Heart Rate Variability Biofeedback (HRVB) With Mothers Who Delivered a Preterm Infant: A Feasibility Study
Phase: NA
Conditions: Premature Birth, Maternal Distress - Delivered, Stress, Anxiety
Sponsor: University of Lausanne Hospitals

 
 
Heart Rate Variability Biofeedback (HRVB) With Mothers Who 
Delivered a Preterm Infant: A Feasibility Study 
 
 
 
 
NCT03565874 
 
 
 
24.07.2019 
 
 

 
Clinical Protocol template for Investigator initiated trials (IIT) 
 
Clinical Study Protocol 
 
 
Heart rate variability biofeedback (HRVB) with mothers having a 
preterm infant: A feasibility study 
 
 
Short title: Heart rate variability biofeedback and prematurity 
 
 
Study Type: 
Other clinical trial  
Study Categorisation: 
Risk category according to LHR (A) 
Study Registration: 
Clinicaltrials.gov and Kofam.ch 
Study Identifier: 
2017-02199 
Sponsor: 
Prof. Kerstin von Plessen 
Principal Investigator:   
Sébastien Urben  
Investigational Product: 
Heart rate variability biofeedback 
 
 
 
 

Table of Contents 
ABBREVIATIONS ................................................................................................................................... 6 
STUDY SCHEDULE ................................................................................................................................ 7 
1. 
ETHICAL AND REGULATORY ASPECTS .................................................................................... 8 
1.1 
Study registration .......................................................................................................................... 8 
1.2 
Categorization of study.................................................................................................................. 8 
1.3 
Competent Ethics Committee (CEC) ............................................................................................ 8 
1.4 
Competent Authorities (CA) .......................................................................................................... 8 
1.5 
Ethical Conduct of the Study ......................................................................................................... 8 
1.6 
Declaration of interest ................................................................................................................... 8 
1.7 
Patient Information and Informed Consent ................................................................................... 8 
1.8 
Participant privacy and confidentiality ........................................................................................... 9 
1.9 
Early termination of the study ........................................................................................................ 9 
1.10 Protocol amendments ................................................................................................................... 9 
2. 
BACKGROUND AND RATIONALE ................................................................................................ 9 
2.1 
Background and Rationale ............................................................................................................ 9 
2.2 
Investigational Product (treatment, device) and Indication ......................................................... 10 
2.3 
Clinical Evidence to Date ............................................................................................................ 10 
2.4 
Dose Rationale / Medical Device: Rationale for the intended purpose in study (pre-market 
MD) 11 
2.5 
Explanation for choice of comparator (or placebo) ..................................................................... 11 
2.6 
Risks / Benefits ............................................................................................................................ 11 
2.7 
Justification of choice of study population ................................................................................... 11 
3. 
STUDY OBJECTIVES ................................................................................................................... 11 
3.1 
Overall Objective ......................................................................................................................... 11 
3.2 
Primary Objective ........................................................................................................................ 11 
3.3 
Secondary Objectives ................................................................................................................. 12 
3.4 
Safety Objectives ........................................................................................................................ 12 
4. 
STUDY OUTCOMES ..................................................................................................................... 12 
4.1 
Primary Outcome ........................................................................................................................ 12 
4.2 
Secondary Outcomes .................................................................................................................. 12 
4.3 
Safety Outcomes ......................................................................................................................... 12 
5. 
STUDY DESIGN ............................................................................................................................ 12 
5.1 
General study design and justification of design ......................................................................... 12 
5.2 
Methods of minimising bias ......................................................................................................... 12 
6. 
STUDY POPULATION .................................................................................................................. 12 
6.1 
Eligibility criteria ........................................................................................................................... 12 
6.2 
Recruitment and screening ......................................................................................................... 13 
6.3 
Criteria for withdrawal / discontinuation of participants ............................................................... 13 
7. 
STUDY INTERVENTION ............................................................................................................... 13 
7.1 
Identity of Investigational Products (medical device) .................................................................. 13 
7.1.1 Experimental Intervention (medical device) ........................................................................ 13 
7.1.2 Storage Conditions.............................................................................................................. 13 
7.2 
Administration of experimental and control interventions ........................................................... 13 
7.2.1 Experimental Intervention ................................................................................................... 13 
7.3 
Compliance with study intervention ............................................................................................. 14 

7.4 
Data Collection and Follow-up for withdrawn participants .......................................................... 14 
7.5 
Trial specific preventive measures .............................................................................................. 14 
7.6 
Concomitant Interventions (treatments) ...................................................................................... 14 
7.7 
Medical Device Accountability ..................................................................................................... 14 
7.8 
Return or Destruction of Medical Device..................................................................................... 14 
8. 
STUDY ASSESSMENTS ............................................................................................................... 14 
8.1 
Study flow chart(s) / table of study procedures and assessments .............................................. 14 
8.2 
Assessments of outcomes .......................................................................................................... 15 
8.2.1 Assessment of primary outcome ......................................................................................... 15 
8.2.2 Assessment of secondary outcomes .................................................................................. 15 
8.2.3 Assessment of safety outcomes ......................................................................................... 15 
8.2.4 Assessments in participants who prematurely stop the study ............................................ 15 
8.3 
Procedures at each visit .............................................................................................................. 16 
8.3.1 Information / consent visit ................................................................................................... 16 
8.3.2 Pre-intervention assessment .............................................................................................. 16 
8.3.3 HRVB training ..................................................................................................................... 16 
9. 
SAFETY ......................................................................................................................................... 16 
9.1 
Medical Device Category A studies ............................................................................................ 16 
9.1.1 Definition and Assessment of safety related events ........................................................... 16 
9.1.2 Reporting of Safety related events ...................................................................................... 16 
9.1.3 Safety events detected by chance ...................................................................................... 16 
10. STATISTICAL METHODS ............................................................................................................. 16 
10.1 Hypothesis ................................................................................................................................... 16 
10.2 Determination of Sample Size ..................................................................................................... 17 
10.3 Statistical criteria of termination of trial ....................................................................................... 17 
10.4 Planned Analyses ........................................................................................................................ 17 
10.4.1 Datasets to be analysed, analysis populations ................................................................... 17 
10.4.2 Primary Analysis ................................................................................................................. 17 
10.4.3 Safety analysis .................................................................................................................... 17 
10.5 Handling of missing data and drop-outs...................................................................................... 17 
11. QUALITY ASSURANCE AND CONTROL .................................................................................... 17 
11.1 Data handling and record keeping / archiving ............................................................................. 17 
11.1.1 Specification of source documents ..................................................................................... 17 
11.1.2 Record keeping / archiving ................................................................................................. 17 
11.2 Data management ....................................................................................................................... 17 
11.2.1 Data Management System ................................................................................................. 18 
11.2.2 Data security, access and back-up ..................................................................................... 18 
11.2.3 Analysis and archiving ........................................................................................................ 18 
11.3 Monitoring .................................................................................................................................... 18 
11.4 Audits and Inspections ................................................................................................................ 18 
11.5 Confidentiality, Data Protection ................................................................................................... 18 
11.6 Storage of biological material and related health data ................................................................ 18 
12. FUNDING AND SUPPORT ............................................................................................................ 18 
12.1 Funding ....................................................................................................................................... 18 

13. INSURANCE .................................................................................................................................. 18 
14. REFERENCES ............................................................................................................................... 18 
15. APPENDICES ..............................................................................ERREUR ! SIGNET NON DEFINI. 
 
 
 

ABBREVIATIONS 
Provide a list of abbreviations used on the protocol - to be completed 
 
AE 
Adverse Event  
CA 
Competent Authority (e.g. Swissmedic) 
CEC 
Competent Ethics Committee 
CRF 
Case Report Form  
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin) 
GCP 
Good Clinical Practice  
Ho 
Null hypothesis 
H1 
Alternative hypothesis 
HF  
High Frequency 
HRA 
Federal Act on Research involving Human Beings 
HR 
Heart Rate 
HRV 
Heart Rate Variability 
HRVB 
Heart Rate Variability Biofeedback 
IMP 
Investigational Medicinal Product 
IIT 
Investigator-initiated Trial 
ISO 
International Organisation for Standardisation 
ITT 
Intention to treat 
KlinV 
Verordnung über klinische Versuche in der Humanforschung (in English: ClinO, in 
French OClin) 
LRH 
Loi fédérale relative à la recherche sur l’être humain 
MD 
Medical Device 
OClin 
Ordonnance sur les essais cliniques dans le cadre de la recherche sur l'être humain 
(in German : KlinV, in English : ClinO) 
PI 
Principal Investigator  
RMSDD 
Root-mean square differences of ssuccessive R-R intervals  
RSA 
Respiratory sinus arrhythmia 
 
 
 

STUDY SCHEDULE  
 
Study Periods 
 
Screening 
Treatment, Intervention Period 
Visit 
 
Pre 
Middle 
Post 
Time in days postnatal 
3 ± 2 
7  
14 ± 3 
21 ± 3 
Patient 
Information 
and 
Informed Consent 
x 
 
 
 
Demographics 
x 
 
 
 
Medical History 
x 
 
 
 
In- /Exclusion Criteria 
x 
x 
 
 
Medical Device 
 
x 
x 
x 
Primary 
outcomes: 
acceptability of the protocol, 
acceptability 
of 
the 
intervention, 
compliance, 
satisfaction 
with 
the 
intervention. 
 
 
 
x 
Secondary outcomes: heart 
rate 
variability, 
perceived 
stress, anxiety, depression.  
 
x 
 
x 
Concomitant Therapy 
 
x 
x 
x 
Adverse Events 
 
x 
x 
x 
 
 
 
 
 

1. ETHICAL AND REGULATORY ASPECTS  
The decision of the Competent Ethics Committee (CEC) concerning the conduct of the study will be 
made in writing to the Sponsor-Investigator before commencement of this study. The clinical study can 
only begin once approval from all required authorities has been received. Any additional requirements 
imposed by the authorities shall be implemented. 
1.1 Study registration  
The study will be registered on two database: an international one (www.clinicaltrials.gov) and a national 
one (www.kofam.ch). 
1.2 Categorization of study  
This feasibility study conforms to a clinical trial of medical devices under Category A as the medical 
device bears a conformity marking and it is used in accordance with the instructions. 
1.3 Competent Ethics Committee (CEC)  
The responsible investigator ensures that approval from an appropriately constituted CEC is sought for 
the clinical study. Duties and allowed time frame (all changes in the research activity and all 
unanticipated problems involving risks to humans; including in case of planned or premature study end 
and the final report) will be reported. No changes will be made to the protocol without prior Sponsor and 
CEC approval, except where necessary to eliminate apparent immediate hazards to study participants. 
Premature study end or interruption of the study will be reported within 15 days. The regular end of the 
study is reported to the CEC within 90 days, the final study report shall be submitted within one year 
after study end. Amendments are reported according to chapter 2.10. 
1.4 Competent Authorities (CA)  
Not applicable  
1.5 Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, in 
case of medical device: the European Directive on medical devices 93/42/EEC and the ISO Norm 14155 
and ISO 14971, the Swiss Law and Swiss regulatory authority’s requirements. The CEC and regulatory 
authorities will receive annual safety and interim reports and be informed about study stop/end in 
agreement with local requirements.  
Add other local requirements in case of medical device or international studies. 
1.6 Declaration of interest  
No conflict of interest to declare 
1.7 Patient Information and Informed Consent 
The investigators will explain to each participant the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits and any discomfort it may entail. Each 
participant will be informed that the participation in the study is voluntary and that she may withdraw 
from the study at any time and that withdrawal of consent will not affect her subsequent medical 
assistance and treatment. The participant must be informed that her medical records may be examined 
by authorized individuals other than their treating physician. All participants for the study will be provided 
a participant information sheet and a consent form describing the study and providing sufficient 
information for participant to make an informed decision about their participation in the study. One day 
will be given to the participants to decide whether to participate or not. The patient information sheet 
and the consent form will be submitted to the CEC (submitted separately) to be reviewed and approved. 
The formal consent of a participant, using the approved consent form, must be obtained before the 
participant is submitted to any study procedure.   
The participant should read and consider the statement before signing and dating the informed consent 
form, and should be given a copy of the signed document. The consent form must also be signed and 
dated by the investigator (or his designee) and it will be retained as part of the study records. 
 

1.8 Participant privacy and confidentiality  
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising subject 
identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorised representatives of the Sponsor (-Investigator) or an ethics 
committee may require direct access to parts of the medical records relevant to the study, including 
participants’ medical history. 
1.9 Early termination of the study  
The Sponsor-Investigator may terminate the study prematurely according to certain circumstances, for 
example: 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
when the safety of the participants is doubtful or at risk, respectively, 
 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise,  
 
early evidence of benefit or harm of the experimental intervention.   
1.10 Protocol amendments 
Substantial amendments are only implemented after approval of the CEC respectively. Under 
emergency circumstances, deviations from the protocol to protect the rights, safety and well-being of 
human subjects may proceed without prior approval of the sponsor and the CEC. Such deviations shall 
be documented and reported to the sponsor and the CEC as soon as possible.  
2. BACKGROUND AND RATIONALE  
2.1 Background and Rationale  
 
Preterm birth and stress 
Preterm births (<37 weeks of gestational age) constitute a public health issue as they compromise 
children’s developmental outcomes (Behrman & Butler, 2007; Sansavini et al., 2011). A growing number 
of preterm births (Brady et al., 2006) is observed, alongside with higher survival rates (Fanaroff et al., 
2007). In Switzerland, preterm births referred to 7.1% of all live births (N=86’559) in 2016 (OFS, 2016). 
Preterm born children’s vulnerability and uncertainty about future development often lead to 
psychological distress and anxiety in their parents, particularly in mothers (Holditch-Davis et al., 2009). 
Furthermore, such adverse experience is reported to lead to posttraumatic stress symptoms (i.e., re-
experiencing of the traumatic event, avoidance of reminders, negative cognitions and mood, and 
hyperarousal) and to other mental health problems (Treyvaud et al., 2010). For instance, 40% of mothers 
of preterm children experienced post-traumatic symptoms at 6 months of infant corrected age (Holditch-
Davis et al., 2003) and 26% still experience post-traumatic symptoms at 18 months of infants corrected 
age (Pierrehumbert et al., 2003). Taken together, these results suggest that a preterm delivery is an 
adverse life event putting mothers at risk for psychological distress.  
 
Physiological aspects of stress  
A widely recognized model apprehending the stress phenomenon is the “allostatic load model” 
(McEwen, 1998). Allostasis refers to dynamic responses aiming at maintaining stability in time (Sterling 
& Eyer, 1988). This is sustained by multiple, non-linearly interconnected systems such as the 
autonomous nervous system (indexed by heart rate [HR] or HRV) that are closely interrelated to 
psychological processes (McEwen, 1998). However, in case of acute or chronic stress, such as a 
preterm birth, the overwhelmed organism may display inappropriate responses that could engender 
deleterious long-term physical effects called “allostatic loads” (McEwen & Stellar, 1993). The allostatic 
load is known to put individuals at risk for physical and mental illnesses.  
HR and HRV (the variability in consecutive beat-to-beat intervals as displayed in an electrocardiogram) 

are indicators of the functioning of the autonomous nervous system and thus of physiological stress 
(Michels et al., 2013). Both indicators allow apprehending the synergy between the brain and 
cardiovascular control systems by adapting responses to the ever-changing environment (Bates et al., 
2011). HR and HRV are thus simple, non-invasive measures to assess stress level and stress reactions. 
High HRV has been related to higher adaptability of the individuals towards its environment and thus is 
linked to reduced stress and anxiety (Goessl et al., 2017) as well as to less negative emotions during 
acute stress (Khodik, 2013). By contrast low HRV has been related to internalizing symptoms 
(Beauchaine, 2001, 2012, 2015; Beauchaine & Thayer, 2015; Porges, 2007; Vasilev et al., 2009) such 
as anxiety (Hastings et al., 2008; Kemp et al., 2014; Thayer et al., 1996), depression (Rottenberg, 2007; 
Rottenberg et al., 2005; Rottenberg et al., 2002), and posttraumatic stress disorder (Cohen et al., 1999).  
 
HRVB – an intervention program on HRV 
  
HRVB programs have been demonstrated to be efficient in increasing HRV and thus in reducing stress 
and anxiety (Goessl et al., 2017), see below section 3.3 for details. The psychophysiological coherence 
model (McCraty, 2011; McCraty et al., 2009; McCraty et al., 2006; McCraty & Childre, 2010; McCraty et 
al., 2012) allows understanding the positive effect of HRVB. It describes a mode of functioning 
characterized by specific positive patterns of physiological activities (i.e., coherence) expressed in 
psychological and behavioral systems. More specifically, HRVB influences HRV parameters  through 
the synchronization of the phase relationship between HR oscillations and breathing (at around 0.1 Hz 
or six breaths per minute) which in turn tends to increase respiratory sinus arrhythmia (RSA) amplitude 
and, consequently, to heighten the amplitude of HRV (Lehrer & Gevirtz, 2014). Because of increased 
RSA amplitude, this synchronization also tends to optimize gas exchange at the alveoli and thus to 
maximize the oxygen supply to the organism (Hayano et al., 1996). These changes may play the role 
of a virtuous circle, in the sense that the positive changes in HRV due to the synchronization of HR and 
breathing may act as a positive feedback loop that further increases HRV (Lehrer & Gevirtz, 2014). 
Moreover, the baroreflex – the reflex that helps regulate blood pressure fluctuations by increasing HR 
when blood pressure falls and conversely by decreasing it when blood pressure rises – is maximally 
stimulated by the synchronization (i.e., coherence) of HR and breathing (Lehrer et al., 2003). It has been 
demonstrated that, probably due to neuroplasticity, training the baroreflex with HRVB sessions leads to 
increases in baroreflex gain at rest (Lehrer et al., 2003). In this regard, HRVB may produce positive 
long-term effects on the organism. 
2.2 Investigational Product (treatment, device) and Indication  
The medical device will be the Nexus product from the Mindmedia company allowing to do biofeedback 
on HRV. The device measures HRV and respiration rate and provides a feedback to the user regarding 
how the breathing rhythm changes HRV. HR will be captured by a finger sensor; the Biotrace software 
will be used to visualize changes in HRV.  
The device will be used with authorisation and in conformity with the intended purpose. The Swiss 
representative, Dr. Eva Otzen, will train the personnel to use the Medical Device (MD). The project’s 
principal investigator, Sébastien Urben, has also received HRVB training by Swiss HRVB specialists : 
Charly Cungy (Clinique de Belmont) and Jérôme Favrod (Clinique de la Source).   
2.3 Clinical Evidence to Date  
Qualitative reviews indicate the effectiveness of HRVB in reducing stress and anxiety (Futterman & 
Shapiro, 1986; Gevirtz, 2013; Tabachnick, 2015). Earlier this year, a meta-analysis (Goessl et al., 2017) 
identified 24 studies (including 484 participants) using a HRVB program in order to reduce stress and 
anxiety. HRVB programs varied in intensity ranging from 1 to 50 sessions. Large effect sizes (Hedge’s 
g=.83) were observed both in group comparisons (HRVB vs control conditions such as treatment as 
usual, waiting list, shame-biofeedback, and progressive muscle relaxation) and in time effects (pre-post 
intervention, Hedge’s g=.81). These results indicate that HRVB is a promising intervention program in 
increasing HRV and thus decreasing stress and anxiety.  
Considering using a HRVB program in order to reduce maternal stress due to a preterm delivery, to 
date, there are no existing studies. However, a pilot study using a HRVB program in women (n=15) 
suffering from perinatal depression indicated reductions in anxiety and depression symptoms (Beckham 
et al., 2013), suggesting promising effects in the perinatal period. Further studies are thus warranted in 
perinatology. Authors of the meta-analysis cited above (Goessl et al., 2017) concluded that HRVB is 
related to a large reduction of self-reported stress and anxiety and is therefore a promising intervention. 
However, authors also highlighted the need of better-designed studies including a robust control 
condition (accounting for the number of contacts with a therapist, for instance) and an assessment of 

both short- and long-term effects.  
Accordingly, in this feasibility study, we aim to examine the efficacy of a HRVB program on physiological 
(i.e., HRV) and psychological (i.e., perceived stress and anxiety) stress in mothers who delivered 
prematurely. We aim at assessing the feasibility of such an intervention program on such individuals in 
order to compile preliminary data for a bigger scale project. 
So far, no clinical trial about HRVB in preterm population (https://clinicaltrials.gov) has been registered.  
2.4 Dose Rationale / Medical Device: Rationale for the intended purpose in 
study (pre-market MD)  
Based on a manual (Lehrer et al., 2000), on the recommendations of Prof. Richard Gevirtz (an 
international expert of HRVB) as well as on advice from Dr. Eva Otzen (the Swiss representative of 
Mindmedia), the HRVB will be provided daily for 2 weeks.  
Before the start of the program and after one week of adherence to the program a session will be 
conducted with a psychologist (Sébastien Urben) in order to define each participant’s individual 
resonance frequency (i.e., breathing rhythm), using the Nexus program from Mindmedia company. After 
establishing  the individual resonance frequency (i.e., breathing rhythm allowing for cardiac coherence), 
each participant will be trained with a portable Nexus device which will allow for monitoring adherence 
and use of the program. We will ask participants to individually perform the HRVB program for 20 min 
daily over the course of two weeks. To enhance participation, participants will receive a text message. 
Each participant will be asked to report in a diary all eventual adverse and/or stressful life events. 
2.5 Explanation for choice of comparator (or placebo)  
Not applicable for this feasibility study.  
2.6 Risks / Benefits  
First we expect to determine the feasibility of such program in the context of premature delivery. We 
also expect clinical benefits consisting of an increase of HRV and the associated reduction of stress and 
anxiety. Participants will not receive a monetary compensation for their participation in this study. 
The medical devices (MD) will be used in accordance with its classical use which has received the 
Central European (CE) certification. This device meets all the requirements of the Medical Device 
Directive (93/42/EEC, see documentation). Concomitant care will be provided as usual but we do not 
anticipate  possible negative interactions with those treatment. In case of contact with psychiatrist, this 
information will be notified.  
This study has been approved by the “Plateforme de recherche interprofessionnelle” of the Departement 
Femme-Mère-Enfant (DFME) of CHUV.  
Potential disadvantages for the participants are the following: the time taken to participate in the study, 
the measurement of HRV (wearing the belt, etc.) and potential distress that may arise from completing 
the questionnaires. For any participant during or after the study who might experience distress related 
to the participation in the study, Dr Mathilde Morisod Harari (or a delegate) will be available for 
professional support.  
 
2.7 Justification of choice of study population  
The population was chosen because of the potential benefit that such an intervention could engender 
for mothers who delivered prematurely. 
3. STUDY OBJECTIVES  
3.1 Overall Objective 
Our objective is to assess the feasibility of HRVB and to test its efficacy in the context of premature 
delivery.  
3.2 Primary Objective 
The primary objective is to assess the acceptability of the study protocol and the intervention as well as 
participants’ satisfaction with the intervention. 

3.3 Secondary Objectives  
The secondary objective is to determine the efficacy of HRVB on the physiological (i.e., HRV) and the 
psychological (i.e., perceived stress and anxiety) aspects of stress in mothers who delivered 
prematurely.   
3.4 Safety Objectives 
The study aims to assess the safety and tolerability to use HRVB in such context.   
 
4. STUDY OUTCOMES  
4.1 Primary Outcome 
Feasibility of the study will be assessed through the number of eligible patients, the rate of study 
participation acceptance and the rate of drop out. Moreover, satisfaction will be rated on a self-report 
questionnaire. 
4.2 Secondary Outcomes 
HRV (i.e., root-mean square differences of successive R-R intervals), perceived stress, and mental 
health (anxiety, depression, PTSD). 
4.3 Safety Outcomes 
The safety outcome variables will consist in tolerability of the procedure.  
 
5. STUDY DESIGN  
5.1 General study design and justification of design  
Ten mothers who delivered prematurely at the maternity ward of CHUV will be invited to undertake a 
HRVB program. The HRVB program consists of a breathing technique to be performed 20 min daily 
over the course of two weeks. Physiological (i.e., HRV) and psychological (i.e., self-reported stress and 
anxiety) stress will be assessed pre- and post-intervention. 
5.2 Methods of minimising bias  
The equipment providing HRVB, the measures of HRV and the assessment of psychological dimensions 
are validated and well-established standard measures. The study research team has the required 
competencies and resources to conduct the study. The PI holds a Good Clinical Practice (GCP) 
certificate. 
  
6. STUDY POPULATION  
6.1 Eligibility criteria  
 
Ten participants from the maternity ward of the University Hospital of Lausanne (CHUV) will be recruited 
for this feasibility study. 
Inclusion criteria are:  
 
Delivery between 33 and 37 weeks of gestational age;  
 
Living in Lausanne or surroundings; 
 
Infant is expected to survive; 
 
Singleton birth ; 
 
Consent of mother to participate in the study; 
 
Sufficient French-speaking to fill out the questionnaires; 

 
Mother older than 18 years of age. 
 
 
 
Exclusion criteria are: 
 
Infant with cranial abnormality/ neurological squeal such as cystic periventricular leukomalacia 
and intraventricular haemorrhage;  
 
Maternal history of drug or alcohol abuse or severe psychiatric disorders before or during 
pregnancy; 
 
Infant with congenital anomalies; 
 
Infant with hearing or vision loss; 
 
Mother and infant participating in another clinical trial. 
6.2 Recruitment and screening  
Dr Juliane Schneider will screen medical record for inclusion and exclusion criteria. Then, she will orally 
inform the mother about the possibility to participate the study and will give the information sheet. The 
next day a member (Sébastien Urben / Nevena Dimitrova) of the Research Unit of the Child and 
Adolescent Psychiatry Department will have a phone contact to respond to any questions the mother 
might have and to obtain oral consent. Then, a meeting will be fixed to obtain written consent and begin 
the study protocol.  
6.3 Criteria for withdrawal / discontinuation of participants  
If a participant does not comply with at least 5 training sessions (for 10 min each) she will be excluded 
from analyses. For this feasibility study, such information is of crucial importance to assess the feasibility 
of a larger study and the tolerability of the intervention. Thus, the acquired data will be analyzed. If a 
participant withdraws her informed consent, such participant will be considered as drop out, their data 
will be analyzed, to assess the rate of drop out.  
7. STUDY INTERVENTION  
7.1 Identity of Investigational Products (medical device)  
This feasibility study represents an open-label trial.  
7.1.1 
Experimental Intervention (medical device) 
The MD providing the HRVB program chosen for this study is the Nexus-4 product from the Mindmedia 
company. The product will be used according to its standard use. 
For the individual training, Emwave products from Hearthmath company will be used according to 
standard use.  
 
7.1.2 
Storage Conditions  
Supply, storage, return or destruction of the medical devices are according to standard procedures. 
 
7.2 Administration of experimental and control interventions  
7.2.1 
Experimental Intervention  
Based on a manual (Lehrer et al., 2000), on the recommendations of Prof. Richard Gevirtz (an 
international expert of HRVB) as well as on advice from Dr. Eva Otzen (the Swiss representative of 
Mindmedia), the HRVB will be provided daily for 2 weeks.  
Before the start of the program and after one week of adherence to the program, two sessions will be 
conducted with a psychologist (Sébastien Urben) in order to define each participant’s individual 
resonance frequency (i.e., breathing rhythm), using the Nexus program from Mindmedia company. After 
establishing the individual resonance frequency (i.e., breathing rhythm allowing for cardiac coherence), 
each participant will be trained with Emwave devices which will allow for monitoring adherence and use 
of the program. We will ask participants to individually perform the HRVB program for 20 min daily over 

the course of two weeks. Five daily sessions of 10 minutes will be considered as the minimum 
intervention. Each participant will be asked to report in a diary all eventual major stressful life events. 
 
7.2.2      Dose / Device modifications  
For this feasibility study, no device modifications are planned. The MD will be used following standard 
procedure.  
7.3 Compliance with study intervention  
To enhance participation and compliance with study intervention, participants will receive, daily during 
the morning, a text message and will be given the opportunity to ask questions. Importantly, the medical 
device chosen for this study provides information about its use and a feedback to the participant. For 
the purpose of this feasibility study, data gathered on compliance is key (assessed by the number and 
duration of training sessions, as well as with complete fulfilling of the questionnaires). 
7.4 Data Collection and Follow-up for withdrawn participants  
The participants who withdraw their consent or who do not comply with the HRVB program will be 
considered as dropouts. Intention-to-treat descriptive analyses will be done on baseline information as 
well as quantifying the training period (if any). All data acquired during the study will be analyzed.   
7.5 Trial specific preventive measures 
Treatment as usual will be provided to the participants. We did not fix any restriction regarding diet, 
and/or medication. Medication and stressful event will be monitored and described. The study aims to 
assess the feasibility of such study in natural settings, thus this event will happen in natural clinical time-
course. We did not see any obstacle for our study objectives related to concomitant treatment.  
7.6 Concomitant Interventions (treatments)  
The treatment usually provided to mothers having a preterm infant will be provided to the participant. 
No specific intervention on stress and anxiety or HRV is usually provided at the maternity ward of CHUV. 
All other treatments that participants might follow will be documented.  
7.7 Medical Device Accountability  
Standard procedure for accurate records and storage will be applied.  
7.8 Return or Destruction of Medical Device  
Return or destruction of the medical devices are according to standard procedures and mentioning this 
in the protocol is enough (no details needed). 
 
8. STUDY ASSESSMENTS  
8.1 Study flow chart(s) / table of study procedures and assessments 
 
Study flow chart: 
 

 
 
 
8.2 Assessments of outcomes  
8.2.1 
Assessment of primary outcome  
Feasibility will be assessed trough the number of eligible participants during a month, the ratio of 
acceptance to participate, compliance with study protocol (number and duration of sessions, fulfilling 
study questionnaires) and the ratio of drop out. Satisfaction will be measured through a questionnaire 
(see appendix).  
8.2.2 
Assessment of secondary outcomes 
HRV will be monitored on an electrocardiogram (ECG) for 5 min at rest with the Nexus-4 product from 
Mindmedia with a standard measurement procedure (sensor at finger). The root-mean square 
differences of successive R-R intervals (RMSDD) as well as High Frequency (HF) will be used as 
measures to assess HRV level before and after participation in the HRVB program. 
Stress, anxiety and depression symptoms will be measured by self-reports questionnaires (see 
appendix):  
 
Perceived stress will be measured on the Perceived Stress Scale (PSS). 
 
Post-traumatic stress disorder symptoms will be assessed with the Post-traumatic symptoms 
checklist 5 (PCL-5).  
 
Anxiety symptoms will be assessed with the State and Trait Anxiety Inventory (STAI).  
 
Depression symptoms will be assessed with the Beck Depression Inventory (BDI).  
8.2.3 
Assessment of safety outcomes 
Adverse events will be monitored during the training phase. The participant will keep a diary marking 
any negative events related to the HRVB program. As the program consists of a simple breathing 
technique, the risk that an adverse event would occur is low. At each session (before the HRVB program 
and after one week), the trainer will discuss with the participant adverse events that might have occurred. 
The participant will also have the opportunity to report adverse events by responding to the daily 
program reminder that she will receive by text message. 
Tolerability of the HRVB protocol will be assessed at the end of the study by a qualitative interview.  
8.2.4 
Assessments in participants who prematurely stop the study 
If a participant drops out from the study, an interview will be done to examine the reason of consent 
withdrawal if the participant agreed to explain her withdrew from the study. The data acquired within the 
study will be described in the grant proposal.  
 

8.3 Procedures at each visit 
8.3.1 
Information / consent visit  
The participants who fulfill inclusion criteria (without presenting exclusion criteria) will be informed orally 
about the study by Dr Juliane Schneider and will receive written information. The next day, they will be 
asked if they have any question about the study and if they agree to participate, written informed consent 
will be collected.  
8.3.2 
Pre-intervention assessment 
The baseline assessment of HRV will take place at the hospital in a quiet room. Pre-intervention reports 
on stress, anxiety and depression will be collected with the instruments outlined in section 9.2.2. 
8.3.3 
HRVB training 
In order to familiarize participants with the HRVB program and its apparatus as well as to assess each 
participant’s individual resonance frequency (i.e., breathing rhythm), two training sessions will be 
provided: one prior to the beginning of the HRVB program (at hospital) and one after one week of HRVB 
program (either at the hospital or at the participant’s home if she has been discharged from the hospital). 
The second training session aims to optimize adherence to the HRVB program and to reassess 
participant’s resonance frequency.  
 
9.3.5      Post-intervention visit 
After two weeks of performing the HRVB program (± 3 days), post-intervention assessment will take 
place (either at the hospital or at the participant’s home if she has been discharged from the hospital). 
Additionally, a satisfaction questionnaire has to be filled out and a debriefing interview will be conducted 
in order to discuss the acceptability of the protocol.  
9. SAFETY  
9.1 Medical Device Category A studies 
9.1.1 
Definition and Assessment of safety related events 
 
Health hazards which may occur during the participation in the study and that require measures will be 
documented.  
Participants at the beginning of the study will be hospitalized, thus, the likelihood of detecting  additional 
health hazards from the study is low. 
9.1.2 
Reporting of Safety related events 
Severe safety related events refer to (a) incident that necessitate inpatient stay or a prolongation of the 
inpatient stay which was not planed in the research protocol; (b) lead to severe or chronic handicap or 
invalidity; (c) caused decease or life threatening; (d) to congenital anomaly or malformation.  Such event 
will be reported to the Sponsor-Investigator within 24 hours upon discovery. The local Ethics Committee 
will be informed within 15 days. At this time, we did not see any other safety related events that might 
be documented here.  
 
9.1.3 
Safety events detected by chance  
Any abnormal ECG patterns detected by chance (no specific assessment by a cardiologist of the ECG 
measurement) that require medical monitoring and/or intervention will be reported. In such case, an 
appointment with a cardiologist will be offered to the participant.  
10. STATISTICAL METHODS  
10.1 Hypothesis 
H0: The HRVB program will not show to be feasible and efficient in terms of increasing HRV and 
reducing stress, anxiety and/or depression. 

H1: The HRVB program will show to be feasible and efficient in terms of increasing HRV and reducing 
stress, anxiety and/or depression. 
10.2 Determination of Sample Size  
The estimated number of participants is 10 which is considered as sufficient in order to assess the 
feasibility of the study. Taking into account the meta-analyses on HRVB that reported large effect sizes 
(Hedges’ g >.81) and the fact that we will conduct one-tailed tests, 10 patients is enough to have 
appropriate statistical power.   
10.3 Statistical criteria of termination of trial  
No criteria for the termination of the trial are a priori determined for this feasibility study.  
10.4 Planned Analyses  
Acceptability of the study protocol and intervention as well as satisfaction will be reported descriptively. 
The inferential analyses will consist in comparing variables (HRV and mental health symptoms) from 
baseline to post-HRVB intervention using non-parametric Kruskall-Wallis tests. By convention, statistical 
significance will be set at .05.  
10.4.1 Datasets to be analysed, analysis populations 
Data from participants who completed the study will be analysed. Drop out data will be used only for 
descriptive purposes.   
10.4.2 Primary Analysis 
Nevena Dimitrova will perform the primary analyses. 
10.4.3 Safety analysis 
The investigator will assess the feedback from the participant about the tolerability of the protocol.  
10.5 Handling of missing data and drop-outs  
We will analyze data only from participants who completed the study. Missing data from drop out 
participants will not be replaced but it will be documented.  
11. QUALITY ASSURANCE AND CONTROL  
11.1 Data handling and record keeping / archiving  
Signed informed consent forms along with all physical documentation yielded by participants of this 
study will be kept in a locked cabinet in a locked room at the Research Unit of the Child and Adolescent 
Psychiatry Department of CHUV. Participants will be referred by a personal study code, without any 
personal information that could identify them (i.e., no names, no date of birth). The correspondence 
between the participant’s identity and code will be known only by the principal investigator. CRF data 
will be first recorded on paper and then entered in an electronic database for analyses (double-check 
on data entry, by a research collaborator of the research unit, will be conducted to assure correctness).  
11.1.1 Specification of source documents  
The CRF of the participant will be the source data which will be kept in the research unit of Child and 
Adolescent Psychiatry Department. Questionnaires assessing stress and mental health will kept in the 
research unit of Child and Adolescent Psychiatry Department.  
11.1.2 Record keeping / archiving  
All study data will be archived for a minimum of 15 years (according to local legislation) after study 
termination or premature termination of the feasibility study. Storage will be handled as described in 
section 12.1.  
 
11.2 Data management  
Data entry into Excel will be double checked (research collaborator from the research unit). Before the 
inferential statistical analyses, descriptive analyses will be conducted to verify the range of values.  

11.2.1 Data Management System  
The paper CRF will be entered and then managed on Excel for this feasibility study.    
11.2.2 Data security, access and back-up  
The data will be saved in a secured database on CHUV’s server. The data will be accessible to the 
research team (members as defined in section 1).  
11.2.3 Analysis and archiving 
The paper data (consent form) will be stored and archived at the Research Unit of Child and Adolescent 
Psychiatric Department during the legal period of time (15 years).  
 
11.3 Monitoring  
No specific monitoring is planned for this feasibility study.  
11.4 Audits and Inspections  
The study documentation and the source data/documents are accessible to auditors/inspectors (also 
CEC and CA) and questions are answered during inspections. All involved parties must keep the 
participant data strictly confidential. 
 
11.5 Confidentiality, Data Protection  
The data will be directly coded (e.g. HRVB_001). The data will be protected and direct access to source 
documents will be permitted for purposes of audits and inspections (12.4). The data will be accessible 
only to the members of the research team (as defines in section 1).   
 
11.6 Storage of biological material and related health data  
No biological material will be collected. Heath data provided in the CRF will be stored in the Research 
Unit.  
12. FUNDING AND SUPPORT  
12.1 Funding  
This study will not be externally funded.  
13. INSURANCE  
As the study refers to risk category “A” no specific insurance will be contracted. 
 
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