The OMWaNA Study: Operationalising Kangaroo Mother Care Before Stabilisation Amongst Low Birth Weight Neonates in Africa: a Multi-site Randomised Controlled Trial to Examine Mortality Impact in Uganda
Phase: NA
Conditions: Kangaroo Mother Care, Preterm Infant, Death; Neonatal, Hypothermia, Newborn
Sponsor: London School of Hygiene and Tropical Medicine

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STUDY PROTOCOL  
  
  
The OMWaNA Study:   
Operationalising kangaroo Mother care before stabilisation 
amongst low birth Weight Neonates in Africa:   
a multi-site randomised controlled trial to examine mortality 
impact in Uganda  
  
 
   
  
Principal Investigator:   
•  Prof Joy Lawn, Professor & Director, MARCH Centre, London School of Hygiene & 
Tropical Medicine  
Co-Principal Investigators:   
• 
Dr Melissa Medvedev (Morgan), Clinical Assistant Professor, MARCH Centre, London 
School of Hygiene & Tropical Medicine & Assistant Professor, Department of 
Pediatrics, University of California San Francisco   
• 
Dr Peter Waiswa, Associate Professor, School of Public Health, & Maternal Newborn 
and Child Health Centre of Excellence, Makerere University  
• 
Dr Cally Tann, Associate Professor, MARCH Centre, London School of Hygiene &  
Tropical Medicine & Honorary Senior Scientist, MRC/UVRI and LSHTM Uganda 
Research Unit  
• 
Prof Elizabeth Allen, Professor and Head, Department of Medical Statistics, London 
School of Hygiene & Tropical Medicine  
• 
Dr Ivan Kiggundu Mambule, Trial Coordinator, MRC/UVRI and LSHTM Uganda 
Research Unit  
• 
Dr Victor Spector Tumukunde, Scientist A and Site Coordinator, MRC/UVRI and 
LSHTM Uganda Research Unit  
  
Sponsoring Institution:   
 
•  
London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK  
Funder:   
 
•  Medical Research Council/Wellcome Trust/DFID Joint Global Health Trials scheme  

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Collaborators in Uganda and Overseas  
  
MRC/UVRI & LSHTM Uganda Research Unit: 49-51 Nakiwogo Road, Entebbe, Uganda   
Prof Moffatt Nyirenda  
Professor of Medicine,  
Director of Non- 
Communicable Diseases  
Theme  
Senior MRC/UVRI member of Trial 
Management Group  
Prof Janet Seeley  
  
Professor of Anthropology 
and Health, Head of Social 
Science Programme  
Support the design and conduct of 
qualitative aspects of the study   
Kenneth R. Katumba  
Health Economist  
Conduct the economic analysis   
Dr Christian Hansen  
Head of Statistics  
Senior supervision of data 
management / randomisation  
Dr Giulia Greco  
  
Assistant Professor of  
Health Economics,  
Honorary Senior Scientist  
Lead women’s well-being 
assessment  
  
  
  
Makerere University: School of Public Health, New Mulago Hill Road, Kampala, Uganda  
Dr Elizabeth Ekirapa-Kiracho  Senior Lecturer of Health 
Policy and Planning  
Lead the economic analysis   
  
London School of Hygiene & Tropical Medicine: Keppel Street, London WC1E 7HT, UK   
Prof Diana Elbourne  
Professor of Healthcare 
Evaluation  
Expertise in neonatal trials and 
ethical issues  
Ruth Canter  
Trial Manager  
Independent statistician and data 
manager  
Helen Brotherton  
Clinical Assistant Professor  
Expertise in KMC trials  
London School of Hygiene & Tropical Medicine: 15-17 Tavistock Place, London WC1H 9SH, UK  
Catherine Pitt  
Assistant Professor of 
Health Economics  
Senior supervision of the economic 
analysis  
Entebbe Hospital:  
Irene Nayiga  
Consultant Paediatrician  
Lead investigator at Entebbe site  
Iganga Hospital:  
Rolland Mutumba  
Consultant Paediatrician  
Lead investigator at Iganga site  
Jinja Hospital:  
Dr Harriet Nambuya  
Consultant Paediatrician  
Lead investigator at Jinja site  

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Kawempe N R Hospital:  
Dr Loy Nabirye  
Consultant Paediatrician  
Lead investigator at Kawempe site  
Masaka Hospital:  
Shiela Oyella  
Consultant Paediatrician  
Lead investigators at Masaka site  
 
Statement of Compliance   
By my signature below, I hereby confirm that the study will be conducted in accordance 
with this protocol and in compliance with the tripartite harmonized ICH Guideline for 
Good Clinical Practice 1996 and the version of such protocol agreed to by the 
applicable regulatory authorities and approved by all Institutional Review Board and 
Ethical Committees.  
  
  
  
Principal Investigator:   
  
  
Name: Joy Lawn  
Signature: _________________________    Date: 1/7/20 
  
  
  
  
  
  
  
  
  
  
  
  
Please note that study responsibilities are documented in the Trial Master and 
Investigator Site Files.  
  
  
 
 
 

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Contents  
  
Principal Investigator: ................................................................................................................................... 1 
Co-Principal Investigators: .......................................................................................................................... 1 
Sponsoring Institution: ................................................................................................................................. 1 
Funder: ............................................................................................................................................................... 1 
Collaborators in Uganda and Overseas .................................................................................................... 2 
Statement of Compliance .............................................................................................................................. 3 
List of Abbreviations ...................................................................................................................................... 8 
Definitions ...................................................................................................................................................... 10 
Executive Summary ..................................................................................................................................... 14 
1. Hypothesis, aim, objectives, and outcomes .................................................................................... 16 
1.1 Aim .............................................................................................................................................................. 16 
1.2 Primary Hypothesis for the trial .................................................................................................... 16 
1.3 Objectives ................................................................................................................................................. 16 
1.4 Outcomes for the trial ......................................................................................................................... 16 
1.4.1 Primary outcome .......................................................................................................................... 16 
1.4.2 Secondary outcomes ................................................................................................................... 16 
2. Background ............................................................................................................................................... 17 
2.1 Kangaroo Mother Care to Improve Neonatal Survival ......................................................... 17 
2.2 Gaps in the Evidence regarding Kangaroo Mother Care ...................................................... 17 
2.3 Neonatal Care in Sub-Saharan Africa and Uganda ................................................................. 18 
2.4 Formative Work .................................................................................................................................... 18 
2.5 Rationale for the OMWaNA study ................................................................................................. 20 
3. Study Setting and Design ....................................................................................................................... 20 
3.1 Study Setting ........................................................................................................................................... 20 
3.2 Design of the Trial ................................................................................................................................ 21 
3.2.1 Randomisation .............................................................................................................................. 21 
3.2.2 Blinding ............................................................................................................................................ 21 
3.2.3 Details of the Intervention arm .............................................................................................. 21 
3.2.4 Details of the Control arm ........................................................................................................ 21 
3.2.5 Clinical Stability Criteria ........................................................................................................... 22 
3.2.6 Concomitant Therapies and Medications .......................................................................... 22 
3.3 Design of the Economic Evaluation .............................................................................................. 22 
3.4 Design of the Process Evaluation ................................................................................................... 22 
4. Selection and Withdrawal of Participants ...................................................................................... 23 
4.1 Participants ............................................................................................................................................. 23 
4.2 Eligibility Criteria for the Trial ....................................................................................................... 23 
4.2.1 Inclusion criteria .......................................................................................................................... 23 
4.2.2 Exclusion criteria ......................................................................................................................... 24 
4.3 Eligibility Criteria for Focus Group Discussions and Interviews ..................................... 24 
4.3.1 Inclusion criteria .......................................................................................................................... 24 
4.3.2 Exclusion criterion ...................................................................................................................... 24 
4.4 Withdrawal of Participants .............................................................................................................. 24 
5. Study Procedures ..................................................................................................................................... 24 
5.1 Internal Pilot ........................................................................................................................................... 24 
5.2 Screening .................................................................................................................................................. 25 

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5.3 Study Schedule ....................................................................................................................................... 26 
5.4 Recruitment ............................................................................................................................................ 27 
5.4.1 Sensitisation ................................................................................................................................... 27 
5.4.2 Informed consent ......................................................................................................................... 27 
5.4.3 Enrolment ........................................................................................................................................ 27 
5.5 Collection of Baseline Data ............................................................................................................... 27 
5.5.1 Clinical data .................................................................................................................................... 27 
5.5.2 Sociodemographic data ............................................................................................................. 28 
5.5.3 Socioeconomic Data .................................................................................................................... 28 
5.6 Randomisation ....................................................................................................................................... 29 
5.7 Intervention and Control Arms ...................................................................................................... 29 
5.7.1 Delivering the intervention arm ............................................................................................ 29 
5.7.2 Delivering the control arm ....................................................................................................... 29 
5.8 Follow-up ................................................................................................................................................. 30 
5.9 Staff Training .......................................................................................................................................... 30 
5.9.1 Clinical trial training workshop at MRC/UVRI before start of trial ....................... 30 
5.9.2 Site staff training on neonatal care and clinical guidelines before start of 
trial31  .......................................................................................................................................................... 31 
5.9.3 Refresher trainings throughout trial ................................................................................... 31 
6. Study Evaluations .................................................................................................................................... 31 
6.1 Clinical Evaluations ............................................................................................................................. 31 
6.1.1 Evaluations during first 24 hours ......................................................................................... 31 
6.1.2 Evaluations from 24 hours to hospital discharge .......................................................... 31 
6.1.3 Evaluations in event of clinical deterioration .................................................................. 32 
6.1.4 Procedures at time of discharge/death .............................................................................. 33 
6.1.5 Procedures at follow-up ............................................................................................................ 33 
6.1.6 Cranial ultrasound imaging ..................................................................................................... 34 
6.2 Economic Evaluation ........................................................................................................................... 34 
6.2.1 Evaluations at time of enrolment .......................................................................................... 34 
6.2.2 Evaluations during hospitalisation ...................................................................................... 34 
6.2.3 Evaluations at follow-up ........................................................................................................... 34 
6.3 Process Evaluation ............................................................................................................................... 35 
6.3.1 Understanding causal pathways for clinical effects ...................................................... 35 
6.3.2 Focus Group Discussions .......................................................................................................... 35 
6.3.3 Interviews ....................................................................................................................................... 36 
6.3.4 Additional health systems and clinical data ..................................................................... 36 
7. Trial Responsibilities & Management .............................................................................................. 36 
7.1 Investigator Team ................................................................................................................................ 37 
7.2 Study Team and Infrastructure at Trial Sites ........................................................................... 39 
7.3 Trial Steering Committee .................................................................................................................. 40 
8. Safety and Monitoring ............................................................................................................................ 40 
8.1 Monitoring of Study Participants ................................................................................................... 41 
8.2 Adverse Events & Assessment of Causality ............................................................................... 42 
8.3 Emergency Procedures ...................................................................................................................... 43 
8.4 Follow-up of Adverse Events ........................................................................................................... 43 

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8.5 Assessment of Causes of Death ....................................................................................................... 43 
8.6 Reporting of SAEs & SUSARS ........................................................................................................... 43 
8.7 Data and Safety Monitoring Board ................................................................................................ 44 
8.8 Stopping Criteria ................................................................................................................................... 44 
8.9 Interim Analyses ................................................................................................................................... 44 
9. Discontinuation Criteria ....................................................................................................................... 44 
9.1 Criteria for stopping the intervention ......................................................................................... 44 
9.2 Criteria for restarting intervention ............................................................................................... 45 
10. Sample Size and Analysis Plan .......................................................................................................... 45 
10.1 Sample Size ........................................................................................................................................... 45 
10.2 Analysis Plan for the Trial .............................................................................................................. 46 
10.2.1 Summary of baseline data and flow of patients ........................................................... 46 
10.2.2 Primary and secondary outcome analyses ..................................................................... 46 
10.2.3 Subgroup and adjusted analyses ........................................................................................ 46 
10.2.4 Definition of analysis population related to protocol non-adherence ............... 47 
10.3 Analysis Plan for Economic Data ................................................................................................. 47 
10.4 Analysis Plan for Qualitative Data .............................................................................................. 47 
11. Quality Control and Quality Assurance ......................................................................................... 48 
11.1 External Monitoring .......................................................................................................................... 48 
11.2 Internal Monitoring .......................................................................................................................... 48 
11.3 Audits and Inspections .................................................................................................................... 48 
11.4 Indemnity .............................................................................................................................................. 48 
12. Data Management ................................................................................................................................. 48 
12.1 Data Transmission and Editing .................................................................................................... 49 
12.2 Data Discrepancy Inquiries ........................................................................................................... 49 
12.3 Qualitative Data .................................................................................................................................. 49 
12.4 Security and Backup of Data ......................................................................................................... 49 
12.5 Study Status Reports ........................................................................................................................ 50 
12.6 Access to Data ...................................................................................................................................... 50 
12.7 Responsibilities ................................................................................................................................... 50 
13. End of Trial and Archiving ................................................................................................................. 50 
14. Ethical Considerations ........................................................................................................................ 50 
14.1 Ethical approvals and general considerations on human subject participation .... 50 
14.2 Rationale for inclusion of vulnerable groups ........................................................................ 51 
14.2.1 Rationale for Neonates ............................................................................................................ 51 
14.2.2 Rationale for children ≥15 years of age (who are parents of included 
neonates) .................................................................................................................................................... 51 
14.3 Evaluation of risks and benefits .................................................................................................. 51 
14.3.1 Potential risks or benefits of standard care in Uganda ............................................. 51 
14.3.2 Potential risks or benefits of KMC in Uganda ................................................................ 52 
14.3.3 Overall assessment of clinical risk ..................................................................................... 52 
14.4 Sensitisation ......................................................................................................................................... 53 
14.5 Informed Consent .............................................................................................................................. 53 
14.6 Confidentiality ..................................................................................................................................... 53 
14.7 Care of families whose newborn dies or who has life-threatening events ............... 54 

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14.8 Transport Reimbursement to Participating Mothers ........................................................ 54 
15. Involvement of Participants and the Public ................................................................................. 54 
15.1 Incorporation of Feasibility Study Findings into Trial Design ....................................... 54 
15.2 Local Advisory Board ....................................................................................................................... 54 
15.3 Workshops and Qualitative Evaluations .................................................................................. 55 
15.4 Sharing of Study Findings with Participating Families ..................................................... 55 
16. Declaration of Interests ...................................................................................................................... 55 
17. Potential Limitations and Anticipated Challenges .................................................................... 55 
18. Significance of the Proposed Work ................................................................................................. 56 
19. Publication and Dissemination Plan .............................................................................................. 56 
19.1 Dissemination Policy ........................................................................................................................ 56 
19.2 Plans to Grant Public Access to Protocol ................................................................................. 56 
20. Timeframe ............................................................................................................................................... 57 
21. Acknowledgments ................................................................................................................................ 57 
References ...................................................................................................................................................... 58 
Appendices ..................................................................................................................................................... 64 
Appendix A: Patient information sheet and informed consent form 
(parents/guardians) ................................................................................................................................... 64 
Appendix B: Information sheet and informed consent form for qualitative evaluations 
(health care workers and key stakeholders) ................................................................................... 64 
Appendix C: Ballard score for estimating gestational age .......................................................... 64 
Appendix D: Case report form ................................................................................................................ 64 
Appendix E: KMC Progress Monitoring Tool for Health Faciities ........................................... 64 
Appendix F: Investigators’ CVs ............................................................................................................... 64 
 
  
  
  
 

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List of Abbreviations  
AE  
Adverse event  
bpm  
Beats per minute  
CI  
Confidence interval  
CONSORT  
Consolidated Standards of Reporting Trials  
CPAP  
Continuous positive airway pressure  
cUS  
Cranial ultrasound  
d  
Day(s)  
DSMB  
Data and Safety Monitoring Board  
eCRF  
Electronic case report form  
EH  
Entebbe Regional Referral Hospital  
FGD  
Focus group discussion  
g  
Grams  
  
  
GCP  
Good Clinical Practice  
HR  
Heart rate  
h  
Hour(s)  
IH  
Iganga District Hospital  
ID  
Identification  
IDI  
In-depth interview  
IRB  
Institutional Review Board  
ICH  
International Conference on Harmonisation  
IV  
Intravenous  
IVH  
Intraventricular haemorrhage  
JH  
Jinja Regional Referral Hospital  
KNRH  
Kawempe National Referral Hospital  
LBW  
Low birthweight  
LMIC  
Low- and middle-income countries  
LSHTM  
London School of Hygiene and Tropical Medicine  
KMC  
Kangaroo mother care  
MH  
Masaka Regional Referral Hospital  

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MIRI  
Maternal Infant Responsiveness Instrument  
MRC/UVRI  
Medical Research Council/Uganda Virus Research 
Institute Uganda Research Unit in Entebbe  
OMWaNA  
‘Operationalising kangaroo Mother care before  
stabilisation amongst low birth Weight neonates in Africa’  
PI  
Principal Investigator  
PIS  
Participant information sheet  
PSBI  
Possible serious bacterial infection  
RCT  
Randomised controlled trial  
RR  
Relative risk  
SAE  
Serious adverse event  
SGA  
Small for gestational age  
SOP  
Standard operating procedure   
SpO2  
Oxygen saturation measured by pulse oximetry   
SSC  
Skin-to-skin contact  
TMF  
Trial Master File  
TSC  
Trial Steering Committee  
UgSh  
Ugandan Shillings  
  
WCI  
Women’s Capabilities Index   
WHO  
World Health Organization  
  

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Definitions  
Adverse event:  
Any untoward medical occurrence in a patient or clinical investigation 
subject administered an experimental therapy, which does not 
necessarily have to have a causal relationship with this therapy (1)  
APGAR score:  
System for assessing newborns and response to neonatal 
resuscitation at the time of delivery; includes 5 components: 1) 
colour, 2) heart rate, 3) reflexes, 4) muscle tone, 5) respiration; 
each component is scored 0 to 2 at 1 and 5 minutes post-birth, and 
at 5-minute intervals thereafter up to 20 minutes for infants scoring 
<7 (2)  
Apnoea:   
  
No spontaneous breathing for 20 seconds, or less than 20 seconds 
and accompanied by colour change, oxygen desaturation 
(SpO2 <88%), or bradycardia (HR <100 bpm)  
Kangaroo mother care:  Package of care that consists of prolonged skin-to-skin contact 
between neonate and caregiver, usually the mother; promotion of 
exclusive breast milk feeding; early hospital discharge; and 
adequate support and close follow-up at home (3)  
Continuous KMC: Skin-to-skin contact between baby and 
caregiver for at least 18h/day  
Intermittent KMC: Skin-to-skin contact between baby and 
caregiver for periodic times of at least 1h duration per session  
Low birthweight:  
Birthweight <2500g; can be sub-categorised as follows (4):  
       Very low birthweight: birthweight <1500g  
       Extremely low birthweight: birthweight <1000g  
Neonatal mortality rate:  Number of neonates dying before reaching 28 days of age, per 
1,000 live births in a year (5)  
Neonatal period:  
First 28 days post-birth; can be sub-categorised as follows (6):  
Early neonatal period: 0-6 days post-birth  
Late neonatal period: 7-28 days post-birth  
Preterm:  
Birth at <37 completed weeks gestation; can be sub-categorised as 
follows (7):  
Extremely preterm: birth at <28 completed weeks  
Very preterm: birth at 28 to <32 completed weeks  
            Moderate to late preterm: 32 to <37 completed weeks  
Serious adverse  
Any untoward medical occurrence which: (1)  

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event:  
a) Results in death  
b) Is life threatening  
c) Requires prolongation of hospitalisation  
d) Results in persistent or significant disability/incapacity  
e) Requires intervention to prevent permanent impairment or  
damage  
INCLUSION CRITERIA  
 
Indication for KMC  
“uncertain” according 
to WHO guideline 
concerning clinical 
stability (8):  
Pragmatically defined as receiving ≥1 of the following therapies:   
• 
Supplemental oxygen: oxygen from cylinder, compressor or 
wall, which is delivered via nasal cannula, mask, or tent  
• 
Continuous positive airway pressure (CPAP): method of 
maintaining low pressure distension of lungs during 
inspiration and expiration when infant is breathing 
spontaneously (9)   
• 
Intravenous (IV) fluids: solution, typically containing 
dextrose and/or electrolytes, that is delivered directly to 
veins; indicated for neonates unable to take adequate 
enteral feeds  
• 
Therapeutic antibiotics: antibiotics given only for presumed 
or confirmed infection (not empirically/prophylactically)  
• 
Phenobarbital: medication used to treat neonatal seizures  
EXCLUSION CRITERIA  
Severely 
lifethreatening 
clinical instability:  
Defined as SpO2 <88% in oxygen AND ≥1 of:   
• 
Respiratory rate <20 or >100 breaths/min   
• 
Apnoea requiring bag-mask ventilation   
• 
HR <100 or >200 bpm  
Major congenital 
malformation:  
A malformation that is present at birth and which is incompatible 
with life or requires immediate surgical management  
Severe jaundice:  
Jaundice occurring within the first 24h after delivery and/or visible 
in sclera, palms or soles  
PRIMARY OUTCOME   

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Early neonatal 
mortality:  
Death of a neonate within the first 7 days after birth (day 0-6)  
SECONDARY OUTCOMES  
 
Hypothermia:  
Axillary temperature below the normal range (36.5°C – 37.5°C); can 
be subcategorised as follows:  
Mild: 36.0°C – 36.4°C  
Moderate: 32.0°C – 35.9°C   
Severe: <32°C  
Duration of hospital 
admission:  
Mean time (days and hours) from hospital admission to discharge  
Breastmilk feeding:  
Process of feeding a mother's breastmilk to her infant, either 
directly from the breast or by expressing milk from the breast and 
feeding it to the infant by nasogastric tube, bottle, cup, or spoon, to 
provide calories, macronutrients, and micronutrients (10)  
Time from 
intervention/control 
procedures starting to 
exclusive breastmilk 
feeding:  
Mean time (days and hours) from initiation of intervention/control 
procedures to exclusive breast milk feeding   
Neonatal mortality:  
Death of a neonate within the first 28 days of life  
Time from 
intervention/control 
procedures starting to 
clinical stabilisation:  
Mean time (days and hours) from initiation of intervention/control 
procedures to clinical stabilisation, with stability defined as having 
met the following criteria for a continuous period of at least 24h:  
(i) Breathing spontaneously with SpO2 >90% in room air  
(ii) No need for supplemental oxygen or CPAP   
(iii) Respiratory rate 40 to <60 breaths per minute  
(iv) No apnoea  
(v) Heart rate 80 to <180 beats per minute  
(vi) Axillary temperature 36.0 to 37.4 degrees Celsius  
(vii) No need for IV fluids  
Time from 
intervention/control 
procedures starting to 
death:  
Mean time (days and hours) from initiation of intervention/control 
procedures to death  

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Frequency of 
readmission:  
Mean frequency of episodes in which an infant who had been 
discharged from a hospital is admitted again during a defined time 
period  
Daily weight gain:  
Mean daily weight gain (g/day) during a defined time period  
Infant-caregiver 
attachment:  
Assessed using the Maternal Infant Responsiveness Instrument  
(MIRI), a 22-item questionnaire measuring maternal  
responsiveness to infant cues (11,12); initially developed in the  
 
United States and being used in Uganda   
Women’s well-being:  
Assessed using the Women’s Capability Index (WCI), a composite 
measure of quality of life that will capture the broader benefits to 
the mother of practising KMC compared to standard care (13); 
originally developed in Malawi, and now being adapted and tested 
for use in Uganda  
OTHER PROCESS OUTCOMES  
Cardio-respiratory 
stability:  
Proportion of time spent with suboptimal HR (<100bpm) and SpO2 
(<85%) over the first 24h post-randomisation, measured and 
recorded continuously using pulse oximetry.  
Hypothermia density:  
Proportion of time temperature <36.5°C during a defined time 
period  
Presence and severity 
of intraventricular 
haemorrhage (IVH):  
Complication of prematurity characterised by bleeding within the 
ventricles (fluid-filled areas) inside the brain, typically originating 
from the periventricular germinal matrix (a highly vascular collection 
of neuronal-glial precursor cells); majority of affected infants are 
asymptomatic; diagnosis is based on screening cranial ultrasound; 
severity ranges from grade 1 (mild) to grade 4 (severe) (14)  
Presence of late 
intracerebral sequelae 
of prematurity:  
Late intracerebral sequelae of prematurity may include, but are not 
limited to the following: cystic degeneration, cerebral atrophy, post-
haemorrhagic hydrocephalus   
Hypoglycaemia:  
Blood glucose level <2.6 mmol/L, as measured by bedside testing   
   
  
 
 

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Executive Summary  
Globally, an estimated 2.5 million neonatal deaths occurred in 2017 (15). Over 80% of these deaths 
occurred in babies who are small at birth, due to prematurity and/or being small for gestational age 
(SGA) (16). Major mortality reductions could be achieved by improving care of small neonates in 
lowresource settings (16–18). Kangaroo mother care (KMC) consists of skin-to-skin positioning (e.g., 
with the mother), breastfeeding, and supportive care (3,19). The most recent Cochrane review and a 
metaanalysis demonstrated that KMC is associated with decreased mortality (20,21), sepsis (20,21), 
hypothermia (20,21), and length of stay (20) amongst stable neonates ≤2000 grams (g). The World 
Health Organization (WHO) recommends KMC for the “routine care of newborns weighing ≤2000g 
initiated as soon as newborns are clinically stable” (8).   
However, estimates suggest that ≥75% of neonatal deaths occur before stabilisation in settings without 
intensive care (16,17,22). The only randomised controlled trial (RCT) evaluating the effect of KMC on 
mortality in neonates before stabilisation, from Ethiopia, reported decreased mortality but had 
methodological issues (23). Among 17 RCTs (14 enrolled only stable neonates) comparing KMC with 
standard care (incubators or radiant heaters) in low birthweight (LBW, <2500g) neonates aged <15 
days, there was significant variability in how clinical stability was defined, with three providing no 
definition at all. Hence codifying stability criteria for KMC is critical. Recent WHO guidelines for preterm 
care have prioritised determining the effect of KMC initiated prior to stabilisation on neonatal mortality 
as a key evidence gap (8).  
The OMWaNA study is a partnership between the Medical Research Council/Uganda Virus Research  
Institute (MRC/UVRI), the London School of Hygiene & Tropical Medicine (LSHTM) and Makerere 
University and includes a RCT with accompanying process and economic evaluations. The primary aim 
of the trial is to examine the impact of KMC initiated before stabilisation on mortality within 7 days 
relative to standard care amongst neonates ≤2000g at four hospitals in Uganda.  
The primary objective of the study is to:  
1. Determine the effect of KMC initiated before stabilisation on mortality within 7 days relative to 
standard care amongst neonates ≤2000g.  
The secondary objectives are to:  
1. Determine the effect of KMC initiated before stabilisation on other important clinical outcomes 
relative to standard care amongst neonates weighing ≤2000g.  
2. Estimate the incremental costs and cost-effectiveness of KMC initiated before stabilisation 
relative to standard care from the societal perspective.  
3. Explore causal pathways for the clinical effects of KMC initiated before stabilisation relative to 
standard care amongst neonates weighing ≤2000g.  
4. Examine the barriers and facilitators to initiating KMC before stabilisation to inform uptake and 
sustainability in Uganda.  
We will conduct an individually randomised, controlled, superiority trial with two parallel groups; an 
intervention arm allocated to receive KMC and a control arm receiving ‘standard’ care. Given the nature 
of the KMC intervention, blinding parents/participants is not possible. Process and outcome data will be 
anonymised, and all analyses will be blinded. We will enrol neonates before stabilisation for whom the 
indication for KMC is currently “uncertain,” defined as receiving ≥1 medical therapy [e.g., intravenous 

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(IV) fluids, oxygen to support breathing] in accordance with the WHO Practical Guide for KMC (3). The 
uncertainty principle states that, if a provider is uncertain about which treatment is best for a patient,  
“offering the patient randomisation to equally preferred treatments is acceptable” (24). This principle has 
been used as an eligibility criterion in many large trials (24). The trial’s primary outcome is mortality 
within 7 days. Secondary outcomes include prevalence of hypothermia at 24 hours post-randomisation; 
mean time from intervention/control procedures starting to clinical stabilisation or death; mean duration 
of admission; mean time from intervention/control procedures starting to exclusive breastmilk feeding; 
mortality within 28 days; mean frequency of readmission; and mean daily weight gain, infant-caregiver 
attachment, and women’s well-being at 28 days.  
  
  
 

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1. Hypothesis, aim, objectives, and outcomes  
1.1 Aim   
To examine the impact of KMC initiated before stabilisation relative to standard care amongst neonates 
≤2000g at four hospitals in Uganda.  
1.2 Primary Hypothesis for the trial  
Neonates ≤2000g in the arm allocated to receive KMC before stabilisation will have a 25% overall 
reduction in mortality within 7 days compared to neonates allocated to receive standard care.  
1.3 Objectives   
The primary objective of the study is to:  
1. Determine the effect of KMC initiated before stabilisation on mortality within 7 days relative to 
standard care amongst neonates weighing ≤2000g.  
The secondary objectives of the study are to:  
1. Determine the effect of KMC initiated before stabilisation on other important clinical outcomes 
relative to standard care amongst neonates weighing ≤2000g.  
2. Estimate the incremental costs and cost-effectiveness of KMC initiated before stabilisation relative 
to standard care from the societal perspective.   
3. Explore causal pathways for the clinical effects of KMC initiated before stabilisation relative to 
standard care amongst neonates weighing ≤2000g.  
4. Examine the barriers and facilitators to initiating KMC before stabilisation to inform uptake and 
sustainability in Uganda.   
1.4 Outcomes for the trial  
1.4.1 Primary outcome  
The primary outcome is early neonatal mortality, defined as mortality within 7 days.   
1.4.2 Secondary outcomes   
• 
Prevalence of hypothermia at 24 hours post-randomisation  
• 
Mean duration of hospital admission (days and hours)  
• 
Mean time from intervention/control procedures starting to exclusive breastmilk feeding (days 
and hours)   
• 
Mortality within 28 days   
• 
Time from intervention/control procedures starting to clinical stabilisation (days and hours)   
• 
Time from intervention/control procedures starting to death (days and hours)   
• 
Frequency of readmission  
• 
Mean daily weight gain (g/day) at 28 days  
• 
Infant-caregiver attachment at 28 days  
• 
Women’s well-being at 28 days  
  

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2. Background  
2.1 Kangaroo Mother Care to Improve Neonatal Survival  
Each year, 15 million babies are born preterm (<37 completed weeks gestation) and 1 million deaths 
occur as a direct result of complications of preterm birth (16,17,25). Sub-Saharan Africa and South Asia 
account for three-quarters of the 2.6 million neonatal deaths that occur annually, and preterm birth is 
the leading cause of these deaths (15). Progress in preventing preterm birth has been limited, but major 
reductions in mortality could be achieved by improving care in low-resource settings (16,17,26,27). In 
such settings, 50% of neonates born at 32 to 34 weeks gestation, a time when nearly all should survive, 
die because newborn special care is not available (17,22). KMC is a package of care, which consists of: 
early, continuous, and prolonged skin-to-skin contact (SSC), usually with the mother; promotion of 
exclusive breast milk feeding; early hospital discharge; and adequate support and close follow-up at 
home (3). The most recent Cochrane review and a meta-analysis demonstrated that KMC among 
stable neonates ≤2000g is associated with decreased mortality (RR 0.60-0.64) (20,21), sepsis (RR 
0.35-0.53) (20,21), hypothermia (RR 0.22-0.28) (20,21), hypoglycaemia (RR 0.12) (21), and length of 
stay (mean difference -1.61 days) (20) compared to conventional care. WHO guidelines recommend 
KMC for “routine care of newborns weighing ≤2000 grams (g)… initiated as soon as newborns are 
clinically stable” (8), where stability has been defined as vital functions (breathing, circulation) not 
requiring “continuous medical support and monitoring,” and not being “subject to rapid and unexpected 
deterioration” (5).   
KMC works through multiple pathways, many of which are mediated by skin-to-skin contact triggering a 
primary neuro-endocrine mechanism involving oxytocin as a key mediator with systemic effects in both 
mother and neonate. The key causal pathways underpinning the protective benefit of KMC are: thermal 
control; reduction in cortisol and stress response; cardio-respiratory stabilisation; enhanced breastmilk 
supply and breastmilk feeding; and empowering the mother as key carer for her baby. Although 
previously extensively researched in stable babies receiving skin-to-skin contact, the validity and 
relative contribution of these pathways in skin-to-skin contact in neonates prior to stability is not fully 
known. Further research is therefore warranted to improve our understanding of the physiological 
processes underpinning any potential benefit of KMC in this population.    
2.2 Gaps in the Evidence regarding Kangaroo Mother Care  
Estimates suggest that ≥75% of neonatal deaths occur prior to stabilisation in settings without intensive 
care (16,17,22). A notable gap exists in the evidence supporting the use of KMC in this vulnerable 
population. The only RCT of KMC in neonates before stabilisation with mortality outcomes was 
conducted in Ethiopia (123 neonates ≤2000g) and reported major mortality impact [RR 0.57, 95% 
confidence interval (CI) 0.33-1.00] (4)] (23). Notably, this trial excluded >50% of eligible neonates, did 
not utilise allocation concealment, and had an apparent imbalance between groups (favouring KMC) at 
baseline, with a greater proportion of those receiving standard care being born at gestational ages (GA) 
<32 weeks or weighing <1250g (4,9). Among 17 RCTs (14 enrolled only ‘clinically stable’ neonates) 
comparing KMC with conventional care in low birthweight (LBW, <2500g) neonates aged <15 days, 
there was significant variability in how clinical stability was defined. Six defined this based on therapies  
(28–33), five on ‘hemodynamic stability’ (23,34–37), and three on specific vital sign parameters (38– 
40), while three provided no definition at all (41–43). Hence codifying stability criteria for KMC is critical.  
A recent WHO guideline for care of preterm neonates highlighted evidence gaps regarding the effect of 
KMC on mortality amongst neonates that are not yet stable. These included absence of criteria to 

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identify which neonates are stable enough to safely receive KMC; the optimal time for initiation; and the 
duration required to reduce mortality (8).   
There are few published economic evaluations of KMC, and none conducted rigorously in low-income 
countries from a societal perspective, or with systematic equity assessment. Cost analyses have 
consistently found that KMC for LBW neonates resulted in cost savings for the hospital or provider 
relative to conventional care but have not considered whether KMC may increase costs to households 
nor specifically considered KMC initiated before stabilisation. Such studies have included a multi-centre 
RCT in Mexico, Ethiopia, and Indonesia (29), an RCT at one hospital in Colombia (44), and 
implementation studies in one Nicaraguan (45) and one Brazilian hospital (46), all of which compared 
costs of KMC and standard care in LBW neonates; and an evaluation of a programme to increase 
overall rates of KMC and breastfeeding at 18 neonatal units in the UK (47).  
2.3 Neonatal Care in Sub-Saharan Africa and Uganda  
Compared to other regions of the world, sub-Saharan Africa has experienced slow progress towards 
reducing neonatal mortality, particularly mortality due to preterm birth (25). This is likely to be due to 
higher preterm prevalence and lower access to care (17,22), and shortages of neonatal healthcare 
providers (18,48). Further, many interventions are introduced to low-resource settings without adequate 
evidence of their effectiveness in such settings (17,18). Incubators, the standard mode of thermal 
support for small and preterm neonates, are often unavailable or fail to function due to resource-related 
difficulties such as inconsistent electricity supply or access to replacement parts. Further, they require 
regular disinfection; however, this is often not done in resource-constrained settings (49). Other 
potential issues include risk of cross-infection from other neonates when incubators are shared, and 
cost (50–52).   
Over the past decade in Uganda, the neonatal mortality rate has remained relatively stagnant (27-28 
deaths per 1,000 live births), while under-5 mortality declined from 83 to 64 deaths per 1,000 live births 
over the same period (53). In Uganda alone, an estimated 36,000 newborn deaths occur annually (15), 
over a quarter of which are due to complications of prematurity (54). In 2006, the Ugandan government 
established a Newborn Steering Committee, which advised immediate action to increase the scale-up 
of KMC in facilities (55), and all district hospitals now have KMC. Evidence for the large-scale 
effectiveness and sustainability of KMC is lacking (17,18). This trial will address these evidence gaps 
and results may facilitate further scale-up in Uganda and in similar hospital contexts elsewhere.  
2.4 Formative Work   
A study demonstrating the feasibility of KMC initiated prior to stabilisation amongst neonates ≤2000g 
was undertaken at Jinja Regional Referral Hospital in Uganda in 2016, led by Dr Medvedev (Morgan). 
The findings, which are summarized below, were published in the Journal of Global Health in 2018 (56).  
Finding 1: Sufficient numbers of neonatal admissions met eligibility criteria: To determine the number of 
eligible neonates, audit data were collected on neonates admitted between June 2015 and May 2016.  
We also reviewed current practices to inform coding of neonates as ‘before stabilisation,’ i.e., for whom 
the indication for KMC is currently “uncertain.” A total of 268 charts were reviewed, among which 254 
met birthweight criteria and were complete. Amongst these, 226 (89%) were receiving ≥2 care 
therapies (Table 1). Among neonates who received only one therapy, the majority received empiric 
antibiotics because they were at risk of infection (i.e., not given for suspected or confirmed infection), a 
common practice in preterm/LBW neonates and frequently given to newborns considered stable. For 

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this reason, this enrolment criterion has been modified to receipt of ≥1 therapy excluding empiric 
antibiotics. Hence based on admission data in JH showing ~480 neonates ≤2000g, we anticipate ≥400 
admissions to be eligible each year at JH (see Section 10.1 for information on other sites).  
  
Table 1: Number of care therapies received amongst neonates in admissions audit (N=254)  
Number of 
therapies 
received*  
Frequency (%) of  
≤2000g neonates 
N=254  
95% CI  
Frequency (%) of  
<1500g neonates 
n=110  
95% CI  
Frequency (%) of  
<1000g neonates 
n=29  
95% CI  
0 to 1  
29 (11.4)  
7.8-16.0  
11 (10.0)  
5.1-17.2  
3 (10.3)  
2.2-27.4  
2  
73 (28.7)  
23.3-34.7  
32 (29.1)  
20.8-38.5  
4 (13.8)  
3.9-31.7  
3  
105 (41.3)  
35.2-47.7  
47 (42.7)  
33.3-52.5  
19 (65.5)  
45.7-82.1  
4 to 5  
47 (18.5)  
13.9-23.8  
20 (18.2)  
11.5-26.7  
3 (10.3)  
2.2-27.4  
*Oxygen, IV fluids, phenobarbital, antibiotics (empiric or for presumed/confirmed infection)  
  
Finding 2: Monitoring and provision of concurrent care therapies was feasible in the KMC position: To 
demonstrate the feasibility of monitoring and providing care therapies (oxygen, IV fluids, etc.) in the 
KMC position, we enrolled a sample of 10 neonates meeting proposed trial eligibility criteria between 
July and December 2016. Gestational age was determined by Ballard examination (57). Mothers were 
counselled to provide KMC ≥18h per day. During interruptions when mothers carried out activities like 
bathing, a family member was encouraged to provide KMC. If none was available, the neonate was 
placed in an incubator until the mother returned. Neonates were otherwise managed according to unit 
guidelines. All neonates received continuous monitoring of SpO2 and HR.   
Among the 10 neonates enrolled, median birthweight was 1310g [interquartile range (IQR) 820-1600g], 
median gestational age was 28 weeks (IQR 26-31 weeks), and median length of stay was 10 days (IQR 
9-14 days). Eight neonates were discharged home and two died. Both neonates that died were 
extremely premature (26-27 weeks) and extremely LBW (700-750g), thus at very high risk of death, 
particularly in a low-resource setting given the lack of ventilatory support and other intensive care 
usually required for survival at this gestational age. The median duration of individual KMC episodes 
ranged from 115 to 134 minutes, and the median daily duration ranged from 4.5 to 9.7 hours, with a 
slight upward trend over time. Two neonates received the target duration of 18 hours of KMC on day 1 
(18.1 and 21.6 hours) and one neonate received the target duration on day 5 (18.3 hours) (see Section  
17 for discussion about KMC compliance). The mean number of care therapies received ranged from 
3.7 to 4.1 per day across the first 14 days, and the number of therapies a neonate was receiving did not 
affect the daily duration of KMC. Continuous SpO2 monitoring was conducted throughout the enrolment 
period for all participants, and providers did not report any problems with monitoring or care provision.  
Finding 3: KMC (prior to stabilisation) and randomisation were acceptable to parents and providers: 
From May to July 2016, we interviewed 10 parents (8 mothers, 2 fathers, different to those above) and 
10 providers (8 nurses, 2 doctors) to evaluate acceptability of KMC for neonates prior to stabilisation. 
Over 80% of stakeholders reported acceptability of KMC among neonates <48 hours post-birth who are 
receiving other therapies. A few mothers expressed concern that KMC might cause pain or displace 
IV/oxygen tubing, as also found in KMC studies in high-income settings (58,59). Parents and providers 
suggested that KMC practice could be improved through staff and peer-counselling, more beds/space, 
and improved availability of monitoring devices. All providers and parents were eager to participate in 
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Among parents who were unwilling, most had stabilised newborns who were already receiving KMC, 
suggesting these parents may be more open to randomisation prior to stabilisation when neonates 
normally receive standard incubator care. Providers expressed confidence that most parents would be 
amenable with thorough counselling.  
Two clinical trials with similar objectives and outcomes to the OMWaNA trial are currently in progress in  
The Gambia [eKMC (60)] and multiple LMICs [(Ghana, India, Nigeria, Malawi, Tanzania); I-KMC (61)], 
and are investigating the use of early (started at <24h of admission) and immediate (started within 2h of 
birth) KMC, respectively, compared to standard care (KMC initiated at >24h of admission) in mild to 
moderately unstable hospitalised neonates. The eKMC lead investigator, Helen Brotherton, is a 
collaborator on the OMWaNA trial, and learning from the eKMC trial has informed the development of 
the OMWaNA trial protocol. Efforts to align study processes and outcomes have been made to 
maximise our understanding of the impact of this intervention.    
2.5 Rationale for the OMWaNA study  
Globally, there are 2.6 million neonatal deaths each year, and most of these deaths occur in small 
neonates before stabilisation. The OMWaNA trial aims to assess the effectiveness of KMC in reducing 
mortality in a population where the benefits of KMC are currently uncertain, a finding that would have 
important implications for global health policies. The OMWaNA trial is innovative in that it will allow us to 
determine the effect of KMC initiated before stabilisation on neonatal mortality within 7 days. By 
comparing the incremental cost and cost-effectiveness of KMC relative to standard care, this trial will be 
the first to assess the value for money of KMC. These findings will be crucial to help ensure the 
sustainability of this intervention. In addition, as part of the wider study we will use data from the trial to 
explore the physiological mechanisms by which KMC may reduce mortality, which have been poorly 
researched to date.  
  
3. Study Setting and Design  
3.1 Study Setting  
The host institution for the trial will be the MRC/UVRI and LSHTM Uganda Research Unit in Entebbe. 
The trial willl be undertaken in collaboration with Makerere University and LSHTM. These institutions 
are internationally recognised centres of excellence for research, with significant experience conducting 
and monitoring RCTs.  
The study will be conducted in five sites in Uganda:  
• 
Jinja Regional Referral Hospital (JH)   
• 
Masaka Regional Referral Hospital (MH)   
• 
Entebbe Regional Referral Hospital (EH)   
• 
Iganga District Hospital (IH)  
• 
Kawempe National Refferal Hospital (KNRH)  
JH, EH, and IH each provide care to ~5,000 to 6,000 neonates per year. MH provides care to ~10,000 
neonates per year, and KNRH provides care to ~8,000 neonates per year. Current practice at these 
sites is to provide KMC for stable neonates ≤2000g, according to WHO guidelines. MH, EH, and KNRH 
have research linkages with MRC/UVRI, and JH and IH have linkages with Makerere. Makerere has 
established health surveillance systems in the Busoga region where JH/IH are located.  

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3.2 Design of the Trial  
This is a four-centre, individually randomised, controlled, superiority trial with two parallel groups; an 
intervention arm allocated to receive KMC and a control arm allocated to receive ‘standard’ care.  
3.2.1 Randomisation  
Treatment allocation will be random and in a 1:1 ratio between groups. The random allocation 
sequence will be computer generated centrally at LSHTM stratified by birthweight (<1000, 1000-1499, 
or ≥1500g) and recruitment site. Birthweight is an important predictor of newborn survival. Neonatal 
mortality is 2-fold higher in SGA term neonates and 15-fold higher in SGA preterm neonates compared 
to appropriately sized term neonates (16). At each site, a laptop will be programmed with the random 
allocation sequence. This will be done in RedCap to avoid any possibility of viewing the allocation 
sequence. Allocation will only be revealed after the study medical officer at the site has completed entry 
of the mother’s and neonate’s details and all required screening data (see Section 5.3) into RedCap. 
The entry details will then be transferred to MRC/UVRI. Each site will have one spare laptop in case of 
breakdown or theft; if both fail, the site will revert to random allocation using telephone as the back-up 
option.  
3.2.2 Blinding  
Given the nature of the KMC intervention, blinding parents/caregivers is not possible. Process and 
outcome data will be anonymised, and all analyses will be blinded.   
3.2.3 Details of the Intervention arm  
Neonates randomised to the intervention group will receive KMC along with conventional therapies  
(e.g., IV fluids, antibiotics, oxygen) delivered according to standardised clinical guidelines (see Section 
3.2.5). Parents will be encouraged to provide KMC as close to continuously as possible. While we 
anticipate the mother will be the primary KMC provider, a family member or close friend (helper) may 
also provide KMC. For interruptions due to mothers carrying out activities like bathing and going to the 
rest room, a family member or helper will be encouraged to take over KMC while the mother is away If 
the mother has no family member or helper to continue KMC, the baby will be placed into an incubator 
or radiant heater according to standard care until the mother or another family member returns.  
KMC will continue to be encouraged until discharge and at home after discharge, as per WHO 
guidelines (commonly practised until the baby is 2500g or around their due date or resists the KMC 
position, and this is often for 4 to 10 weeks).  
3.2.4 Details of the Control arm  
Infants randomised to the control group will receive standard neonatal care for that centre. Incubators 
and radiant heaters are the standard mode of thermal support for small and preterm neonates. It is 
common practice for several babies to share a single incubator. Conventional therapies will be 
administered according to standardised guidelines, as in the intervention arm. These include IV fluids 
(given by bolus or burette), respiratory support with nasal cannula oxygen and CPAP, first line IV 
antibiotics (ampicillin and gentamicin), and first line anti-seizure medications (phenobarbital). Feeding 
support in small and preterm infants is typically via nasogastric tube, spoon, syringe or cup. Infants in 
the control group can transition to routine (intermittent) KMC once stable (see Section 3.2.5), in line with 
study site standard clinical procedures.  

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3.2.5 Clinical Stability Criteria  
Neonates will be considered stable when the following criteria have been met for a continuous period of 
at least 24h [criteria consistent with the WHO I-KMC trial (61)]:  
(i) Breathing spontaneously with SpO2 >90% in room air  
(ii) No need for supplemental oxygen or CPAP   
(iii) Respiratory rate 40 to <60 breaths per minute  
(iv) No apnoea  
(v) HR 80 to <180 beats per minute  
(vi) Axillary temperature 36.0 to 37.4 degrees Celsius  
(vii) No need for IV fluids  
3.2.6 Concomitant Therapies and Medications  
All enrolled neonates will receive clinically indicated treatments, including but not limited to oxygen, IV 
fluids, antibiotics, aminophylline, anticonvulsant medicines, and phototherapy. Standardised clinical 
guidelines will be followed for common neonatal conditions, including preterm fluids/feeding (including 
breastfeeding), presumed and proven sepsis, respiratory distress, jaundice, and seizures. Bubble 
CPAP will be provided at the discretion of the on-duty paediatrician, if this is local standard of care. 
Jaundice will be treated with phototherapy for neonates in both arms. All caregivers will be trained in 
KMC regardless of study arm.  
3.3 Design of the Economic Evaluation  
The incremental cost, cost-effectiveness, budget impact, and equity of KMC for neonates before 
stabilisation relative to standard care, from the societal perspective (provider and household combined) 
will be examined, along with the effects of the intervention on both the health of babies (measured in 
disability-adjusted life-years, DALYs) and the wellbeing of the mothers and babies in the study. The 
economic evaluation will respond to decision makers’ key policy questions regarding KMC and adhere 
to the principles, methodological specifications, and reporting standards of the latest reference cases 
for economic evaluations (62,63). Both financial costs – actual monies paid – and economic costs – the 
full value of all resources used – will be assessed. We will consider cost variation (e.g., between 
hospitals) and how costs may differ outside the trial setting.  
We will utilise the Women’s Capabilities Index (WCI) to assess women’s well-being (13). The WCI is a 
multidimensional measure based on Sen’s capability framework for assessing women’s quality of life. 
Originally developed in Malawi, the WCI is now being adapted and tested for use in Uganda. It is an 
innovative composite measure of quality of life that will allow the broader benefits to the mother of 
practising KMC compared to standard care to be captured.   
3.4 Design of the Process Evaluation  
The process evaluation will explore causal pathways for the clinical effects of KMC initiated before 
stabilisation relative to standard care (Objective 2) and examine barriers and facilitators to initiating 
KMC before stabilisation to inform uptake and sustainability in Uganda (Objective 3). This evaluation 

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will consider both intended (beneficial) and unintended (negative) clinical effects, assessing how and 
why effects were attained and what systems changes will be required by whom as a result. The process 
evaluation will include focus group discussions (FGD) with neonatal healthcare providers, parents 
(intervention and control arms), and hospital administrators after 6 and 18 months of recruitment. In-
depth interviews (IDI) with mothers will explore social and cultural factors that may influence maternal 
coping and compliance with care recommendations. IDIs with parents whose babies died during the 
hospital stay, including those who experienced a death in the KMC position, will explore parental 
experiences of trauma and bereavement.  The process evaluation will include four phases (64):   
1) Design  
2) Pilot  
3) Evaluation  
4) Formation of recommendations to improve uptake (if intervention is found to be beneficial)   
The process evaluation will be designed with stakeholder inputs, conducting two half-day workshops 
prior to the start of the trial at MRC/UVRI in Entebbe. The first workshop will include district health 
authorities, local community leaders, paediatricians, newborn nurses, and parents. The second will 
include local academics (MRC/UVRI, Makerere University), professional health organisations (Uganda 
Paediatric Association), and national (Ministry of Health) and international (UNICEF, International KMC 
Network) policy-makers.  
  
4. Selection and Withdrawal of Participants  
4.1 Participants  
The trial will include neonates born weighing ≥700g and ≤2000g, aged >1 and <48 hours, and for whom 
the indication for KMC is “uncertain” according to WHO guidelines concerning clinical stability (3). The 
process and economic evaluations (Objectives 2-4) will include administrators, providers, and parents 
of neonates at the four hospitals.  
4.2 Eligibility Criteria for the Trial  
Participants must meet the following inclusion criteria and not have any of the exclusion critieria to be 
able to participate in the trial.   
4.2.1 Inclusion criteria  
• Neonate admitted to JH, MH, EH, IH, or KNRH (inborn or outborn)  
• Singleton, twin, or triplet (if triplet pregnancy resulted in demise/stillbirth of one or more fetuses)  
• Birthweight ≥700g and ≤2000g  
• Chronological age 1-48 hours at time of screening  
• Alive at time of recruitment  
• Parent/caregiver able and willing to provide KMC   
• Parent/caregiver willing to attend follow-up visit  
• Indication for KMC “uncertain” according to WHO guideline concerning clinical stability: 
pragmatically defined as receiving ≥1 therapy: oxygen, CPAP, IV fluids, therapeutic antibiotics, 
phenobarbital  

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4.2.2 Exclusion criteria  
• 
Result of multifetal pregnancy (triplets and above, unless triplet pregnancy resulted in demise/ 
stillbirth of one or more fetuses)   
• 
Indication for KMC “certain” according to WHO guidelines: pragmatically defined as clinically 
well neonates receiving none of the above therapy-based criteria  
• 
Severely life-threatening instability defined as SpO2 <88% in oxygen AND ≥1 of:   
- 
Respiratory rate <20 or >100 breaths/min   
- 
Apnoea requiring bag-mask ventilation   
- 
HR <100 or >200 bpm  
• 
Severe jaundice requiring immediate management   
• 
Active neonatal seizures  
• 
Major congenital malformation  
• 
Parent does not provide written informed consent to participate in trial (Appendix A)  
4.3 Eligibility Criteria for Focus Group Discussions and Interviews  
Participants must meet the following inclusion and exclusion criteria to participate in FGDs and 
interviews.   
4.3.1 Inclusion criteria  
• 
Key stakeholder (parent of hospitalised neonate, neonatal healthcare provider (nurse or doctor), 
hospital administrator) at JH, MH, EH, IH, or KNRH  
• 
Policy makers (WHO, UNICEF, Ministry of Health and Uganda Peadiatric Association member 
and other international bodies that support maternal and child health) 
• 
≥18 years of age (providers, administrators) or ≥15 years of age (parents)  
4.3.2 Exclusion criterion   
• Participant does not provide written informed consent to take part in FGD/interview (Appendix B)  
4.4 Withdrawal of Participants   
A study participant will be discontinued from participation in the study if any situation occurs such that 
continued participation in the study would not be in the best interest of the participant (see Section 9 for 
additional details). Participants are free to withdraw from the study at any time without giving a reason.  
  
5. Study Procedures  
All study procedures will be conducted in accordance with ICH-GCP principles and all research 
personnel involved in the study will undergo ICH-GCP training. Healthcare workers at the study sites 
will be trained on study objectives, overview of procedures, standardised management protocol and 
asked to inform study personnel of any potential participants and in the event of a clinical deterioration.   
5.1 Internal Pilot  
All study personnel will undergo training according to study specific procedures to ensure high quality 
recruitment, data collection, and intervention implementation (see Section 5.9). This will take place prior 

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to an internal pilot phase involving recruitment of 10 participants at each site; piloting of data collection 
tools and processes; and provision of the intervention alongside other medical therapies (e.g., oxygen, 
IV fluids). This will enable refinement of the study procedures and documentation. Initially, the internal 
pilot will take place at EH only. Once study personnel at EH demonstrate successful performance of 
trial procedures, the internal pilot phase will commence at the four remaining hospital sites (IH, JH, MH, 
KNRH). If procedures are judged to be adequate and in accordance with ICH-GCP principles, internal 
pilot participants will be included in the sample for the overall trial.   
5.2 Screening  
All new admissions to the newborn units at JH, IH, EH, KNRH and MH will be screened for eligibility by 
trained study staff. Eligibility will be assessed as soon as possible after admission and once the baby is 
aged 1h or older. This is in recognition of the large physiological changes that take place following 
delivery and that the stability of a newborn aged <1h may change rapidly and not accurately reflect the 
stability over the following 24h. All screening procedures will be performed by study nurses or medical 
research officers, with support from the study paediatrician at each site. Oral informed consent will be 
obtained from a parent/caregiver prior to the initiation of screening procedures.  
Screening procedures will take place at the radiant heater or incubator where the neonate has been 
admitted in the following order:   
1. Neonatal chronological age will be ascertained by questioning the parent/caregiver and/or examining 
the antenatal card, medical record, or referral notes.   
2. Weight will be measured using the study scale (Seca) to ensure weight is ≥700g and ≤2000g.   
3. A focused physical examination will be conducted to assess for the presence of visually recognisable 
major congenital malformations, severe jaundice, and seizures.   
4. A pulse oximeter with neonatal probe will be attached for continuous monitoring and documentation 
of HR and SpO2 for an initial 10 minutes.   
  
  

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5.3 Study Schedule  
Figure 1. Study schedule with overview of procedures and evaluations   
  

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5.4 Recruitment   
5.4.1 Sensitisation  
General sensitisation will be conducted at the four study sites, surrounding antenatal clinics, and major 
referral centres, aiming to raise awareness of both KMC and the planned study. This will begin prior to 
the internal pilot and continue throughout the duration of the study.   
Following identification of an eligible participant, initial sensitisation of the parent/caregiver will be done 
by telling them about the study and inviting them to participate.  
5.4.2 Informed consent  
Written informed consent will be sought from the parents of all participants for the following neonatal 
participation: inclusion in the study; collection of sociodemographic data; collection of clinical data; and 
randomisation to study arm. Consent will also be taken for the possibility that the parent/caregiver will 
provide continuous skin-to-skin contact, if randomised to that arm. Additionally, consent will be taken for 
the collection of household socioeconomic and cost data, as well as data on infant-caregiver 
attachment and women’s well-being.  
Medical officers or study nurses will obtain informed consent. The preferred person to provide informed 
consent for neonatal involvement is the mother. If a mother is unavailable or too ill to provide consent, 
informed consent will be obtained from the father. Once the mother is available and feeling well 
enough, the informed consent process will be repeated to confirm her consent for her baby’s continued 
participation in the study.   
Impartial and literate witness will be used during consent for illiterate parents, as per ICH-GCP 
guidance.   
Further details regarding the informed consent process are detailed in section 14.5.  
5.4.3 Enrolment  
Following informed consent, a unique study identification number will be allocated, and the neonatal 
enrolment log will be completed. A separate maternal/caregiver enrolment number will be allocated, 
and a maternal/caregiver enrolment log sheet completed to identify and link the unique study ID 
numbers of parent/caregiver and neonate. This will include options for entering multiple caregivers, in 
the event of the mother not being available immediately and other family members providing the 
intervention.  
5.5 Collection of Baseline Data  
5.5.1 Clinical data  
Study staff will collect the following clinical data as soon as possible after enrolment, with the exception 
of gestational age assessment and length measurement, which may be delayed to within 48h of 
admission. If any medical therapies (e.g., oxygen) have already been started by study staff, these will 
be continued throughout the clinical data collection process.  

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Research staff will be trained in appropriate infection control procedures and study specific protocols 
will detail infection control measures for the use of study equipment (pulse oximeters, weighing scales, 
etc.) to avoid cross-infection and contamination between participants.  
• 
Axillary temperature will be measured with a digital thermometer (in degrees Celsius). Three 
measurements will be taken to enable calculation of the mean value.  
• 
A capillary sample for blood glucose measurement will be obtained by heel prick using 
appropriately sized lancets and study-specific blood glucose machines at each site.   
• 
Physical examination will be conducted.  
• 
Head circumference [occipitofrontal circumference (OFC)] will be measured. •  
Gestational 
age will be estimated using the Ballard score (Appendix C)  
• 
Crown-foot length will be measured.  
The collection of baseline clinical data is estimated to take approximately 30 minutes, not including 
gestational age and length measurement. Data will be recorded in the eCRF (Appendix D) by trained 
study staff.    
5.5.2 Sociodemographic data  
Following the collection of baseline clinical data (with exception of gestational age and length 
measurement), trained study staff will collect the following sociodemographic data using standardised 
parent interviews and medical records (antenatal and hospital). Data will be recorded in the eCRF by 
trained study staff.    
• 
Maternal details: contact details; date of birth; marital status; employment; highest level of 
education; date of last menstrual period (LMP); significant medical history; antenatal history 
(gravidity, parity, complications, interventions)   
• 
Perinatal details: mode of delivery; presence of sepsis risk factors; administration of antenatal 
steroids and antibiotics in preceding 7d; APGAR scores; date and time of birth   
• 
Neonatal details: gender; age at admission; admission diagnoses; multiple birth; interventions 
since birth (resuscitation, medications, other therapies)   
• 
SARS-CoV-2 signs/symptoms and testing status/results for mothers and babies recruited after 
25 March 2020   
5.5.3 Socioeconomic Data  
Trained study staff will collect the following socioeconomic data within 48h of admission, using 
standardised parent interviews. Data will be recorded in eCRF by trained study staff.    
• 
Women’s Capability Index: questionnaire to be administered to mothers immediately following 
collection of the above maternal sociodemographic data   
• 
Household details: household density; number of children; occupation and highest educational 
level of other household members; data to be obtained as soon as is practical (may be collected 
after randomisation/allocation in order to avoid delays in starting intervention)  
Trained study staff will also inform families that, over the coming month, they will be asked about their 
expenditures and the activities of members of their household (and any extended family members who 
become involved in care provision) in order to evaluate the economic impact of KMC relative to 
standard care. Data that will be collected includes the following:  

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• 
Expenditures: Medical supplies/hospital fees; food; transport  
• 
Activities: Extent to which members of their household (and any extended family who become 
involved in care provision) were able to participate in their usual activities (paid work, household 
work, farming own land, or school/play) versus took time to care for/support the baby and/or 
parents, and any income/revenue lost as a result of this.  
5.6 Randomisation  
Randomisation will take place following collection of necessary baseline data and before the 
intervention or control procedures start. The details of the randomisation method are outlined in section 
3.2.1. In situations where both twins are eligible for enrollment, they will be allocated to the same arm.  
5.7 Intervention and Control Arms  
After the completion of recruitment and randomisation procedures and any required medical procedures 
according to clinical care guidelines, neonates will be allocated to receive either the intervention or 
standard care.   
5.7.1 Delivering the intervention arm  
KMC will be initiated as soon as possible following randomisation. Neonates allocated to the 
intervention arm will be naked except for hat and diaper. They will be secured to the exposed chest of 
the mother/caregiver using a KMC wrap. Prior to placing the neonate in the skin-to-skin position, a 
study nurse or medical officer will attach a pulse oximetry probe to the hand and a temperature probe to 
the torso. These procedures will take place in the admission area, prior to moving the baby to the study 
area. On arrival at the study area, the mother/caregiver will be seated on an adjustable bed. If required, 
oxygen will be provided from a cylinder or concentrator (depending on available resources at each site). 
Oxygen will be delivered to the neonate via nasal cannula or mask (if CPAP is required). If IV fluids are 
required, a bag of IV fluids will be hung and an IV cannula will be placed by a study nurse or medical 
officer. The study nurse or medical officer will then initiate IV fluids, with drip rate calculated according 
to standardised guidelines. If the mother/caregiver needs to take a short break (e.g., to shower or use 
the restroom), the neonate will be placed in an incubator or under a radiant heater. Every effort will be 
made to encourage skin-to-skin contact for 18h/day, unless otherwise clinically indicated. While we 
anticipate the mother will be the primary KMC provider, a family member or close friend (helper) may 
also provide skin-to-skin care in order to avoid disruptions. Clinical study staff at each site will counsel 
mothers/caregivers about KMC throughout the hospital stay, including the time of discharge. In addition, 
mothers who practised KMC as participants may be engaged as peer-counsellors when they return for 
follow-up. For each episode of skin-to-skin contact, the caregiver providing KMC (e.g., mother, father, 
helper) and the time of initiation and duration will be monitored and recorded in the electronic CRF 
(using bedside tablets).   
5.7.2 Delivering the control arm  
Neonates allocated to the control arm will be placed in an incubator or under a radiant heater, as per 
standard management at the study sites. They will wear a hat and be wrapped as per standard care.  
Oxygen will be provided from an oxygen cylinder or concentrator and IV fluids will be securely attached 
via an IV cannula with drip rate calculated, as in the intervention arm. The pulse oximeter will be placed 
inside the incubator or next to the radiant heater. The parent/caregiver will be able to touch the baby, if 

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requested, but will not provide any skin-to-skin contact until he/she meets clinical stability criteria (see 
Section 3.2.5), which are consistent with those used in the WHO I-KMC trial and in line with standard 
clinical procedures at the study sites. Once stable, the baby can transition to routine (intermittent) KMC 
with the parent/caregiver in a chair or bed in the study area.   
  
5.8 Follow-up  
Participants will be followed daily while admitted to the hospital (see section 6.1.2 for additional details).   
At the time of discharge, all parents/caregivers will be provided with an illustrated handout on neonatal 
danger signs and instructed to contact the site study team or seek medical help if their baby becomes 
unwell. All families will be provided with phone numbers to contact the study team and a study 
participant ID card. Parents/caregivers will receive UgSh 20,000 (per enrolled neonate) to cover the 
costs of transport home and they will be able to keep the KMC wrap, so they can continue KMC at 
home (parents/caregivers of babies in both arms will be encouraged to continue KMC at home).  
All participants will be given an appointment to attend the neonatal follow-up clinic at the respective 
study site on day 28-30. Transport costs (UgSh 20,000 per enrolled neonate) will also be provided to 
cover the costs of return transport to the study site for the follow-up visit. At this visit, repeat cUS 
(KNRH and JH only) and anthropometry will be performed; feeding practices and outcomes (alive, 
dead, readmitted) will be documented; and the WCI and Maternal Infant Responsiveness Instrument 
(MIRI) questionnaires will be administered to mothers.   
If participants are discharged prior to day 7, additional follow-up will be arranged according to study 
site:   
• 
At KNRH and JH, participants will be given an additional appointment to attend the neonatal 
follow-up clinic on day 7, where repeat cUS will be performed and outcomes (vital status, 
readmitted) will be recorded. If day 7 falls on a weekend, participants will be phoned on day 7 to 
ascertain outcome and the appointment will be made for the closest working day (e.g., if day 7 
is Saturday, appointment on Friday; if day 7 is Sunday, appointment on Monday).  
• 
At IH and MH, participants will be phoned on day 7 to ascertain outcome (alive, dead, 
readmitted) and reminded to attend the neonatal follow-up clinic appointment on day 28-30.  
If participants do not attend follow-up clinic, a telephone call will be made the same day to ascertain 
outcome and feeding practices and to arrange follow-up, either in the clinic or at the families’ home, as 
soon as possible. Routine follow-up beyond the planned study follow-ups will be provided by the study 
site staff according to standard practice and clinical need of the baby.   
5.9 Staff Training  
5.9.1 Clinical trial training workshop at MRC/UVRI before start of trial  
The trial coordinator, data managers, and all site staff will attend a 5-day clinical trial training workshop 
at MRC/UVRI in July/August 2019. The workshop will facilitate staff becoming knowledgeable about the 
trial protocol and procedures; data entry and data management; other standard operating procedures; 
ethical conduct of research; and ensuring privacy and confidentiality.   

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5.9.2 Site staff training on neonatal care and clinical guidelines before start of trial   
The trial coordinator and the paediatricians, medical officers, and nurses at the 4 sites will attend an 
additional 5-day training on neonatal care and clinical guidelines at MRC/UVRI in July/August 2019. 
This training will facilitate staff members’ proficiency in the following areas: KMC guidelines; 
standardised guidelines for common neonatal conditions; Ballard gestational age scoring; pulse 
oximetry monitoring and recording; and counselling parents/caregivers. Training will emphasise 
counselling parents/caregivers about the potential for mortality at the time of enrolment, as well as 
counselling parents/caregivers of neonates who die or have a life-threatening event and those who 
witness a death. Paediatricians and medical officers at KNRH  and JH will also be trained in the 
acquisition of cranial ultrasound (cUS) images.   
5.9.3 Refresher trainings throughout trial  
The trial coordinator and site paediatricians will conduct regular quality improvement activities, including 
refresher training on KMC and standardised guidelines, throughout the duration of the trial.  
  
6. Study Evaluations  
6.1 Clinical Evaluations   
6.1.1 Evaluations during first 24 hours  
All participants will receive continuous monitoring and recording of HR and SpO2, using a pulse 
oximeter, for 72h post-randomisation. Continuous monitoring will continue until participants no longer 
require any form of respiratory support.   
Axillary temperature and respiratory rate will be manually measured every 6h for the first 24h. All 
participants will be evaluated at least once by a study paediatrician or medical officer during the first 
24h post-randomisation. Blood glucose will be measured every 6h, unless <2.6 mmol/l in which case it 
will be measured hourly until 2 or more consecutive readings are in normal range (2.6 – 6.9 mmol/L).  
6.1.2 Evaluations from 24 hours to hospital discharge  
All participants will be followed at least daily while admitted to the hospital. Unless otherwise noted, the 
following data will be collected and recorded in eCRFs daily from 24h through day 7 of life, then weekly 
on days 14, 21, and 28. If participants are discharged prior to day 7, additional follow-up will be 
arranged according to study site (see Section 5.8 for additional details).   
a) Participants will receive monitoring of HR, SpO2, respiratory rate, and axillary temperature every 
6h until they meet stability criteria (see Section 3.2.5), after which the frequency of monitoring will 
transition to daily. Measurements will be recorded in eCRFs. Please refer to Section 8.1 for 
additional details on clinical monitoring.    
b) Daily review with the following data documented:  
• 
Date and time of starting to receive breast milk (may be given by nasogastric tube, spoon, 
syringe, etc)   
• 
Date and time of starting breastfeeding   

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• 
Date that full breast milk feeding is established   
• 
Daily IV fluid volumes and drip rates   
• 
Medications administered each day, including dosage and route of administration  
• 
Therapies administered each day, including flow rate and mode of delivery for neonates 
receiving oxygen  
• 
Daily measurement of blood glucose (may be discontinued once neonate is tolerating full 
enteral feeds)  
• 
Compliance with the standardised management protocol and discussion of any deviations 
with the site paediatrician or medical officer   
• 
Documentation about skin-to-skin contact:   
o Date and time of skin-to-skin contact initiation   
o  Duration of skin-to-skin contact/day (hours and minutes) o Caregiver 
providing skin-to-skin contact   
o Whether skin-to-skin contact is temporarily discontinued and 
date/time of this event   
• 
Documentation of any change in clinical condition warranting temporary cessation of 
intervention and date/time of temporary cessation   
• 
Identification of any SAE  
• 
Documentation of any reason to suspect mother and/or baby is infected with SARS-CoV-2  
(based on signs/symptoms or testing status) for babies recruited after 25 March 2020  
c) Weighed on day 5, then daily until discharge (unless deemed too unstable by site study staff); 
weighing to be in clustered with other activities (e.g., diaper changes)  
d) OFC and length will be measured weekly using study-specific equipment  
e) For participants at KNRH and JH, cranial ultrasounds (cUS) will be performed on days 1, 3, and 
7 of the hospitalisation, or as an outpatient if discharged before day 7 (see Section 6.1.6 for 
additional details)  
6.1.3 Evaluations in event of clinical deterioration  
Study staff at all sites will be trained to recognise signs of severe illness according to adapted possible 
serious bacterial infection (aPSBI) criteria (Figure 2a) and to inform study staff if a participant meets any 
of these criteria. The study paediatrician or medical officer (or study nurse if neither is present) will then 
examine the neonate as soon as possible to assess whether signs of early-onset (<72h of age) or late-
onset (≥72h of age) infection (Figure 2b) are present. Neonates will be reassessed for signs of severe 
illness and infection during daily rounds. Where available, a blood culture will be obtained as soon as 
possible if a neonate meets criteria for suspected infection; however, this will not delay administration of 
antibiotic therapy. The site paediatrician (or medical officer, if paediatrician not present) will direct 
management in accordance with standardised clinical guidelines, including starting CPAP if this is local 
standard of care. The paediatrician or medical officer will then complete the appropriate safety 
monitoring documentation. Study staff will also assess if the neonate meets criteria for temporary 
withdrawal from the intervention arm (see Section 9). At the discretion of the study paediatrician and in 
line with current neonatal unit policies at each site, neonates may be referred to a higher-level facility 
for more specialised care; however, existing data indicate that this is an uncommon occurrence.   

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Figure 2a. Screening criteria for severe illness   
Newborn unit staff to inform the study team as soon as possible if any of the following are present:   
- Refusal to feed, feed intolerance or abdominal distension (after starting to feed)  
- Lethargic (unresponsive or responsive only with tactile stimulation)   
- Respiratory rate >80 breaths/min or severe chest wall in-drawing or new oxygen/CPAP requirement  - 
Apnoea (new onset and/or persistent)  
- Seizures  
- Axillary temperature >37.5 degrees Celsius  
- Axillary temperature <35.5 degrees Celsius (after 1h of observed skin-to-skin contact, not associated 
with environment or with hypoglycaemia)  
Figure 2b. Additional criteria for investigation of suspected early- or late-onset infection amongst 
neonates screened positive for signs of severe illness   
Obtain blood culture if criteria for severe illness met, plus 1 of:   
- Axillary temperature >37.5 degrees Celsius   
- Axillary temperature <35.5 degrees Celsius (after 1h of observed skin-to-skin contact)  - Jaundice  
- Apnoea (new onset and/or persistent)  
- Hepatomegaly  
- Pallor  
- Lethargy (unresponsive or responsive only with tactile stimulation)  
6.1.4 Procedures at time of discharge/death  
Participants will be discharged by site study staff when they meet criteria for discharge from the 
newborn unit. The following data will be documented on the eCRF within 24h of discharge or death.   
• 
Date and time of discharge/death  
• 
Cause of death if died  
• 
Diagnoses at time of discharge/death  
• 
Most recent weight before discharge/death  
• 
Details of feeding at time of discharge/death  
• 
SARS-CoV-2 signs/symptoms and testing status/results for mothers and babies recruited after 
25 March 2020   
At time of discharge, parents/caregivers will be provided with an illustrated handout on neonatal danger 
signs and instructed to contact the site study team or seek medical help if their baby becomes unwell 
before the day 28-30 follow-up appointment. Families will be provided with phone numbers to contact 
the study team and a study participant ID card.  
6.1.5 Procedures at follow-up  
At the 28-30-day follow-up visit, we will record:  
• 
Breastfeeding status  
• 
Anthropometric measures (weight, OFC, length)  

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• 
SARS-CoV-2 signs/symptoms and testing status/results for mothers and babies recruited after 
25 March 2020   
For participants at KNRH EH and JH, repeat cUS will be performed at the 28-30-day visit (see Section 
6.1.6 for additional details). For the MIRI, trained study staff will administer a brief, validated set of 
questions to all mothers at the 28-30-day visit.  
6.1.6 Cranial ultrasound imaging  
For participants at KNRH  and JH, cUS will be performed on days 1, 3, 7, and 28-30 to examine for the 
presence of intracerebral pathology associated with morbidity and mortality amongst preterm infants. 
This includes intraventricular haemmorhage, cystic degeneration, and later hydrocephalus. The study 
paediatrician or medical officer at the respective sites will perform cUS using a portable ultrasound 
machine (Sonosite Edge II). Both standard and linear probes will be used to assess for abnormalities 
according to a defined protocol and to include a minimum of 11 coronal and sagittal views. Images will 
be read by an independent expert.    
6.2 Economic Evaluation  
For cost data collection for households, the project, and the hospital perspectives, multiple data sources 
will be triangulated to arrive at best estimates. Where possible, resource use and unit costs will be 
collected and presented separately, although some costs, such as out-of-pocket payments for transport 
do not permit this. Household costs will be collected through surveys that will be conducted with a 
sample of the caretakers at the time of discharge and during follow-up visits.       
Project costs will be collected prospectively from project accounts using an Excel-based costing tool. 
These will be supplemented with time sheets and key informant interviews to inform allocation of joint 
costs. Direct and indirect costs incurred by providers will be collected prospectively and retrospectively 
using key informant interviews, facility audits, direct observations, and time-use surveys. As necessary, 
we may supplement secondary data on costs of treating subsequent conditions with limited primary 
data collection in the Ugandan study hospitals. We will model costs and effects using a lifetime time 
horizon.  
6.2.1 Evaluations at time of enrolment  
For the WCI, trained study staff will administer a brief, validated set of questions to all mothers at the 
time of enrolment (may be delayed to within 48h of admission). Study staff will also collect 
socioeconomic data at this time using standardised parent interviews (see Section 5.5.3).   
6.2.2 Evaluations during hospitalisation  
For household costs, direct and indirect household costs will be collected prospectively using time-use 
and expenditure surveys and observation of families during their hospital stay. At time of 
discharge/death, information regarding the time period from admission to discharge will be captured 
using standardised parent interviews.  
6.2.3 Evaluations at follow-up  
At the 28-30 day follow-up appointment, trained study staff will readminister the WCI questionnaire to all 
mothers. In addition, they will ask questions to ensure that costs are captured for the entire neonatal 
period and to inquire about families’ plans going forward.   

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6.3 Process Evaluation  
The process evaluation will be conducted in accordance with the MRC guidance on process evaluation 
of complex interventions (65) and will integrate both quantitative and qualitative data. In-depth 
interviews and focus group discussions (FGD) will be undertaken with parents/caregivers, staff, and 
other key stakeholders as part of the qualitative evaluation to identify experiences of KMC, facilitators 
and barriers to implementation and complex causal pathways. An iterative approach to qualitative 
analysis will be used with data collected at several time points and then used to inform later 
explorations.  
6.3.1 Understanding causal pathways for clinical effects  
Understanding the causal pathways for clinical effects of the intervention (Objective 2) will be achieved 
by measurement of the following process outcomes, which are categorised as providing very early 
(within 24 hours), early (within 72 hours), or late clinical impact:  
Very early impact:  
• 
Cardio-respiratory stability within 24 hours post-randomisation  
• 
Prevalence of hypothermia within 24 hours post-randomisation  
• 
Hypothermia density within the first 24 hours post-randomisation  
• 
Prevalence of hypoglycaemia within 24 hours post-randomisation  
Early impact:  
• 
Cardio-respiratory stability within 72 hours post-randomisation  
• 
Prevalence of hypothermia within 72 hours post-randomisation  
• 
Hypothermia density within the first 72 hours post-randomisation  
• 
Prevalence of hypoglycaemia within 72 hours post-randomisation  
• 
Presence and severity of IVH within 72 hours post-randomisation  
Late impact:  
• 
Presence and severity of IVH at day 7  
• 
Proportion of neonates exclusively breastmilk feeding at discharge  
• 
Presence of late intracerebral sequelae of prematurity (e.g., hydrocephalus, cystic 
degeneration) at day 28-30  
6.3.2 Focus Group Discussions  
To examine the barriers and facilitators to initiating KMC before stabilisation to inform uptake and 
sustainability (Objective 3), we will conduct FGDs with each of the following groups: 1) providers 
(nurses); 2) parents (intervention and control arms). Each FGD will include 4-8 participants. FGDs 
conducted will broadly explore barriers and enablers to implementation of KMC before stabilisation and 
encourage participants to collectively identify potential solutions. Based on findings from the literature 
(58,59,66) and our feasibility study (56), discussion topics may include perceptions about initiating KMC 
before stabilisation (e.g., fear of touching small babies or dislodging oxygen masks/IV lines); parent and 
provider experiences with clinical care and monitoring during KMC and/or incubator care; and 
implementation experiences in the four hospitals [e.g., staff and peer-counselling (for parents), clinical 
training and guidelines (for providers), and administrative support].   

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6.3.3 Interviews  
IDIs will be conducted with a random sample of ~24-32 care givers/family members (mother, father, and 
grandmother) selected for from both arms of the trial to explore social and cultural factors (e.g., 
family/community support, faith, stigma about preterm birth) that may influence maternal coping and 
compliance with care recommendations. To further inform context specific evidence on the uptake and 
sustainability of KMC, additional IDIs will be conducted at each site with the following stakeholders: 
healthcare providers involved in the care of LBW babies (1 paediatrician, 1 medical officer, 2 nurses); 
hospital leadership (hospital director or administrator). More interviews will be conducted with national 
leadership (Ministry of Health/Newborn Steering Committee and Uganda Paediatric Association 
member) and policymakers (WHO, UNICEF and other international bodies that support maternal and 
child health). 
IDIs with a purposive sample of ~16 parents (8 from each arm) whose babies died during the hospital 
stay will explore parental experiences of trauma and bereavement. The sub-sample from the 
intervention arm will include parents who experienced a neonatal death while performing KMC. A 
Ugandan interviewer, who is fluent in Luganda/Lusoga and has experience working in a hospital 
setting, will receive further training on how to approach sensitive issues prior to conducting any 
interviews.   
6.3.4 Additional health systems and clinical data  
The following additional health systems and clinical data will be prospectively collected for the process 
evaluation:  
• 
Admission data for all neonatal unit admissions across the five study sites to observe changes 
in bed capacity; referral patterns; proportion of preterm/LBW admissions; mortality rates, etc   
• 
Triannual (every 4 months) surveys of staffing, equipment, drug/supply availability, and 
infrastructure at the 5 study sites  
• 
Biannual (every 6 months) neonatal quality of care survey, including progress monitoring of 
KMC provision/services (Appendix E) at the five study sites  
• 
Annual documentation of national health delivery, finances and staffing levels, including national 
survey of neonatal/KMC provision    
  
7. Trial Responsibilities & Management  
The OMWaNA trial is a partnership between MRC/UVRI, LSHTM and Makerere, with implementation at 
four Ugandan hospitals. The host institution is the MRC/UVRI and LSHTM Uganda Research Unit in 
Entebbe. The trial management structure is outlined in Figure 2.   
  
  
 
 
 
 
 
 

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Figure 2. OMWaNA Trial Management Structure  
 
7.1 Investigator Team   
Principal Investigator: Professor Joy Lawn   
The principal investigator for the trial is Joy Lawn, Professor of Maternal, Reproductive and Child Health 
and Director of the MARCH Centre Director at LSHTM. She is a paediatrician and epidemiologist with 
>25 years of experience, including global estimates for neonatal conditions and design and evaluation 
of RCTs for maternal and newborn care, especially in Africa. She is an expert in newborn care 
research, a leader in the UN’s Every Newborn Action Plan, and sits on WHO guideline review 
committees. Prof Lawn will provide overall trial oversight, serve as a liaison with academic partners, 
and lead linkage to policy uptake.  
Co-principal investigators:  
Melissa Medvedev (Morgan) is an Assistant Professor of Neonatology at the University of California San 
Francisco and a Clinical Research Fellow at LSHTM. She has been leading neonatal research in East 
Africa since 2006 and has worked on multiple RCTs. In Uganda, she led an RCT evaluating the feasibility 
of a novel paediatric mask for oxygen delivery, and she was the PI of the KMC feasibility study at JH (56). 
Dr Medvedev will serve as neonatal trialist, supervising the Ugandan coordination team to optimise the 

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protocol and reporting procedures, and she will lead the process evaluation. Peter Waiswa is Associate 
Professor of Health Policy and Planning and directs the Maternal & Newborn  
Centre of Excellency at Makerere University. He is a physician with a PhD in Health Systems Research 
and has served as PI of several neonatal RCTs in Uganda. He will provide regulatory and technical 
oversight, lead the in-country team, and coordinate relationships with the Ministry of Health and Uganda 
Paediatric Association. Cally Tann is an Associate Professor at LSHTM, Consultant Neonatologist at 
University College London, and Honorary Senior Research Associate at the MRC/UVRI and LSHTM 
Uganda Research Unit. She has been leading neonatal and developmental research at MRC/UVRI 
since 2006 and has previously lived and worked in Uganda. She is currently PI of an RCT of an early 
intervention programme for children at high-risk for developmental disability. Dr Tann will be the 
MRC/UVRI study coordinator and will work in partnership with a Ugandan coordination team. Dr Tann 
will provide expertise on neonatal care, physiologic data and cranial ultrasound imaging and 
interpretation. Elizabeth Allen is Professor and Head of the Department of Medical Statistics at 
LSHTM, specialising in the design and analysis of RCTs. She is a member of the Clinical Trials Unit 
management group and has extensive experience running and analysing RCTs in East Africa. Prof 
Allen will perform blinded analyses related to primary outcomes and give advice on other analyses. Dr 
Victor Tumukunde, is a Ugandan paediatrician with over 7 years of experience in neonatal care, 
including spearheading the establishment of six neonatal units at district hospitals and health centre 
IVs; training/ mentoring nurses to manage sick newborn babies at 78 health facilities; and coordinating 
a randomized controlled trial that evaluated a decision support system to empower health workers to 
save newborn lives in Western Uganda. He is currently coordinating the implementation of the 
OMWaNA trial. He will continue to provide in-country oversight of the clinical and operational activities 
of the trial along with the trial coordinator. Dr Ivan Kiggundu Mambule is a Ugandan medical doctor, 
currently a PhD scholar and has over 12 years of experience in clinical research in both Uganda and 
Malawi. He is also currently coordinating the implementation of the OMWaNA trial. He will continue to 
provide in-country oversight of the ethical and operational activities of the trial along with the site 
coordinator.  
MRC/UVRI and LSHTM Uganda Research Unit investigators:   
Cally Tann is a co-PI on this study and an Honorary Senior Research Associate at the MRC/UVRI and 
LSHTM Uganda Research Unit with experience leading RCTs at MRC/UVRI. The trial will be hosted 
under the Non-Communicable Diseases theme led by Moffat Nyirenda, a Professor of Medicine at 
LSHTM. Prof. Nyirenda has >25 years of experience of leading non-communicable disease research in 
Africa with a particular interest in the effects of early life exposures through the life course. He will serve  
as the senior MRC member of the Trial Management Group. Janet Seeley is a Professor of 
Anthropology and Health at LSHTM, and she directs the Social Aspects of Health Programme at 
MRC/UVRI. She has >30 years of experience, including 14 years in Uganda. Prof Seeley will serve as 
the senior advisor on the qualitative aspects of the trial and the associated process evaluation. 
Christian Hansen is the Head of Statistics at MRC/UVRI with expertise in clinical trials and maternal 
health. He will provide supervision and support in randomisation and data management, particularly 
electronic CRF data.  
LSHTM investigators/collaborators:  
Ruth Canter is a Trial Manager at LSHTM with a background in trial data management and statistics.  

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She will be responsible for producing DSMB reports, metadata creation and data sharing. Diana 
Elbourne, Professor of Healthcare Evaluation at LSHTM, is an expert in neonatal trials and ethics. She 
led the BRACELET study, which explored bereavement in neonatal trials (67). She will serve as senior 
trial and ethics advisor. Helen Brotherton (collaborator) is an Assistant Professor of Infectious Disease 
Epidemiology and a Wellcome Trust Research Training Fellow. She is the lead investigator of the 
eKMC trial hosted at MRC Gambia. Her research interests are in management of small and sick 
newborns, nosocomial infections, clinical trials and implementation of quality improvement measures.   
Economic evaluation  
Elizabeth Ekirapa-Kiracho is a Senior Lecturer in Health Policy and Planning at Makerere, where she 
focuses on maternal and neonatal health systems. She is a physician with a PhD in Health Economics. 
Dr Ekirapa-Kiracho will lead the economic evaluation. Kenneth R. Katumba is a Ugandan health 
economist with an MPH, who conducts a range of health economics research, including evaluating the 
cost and cost-effectiveness of health interventions at MRC/UVRI. Together they will design the 
evaluation and be responsible for data collection, analysis, and interpretation. He will conduct the 
economic evaluation under the guidance of Dr Ekirapa-Kiracho. Catherine Pitt is Assistant Professor of 
Health Economics at LSHTM. For >10 years, she has worked on economic evaluations in RCTs of 
maternal/child health interventions in Africa. She will contribute expertise in model design, data 
collection, and analysis. Dr Giulia Greco is a health economist at LSHTM, visiting Lecturer at Makerere 
University, and Honorary Senior Scientist at MRC/UVRI. She will lead the women’s well-being 
assessment in partnership with Dr Ekirapa-Kiracho, Mr Katumba, and Ms Pitt.   
7.2 Study Team and Infrastructure at Trial Sites  
Members of the study team at each site will include 1 study paediatrician/co-investigator (20% effort), 1 
study medical officer (full-time), 4 study nurses (full-time), and 1 nurse counsellor (full-time). Study 
paediatricians will oversee clinical decisions, supervise site staff, and ensure reporting procedures are 
followed (with support from the trial coordinator). Study medical officers will perform screening, 
recruitment, and randomisation/allocation procedures. Study nurses will assist with screening and 
recruitment procedures, collect and record clinical data in eCRFs, and conduct follow-up assessments, 
including home visits as needed. Nurse counsellors will counsel parents of seriously ill infants. In 
addition, local newborn unit nurses at each site will receive a stipend to assist with clinical care and 
data collection/entry.  
Substantial expansion of neonatal care capacity and infrastructure has been embedded within the 
OMWaNA trial. Each hospital has a neonatal unit currently taking referrals from their respective 
region/district and each led by the paediatrician. The level of equipment in these government facilities 
differs but all have: warming areas (incubators and/or overhead radiant heaters), oxygen supply (either 
piped or through concentrators and cylinders), and standard operating procedures for the management 
of neonates including respiratory distress, apnoea, infection/ sepsis, seizures, hypothermia, and 
hypoglycaemia (referred to here as ‘standard of care’). In addition to the government services available, 
substantial additional infrastructure will be added to all neonatal units to accommodate the trial. This 
includes improved facility building infrastructure with all study hospital neonatal care units being 
restructured to ensure adequate facilities for screening, recruitment and randomisation of infants and 
facilitation of care of non-trial participants. Site remodelling will include expansion of KMC areas within 
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acutely within the neonatal units. Site expansion includes an office for clinical staff and bathrooms and 
toilets for mothers attending to their babies in the neonatal care unit. All plans include fully functioning 
sinks in all clinical areas to provide an optimal environment for infection control.   
In addition to improved building infrastructure, each unit will be supported with additional staffing and 
equipment. At each site, a minimum of four additional neonatal research nurses and one Medical Officer 
will be recruited in partnership with the neonatal Paediatrician and Neonatal Nurse In-Charge at each 
unit. These will be integrated within the existing staff of the neonatal units and will provide some continuity 
despite the staff rotations that are common in these government hospitals. Each site will  also be 
supported by the provision of: 6 pulse oximeters (Masimo Rad-8 with neonatal sensors); 1 oxygen 
concentrator; 2 thermometers;1 glucose meter and glucose strips; 1 ventilation bag and mask (neonatal 
size); 1 neonatal weighing scale (Seca 385); 1 neonatal measuring mat (Seca 210); 2-3 paediatric 
stethoscopes; and a minimum of 4 adjustable KMC beds. In addition, KMC wraps will be provided to 
support practice in each unit. CPAP will be provided by the duty paediatrician where this is standard of 
care.  
All participating units will receive a comprehensive training programme in neonatal care developed from 
established UNICEF and WHO protocols including care of the small and sick newborn, feeding and 
resuscitation. This includes training of neonatal resuscitation (Helping Babies Breathe) and the provision 
of equipment including neonatal bag and masks and resuscitation mannikins. See sections  
5.9.2 “Site staff training on neonatal care and clinical guidelines before start of trial” and 5.9.3 “Refresher 
trainings throughout trial” for details. Continuous on-the-job support and mentorship will be provided by 
the resident paediatrician and site co-ordinator, a Ugandan paediatrician with wide experience in newborn 
care (see below for additional details) specialising in care of the preterm infants.  
  
7.3 Trial Steering Committee   
The Trial Steering Committee (TSC) will approve the main study protocol and any amendments, 
monitor, and supervise the trial towards its interim and overall objectives, review relevant information 
from other sources, consider the recommendations of the Data and Safety Monitoring Board (DSMB), 
and resolve problems brought by the trial coordinating centre. The TSC will meet every 6 months, with 
those not in the UK joining by teleconference.  
Chair: Prof Elizabeth Molyneux, College of Medicine, Blantyre, Malawi   
Members:   
• 
Dr Rebecca Nantanda, President, Uganda Paediatric Association, Kampala  
• 
Prof Stefan Peterson, Chief of Health, UNICEF, New York  
• 
Dr Adriano Cattaneo, International Network in Kangaroo Mother Care, WHO Collaborating 
Centre for Maternal & Child Health (retired), Trieste, Italy  
  
8. Safety and Monitoring   
Safety oversight will be the responsibility of the investigators led by the PI, and the DSMB.   
 

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8.1 Monitoring of Study Participants  
The minimum clinical monitoring schedule is shown in Table 2. In order to assess the validity of axillary 
temperature measurements, temperature will be continuously recorded during the first 24h post-
randomisation using Grant Instruments YL-T11 temperature loggers in approximately 5% of neonates in 
each arm of the trial.   
 
Table 2. Clinical Monitoring Schedule  
Every 6 hours in unstable neonates in both 
intervention and control arms  
Daily in stable neonates in both 
intervention and control arms  
Measurement  
Method  
Measurement  
Method  
Heart rate (continuous 
monitoring during first 72h 
post-randomisation)  
Pulse oximeter  
Heart rate  
Pulse oximeter  
Axillary temperature  
Clinical thermometer  
Axillary temperature  
Clinical thermometer  
Respiratory rate  
Observe and count 
breaths for 1 minute  
Respiratory rate  
Observe and count 
breaths for 1 minute  
Oxygen saturation 
(continuous monitoring 
during first 72h 
postrandomisation)  
Pulse oximeter  
Oxygen saturation  
Pulse oximeter  
Respiratory distress  
Observe for chest 
indrawing, nasal 
flaring, and grunting  
Respiratory distress  
Observe for chest 
indrawing, nasal 
flaring, and grunting  
Blood glucose (every 6h 
during first 24h, then daily 
while advancing enteral 
feeds)  
Glucometer and blood 
glucose test strips  
  
  
  
Alarms on pulse oximeters will be set to detect bradycardia (HR <100 bpm) or hypoxaemia (SpO2 
<88%), so these neonates can be assessed by a study nurse and followed more closely. Clinically 
significant episodes of apnoea and/or bradycardia, which necessitate initiation of bag-mask ventilation, 
will be recorded as serious adverse events (SAE). See Section 6.1.3 for further details on evaluations 
to be completed in the event of clinical deterioration.    

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8.2 Adverse Events & Assessment of Causality  
Adverse event (AE) terminology is outlined in Table 3. Guidelines for assessing the relationship of the 
intervention to the SAE are outlined in Table 4.   
Table 3. Serious Adverse Events Terminology  
Term  
Definition  
Serious Adverse Event 
(SAE)  
A serious adverse event is any untoward medical occurrence that:  
 
•  results in death  
 
• 
is life-threatening  
• 
requires prolongation of existing hospitalisation  
• 
results in persistent or significant disability/incapacity   
• 
requires intervention to prevent permanent impairment or damage  
Suspected and  
Unexpected Serious  
Adverse Reaction  
(SUSAR)  
These are the reactions that are serious (as defined above) but not 
expected AND considered to be related to the intervention. This definition 
captures the important events that are attributed to the intervention but do 
not follow known pattern of response.  
  
Table 4. Guidelines for assessing the relationship of an intervention to an Adverse event  
0  
No Relationship  
No temporal relationship to intervention and alternate aetiology (clinical state, 
environmental or other interventions); and does not follow known pattern of 
response to intervention  
1  
Unlikely  
Unlikely temporal relationship to intervention and alternate aetiology likely 
(clinical state, environmental or other interventions) and does not follow 
known typical or plausible pattern of response to intervention.  
2  
Possible  
  
Reasonable temporal relationship to intervention; or event not readily 
produced by clinical state, environmental or other interventions; or similar 
pattern of response to that seen with other interventions  
3  
Probable  
  
Reasonable temporal relationship to intervention; and event not readily 
produced by clinical state, environment, or other interventions or known 
pattern of response seen with other interventions  
4  
Definite  Reasonable temporal relationship to intervention; and event not readily   produced by 
clinical state, environment, or other interventions; and known pattern of response seen with other 
interventions  
 
  

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8.3 Emergency Procedures  
In the event of an abnormal clinical or laboratory finding by study staff, the site paediatrician (or medical 
officer if paediatrician is not present) will direct management in accordance with standardised clinical 
guidelines. The site paediatrician or medical officer will then complete the appropriate safety monitoring 
documentation. See Section 6.1.3 for further details on evaluations to be completed in the event of 
clinical deterioration.  
Providers (medical research officers and nurses) will inform the relevant site 
paediatrician/coinvestigator of any serious adverse event (SAE) or death occurring from the time of 
randomisation until the date of hospital discharge within 24 hours. The site co-investigators will notify 
the Trial Coordinator, who will ensure appropriate reporting procedures are followed (see Section 8.6 
for further details).   
8.4 Follow-up of Adverse Events  
Serious Adverse Events will be followed up by the site paediatrician co-investigator until their resolution 
or stabilisation or until causality is determined to be unrelated to trial interventions. The outcome will be 
assessed as:  
• 
Recovered/resolved  
• 
Not recovered/not resolved  
• 
Recovering/resolving  
• 
Recovered with sequelae/resolved with sequelae  
• 
Fatal   
8.5 Assessment of Causes of Death  
An endpoint review committee, comprising two individuals experienced in paediatric care in subSaharan 
Africa, will review all clinical, laboratory and radiological information for neonates who die during the 
trial to determine the causes of death that will be used in the final analysis. The endpoint review 
committee will remain blinded to the randomised allocations.  
8.6 Reporting of SAEs & SUSARS  
Information for the SAE forms will be collected as part of routine outcome data collection by the 
research team. The Data and Safety Monitoring Board (DSMB) will receive a summary of SAEs after 1 
month of recruitment, then move to three- or six-monthly; the DSMB will decide the frequency following 
the first report. The DSMB will note these and, unless there is a special cause of concern, will consider 
them as part of the planned DSMB meetings which will discuss interim analyses. All SAEs will also be 
reported to the Sponsor and ethical review committees (MRC/UVRI and LSHTM) as part of their 
respective annual progress and safety report.  
In addition, if any other serious but unexpected adverse event occurs, which might be related to a trial 
intervention, a written SAE report should be submitted to the ethical review committees (MRC/UVRI 
and LSHTM) within 48 hours of the investigators becoming aware of the event with a follow-up report 
provided within a further five working days. This expedited reporting will be limited to those outcomes 
not already listed as primary or secondary outcomes, yet which might reasonably occur as a 
consequence of the trial intervention.  

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It may be necessary to take appropriate urgent safety measures to protect participants from any 
immediate hazard to their health and safety. These measures will be taken immediately. It is not 
necessary to wait for ethical approval before implementing the safety measure; however, both ethical 
review committees and the Sponsor will be informed in writing within three working days by submitting a 
substantial amendment.  
8.7 Data and Safety Monitoring Board  
A Data Safety and Monitoring Board (DSMB) will oversee the overall integrity of the study, its safety and 
its continued relevance and ability to answer the primary objective.   
The DSMB will meet approximately yearly during the study.  
Chair: Prof Maria Quigley, Professor of Statistical Epidemiology, National Perinatal Epidemiology Unit,  
University of Oxford, Oxford, UK   
Members:   
• 
Dr Natasha Rhoda, Consultant Neonatologist, Department of Paediatrics and Child Health, 
University of Cape Town, Cape Town, South Africa  
• 
Dr Maureen Kelley, Professor of Bioethics, Nuffield Department of Population Health, University 
of Oxford, Oxford, UK  
8.8 Stopping Criteria   
The DSMB will regularly monitor all data to consider any potential harm to participants. Formal rules for 
stopping due to harm will be discussed with the DSMB at their first meeting.  
8.9 Interim Analyses   
An interim analysis will be performed on the primary outcome when approximately half of neonates 
have been randomised (around 1 year into the trial). An earlier interim analysis may be carried out if 
requested by the DSMB. The DSMB will have access to all data. An independent statistician will 
perform the interim analysis, blinded to treatment allocation, and report to the DSMB. The Chair of the 
DSMB may request additional meetings/analyses, as he or she feels necessary. In the light of these 
data and other evidence from relevant studies, the DSMB will inform the TSC if in their view:  
i. It is evident that no clear outcome will be obtained with the current trial design.  
ii. They have a major ethical or safety concern.  
iii. It is evident that the intervention is clearly superior and continuing the trial would be unethical 
to those in the control arm.  
  
9. Discontinuation Criteria  
9.1 Criteria for stopping the intervention  
Those neonates under close monitoring who meet any of the following criteria at any point during 
enrolment will be temporarily withdrawn from the intervention and kept in an open warmer or an 
incubator based on the discretion of the on-duty study paediatrician:  
Stopping criteria:    

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Severely unstable for >10 minutes if:   
- 
SpO2 <88% in oxygen   
AND ≥1 of:   
- 
Respiratory rate <20 or > 100 breaths/min   
- 
Apnoea requiring bag-mask ventilation   
- 
HR <100 or >200 bpm   
  
Any other condition which precludes continuous skin-to-skin contact:   
a. Severe jaundice requiring immediate management   
b. Severe anaemia requiring blood transfusion   
c. Active seizures   
d. Severe abdominal distension   
e. Omphalitis or infection of the umbilical cord   
f. Apnoea requiring bag-valve-mask ventilation   
g. Widespread skin infection of baby or caregiver providing skin-to-skin contact  
h. Mother or caregiver not available or willing to do continuous skin-to-skin contact  
9.2 Criteria for restarting intervention  
If a neonate is temporarily withdrawn for any of the above reasons, the intervention can be restarted 
once all the following criteria are met:  
• 
No longer fill the stopping criteria  
• 
No apnoea requiring bag-mask ventilation for 24h  
• 
Not on phototherapy  
• 
No seizures for 24 hours  
• 
No abdominal distension  
• 
Mother or caregiver available and willing to do skin-to-skin contact  
• 
No healthcare worker concerns about clinical condition  
  
10. Sample Size and Analysis Plan  
10.1 Sample Size  
Surveillance data collected on admissions to the JH neonatal unit between January and December 
2016 (Perinatal Audit Data from Uganda Paediatric Association) suggest that the mortality rate in the 
control arm will be at least 25% across the four sites. The most recent Cochrane review and a 
metaanalysis demonstrated large mortality reductions among stable neonates (RR 0.60 and 0.64 
respectively) (2,3), and the RCT in Ethiopia published a RR for mortality amongst neonates before 
stabilisation of 0.57 (4). Assuming a conservative control mortality rate of 25% across the 4 hospitals in 
our study, 1750 neonates (875 per arm) would enable us to detect a relative difference between arms 
of 22.4% (5.6% absolute difference) with 80% power and a significance level of 5%. If the control 
mortality rate were in fact as low as 18%, we would still be able to detect a relative difference of 27% 
(absolute difference of 4.8%). We plan to recruit 2188 neonates (1094 per arm) in order to allow for 
10% withdrawal due to clinical deteriorations and consent withdrawal, and 10% dilution due to 

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noncompliance and loss to follow-up. This sample size would enable us to detect absolute reductions 
of 6.3% and 5.4% from control rates of 25% and 18%, respectively, with 90% power. Results from the 
feasibility study suggest that ≥400 eligible neonates are admitted to JH per year. Preliminary data 
suggest ~500 eligible neonates each are admitted to IH and EH per year and ~800 eligible neonates 
are admitted to MH per year. Recruitment will take place over 24 months, leading to an eligible 
population of ~4400 neonates. Thus, we have applied a conservative recruitment rate of ~50% to 
achieve the target sample of 2188. The admissions audit data from our feasibility study suggest that a 
higher recruitment rate should be achievable. Recruitment will continue until the target sample is 
reached, up to a maximum of 27 months, which includes a 3-month buffer period in case recruitment is 
delayed or slower than expected.  
10.2 Analysis Plan for the Trial  
10.2.1 Summary of baseline data and flow of patients  
Baseline characteristics of enrolled neonates will be summarized by treatment arm. Descriptive 
statistics for continuous variables will include mean, SD, median, range, and number of observations. 
Categorical variables will be summarized as counts and proportions. Screening, enrolment, reasons for 
non-enrolment, randomisation, and loss to follow up will be detailed in a CONSORT diagram (68).   
10.2.2 Primary and secondary outcome analyses  
The primary and secondary outcome analyses will be carried out on all neonates as randomised  
(‘intention to treat’). Analysis will follow a pre-specified analysis plan approved by the TSC and DSMB 
prior to unblinding the study database. The criterion for statistical significance at the final analysis will 
be P<0.05. The rate of loss to follow up will be reported. We will report risk ratios for mortality seven 
days after enrolment (primary outcome) and 28 days after enrolment (secondary outcome) for 
intervention versus control with associated 95% confidence intervals. Secondary outcomes: time from 
intervention/control procedures starting to death and length of hospital stay, will be analysed using 
Kaplan-Meier plots and the hazard ratios with accompanying 95% CI calculated using Cox proportional 
hazards regression. All other secondary outcomes will be analysed using appropriate regression 
models accounting for the nature of the distribution of the outcome and results will be presented as 
appropriate effect sizes with a measure of precision (95% confidence intervals). Both unadjusted 
analyses and analyses adjusted for stratification factors will be carried out. Additional exploratory 
analyses will control for any baseline measures that appear to be imbalanced between arms.  
10.2.3 Subgroup and adjusted analyses  
Subgroup analyses are planned to explore between-group difference in the impact of KMC compared to 
standard of care on mortality, by GA (<28, 28-32, or >32 weeks), birthweight (<1000, 1000-1499, or 
≥1500g), hospital site, and level of predicted mortality risk based on the NMR-2000 score [high (≤16), 
medium (17-22), low (≥23)]. A paediatrician or medical research officer will conduct a Ballard 
examination to determine GA (27). GA is an important predictor of newborn survival. In settings with 
specialised neonatal care without intensive care, such as the five recruitment sites, neonatal mortality 
rates are 86% in neonates born at <28 weeks and 41% in neonates born at 28 to 31 weeks (51). The 
NMR-2000 is a simplified score to predict in-hospital mortality among neonates ≤2000g, which has 
been validated in the UK and The Gambia (69). NMR-2000 uses data on three parameters (birthweight, 
SpO2 at admission, highest level of respiratory support at any point within 24 hours of birth), which are 
already being collected on enrolled neonates.  

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Further exploratory analyses will be carried out to explore the association between mortality and time of 
initiation (<12, 12-<24, or ≥24 hours), and continuity of KMC (median hours per day: <6, 6-<12, 12-<18, 
or 18-24 hours).  
10.2.4 Definition of analysis population related to protocol non-adherence  
As described above, intention to treat analyses will be conducted on the primary and secondary 
outcomes. All neonates will be included, regardless of protocol adherence, to prevent the effects of 
attrition bias.  
We will also report results of per protocol analyses and complier average causal effects to account for 
children for whom major protocol violations were recorded such as those relating to non-compliance 
with the study treatments.   
10.3 Analysis Plan for Economic Data  
To model DALYs and costs over a lifetime time horizon in accordance with reference case 
specifications, we will firstly calculate the costs and discounted years of life lost (YLLs) due to neonatal 
deaths within the neonatal period measured in the trial. Secondly, for neonates who survive beyond 1 
month, we will develop a Markov model to estimate the costs and discounted years of life with disability 
(YLDs) lost and additional YLLs from premature mortality attributable to health conditions associated 
with prematurity and LBW. If there is a difference between trial arms in rates of breastfeeding, the 
impact on morbidity and mortality of the differential rates of breastfeeding will also be modelled. The 
model structure and parameters will be informed by existing literature (47) and by consultation with 
clinical experts, including the PI and other members of the trial team. If neither intervention exhibits 
strict dominance (i.e., is less costly and more effective), we will model incremental cost per neonatal 
death averted and per DALY averted, in line with reference case specifications. Deterministic and 
probabilistic sensitivity analyses will be conducted to assess the robustness of results to uncertainty 
and heterogeneity.  
We will examine budget impact by using the incremental financial costs incurred in the trial context to 
project how these costs may vary at scale and which budgets would bear the incremental costs or reap 
the cost savings. For example, we envisage additional cost burden at the national level to train on KMC, 
which is likely to require donor support, but potential cost savings at the hospital level in reduced 
equipment and maintenance costs. We will compare cost burden with existing budgets, where relevant, 
and engage with policy makers to understand affordability at different levels.    
Equity will be explored by examining variation in incremental costs to households and in health and 
well-being outcomes across socioeconomic groups.  
10.4 Analysis Plan for Qualitative Data  
Interview/FGD data will be transcribed and, where necessary, translated into English. Data will be 
analysed using the thematic content approach (70,71). Using this approach, data analysis will consist of 
four steps: (1) familiarisation; (2) identifying codes and themes; (3) developing a coding scheme and 
applying it to all of the data; (4) organising codes and themes. Dr Medvedev and the Ugandan 
interviewer will read all interview/FGD transcripts and develop the preliminary coding schemes together. 
Dr Medvedev and the interviewer will individually code 10% of transcripts from each portion of the 
qualitative evaluation. Any discrepancies will be discussed and resolved to develop the final coding 
frameworks. Dr Medvedev will code all remaining transcripts. New themes that emerge outside the 

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coding framework will also be included in the analysis (72,73). Qualitative manuscripts will follow the 
consolidated criteria for reporting qualitative research (74).  
  
11. Quality Control and Quality Assurance  
The PI will ensure that staff involved with the trial are:  
• 
Properly qualified to assume responsibility for conduct of the study  
• 
Willing to comply with GCP and applicable regulations   
• 
Prepared for audits and monitoring  
• 
Able to recruit study participants in sufficient numbers and on time  
• 
Well informed about the protocol and their study responsibilities The site clinical leads will 
ensure that their respective sites have:  
• 
Sufficient human and material resources to sustain routine standards of care  
• 
Staff who are well informed about the protocol, the IP, and their study responsibilities and are 
fully trained in the relevant SOPs  
11.1 External Monitoring  
The study will be monitored by the Clinical Studies Support Office at MRC/UVRI, who will develop a 
risk-based monitoring plan for the study. The monitoring team comprises of trial coordinators and trial 
managers from the various trials currently running within the unit. To achieve independence during the 
monitoring, one dedicated study monitor, independent of the study team, will be assigned to monitor 
this study.  The monitor’s role is part of the quality system and will oversee the progress of the trial and 
ensure that the trial is conducted and data are handled in accordance with trial SOPs, the protocol, 
Good Clinical Practice (GCP) and applicable ethical and regulatory requirements.  
11.2 Internal Monitoring  
Internal monitoring will be conducted by the central study team (PIs and trial coordinator) as a 
continuous process through direct communication with the site paediatricians and medical research 
officers via telephone or email and physical site visits.  
11.3 Audits and Inspections   
The study may be subject audit by the London School of Hygiene & Tropical Medicine under their remit 
as sponsor, the Study Coordination Centre and other regulatory bodies to ensure adherence to GCP.   
11.4 Indemnity  
London School of Hygiene & Tropical Medicine holds Public Liability ("negligent harm") and Clinical 
Trial ("non-negligent harm") insurance policies that apply to this trial.  
  
12. Data Management  
At the hospitals, trial data will be electronically entered on tablets into a GCP-compliant, offline, 
trialspecific mobile application [Research Electronic Data Capture (RedCap), Nashville, TN, USA]. 
REDCap has a built-in audit trail that automatically logs activity including log-ins, user rights, data 
entry/modification, data export, and running reports. Only the PIs, the trial coordinator, and the data 
managers will have access to this database.  

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12.1 Data Transmission and Editing  
Data from tablets, which will be partially anonymised (participant names excluded), will be synced once 
daily over a secure 3G connection with a web-based RedCap database. The system will be centrally 
hosted at the MRC/UVRI data centre. Anonymised pulse oximeter and temperature logger recordings 
(linked by participant ID) will be captured in MS Excel files, securely transmitted to MRC/UVRI, and 
entered into the trial database. Data including pulse oximeter / temperature recordings, will be 
transferred to Stata for analysis. Cranial ultrasound images will be stored in OsiriX Dicom imaging 
software and interpreted blind to allocation and clinical details. Logs linking parent/guardian names and 
residence location will be stored separately on a password-protected computer, with a hard copy stored 
in locked cabinets in secure rooms at the sites.  
We will utilize the inbuilt access management and audit trail functions of REDCap to track changes to 
the data, implement role assignment and restrict unauthorized access to study data.  
12.2 Data Discrepancy Inquiries  
REDCap has a built-in audit trail that automatically logs activity, including log-ins, user rights, data 
entry/modification, data export, and running reports. Only the PIs, the trial coordinator, and the data 
managers will have access to this database.  
Internally developed Stata verification/cleaning do-files will be run by data managers to identify data 
that are missing, inconsistent, or out-of-range. The trial coordinator will perform clinical quality checks to 
identify potential errors not captured in the automated verification process.  
Query resolution: The trial coordinator or data managers will raise queries through the RedCap query 
management system and assign it to a member of the study team at the respective site, who will 
respond to it. Only after a satisfactory response is given will the query be closed. Pending queries will 
be allowed up to 2 days if the patient is still hospitalised or 5 days if patient has been discharged.  
12.3 Qualitative Data  
To ensure a standardized approach is used for FGDs/interviews at all sites, interviewers will be issued 
a FGD or interview guide and a pre-specified list of target respondents. FGD/interview data will be 
collected, with consent of participants, through audio-recording and field notes. Transcripts will be 
linked by study ID to other forms of data collected for the study. Master records with ID numbers and 
identifying information will be stored separately.  
12.4 Security and Backup of Data  
All data will be stored in institutional servers at MRC/UVRI during the study. A complete backup of the 
database onto external hard drives will be performed twice per month. Hard drives will be stored at 
MRC/UVRI and retained for a minimum of three years after publication of the research. Audio files will 
be digitally recorded and securely stored on a computer as password protected files until transcription 
and verification are completed. At the end of the study, all study documents with names or addresses 
will be destroyed.   
Data from the web-based RedCap database will be downloaded and stored on institutional servers at 
LSHTM for access by the PIs and independent statistician for analysis and preparation of reports for the 
DSMB, respectively. These secure, password-protected servers are only accessible within the LSHTM 
network from specified user accounts. Access is controlled by Firewall policy based on the host address 

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and application. Activity on LSHTM servers are fully audited recording both login details and file system 
access. Access will be limited to essential research personnel.  
No names or other direct identifiers will appear in typed documents, transcripts, or recordings. FGD/IDI 
transcripts will be pseudo-anonymised with unique confidential codes and identification codes will be 
kept in a separate secure location. The electronic master-log linking participant-identifying information 
will be stored on a password-protected computer and a hard copy master-log stored in a locked filing 
cabinet under the custody of the trial coordinator. Consent forms will be stored in locked cabinets in 
secure rooms at the sites.  
12.5 Study Status Reports  
The data manager at MRC/UVRI will prepare weekly email reports with information on missing and 
incongruent data. The trial coordinator will review these reports and inform the data manager regarding 
any necessary corrections.  
12.6 Access to Data  
Data from the web-based RedCap database will be downloaded and stored on institutional servers at 
LSHTM for access by the PIs and independent statistician for analysis and preparation of reports for the 
DSMB, respectively. These secure, password-protected servers are only accessible within the LSHTM 
network from specified user accounts. Access is controlled by Firewall policy based on the host address 
and application. Activity on LSHTM servers is fully audited recording both login details and file system 
access. Access will be limited to essential research personnel.  
12.7 Responsibilities  
The PIs, trial coordinator, data advisor, and data managers will be responsible for data management, 
quality assurance, and data security. Ms Canter (UK data manager) will be responsible for metadata 
creation and data sharing. Policies of the LSHTM Research and Governance Office will govern study-
wide data management and metadata creation activities, and policies of LSHTM Information 
Technology will govern data security.  
  
13. End of Trial and Archiving  
At the termination of planned recruitment, the Trial Coordinating Centre will contact the site by 
telephone or email in order to terminate all patient recruitment as quickly as possible. If the study is 
terminated prematurely by the Steering Committee, the site will be informed immediately. When all 
recruited patients have been followed until hospital discharge or death, a declaration of the end of trial 
form will be sent to the relevant IRBs. The following documents: original consent forms, data forms, trial 
related documents and correspondence, will be archived in the Site File and kept for at least five years. 
At the end of the analysis and reporting phase, the Trial Master Files at the Trial Coordinating Centre 
will be archived for 15 years.   
  
14. Ethical Considerations  
14.1 Ethical approvals and general considerations on human subject participation  
Approval will be obtained from the UVRI Research Ethics Committee, the Uganda National Council for 
Science and Technology, and LSHTM. Annual progress reports will be submitted to the IRBs within 30 

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days of the anniversary date on which the favourable opinion was given until the trial is declared ended. 
The PI will notify the IRBs of the end of the study. Substantial amendments that require review by IRB 
will not be implemented until the IRB grants a favourable opinion for the study. All correspondence with 
the IRB will be retained in the Investigator Site File.  
14.2 Rationale for inclusion of vulnerable groups  
14.2.1 Rationale for Neonates  
Our study aims to investigate KMC, initiated before stabilisation, amongst neonates ≤2000g. As such, 
we are obligated to study neonates. These small neonates are at high risk, and in these low-resource 
Ugandan hospitals without intensive care, standard care using incubators, often shared with other 
neonates, exposes them to significant risks (e.g., infection). KMC has been shown to reduce many of 
these risks and could have major mortality gain. WHO and others have stated that determining the 
effect of KMC initiated prior to stabilisation is an important and justifiable research question, 
notwithstanding these risks. Our team includes neonatal trialists, including an expert in ethical issues in 
neonatal trials, and we will address concerns through careful monitoring of neonates and DSMB 
monitoring.  
14.2.2 Rationale for children ≥15 years of age (who are parents of included neonates)  
According to the Uganda National Council of Science and Technology, “emancipated minors are 
individuals below the age of majority who are pregnant, married, have a child or cater for their own 
livelihood,” and “mature and emancipated minors may independently provide informed consent to 
participate in research” (75). Uganda has a high rate of teenage pregnancy. According to the Uganda 
Demographic Health Survey (UDHS 2011), 24% of women are already mothers or pregnant with their 
first child before the age of 19, and 39% of women aged 20 to 49 gave birth by age 18 (2).  
14.3 Evaluation of risks and benefits  
14.3.1 Potential risks or benefits of standard care in Uganda  
Incubators are the standard alternative to KMC for maintaining normothermia in preterm and low 
birthweight neonates. In resource-limited facilities such as the four trial hospitals, it is common for 
several neonates to share one incubator or radiant heater. In this trial, neonates randomised to the 
control group will receive standard care. Risks associated with standard care with an incubator or 
radiant heater include hypothermia (40,76); hyperthermia (77); nosocomial infections, related to lack of 
effective cleaning standards (78–80); and cross-infection from other neonates when incubators are 
shared, a common practice in low-resource facilities. Failure of incubators/heaters to properly regulate 
temperature may be related to malfunction (e.g., over- or under-heating) (77,80–83), loss of electrical 
supply (51), ignorance of how to regulate set-points (77), as well as environmental factors (81). In 
lowresource hospitals, where there may be few nurses and doctors available, neonates nursed in 
incubators/heaters may not be monitored well, and illness or serious events (e.g., apnoea) may not be 
detected in time. Such events may be detected more rapidly when neonates are in the KMC position 
with their mother (or another caregiver). Further, due to high purchase cost and poor routine 
maintenance practices, hospitals in low-resource settings commonly face shortages of functional 
incubators (50–52,84).  

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14.3.2 Potential risks or benefits of KMC in Uganda   
Evidence from meta-analyses: The most recent Cochrane review found that KMC is associated with 
decreased mortality [RR 0.60, 95% CI 0.39-0.92 (8 trials)], sepsis [RR 0.35, 95% CI 0.22-0.54 (5 trials)], 
and hypothermia [RR 0.28, 95% CI 0.16-0.49 (9 trials)] at discharge or 40-41 weeks postmenstrual age, 
compared to standard care amongst stable neonates ≤2000g (20). A meta-analysis showed that KMC 
is also associated with decreased mortality at latest follow-up among infants <2000g [RR 0.64, 95% CI 
0.46-0.89 (15 studies)], sepsis [RR 0.53, 95% CI 0.34-0.83 (8 studies), hypothermia [RR 0.22; 95% CI 
0.12-0.41 (9 studies), and hypoglycaemia [RR 0.12; 95% CI 0.05-0.32 (2 studies)] (21).   
Evidence from high- and middle-income countries: Most studies of KMC have suggested enhanced 
autonomic stability (39,40,85,86) and decreased frequency of apnoea and desaturation (31,33,36,87), 
as well as improved breastfeeding, weight gain and lower rate of infections (20). One German study of 
22 spontaneously breathing neonates less than 32 weeks’ gestation found that the combined frequency 
of bradycardia and hypoxaemia increased from 1.5/hour before to 2.8/hour during skin-to-skin contact 
episodes (P<0.05) (88). In a follow-up study, they showed that the total rate of bradycardia and 
desaturation was higher during skin-to-skin contact (median 3.0 per hour) than incubator care following 
skin-to-skin contact (with ambient temperature elevated by 1°C) (1.7 per hour, P<0.02) (89).  
Numerous studies have reported improved thermal control with KMC (28,32–34,36,41,42,76,90), whilst 
one found no difference in the incidence of hypothermia (31). In a study of 34 ventilated neonates 
(mechanical or nasal continuous positive airway pressure ventilation) in the Netherlands (91), neonates 
at gestational ages between 25+0-26+6 weeks had a mean skin temperature decrease of 1.1% during 
KMC (P= 0.0001) and 1.4% after KMC (P=0.0002). Neonates between 27+0-29+6 weeks gestation had a 
decrease of 0.5% during KMC, which was not statistically significant, and a decrease of 0.8% after 
KMC (P=0.012). Importantly, heart rate, respiratory rate, and SpO2 remained within safe ranges at all 
times in both groups. They concluded that KMC is safe for ventilated neonates under 30 weeks’ 
gestation “as long as skin temperature is monitored and extra warmth is provided if necessary” (91). 
These studies underline the importance of adequate monitoring of preterm neonates during KMC.  
Evidence from low-income countries: Only two RCTs have evaluated the effect of KMC on mortality 
at discharge or term-equivalence (40-41 weeks postmenstrual age) in low-income countries. The only 
RCT for mortality effect in neonates before stabilisation, which was conducted in Ethiopia, reported 
major mortality reduction in neonates in the KMC group compared to those in the radiant warmer group 
(RR 0.57, p<0.05) (23); however, it had important methodological deficiencies. An RCT amongst 285 
stabilised neonates in Ethiopia, Indonesia, and Mexico found no difference in mortality, but did report 
decreased hypothermia and increased weight gain in the KMC arm (29). A more recent RCT of 126 
stable neonates in Nepal also found that neonates in the KMC arm had decreased hypothermia and 
increased weight gain (28). An RCT in Madagascar, which compared KMC initiated within 24 hours to 
KMC initiated 48-72 hours post-birth in a sample of 73 stable neonates, found no difference in 
incidence of mortality at 28 days, hypothermia, apnoea, or severe infection (38).  
14.3.3 Overall assessment of clinical risk  
Preterm birth is associated with a significant risk of mortality, particularly in settings without neonatal 
intensive care. This study will enrol neonates before stabilisation, according to the eligibility criteria 
above. Based on the available evidence, and a comparison of the risks and benefits of KMC and 
standard care in a low-resource setting, KMC is unlikely to present any greater risk to participants 

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meeting eligibility criteria than conventional care, however, to ensure clinical safety neonates will have 
continuous monitoring of vital function (heart rate, oxygen saturations).  
14.4 Sensitisation  
Antenatal, maternity and neonatal staff at each study site will be sensitised to the study (see page 26)  
14.5 Informed Consent   
Obtaining informed consent for this RCT may be challenging given the involvement of sick neonates 
(30); the fact that KMC needs to be started as soon as possible after birth; the fact that some women 
are not literate; and the fact that some women may be too ill, especially within the first 24 hours, to 
provide consent or participate. Parental stress is compounded by the fact that complications may be 
unexpected, especially in low-resource settings, where knowledge of preterm birth is generally low. To 
help address these issues, this RCT will utilise the continuous consent approach (31), which involves 
giving parents/caregivers information at multiple time points both before and after recruitment (32). 
Studies have found that the validity of consent improves when discussion continues after recruitment 
(31,33). The continuous consent process was utilised in the Total Body Hypothermia (TOBY) trial, 
which investigated the use of whole-body cooling for neonates with evidence of perinatal asphyxia (92). 
The continuous consent approach has three main elements (92), all occurring after delivery, which are 
outlined here in the context of the OMWaNA trial:    
1. While a neonate is assessed for eligibility (upon admission to the newborn unit, or the following 
morning if admission occurs outside normal working hours), parents will be given preliminary 
information about the trial.   
2. If the neonate is eligible, a comprehensive information sheet will be provided and further 
discussion will take place, including assessment of whether the parents are willing and able to 
participate. At this point, parents will be asked for their written consent and neonates will be 
randomised.   
3. During the intervention period, the site paediatrician or medical officer will meet with parents to 
ensure that they understand the trial procedures and wish to continue to participate in the trial. It 
will be made clear that they may withdraw their baby from the trial at any time.  
Information about the trial will be made available to women attending the antenatal clinic and labour 
ward. If a mother is unavailable or too ill to provide consent, informed consent will be obtained from the 
father. Site staff will receive training on obtaining consent, including legal and ethical constraints 
governing the process (34). Information sheets (Appendix A) will be available in English, Luganda, and 
Lusoga (local dialects). Oral and written explanations will be provided at the same time to improve 
parent/caregiver understanding and ensure information is accessible to those with lower levels of 
literacy (34). Medical officers or study nurses will obtain consent prior to enrolment. Consent will be 
documented with a thumbprint if a parent/caregiver cannot write. During the informed consent process, 
parents will be reminded that they have a right to refuse participation (or their neonate’s participation), 
with no consequences. They also have the right to withdraw from the study at any point with no 
consequences.  
14.6 Confidentiality  
All enrolled neonates will be assigned a trial number. All reports, data collection, and administrative 
forms will be identified with the trial number only to maintain confidentiality. All study-related materials 
will be stored securely at the study site. All information on enrolled neonates will be stored in locked file 

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cabinets in areas with limited access. All records that contain personal identifiers will be stored 
separately from study records identified by trial number. The local database will be password-secured.   
14.7 Care of families whose newborn dies or who has life-threatening events    
Training of site staff will emphasise counselling parents/caregivers about the potential for mortality at 
the time of enrolment as well as counselling parents/caregivers of neonates who die or have 
lifethreatening events and those who witness a death. Each site will have one full-time study nurse 
counsellor to counsel parents of seriously ill infants. In addition, women who have practised KMC may 
be engaged as peer-counsellors. After the trial ends, findings will be shared with families and 
thoughtfully adapted for those affected by a death (67).  
14.8 Transport Reimbursement to Participating Mothers  
Transport costs (UgSh 20,000 per enrolled newborn) will be provided for participating women on 
discharge to cover the costs of transport home at the end of the study. Mothers will be able to keep the 
KMC wrap provided for babies enrolled in the study, so they can continue KMC at home. Transport 
costs (UgSh 20,000 per enrolled newborn) will also be provided to cover the costs of return transport to 
the hospital for the 28-day follow-up visit. The reimbursement will be provided to women when they 
come to the hospital for the follow-up visit.  
  
15. Involvement of Participants and the Public  
15.1 Incorporation of Feasibility Study Findings into Trial Design  
The feasibility study showed that the majority of parents and healthcare providers felt confident to use 
KMC in neonates prior to stabilisation. Challenges included lack of beds/space, and lack of staff and 
devices to monitor neonates. Stakeholders believed that KMC practice, and neonatal care more 
generally, could be improved through staff and peer-counselling, more beds, and improved availability 
of clinical monitoring devices. This feedback has been incorporated into our trial design as follows:   
• 
Clinical staff at the four study sites will counsel parents/caregivers throughout the hospitalisation 
of their newborn.   
• 
KMC peer-counselling programmes will be established, enlisting mothers who practiced KMC 
when they return for follow-up, at the four study sites.   
• 
Hospital administrators at the four study sites will be engaged regarding KMC guidelines.   
• 
Adjustable beds will be provided to improve adherence with the recommended duration of KMC 
in the intervention arm.   
• 
Increased space is being organised for the JH and MH newborn units to provide room for KMC 
beds/chairs and existing incubators.  
• 
Masimo Rad-8® pulse oximeters and digital thermometers will be provided to the four study 
sites to enable improved monitoring of HR, SpO2, and temperature.   
15.2 Local Advisory Board  
We will engage a local advisory board including district health authorities, local community leaders, 
academics (MRC/UVRI, Makerere University), national health organisations (Uganda Paediatric 
Association), and policymakers (Newborn Steering Committee of Ugandan Ministry of Health). The 

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advisory board will be led by Prof Waiswa (Co-PI), who has previously engaged similar advisory boards 
for other newborn studies in Uganda. This advisory board will meet quarterly to provide guidance on 
local issues related to trial implementation and implications for local households and communities.  
15.3 Workshops and Qualitative Evaluations  
The process evaluation will include two half-day workshops in Uganda after the first 6 months of 
recruitment. The first, focused on local communities, will include district health authorities, community 
leaders, paediatricians, nurses, and parents. During the trial, we will conduct FGDs with healthcare 
providers, parents, and hospital administrators to explore barriers and enablers to implementation of 
KMC before stabilisation, and to help inform context-specific evidence on the uptake and sustainability 
of KMC. Throughout the trial, IDIs with mothers will explore social and cultural factors that may 
influence maternal coping and compliance with care recommendations. IDIs with parents whose babies 
died during the hospital stay will explore their experiences of trauma and bereavement.  
15.4 Sharing of Study Findings with Participating Families  
After the study ends, findings will be shared with families, and thoughtfully adapted for those affected by 
a death (62).  
  
16. Declaration of Interests   
The PI, Co-PI, co-investigators, supervisors, and collaborators have no financial relationships to 
disclose or conflicts of interest to resolve. The proposed research does not use technology or materials 
subject to IP protection, nor will it lead to commercially exploitable results. Further, it is not subject to 
agreements with commercial, academic or other organisations.  
  
17. Potential Limitations and Anticipated Challenges  
Among neonates in the control group, non-compliance with allocation (e.g., parents demanding early 
KMC) is a potential issue; however, this has not been reported in other trials (20). Compliance in both 
arms, particularly the KMC arm, could be affected by parents witnessing a death (e.g., in the KMC 
position). Some babies will die regardless of the trial arm to which they are randomised. Preterm 
neonates can die quickly, even in settings with intensive care, and such deaths are a recognised 
impediment to KMC practice (93). Stigma regarding preterm birth is common in Uganda, but has not 
impeded KMC practice for stable babies (94). Notably, the two deaths in the feasibility study did not 
negatively impact recruitment or discourage other parents from practicing KMC. Clinical study staff at 
each site will counsel parents about the potential for mortality at the time of enrolment as well as 
counsel parents of neonates who die and those who witness a death.   
In the intervention arm, adherence to the target duration of KMC (≥18 hours/day) may be difficult to 
achieve. Among five RCTs that promoted continuous KMC, three reported durations of ≥20 hours per 
day (29,30,43) and two did not report duration (23,38). Among 10 RCTs evaluating intermittent KMC, 
one reported mean/median duration of 17 hours/day (42), five reported 10-14 hours/day  
(32,33,35,36,41), and three reported <10 hours/day (28,34,37). A comprehensive approach will be used 
to improve adherence. An illustrated KMC handout will be provided to mothers at the time of enrolment. 
Clinical site staff will counsel mothers throughout the hospital stay, including the time of discharge. 
Studies have noted the importance of staff training and counselling for KMC (95,96). We will establish 
KMC peer-counselling programmes at each hospital, enlisting mothers who practiced KMC as 

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participants when they return for follow-up. Peer counselling will address many maternal concerns and 
may help facilitate longer durations of KMC. A related RCT demonstrated the efficacy of 
peercounselling in promoting breastfeeding amongst hospitalised neonates (97). We will also engage 
hospital administrators about KMC guidelines. Adjustable beds and KMC wraps will be provided, as 
these have been shown to improve adherence (98). Increased space is being organised for the JH and 
MH newborn units for KMC beds/chairs and existing incubators.     
  
18. Significance of the Proposed Work  
Globally, there are an estimated 2.5 million neonatal deaths each year (15), among which >80% occur 
in neonates who are small at birth, due to being preterm and/or SGA (16). Major mortality reductions 
could be achieved by improving care of small neonates in low-resource settings (16–18). WHO 
guidelines recommend KMC for “routine care of newborns weighing ≤2000g… initiated as soon as 
newborns are clinically stable” (8), where stability has been defined as vital functions (breathing, 
circulation) not requiring “continuous medical support and monitoring,” and not being “subject to rapid 
and unexpected deterioration” (3). However, estimates suggest that ≥75% of neonatal deaths occur 
before stabilisation in settings without intensive care (16,17,22). Further, over three-quarters of 
neonates in sub-Saharan Africa and south Asia lack access to intensive care (99). The only RCT of 
KMC in neonates before stabilisation with mortality outcomes was conducted in Ethiopia (123 neonates  
≤2000g). It reported a 43% reduction in mortality (RR 0.57); yet, 66% of deaths and the major difference 
between arms occurred within 12 hours of birth (18,23). In addition, this RCT excluded >50% of eligible 
neonates, did not utilise allocation concealment, and had an apparent group imbalance at baseline 
(favouring KMC) (23), compromising robustness (18,100). Thus, the effect of KMC initiated before 
stabilisation in hospitals without neonatal intensive care remains a research priority, still not being 
addressed, and a well-designed RCT is warranted to examine mortality impact in non-intensive care 
settings (18).  
  
19. Publication and Dissemination Plan  
19.1 Dissemination Policy  
We will aim to publish the trial protocol and results as well as the economic, qualitative, and process 
evaluations in prestigious, peer-reviewed academic journals with open access, guided by a 
dissemination plan. The main trial results will be launched with a press release from MRC/UVRI, 
LSHTM’s MARCH Centre, and Makerere University, with social media in Uganda, UK and globally. This 
material would also lend itself to film for public engagement, and our group have a track record of major 
media uptake globally and also specifically on Ugandan TV. We will aim to present the study results at 
international meetings such as the International Paediatric Association and Paediatric Academic 
Societies, and to key audiences (WHO, UNICEF, International KMC Network) and funders (including 
MRC, Wellcome Trust, DFID, Gates Foundation, CIFF, ELMA). All manuscripts resulting from the trial 
will adhere to the Consort Guidelines (68).   
19.2 Plans to Grant Public Access to Protocol  
Per the recommendation set forth in the Ottawa statement (101), the full protocol will be made publicly 
available through clinicaltrials.gov or through publication in a scientific journal.    

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20. Timeframe  
The timeframe for the proposed work is set out in the following figure (Figure 3). Figure 
3. OMWaNA Study Timeline  
  
  
21. Acknowledgments  
The formative work investigating the feasibility of KMC initiated before stabilisation was funded by the 
UCSF Preterm Birth Initiative and the Thrasher Research Fund. This protocol has been developed in 
collaboration with the eKMC trial investigators led by Dr Helen Brotherton, and the experiences of the 
eKMC trial have substantially informed the development of this protocol.     
  
 

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Appendices  
  
  
Appendix A: Patient information sheet and informed consent form (parents/guardians)  
  
Appendix B: Information sheet and informed consent form for qualitative evaluations 
(health care workers and key stakeholders)   
  
Appendix C: Ballard score for estimating gestational age   
  
Appendix D: Case report form   
  
Appendix E: KMC Progress Monitoring Tool for Health Faciities  
  
Appendix F: Investigators’ CVs