5. 
Statistical analyses ................................................................................................................................ 14 
6. 
Harms: safety reporting ........................................................................................................................ 15 
7. 
Quality assurance ................................................................................................................................. 15 
8. 
Direct access to source data and documents ....................................................................................... 15 
9. 
Ethics and regulatory approvals ........................................................................................................... 15 
9.1 
Regulation statement ........................................................................................................................ 15 
9.2 
Recruitment and ICF .......................................................................................................................... 16 
10. 
Publication Policy .............................................................................................................................. 16 
11. 
Insurance/Indemnity ........................................................................................................................ 16 
12. 
Financial Aspects .............................................................................................................................. 17 
13. 
References ........................................................................................................................................ 17 
 

 
 
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1. Study synopsis  
Title of clinical trial 
The PreLiFe study: Effectiveness of a mobile preconception lifestyle programme in couples 
undergoing fertility treatment: a multicentre randomized controlled trial 
Principal Investigator 
Dr. Sharon Lie Fong 
Medical condition or 
disease under 
investigation 
Couples undergoing in vitro fertilisation (IVF) with or without Intracytoplasmic sperm injection 
(ICSI) 
Purpose of clinical trial 
Evaluating the added value of a mobile preconceptional lifestyle programme in comparison 
to care as usual in couples undergoing IVF. 
Primary outcome(s) 
 
Cumulative ongoing pregnancy rate (COPR) within 12 months after randomization (i.e. viable 
intrauterine pregnancy of at least 12 weeks duration confirmed on ultrasound scan) and IVF 
discontinuation rate. 
Secondary outcome(s) 
 
Other reproductive outcomes (e.g. implantation and clinical pregnancy), lifestyle parameters 
(diet, physical activity, personal wellbeing), physical health and fertility related quality of life.  
Partners’ support, the adherence to the programme and subjective quality of the programme. 
 
Trial Design 
Multicentre randomized clinical trial 
Sample Size 
460 couples (230 per group) 
Summary of eligibility 
criteria 
 
Infertile heterosexual couples starting a first IVF-cycle (with or without ICSI) 
 
Women ≤ 38 years  
 
Both partners possess a smartphone 
 
Both partners understand and speak Dutch 
 
Written informed consent after been informed on all aspects of the study 
Intervention  
A mobile preconceptional lifestyle programme (PreLiFe app) and treatment specific 
information in addition to care as usual for 12 months or until an ongoing pregnancy has been 
confirmed by ultrasound. 
Control 
 
Attention control: Care as usual + a mobile application only providing the treatment specific 
information of the PreLiFe app including reminders of medication and time of fertility 
treatment appointments for 12 months or until an ongoing pregnancy has been confirmed by 
ultrasound. 
Maximum duration of 
treatment of  a subject 
12 months 
Version and date of final 
protocol (and 
ammendements) 
Version 1 

 
 
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2. Background and rationale 
 
The life plan of the vast majority of people includes having children. Unfortunately many couples are faced 
with fertility problems (prevalence=9%) and decide to turn to fertility treatment, including in vitro fertilisation 
(IVF) with or without Intracytoplasmic Sperm Injection (ICSI)(1). Infertility and its treatment result in a 
considerate emotional and economic burden (2, 3). In Belgium, the IVF-success rate, i.e. a live born baby is 
58.6% after 3 treatment cycles or approximately one year (4). However, during this period, 33 % of the couples 
prematurely discontinue IVF, with the main reason for discontinuation the perceived burden of the treatment 
(4, 5). 
So far no lifestyle support is offered to Belgian IVF-couples although a recent guideline of the European Society 
of Human Reproduction (ESHRE) highlighted the importance for fertility clinics to support their patients (6) 
and the lack of support in  fertility clinics is shown as one out in three IVF-couples seek complementary therapy 
on their own including lifestyle and/or psychosocial support (7, 8).  
The majority of randomized controlled trials on IVF-patients evaluate medical drugs, clinical decisions 
(medication dose, day of embryo transfer) or laboratory procedures. Recently, some observational and 
interventional studies in fertility patients, have shown that improving diet, physical activity and/or personal 
wellbeing, is not only beneficial for patient’s general health but also for their IVF-success rate and treatment 
burden (9-12).  
Observational studies regarding lifestyle factors and fertility treatment 
Couples’ healthy diet, normal body mass index (BMI) and moderate physical activity are associated with 
increased IVF-pregnancy rates (10, 13-16). The evidence regarding the association between couples’ personal 
wellbeing and their IVF-outcome is conflicting as highlighted by two meta-analyses with opposing conclusions 
(17, 18).  
Interventional studies regarding lifestyle support and fertility treatment 
One non-randomized controlled trial (RCT) reports improved diet and physical activity and increased 
pregnancy rates after IVF (p= 0.02) in subfertile women receiving lifestyle education on diet and physical 
activity (9). Regarding personal wellbeing, a recent meta-analysis concluded that psychosocial interventions 
for couples undergoing IVF are effective, both in reducing psychological distress (p=0.001)  and in improving 
clinical pregnancy rates (p<0.001) (19). Mindfulness, as a psychosocial intervention, is a promising method as 
it is an easy access approach. A recent study showed significant improvements in the fertility related quality 
of life of women and in IVF-pregnancy rates after a mindfulness intervention (20).   
Mobile health (mHealth) interventions have been recognised by (inter-)national policies as a promising 
method for promoting healthy behavioural change of both the general population and couples trying to 
conceive (12, 21, 22). A recent Dutch study showed that a personalized mHealth intervention acting on diet 
and other lifestyle factors such as smoking and physical activity in the reproductive population improved their 
diet and lifestyle behaviour and enhanced pregnancy chance. This programme worked better if both partners 
of couples participated (22, 23). Nevertheless, no (mobile) preconceptional lifestyle programme integrating all 
three elements (diet, physical activity and personal wellbeing) and targeting as well subfertile men and women 
i.e. IVF-couples, is routinely available in the fertility setting.   
 
 

 
 
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3. Study objectives and design 
 
3.1 
Study objectives 
 Evaluate the added value of a mobile preconceptional lifestyle programme in comparison to care as usual in 
couples undergoing IVF. 
3.2 
Primary endpoints  
The primary outcome is cumulative ongoing pregnancy rate (COPR) within 12 months after randomization and 
IVF-discontinuation rate. Ongoing pregnancy is defined as a viable intrauterine pregnancy of at least 12 weeks 
duration confirmed on ultrasound scan (24). All pregnancies (Spontaneous and IVF pregnancies) conceived 
within these 12 months are followed up until the 12 weeks ultrasound scan. IVF-discontinuation is described 
as couples undergoing IVF who do not return for a further IVF cycle in our fertility centres after the failure of 
a previous cycle. To calculate our primary endpoint, an ongoing pregnancy within 12 months after 
randomization is counted as a positive event, whereas IVF discontinuation and absence of pregnancy are 
counted as a negative event.  
3.3 
Secondary endpoints 
The secondary outcomes are changes in other reproductive outcomes including transfer outcome, 
implantation and clinical pregnancy, changes in lifestyle parameters (diet, physical activity, personal 
wellbeing), and fertility related quality of life. Additionally, the partners’ support, adherence to the programme 
and the subjective quality of the programme is evaluated. Data collection and analysis of this data is described 
below (4.4 data collection). 
 
3.4 
Study Design and setting 
PreLiFe is a non-commercial multicentre randomised controlled trial in which 5 fertility centres from 3 
provinces in the Flanders region of Belgium are involved: University Hospital of Leuven, University Hospital 
Antwerp, Imelda Hospital Bonheiden, Academic Hospital Diest and Academic Hospital Sint Jan Bruges. The 
intervention group will receive a mobile preconceptional lifestyle programme (PreLiFe app) and fertility 
treatment specific information in addition to care as usual for 12 months or until ongoing pregnancy occurs. 
The control group will receive care as usual and fertility treatment specific information via a mobile app. Due 
to the nature of the intervention participants, study nurses and PhD student are aware of allocations.  Figure 
1 and 2 give an overview of the study. 
 
Figure 1: Study diagram 
 
 

 
 
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4. Methods  
 
4.1 
Study population and sample size  
Eligibility criteria  
The following inclusion criteria are applied: 
 
Infertile heterosexual couples starting a first IVF-cycle (with or without ICSI) with infertility defined as 
the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual 
intercourse 
 
Women aged ≤ 38 years  
 
Both partners possess a smartphone 
 
Both partners understand and speak Dutch 
 
Written informed consent after been informed on all aspects of the study 
 
The following exclusion criteria are applied:  
 
Couples with previous IVF/ICSI treatment cycles  
 
Couples where one of the partners has special dietary requirements including patients that underwent 
bariatric surgery, patients with Coeliac disease, renal disease, or diabetes mellitus 
 
Couples where one of the partners has specific movement’s constraints including Cerebral Palsy, 
Hemiparesis… 
 
Couples starting IVF/ICSI with preimplantation genetic diagnosis (PGD) 
 
Couples using donor gametes or donor embryos  
Sample size calculation   
We calculated sample size for an intention-to-treat analysis of the primary endpoint. The null hypothesis is 
that the cumulative ongoing pregnancy rate is the same in both arms. 
Calculations were performed in collaboration with a statistician from KU Leuven based on literature from the 
field of reproductive medicine regarding: (i) the cumulative IVF-pregnancy rates in Belgium (4), (ii) the IVF-
discontinuation rates in Belgium (4), (iii) data on the impact of  a preconception lifestyle intervention on 
ongoing pregnancy rates (9) and (iv) data on the impact of a self-administered psychosocial intervention on 
IVF-discontinuation rates(25).  
In Belgium, the cumulative pregnancy rate is 58.6 % after 3 cycles or approximately one year. However, 
during this period, 33 % of the couples prematurely discontinue IVF(4). These assumptions result in 
expecting the cumulative ongoing pregnancy rate to be 39 % in the control arm:  (1-0.33)*0.586 = 0.39. For 
the intervention arm, we assume a cumulative pregnancy rate of 61.9% (9) and IVF discontinuation rate of 
15% (25). Hence, we assume that the intervention will mainly influence the likelihood that couples continue 
treatment rather than the true pregnancy rate. Further, in this arm we assume that 20% will stop with the 
intervention but continue with IVF (26). In such cases, we assume that the cumulative pregnancy rate is 58.6 
instead of 61.9%. These assumptions result in expecting the cumulative ongoing pregnancy rate to be 52% in 
the intervention arm: (1-0.15)*(0.2*0.586+0.8*0.619) = 0.52.  
Assuming the primary outcome to be 39% in the control arm and  52% in the intervention arm, we need 230 
couples per arm to have 80% power at 5% alpha for comparing success rates with a likelihood ratio chi-
squared test. Calculations were performed using PASS14 software. 

 
 
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Feasibility 
The multicentre set-up of the study will ensure that a sufficient number of participants can be included. In 
LUFC and AZ Diest on average 250 couples/year are starting IVF. In the University Hospital of Antwerp there 
are 200 couples/year, In Imelda hospital Bonheiden 80 couples/year and in the hospital of Bruges there are 
200 couples/year starting IVF. Estimating that at least 60% of the couples will agree to participate in the trial 
our recruitment will take maximum 15 months. The follow up of our study consist of approximately 12 months 
+ 12 weeks until ongoing pregnancy. We expect many couples undergoing IVF to take part in our intervention 
since this population is highly motivated to achieve a healthy pregnancy and child. 
4.2 
Interventions (treatment of participants) 
Care as usual/ control group 
The care as usual serving as control for this intervention is fertility treatment i.e. IVF with or without ICSI 
according to local protocols for infertility patients. This means no guidance on lifestyle. However, the control 
group will receive treatment specific information, including reminders of injection of human Chorionic 
Gonadotropin (hCG) and time of fertility treatment appointments through a mobile application for 12 months 
or until an ongoing pregnancy has been confirmed by ultrasound. We will give them this information through 
our PreLiFe app to have attention control. 
 
Investigational treatment/ intervention group  
 
The intervention group will receive a mobile preconceptional lifestyle programme (PreLiFe app) in addition to 
care as usual for 12 months or until an ongoing pregnancy has been confirmed by ultrasound. This novel 
PreLiFe app will provide  information, feedback through monitoring and skills training on diet, physical activity 
and personal wellbeing. As in the control group, treatment specific information will also be provided through 
the PreLiFe app to the intervention group, to enhance adherence. This includes reminders of injection of hCG 
and time of fertility treatment appointments 
Theoretical framework of the PreLiFe app 
The intervention will be based on concepts of patient-centredness and the self-determination theory (SDT) 
and designed according to the intervention taxonomy (27). The concept of patient-centred care in our 
intervention is implemented by applying human-centred design meaning the end-user, patient in the current 
situation, is put first in every step of the design and development process (28). This work is conducted by the 
user experience research group of KU Leuven, specialized in human-centred design. The SDT is a theory of 
human motivation to induce healthy lifestyle behaviour. The SDT proposes that when the basic psychological 
needs of autonomy, competence and relatedness are met, an individual’s inherent activity will be supported, 
optimal motivation will be promoted, and positive psychological and behavioural outcomes will be obtained 
(29). Autonomy deals with peoples’ perception of the extent to which they can decide for themselves whether 
or not to behave in a certain way. To promote autonomy, participants can choose themselves on which 
lifestyle topic they want to work in the PreLiFe app. Competence refers to the confidence people have in their 
knowledge and skills, necessary to show the right behaviours. Therefore, our intervention will focus on 
improving confidence and self-efficacy by providing education and exercises on lifestyle factors. Relatedness 
pertains the feeling of connectedness with others, of belonging, therefore we focus on couples in our 
intervention. Both partners will receive the PreLiFe app to enhance partner involvement and relatedness. 
 
Lifestyle content of the PreLiFe app 
The content of the PreLiFe app will focus on diet, physical activity and personal wellbeing as these parameters 
can as well affect general and reproductive health. Additionally treatment specific information is included. 

 
 
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Following the principle of autonomy, subjects can choose themselves on which of these lifestyle topics they 
want to work.  
 
Diet:  
In this part we want to improve food literacy by promoting healthy eating which leads to an overall improved 
dietary quality. Food literacy is an evidence-based model to promote healthy eating, based on developing a 
lifelong healthy relation to food based on four broad domains: food planning, selecting the right foods, food 
preparation and eating (30, 31).Our research team included as well a fifth domain, which is about information 
gathering and interpretation about food. Eating healthy is not just about what you eat or how to cook, but 
also about knowing how to make the right choices, and knowing that planning your food intake can lead to 
healthier choices. This part is guided by experienced members of the Nutrition research group (CEE). Food 
literacy and diet quality will be monitored at baseline using a Food Frequency Questionnaire (FFQ) and 
questions on food literacy. Based on these results participants will receive tailored advice, tips and recipes to 
improve their food literacy and diet quality. 
 
Physical activity:  
The aim of our physical activity part is to stimulate physical activity and reduce  sedentary behaviour as advised 
in the WHO Global recommendations on physical activity for health (63). This part is guided by experienced 
members of the Physical Activity, Sport & Health research group (PASH) of the KU Leuven. Daily steps will be 
monitored using a pedometer (via their own wearable device or via smartphone pedometer applications) and 
structured physical activity will be monitored using a questionnaire and physical activity log. Participants will 
receive a tailored movement plan and tips to improve their daily and moderate physical activity level. 
 
Personal well-being: 
To improve personal wellbeing, short mindfulness based exercises guided by Dr. Edel Maex (Psychiatrist and 
expert in mindfulness) and based on the book “Mindfulness. In de maalstroom van je leven” (62) will be 
provided to participants using audio files and videos. This part is guided by experienced members of the 
psychology research group (Psycho). 
 
Workflow of PreLiFe app 
The PreLiFe app includes a backend server, a secure login and messaging module and a dashboard for the 
health care providers. It consist of a monitoring and a coaching/feedback module. The monitoring module will 
collect information through questionnaires, and will collect information regarding the use of the app. Physical 
activity will be measured via their own wearable device or via a smartphone pedometer application. Together 
with the data from the assessments, it will be send to a backend server and mined to derive personal profiles 
of the participants. Based on these profiles, personalized advice and feedback is offered in the form of 
tips/tricks, education, exercises and personalised goals. The coaching will be offered by using the latest insights 
in user interface and interaction design. A conversational interface will be used to structure the content in the 
app. This type of interface presents the data in a dialogue with the user, like the user is having a conversation 
with the system. This user interface design pattern allows high levels of context awareness and 
personalisation, which is beneficial for long-term engagement and thus adherence. 
Coaching with the PreLife app 
The coaching or feedback module of the PreLife app consists of the following features: 
 
Individual goal setting on one or more of our topics. The patients can prioritize goals themselves 
through the application. 

 
 
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 
Automatically generation of personal recommendations, exercises or tips via e.g. pop-up messages 
based on the monitoring. 
 
Library with links to relevant information, recipes, exercises and FAQ’s in related topics.   
Additionally, a PhD student, who will be trained in motivational interviewing prior to the study will guide the 
patients in the intervention group during the study. In general, this PhD student will contact the couples by 
telephone once every 3 months (1, 4 ,7 and 10 months after randomization). During this contact, along the 
principles of motivational interviewing the participants will be questioned about the lifestyle programme. 
Motivational interviewing is  a method of communication, designed to facilitate natural change (stimulate the 
patient’s intrinsic motivation) (32). We will start with a general open question on their experience with the 
lifestyle programme. If patients want, we can provide feedback on their personal lifestyle parameters, tackle 
perceived barriers and address benefits associated with the PreLife app. Additionally we will provide ‘just in 
time coaching’ when the patients are in need for additional support.  The couples can contact the coach via 
the “contact coach button” in the application and write a short text message. The responsible PhD student will 
reply to this text message through the app within 72 hours (if necessary after consultation of the expert 
(medical doctor, dietician, psychologist…). Only lifestyle related questions will be answered. For fertility 
treatment related questions, the participants are referred to the treating fertility centre. 
 
4.3 
Study procedures  
Participant timeline  
Figure 2 gives an overview of the study procedure from recruitment, study intake and randomisation till end 
of follow-up period. Due to the nature of the fertility treatment process our study will consist of 2 different 
phases. Phase 1, where all patients are undergoing a fresh IVF cycle and phase 2 with possible pregnancies, 
follow-up cryo cycles (if embryos are available after freezing/thawing) and next fresh cycles which differs in 
time for all couples (see figure 2).   
 
 
Figure 2: Time line of PreLiFe study 
 

 
 
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Selection and recruitment of participants  
The treating physician will introduce the study to eligible couples at the fertility consultation. If couples are 
interested to participate they are referred to an experienced study nurse present at the fertility consultation. 
This recruiter will explain the PreLiFe study more in depth and provide the couples with an informed consent. 
Study intake & baseline measurements (T0) 
Consenting couples are invited for study intake. The timing of this intake session is fitted in the conventional 
appointment prior to start of an IVF to enable easy access. During this standard appointment, couples will 
receive practical information on their IVF treatment including the use of the medication. The study intake will 
be conducted by an experienced study nurse. The study intake consists of the following elements: 
- Addressing additional questions of couples on the study. 
-Collecting baseline measurements (see data collection). 
- Retrieving patient’s medical and fertility related history from medical records. 
-Randomization 
-Installing and explaining PreLiFe app. 
 
Randomisation procedure, blinding and treatment allocation  
The randomization of couples will take place after eligibility check and informed consent approval. For the 
randomisation, a computer generated randomisation procedure via a password-protected website will be 
used. The computer generated randomisation scheme is 1:1 by trial arm and stratified by centre. In view of 
the nature of the intervention, participants, study nurses and the PhD student are aware of allocations. In this 
RCT only the statistician will be blinded. 
Follow-up measurements of participants (T1-T4) 
At baseline and 3, 6, 9 and 12 months after randomisation, the study nurse performs the follow up 
measurements which consists of web-based questionnaires on lifestyle behaviour and measurements of 
physical health including weight and waist circumference (see data collection and table 1). The follow-up 
measurements are planned simultaneously with regular appointments during the fertility treatment. In our 
group, we are used to measure these outcomes, to work with validated instruments and scales. The study 
nurses are trained by experienced researchers to adequately measure these parameters; nevertheless, 
Standard Operating Procedures (SOP) will be available. Reminders will be sent to participants to ensure 
attendance at the follow-up study days and prevent drop-out of the study. Moreover, the study nurse will 
register fertility treatment and the course and outcome of subsequent pregnancies for a period up to 12 
months after randomization. 
 
End of study  
The study ends 12 months after randomization or if an ongoing pregnancy occurs within 12 months after 
randomization (i.e. viable intrauterine pregnancy of at least 12 weeks duration confirmed on ultrasound scan). 
All pregnancies occurring within these 12 months are followed up until the 12 weeks ultrasound scan. At the 
end of the study we will perform a post study measurement, were we will measure changes in lifestyle 
behaviour since the last measurement and the subjective quality of the app in the intervention group.  
 
Withdrawal of participants 
Participants can withdraw from the study at any time for any reason if they wish to do so without any 
consequences. Patients who drop out of the study will be treated according to local protocols for infertility 
patients. 
 

 
 
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4.4 
Data collection and data management 
Data collection 
Table 1 gives an overview of the different measurements and time points during the study.  
Data will be collected from medical records, web-based questionnaires, physical assessments and the 
PreLiFe app itself. All questionnaires can be found in appendix 1. 
 
 
Data collected at baseline:  
Socio-demographic data (age, ethnicity, level of education and work situation), medical history and fertility 
related history (indication, type and duration of infertility).  These data are obtained from questionnaires 
and medical records and will be transferred immediately to the eCRF. 
Data collected at baseline and follow-up every 3 months:  
General Lifestyle behaviour: a web-based questionnaire based on the questionnaires of the INTERACT study 
is used to evaluate if the couples smoke, drink alcohol, take supplements or follow other complementary 
therapy (33).  
Diet (quality): A validated food frequency questionnaire (FFQ) with questions on frequency and portion size 
of food items is used to evaluate dietary pattern and diet quality (34).  Diet quality is an index to reflect 
compliance with the food based dietary guidelines based on the dietary guidelines of the Belgian Superior 
Health Council (35). 
Physical activity: Self-reported physical activity is measured and classified as low, moderate or high 
physically active, using the International Physical Activity Questionnaire (IPAQ). The IPAQ is a reliable and 
validated instrument for monitoring physical activity in population health surveillance systems (36). In the 
intervention group, via a pedometer in the PreLife app, the daily steps are monitored as well. 
Personal wellbeing:  The Depression, anxiety and stress scale (DASS-21) is a validated and reliable scale to 
measure symptoms of emotional distress, anxiety and depression (37).  
Fertility related quality of life will be measured using the FertiQOL. This is a reliable and valid tool in 
measuring QOL in couples facing infertility (38).   
Physical health will be assessed by measuring the following parameters:  
Weight and height is measured to calculate the body mass index of couples (BMI). Couples are weighted 
wearing light clothes and no shoes on a calibrated scale. The height is measured without shoes on a 
stadiometer. The measurement of height is only performed at baseline. 
Table 1: Measurements and time points of PreLiFe Study 
Method or sample used 
Baseline 3 
6 
9 
12 
Every 
General Lifestyle
Supplement use, smoking, complementary therapy use  
Questions (Q)
x
x
x
x
x
Diet 
Diet (quality)
FFQ (Q)
x
x
x
x
x
Physical activity (self reported)
IPAQ (Q)
x
x
x
x
x
Physical activity (objective) **
Pedometer in app
x
x
x
x
x
x
Personal Wellbeing
Stress, depression and anxiety
DASS-21 (Q)
x
x
x
x
x
QOL
Fertility related QOL
FERTIQOL (Q)
x
x
x
x
x
Fertility treatment
Medical records
x
x
x
x
x
x
Pregnancy follow-up
Medical records
x
x
x
x
x
IVF-discontinuation
Medical records
x
x
x
x
x
Weight
Scale (twice) 
x
x
x
x
x
Height
Stadiometer (twice)
x
Waist circumference
Tape (twice)
x
x
x
x
x
Socio-demographic data 
Questionnaire/Medical records x
Past/current medical and fertility history
Medical records 
x
 Support
Partners support **
Q 
x
x
x
x
Adherence
Adherence to the programme **
Q + app data 
x
x
x
x
Quality
Subjective quality of the application * **
MARS subscale (Q)
x
Measurements 
Phase 1
Phase 2
Lifestyle parameters 
Physical activity
Baseline data
* Measured at the end of the study  ** Only measured in intervention group 
Other 
Fertility treatment and reproductive outcomes 
IVF-success
Physical examinations
Physical Health

 
 
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Waist circumference: Measured according to the International Standards for Anthropometric Assessment 
with a SECA measuring tape to estimate abdominal fat.  
Data on fertility treatment and reproductive outcomes are obtained from medical records. The study nurse 
will register fertility treatment and the course and outcome of subsequent IVF and spontaneous pregnancies 
for a period up to 15 months after randomization. Following data is collected: 
 
Self-reported start time of active pregnancy wish 
 
Number and type of fertility treatment (i.e. IVF/ICSI) 
 
Date of stimulation, aspiration, thawing and embryo transfer (or if cancelled, date and reason of 
cancellation) 
 
Transfer outcome (Detection of hCG) 
 
Implantation defined as the presence of a gestational sac (intra and extra uterine gestational sac) 
(39). 
 
Clinical pregnancy with fetal heart beat defines as a pregnancy diagnosed by ultrasound or clinical 
documentation of at least one fetus with a discernible heartbeat (39). 
 
Ongoing pregnancy defined as a viable intrauterine pregnancy of at least 12 weeks duration 
confirmed on ultrasound scan (24). 
 
IVF-discontinuation described as couples undergoing IVF who do not return for a further IVF cycle in 
our fertility centres after the failure of a previous cycle (40). 
 
At the follow-up moments in the intervention group, we additionally collect data on:   
Adherence to the programme by evaluating the % of patients using the PreLife app in combination with a 
question on their motivation of (not) using the PreLife app. 
Social support: a short questionnaire to evaluate if they feel supported by their partner in maintaining a 
healthy lifestyle (41). 
 
Data collected at the end of the study:   
Next to fertility treatment and follow-up of pregnancy data, data on the subjective quality of the PreLiFe app 
is collected at the end of the study in the intervention group. 
Subjective quality of the application is assessed with a shortened version of the subjective quality subscale 
of the Mobile App Rating Scale (MARS) (40). 
Data management 
Medical record data, and anthropometric data will be entered and stored by the study nurse in a good clinical 
practice compliant Electronic Data Capturing (eCRF) system developed by our IT-specialist, Steve De Backer, 
ESAT, KU Leuven. In case of no database access, data will be entered on paper CRF and subsequently entered 
into the data system when access is possible. Data from questionnaires will be collected using Qualtrics, a 
secure website. A link to the questionnaires will be sent by email to the participants at baseline at 3, 6,9,12 
months after randomization and at the end of the study. Deviation of 2 weeks before and after the planned 
time point is allowed. Questionnaire data will be exported and stored in the eCRF. The data from the mobile 
application (i.e. use of application and physical activity from pedometer) can be retrieved from the secured 
website of PreLiFe of which only the research team and the participants have access. 

 
 
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5. Statistical analyses  
 
 
Descriptive statistics for baseline values in the two arms will be presented. There will be no tests of statistical 
significance for differences between the two arms as these are randomised groups.The statistical analysis will 
be performed according to the intention-to-treat principle. This implies that couples will be analysed according 
to the arm to which they were randomized, and that patients who withdraw from the study or discontinue IVF 
treatment will be included.  The withdrawal rate of the study will be assessed and compared between the two 
arms.  
 
Primary study parameters 
The primary outcome is cumulative ongoing pregnancy rate (COPR) within 12 months after randomization (i.e. 
viable intrauterine pregnancy of at least 12 weeks duration confirmed on ultrasound scan) and IVF 
discontinuation rate.  To calculate this, an ongoing pregnancy conceived within 12 months after randomization 
is counted as a positive event, whereas IVF discontinuation and absence of pregnancy are counted as a 
negative event. The COPR in both groups will be compared using logisitic regression models that allow to 
control for predictive variables including both partners’ BMI and age.  Analysis will be according to intention 
to treat. Odds ratios with 95% confidence intervals will be reported. A p-value <0.05 will be used to determine 
statistical significance for the intervention. Additionally, Cumulative incidences of ongoing pregnancy and IVF 
discontinuation will be described in the intervention and control group.  
 
Secondary study parameters 
Binary secondary outcomes are differences in other fertility and pregnancy outcomes such as implantation 
and clinical pregnancy between the intervention and control group. These require similar analyses as the 
primary outcome. Additionally we will evaluate changes in lifestyle parameters including changes in the 
dietary pattern, physical activity level, personal wellbeing, physical health and fertility related quality of life 
over time and we will evaluate the differences between the intervention and control group in these 
parameters. Self-reported questionnaires will be processed according to the standard for that test. Mixed 
models for repeated measurements (MMRM) will be used to evaluate treatment, time and interactive 
effects on continuous secondary outcomes. The determination of statistical significance is not central to the 
analysis of secondary endpoints, yet nominal p-values may be reported. 
 Additional parameters measured in the intervention group are the partner’s support, the adherence to the 
programme and subjective quality of the application. Descriptive analysis will be conducted on these 
parameters.  
 
Missing data 
For the primary endpoint, we do not expect missing data. For the binary secondary endpoints, the same 
argument applies. For continuous secondary endpoints, MMRM is used which is consistent under the 
‘missing at random’ assumption and in line with the intention-to-treat principle (42). 
 
A fully statistical analysis plan will be written in collaboration with the statistician prior to any analysis being 
undertaken.  

 
 
Page 15 of 19 
 
 
6. Harms: safety reporting 
 
Throughout the whole PreLiFe study, participant's health and safety will be warranted. All solicited and 
spontaneously reported adverse events and other unintended effects of the PreLiFe study will be collected, 
assessed, reported and managed according to good clinical practice guidelines (GCP).  The investigator shall 
report all serious adverse events immediately, after first knowledge to the sponsor. If necessary, the 
immediate report shall be followed by detailed, written reports. The sponsor shall keep detailed records of 
all adverse events which are reported to him by the investigators. For reported deaths of a subject, which is 
highly unlikely in this study, the investigator shall supply the sponsor and the accredited ethics committee 
with any additional information requested. 
Regarding follow-up of those adverse events and serious adverse reactions the principal investigator will 
take all reasonable measures, in consultation with the sponsor, to protect subjects at risk following the 
occurrence of such events. 
 
The sponsor will suspend the study if there is sufficient ground that continuation of the study will jeopardize 
the participant’s health or safety. The study will be suspended pending further review by the accredited EC. 
The investigator will take care that all study participants are kept informed.  
7. Quality assurance 
 
Standard operating procedures (SOP’s) on all the previously mentioned procedures will be available to 
maintain quality assurance.  
8. Direct access to source data and documents 
 
The investigator(s) will permit study related monitoring,  EC review and regulatory inspections (where 
appropriate) by providing direct access to source data and other documents (i.e. study visit checklists, SOP’s 
etc.). 
9. Ethics and regulatory approvals 
 
9.1 Regulation statement 
The PreLiFe study will be conducted in compliance with the principles of the Declaration of Helsinki 
(Fortaleza, Brazil, October 2013), the principles of GCP and in accordance with all applicable regulatory 
requirements. 
The study protocol and all other study-related information will be submitted to the Ethics Committees of the 
Participating sites and the national competent authorities where applicable, in order to obtain prior approval 
before the study is initiated, unless such submission to the Ethics Committee is not required by applicable 
national legislation or in the event of a waiver for submission has been granted. Any subsequent protocol 
amendments will be submitted to the appropriate Ethics Committees and national Regulatory Authorities for 
approval. 

 
 
Page 16 of 19 
 
 
The study can and will be conducted only on the basis of prior informed consent by the participants, to 
participate in the Study. The participating sites shall obtain a signed informed consent form (ICF) for all 
participants prior to their enrolment and participation in the study in compliance with all applicable laws, 
regulations and the approval of the (local) Ethics Committee, if required. The participating sites shall retain 
such ICFs in accordance with the requirements of all applicable regulatory agencies and laws. 
The Investigators and the participating sites will treat all information and data relating to the study disclosed 
to participating sites and/or investigators in this study as confidential and shall not disclose such information 
to any third parties or use such information for any purpose other than the performance of the study. 
The collection, processing and disclosure of personal data, such as patient health and medical information is 
subject to compliance with applicable personal data protection and the processing of personal data 
(Directive 95/46/EC and Belgian law of December 8, 1992 on the Protection of the Privacy in relation to the 
Processing of Personal Data). 
The data will be coded, which means that there continues to be a link between the data and the individual 
who provided it. The research team is obligated to protect the data from disclosure outside the research 
team according to the terms of the research protocol and the informed consent document. The subject’s 
name or other identifiers will be stored separately from their research data and replaced with a unique code 
to create a new identity for the subject.  
9.2 Recruitment and ICF  
Eligible patients will be informed about the study by the gynaecologist, the attending resident or the fertility 
doctor. These patients will be invited for additional counselling by a research nurse, to ensure that they are 
fully informed on the nature of the study by means of both oral and written information. Patients who agree 
to participate will be asked to sign a written informed consent of which they will receive a copy. The partner 
of the patient will also be asked to sign the written informed consent. Randomisation will only be performed 
after receiving informed consent. 
10. 
Publication Policy 
 
It is anticipated that the results of the overall study shall be published in an international peer reviewed 
journal. The parties agree that publications or presentations of any of the results from the study shall be in 
accordance with accepted scientific practice, academic standards and customs. Authorship to publications 
will be determined in accordance with the requirements published by the International Committee of 
Medical Journal Editors and in accordance with the requirements of the respective medical journal.  
11. 
Insurance/Indemnity 
 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, the 
sponsor shall assume, even without fault, the responsibility of any damages incurred by a study participant 
and linked directly or indirectly to the participation to the study. The sponsor shall enter into an insurance 
agreement in order to cover the liability for any damages incurred by the Belgian study participants. 

 
 
Page 17 of 19 
 
 
12. 
Financial Aspects 
 
This research project is funded by the FWO as part of the TBM programme (Applied Biomedical Research 
with a Primary Social finality). 
13. 
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