Use of Probiotics to Reduce Infections and Death and Prevent Colonization With Extended-spectrum Beta-lactamase Producing Bacteria, Among Newborn Infants in Haydom and Surrounding Area, Tanzania, a Randomized Controlled Clinical Trial
Phase: PHASE3
Conditions: Neonatal Sepsis
Sponsor: Haydom Lutheran Hospital

 
 
 
           ProRIDE Trial in Tanzania 
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Title: Use of Probiotics to Reduce Infections and Death and Prevent 
Colonization 
with 
Extended-spectrum 
beta-lactamase 
(ESBL) 
producing bacteria, among newborn infants in Haydom and 
surrounding area, Tanzania, a randomized controlled clinical trial. 
 
 
Protocol Number: ProRIDE-HLH#01 
Clinicaltrials.gov identifier: NCT04172012 
Protocol Date: 19th December 2021  
Protocol Version: 2.0 
 
Sponsor name: Haydom Lutheran Hospital 
Signature:   
 
Date:  
 
Study Principle investigator  
Dr. Joshua G Gidabayda, MD, MMed-Haydom Lutheran Hospital 
Signature:   
 
Date: 
 
 
 
                                                                                                         

 
 
 
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Study title 
Use of Probiotics to Reduce Infections and Death and Prevent 
Colonization with Extended-spectrum beta-lactamase (ESBL) 
producing bacteria, among newborn infants in Haydom, Tanzania, a 
randomized controlled clinical trial 
Study acronym  
ProRIDE trial  
Short title  
Use of Probiotics to reduce Infections, Death and ESBL colonisation.  
Version and date of the protocol  
Version 1.0, June 2019  
Principal investigator  
 
 
 
 
Internal Principal investigator 
1. Nina Langeland, MD, PhD 
Department of Clinical Science, University of Bergen, Norway 
National Centre for Tropical Infectious Diseases, Haukeland 
University Hospital, Bergen, Norway 
 
2. Joshua G Gidabayda, MD MMed, Department of Paediatrics, 
Haydom Lutheran Hospital, Tanzania 
Co- investigators and collaborators  3. Bjørn Blomberg, MD, PhD 
Department of Clinical Science, University of Bergen, Norway 
National Centre for Tropical Infectious Diseases, Haukeland 
University Hospital, Bergen, Norway 
4.  Iren Löhr, MD, PhD  
Department of Medical Microbiology, Stavanger University Hospital, 
Norway 
5. Claus Klingenberg, MD, PhD 
Department of Paediatrics, University Hospital of North Norway 
Department of Clinical Medicine, UiT-The Arctic University of 
Norway 
6.  Kanika Kuwelker, MD, PhD 
National Centre for Tropical Infectious Diseases, Haukeland  
University Hospital, Bergen, Norway 
7. Esto Mduma, DipMed, DLSHTM, MSc PH 
Haydom Global Health Research Center 
8. Dr. Paschal Mdoe, MD, PhD, 
Haydom Lutheran Hospital 

 
 
 
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9. Museveni Justine, MD 
Haydom Global Health Research centre 
10. Samweli Jatosh. BSc. chemistry 
Haydom Global Health Research centre. 
11. Joel Manyahi, MD, MMed, PI Microbiology Tanzania 
Department of Microbiology and Immunology, Muhimbili University 
of Health and Allied Sciences, MUHAS, Dar-es-Salaam, Tanzania 
12. Sabrina Moyo, MD, Mmed, PhD 
Department of Clinical Science, University of Bergen, Norway 
Department of Microbiology and Immunology, Muhimbili University 
of Health and Allied Sciences, MUHAS, Dar-es-Salaam, Tanzania. 
13. Anania Daniel Tippe, BSc in Medical Lab Technology 
Head of Clinical Laboratory, Haydom Lutheran Hospital, Haydom, 
Manyara, Tanzania 
Funding source /Sponsor 
Name: The Western Norway Regional Health Authority  
Address: Nådlandskroken 11, 4034 Stavanger, Norway 
Phone number: +47 51 96 38 00 
Email: helse@helse-vest.no   
Data safety monitoring 
committee (DSMC) 
Ketil Størdal, Sven Gudmund Hinderaker, Charles Makasi and 
Blandina Mbaga 
Study pharmacist  
William Mollam, Haydom Lutheran Hospital 
Clinical site  
Haydom Lutheran Hospital, Manyara region, Tanzania 
Laboratory sites  
1. Haydom Lutheran Hospital 
2. Department of Clinical Science, University of Bergen, 
Norway 
3. The Arctic University of Norway (UiT), Tromso, Norway 
4. Department of Medical Microbiology, Stavanger University 
Hospital, Norway 
Ethical review Boards  
1. Regional Committee for Medical and Health Research Ethics 
(REK) in Norway 
2. National Institute of Medical Research Review Board, NIMR 
in Tanzania  
Regulatory Review  
Tanzania Food and Drug Authority (TFDA) 

 
 
 
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List of abbreviations ......................................................................................................... 6 
Summary .......................................................................................................................... 7 
1. 
Introduction ............................................................................................................. 10 
1.1 Background Information.................................................................................................... 10 
1.2 Main challenges and gaps of knowledge ............................................................................ 13 
1.3 Rationale to conduct this study ......................................................................................... 14 
1.4 Study hypothesis ............................................................................................................... 14 
2. Objectives of the study................................................................................................ 15 
2.1 Overall objective of the study ............................................................................................ 15 
2.2 Specific objectives of the study .......................................................................................... 15 
2.3 Study end point measures ................................................................................................. 16 
2.3.1 Primary end point ................................................................................................................. 16 
2.3.2 Secondary end points ........................................................................................................... 16 
3.0 Methods ................................................................................................................... 17 
3.1 Study design ..................................................................................................................... 17 
3.2 Study site .......................................................................................................................... 18 
3.3 Study setting and population ............................................................................................. 18 
3.4 Research question and statistical power ............................................................................ 19 
3.5 Inclusion and exclusion criteria .......................................................................................... 20 
3.5.1 Inclusion criteria: .................................................................................................................. 20 
3.5.2 Exclusion criteria: ................................................................................................................. 20 
3.6 Study period ..................................................................................................................... 20 
3.7 
Investigational product (IP) .......................................................................................... 21 
3.7.1 Description and formulation ................................................................................................ 21 
3.7.2 Dose preparation and administration .................................................................................. 21 
3.7.3. Storage and stability (shelf-life) .......................................................................................... 21 
3.7.4 Packaging and labelling ........................................................................................................ 21 
3.7.5 Accountability ....................................................................................................................... 21 
3.8 Study procedures .............................................................................................................. 22 
3.8.1 Recruitment of pregnant women and enrolment of study participants .............................. 22 
3.8.2. Filling of the electronic CRF using RED cap ......................................................................... 22 
3.8.3 Randomization and blinding ................................................................................................. 23 
3.8.4 Unmasking in emergency situations .................................................................................... 23 
3.8.5 Visit schedule and follow-up activities ................................................................................. 24 
3.9 Specimen collection and storage........................................................................................ 24 

 
 
 
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3.10 Data collection and handling during the study period ....................................................... 25 
3.11 Microbiological methods ................................................................................................. 26 
3.11.1 Laboratory tests to be performed at Haydom Lutheran Hospital ...................................... 26 
3.11.2 Laboratory tests which to be performed at UiB/SUH/UNN ............................................... 26 
4.0 Monitoring of the study ............................................................................................ 28 
5.0 Criteria for withdrawal of individual study participants ............................................. 30 
6.0 Ethical considerations ............................................................................................... 31 
6.1 Potential benefits and risks associated with the study ........................................................ 31 
6.2 Regulation statement, Ethical approval and Protocol registration ....................................... 31 
6.3 Recruitment and consent .................................................................................................. 32 
6.4 Treatment during the study period .................................................................................... 32 
6.5 Compensation for injury .................................................................................................... 33 
6.6 Transfer of Data and Biological Material ............................................................................ 33 
6.7 Data Safety Monitoring Body (DSMB) and schedule of work ............................................... 33 
7.0 Statistical analysis ..................................................................................................... 36 
8.0 Organization, collaboration and research environment .............................................. 38 
9.0 Budget ...................................................................................................................... 40 
10.0 Time schedule ......................................................................................................... 43 
11.0 End of study report ................................................................................................. 44 
12.0 Plan for Dissemination of results ............................................................................. 45 
13.0 Planned publications ............................................................................................... 46 
14.0 User Involvement .................................................................................................... 47 
15.0 References .............................................................................................................. 48 
16.0 Informed consent form ............................................................................................ 51 
 
 
 
 

 
 
 
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List of abbreviations  
 
AMR  
Antimicrobial resistance  
BSI  
Blood stream infection 
CRF 
Case Report Form  
DNA  
Deoxy Ribose Nucleic acid  
ESBL  
Extended-spectrum beta-lactamase 
PhD  
Doctor of Philosophy  
PI 
Principal Investigator 
WHO  
World health organization  
NEC 
Necrotizing Enterocolitis 
MDR  
Multi Drug Resistance  
RCT 
Randomized Clinical Trial 
HIV  
Human Immunodeficiency Virus  
IRB 
Institutional Review Board 
UiB 
UiT  
University of Bergen  
The Arctic University of Norway 
NIMR  
National Institute of Medical Research  
TFDA  
Tanzania Food and Drug Administration  
GCP 
Good Clinical Practice  
SUH 
Stavanger University Hospital 
MUHAS Muhimbili University of Health and Allied Sciences  
HUH 
Haukeland University Hospital  
HLH  
Haydom Lutheran Hospital  
SOP 
Standard Operating Procedures  

 
 
 
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Summary 
Background and objectives: 
Infections continue to be a considerable cause of death and disease among infants in low-and 
middle-income countries. In sub-Saharan Africa, infections contribute to 3/4 of under-five 
mortality. In previous studies of children in Tanzania, we observed that blood-stream 
infections (BSIs) caused by Gram-negative bacteria (Enterobacteriales) with extended-
spectrum beta-lactamase (ESBL)-type resistance gave a mortality rate of more than 70%, 
compared to 20% or less for malaria infections or BSI with susceptible bacteria. An 
increasing prevalence of ESBL-producing Enterobacteriales (ESBL-E) are among the most 
urgent global health threats, and ESBL-E are by WHO ranked on priority 1 among pathogens 
in need of new treatment. We have previously shown in a study from Tanzania that around 
2/3 of infants below three months of age had faecal carriage of ESBL-E. 
Probiotics are live microorganisms that, when administered in adequate amounts, confer a 
benefit to the host. Probiotics are currently widely used in newborns and children. They have 
proven beneficial effects in preterm infants with reductions in the incidence of necrotizing 
enterocolitis (NEC) and sepsis. For this patient group the use of probiotics in high-income 
countries has entered what has been called a “golden age”, and similar beneficial effects have 
also been observed among preterm infants in low- and middle-income countries. Probiotics 
may also reduce colonization by ESBL-E and other antibiotic resistant bacteria through 
“colonization resistance”, but there is limited data on which probiotic strains that most 
effectively reduce ESBL-E carriage in children. In adults and older children lactobacilli are 
often used to prevent or treat other conditions like antibiotic-associated diarrhea, 
gastroenteritis and infantile colic. A recent large clinical trial from India reported reduced 
mortality and fewer severe infections in children receiving probiotics combined with a fructo-

 
 
 
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oligosaccharides (prebiotic). 
The present clinical trial will evaluate whether use of probiotics can reduce infection-related 
morbidity and mortality by preventing colonization and/or infections with ESBL-E among 
infants in Haydom, Tanzania. 
Methods and expected results:  
This is a single center randomized double-blind controlled clinical trial (RCT) with two arms, 
one intervention group (n=1000) randomized to receive a triple-strain probiotic product 
(Investigational product-IP) and one group (n=1000) randomized to receive placebo. The 
study will be conducted at Haydom Lutheran Hospital (HLH), in the northern-central part of 
Tanzania. A total of 2000 newborn infants will be enrolled in the study from day 0 - 3 after 
birth and they will be followed-up for a period of six months. We are planning to have three 
follow-up visits after enrollment between day 0-3. The first visit will be after 7 (6-9) days, the 
second at six weeks (35-50 days) and the third at six months (170-190 days) after study 
enrollment. Three electronic case report form (CRF) using RED cap, one for each visit, will 
be used to collect clinical and demographic information of the infants enrolled in the study. 
The initial data at enrollment will also be filled with mother’s demographic and clinical 
information.  
The IP and the placebo will be administered to the infant daily by the caretaker, from the day 
of enrollment and for a period of four weeks or more. One fecal swab and one fecal sample 
will be collected at the second and third visit, respectively, and analyzed for i) carriage of 
ESBL-E; ii) gut microbiota/metabolome composition incl. antibiotic resistome and iii) gut 
inflammation markers. 
During the study period, we will also in a separate study investigate all causes of fever among 
children below 6 months  admitted to the pediatric ward at HLH, including both study 
participants and children not included in the RCT. For this sub-study a separate inclusion 
form will be used. All children below 6 months admitted to HLH with fever during the study 

 
 
 
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period, will be offered blood culture diagnostics, including species identification and 
antibiotic susceptibility testing of pathogens in positive cultures, C-reactive protein (CRP) 
test, and malaria rapid test, the latter only if clinically indicated. An additional fecal swab 
sample will be obtained on acute admissions. Results will be communicated back to the 
attending clinician to assist management of these children. At a later stage, the stored fecal 
swab samples will be screened for ESBL-E using selective media (e.g. ESBL ChromID, 
BioMerieux). ESBL-E isolates from the fecal swab samples and from blood cultures obtained 
from children with fever will be further characterized using whole genome sequencing to 
detect ESBL-encoding genes and other genes encoding antibiotic resistance, and for 
molecular epidemiology purposes. Microbiota analysis will be performed on stored fecal 
samples using a metagenomics approach.  Bioinformatic analysis will be performed using 
available and relevant software and methods. Statistical analysis of the study results will be 
performed using Stata 13 software.  
This study is expected to show reduction in ESBL-E carriage in infants receiving probiotics. It 
is also powered to detect a 50% reduction in infection related morbidity and mortality among 
the group of infants treated with probiotics.  
Budget and source of funding: The budget for conducting the RCT will be 184.000 USD.  
This RCT received funding from the Regional Health Trust of Western Norway.  
 
 

 
 
 
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1. Introduction  
1.1 Background Information 
Infections continue to be a considerable cause of death and disease among infants in low-and 
middle-income countries. In sub-Saharan Africa, infections contribute to 3/4 of under-five 
mortality (Kipp 2016). Although child mortality is declining in Sub-Saharan Africa, it is still 
very high. In Tanzania, the under-five mortality was reported at 55 per 1000 live births in 
2016, whereof 42 deaths occurred before the age of one year (Wang 2017). Newborns are 
susceptible to infection because key parts of their immune systems are still developing and 
not fully functional (Goenka 2015 & Shane 2017). From our previous studies of hospitalized 
children in Tanzania, we have shown that blood-stream infections (BSIs) caused by Gram-
negative bacteria (Enterobacteriales) with extended-spectrum beta-lactamase (ESBL)-type 
resistance gave a mortality rate of more than 70%, compared to 20% or less for malaria 
infections and BSI with susceptible bacteria (Blomberg 2005 & Blomberg 2007).  
Antimicrobial resistance (AMR) threatens the very core of modern medicine and the 
sustainability of an effective, global public health response to the enduring threat from 
infectious diseases (WHO 2015). An increasing prevalence of ESBL-producing 
Enterobacteriales (ESBL-E) are among the most urgent global threats, and ESBL-E are by 
WHO ranked on priority one among pathogens in need of new treatment (WHO 2018). Fecal 
carriage of ESBL-E is a potential risk for transmission and infection. We have previously 
shown in a study from Tanzania (Fig. 1) that around 2/3 of infants below three months of age 
had fecal carriage of ESBL-E (Tellevik, 2016). 

 
 
 
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Probiotics are live microorganisms that, when administered in adequate amounts, confer a 
benefit to the host. Probiotics are currently widely used in newborns and children (Lenfestey 
2017). They have proven beneficial effects in preterm infants with reductions in the incidence 
of necrotizing enterocolitis 
(NEC) and sepsis (AlFaleh 
2014 & Rao 2016). For very 
preterm infants the use of 
probiotics in high-income 
countries has entered what has 
been called a “golden age”, 
and similar beneficial effects 
have also been observed 
among preterm infants in low- 
and middle-income countries 
(Deshpande 2017). It is 
important to acknowledge that 
there are numerous probiotic products with possibly strain-specific effects (Lenfestey 2017). 
In preterm infants, multiple-strain probiotics have proved more efficient in reducing NEC, 
sepsis and mortality than single-strain products (Chang 2017).  
 
In a recent study from India, more than 4500 infants were randomized to receive either the 
probiotic bacteria Lactobacillus plantarum along with fructo-oligosaccharide, a plant-derived 
prebiotic (the combination of probiotic and prebiotic is coined “synbiotic”) or placebo 
(Panigrahi 2017). The synbiotic treatment was started on day 2-4 of life and was given for 7 
days. This simple intervention reduced the composite outcome severe infections and/or death 
Fig. 1. Prevalence of ESBL carriage in different age groups. The graph 
shows the prevalence (%) of ESBL carriage among the participants when 
categorized into five different age groups.  

 
 
 
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by 40%, from 9.0% in the 
placebo group to 5.4% in the 
synbiotic group (Fig. 2). This 
study has caused great attention 
in the scientific community and 
in the general public. Panigrahi 
has suggested that more studies 
are needed in order to develop 
guidelines for clinical care (The 
Wire 2017). 
 
A stable and resilient commensal gut microbiota is essential for “colonization resistance”; the 
ability to prevent intestinal colonization and invasion by pathogens. Resurrecting the gut 
microbiota by the use of probiotics has recently been put forward as a potential new strategy 
in combatting intestinal carriage of multi-drug-resistant (MDR) bacteria (Pamer 2016). To 
what extent probiotics directly reduce the spread of AMR is still much under investigation 
(Arthur 2016). However, probiotic bacteria can produce bacteriocins that improve mucosal 
integrity and thereby reduces the pathogenic bacterial population and promote “colonization 
resistance” (Pamer 2016), but there is so far no data on which probiotic strains that most 
effectively may reduce AMR in children. In adults and older children lactobacilli are often 
used to prevent or treat other conditions like antibiotic-associated diarrhea, gastroenteritis and 
infantile colic (Agamennone 2018 & Gutiérrez-Castrellón 2017). However, in breastfed 
infants, bifidobacteria constitute more than 80% of the gut microbiota (Fig. 3) and has several 
beneficial effects that make them attractive as probiotic agents for this age group.  
Fig. 2. Morbidity and mortality in infants given synbiotic versus 
placebo. Panigrahi, Nature 2017 

 
 
 
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In infants, B. infantis given in combination 
with human milk decreases the level of 
Enterobacteriales in the feces (Underwood 
2015). In a clinical trial, we observed that 
among extremely preterm infants 
supplemented with a probiotic product 
containing bifidobacteria and lactobacilli, 
we found no ESBL-E in stool samples 
despite massive exposure to antibiotic 
therapy. In contrast, ESBL-E was detected 
in the stool of moderate preterm infants and 
full-term infants not given probiotics and 
with less or no antibiotic exposure (Esaiassen 2018). In this study (Esaiassen 2018), a 
metagenomics approach was used in order to analyze the gut microbiota and antibiotic 
resistome.  
 
1.2 Main challenges and gaps of knowledge 
Except from the study by Panigrahi (Panigrahi 2017) there is little data on the effect of 
probiotics in reducing mortality and infection-related morbidity in infants in low-income 
countries. There is also very limited clinical data on the effect of probiotics to reduce AMR 
carriage and AMR-related infections in infants and children, even though this approach has 
been put forward as a promising new strategy. Increasing AMR, according to the World 
Health Organization, is one of the most important threats to human health 
(www.who.int/entity/drugresistance/en). It affects both high- and low-income countries, but 
consequences are more severe in low income countries due to the prohibitive costs and thus 
Fig. 3. Level of Bifidobacteria in the gut during 
different stages in life (by Kenneth Kristensen). 

 
 
 
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lack of specific diagnostic and second line antibiotics. No randomized clinical trial (RCT) has 
investigated whether probiotics may reduce ESBL-E carriage in infants. 
 
1.3 Rationale to conduct this study 
Our own research has shown a high mortality of Tanzanian children with ESBL-E infections 
(Blomberg 2005 & Blomberg 2007), a high carriage rate of ESBL-E in Tanzanian infants 
(Tellevik 2016) and promising results using probiotics to reduce AMR (Esaiassen 2018). The 
recent large RCT from India showed a reduction in severe infections and death among 
newborns given probiotics/synbiotics (Panigrahi 2017), and these beneficial findings are 
supported by data from systematic reviews indicating a reduction in sepsis and mortality in 
preterm infants given probiotics. However, studies in other developing countries are needed to 
confirm the positive findings from the Panigrahi trial. 
We therefore propose to do an RCT on probiotics versus placebo in healthy Tanzanian 
infants. The primary endpoints, for which the study is powered, is a reduction in the 
composite outcome mortality and hospitalizations. Secondary endpoints are rates of ESBL-E 
gut carriage, growth, microbiota/metabolome composition and gut inflammatory markers. 
 
1.4 Study hypothesis 
Our hypothesis is that probiotics will significantly reduce the composite outcome death and/or 
infections in children up to 6 months of age. We hypothesize that this reduction will partly be 
mediated by a concomitant reduction in prevalence of ESBL-E-carriage in this group of 
children.  
 
 
 

 
 
 
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2. Objectives of the study  
2.1 Overall objective of the study 
The present clinical trial will evaluate whether 4 weeks administration of probiotics in the 
first 4 weeks of life can reduce mortality and/or hospitalizations, and colonization with ESBL-
E, among infants in Haydom and surrounding area, Tanzania. 
 
2.2 Specific objectives of the study 
2.2.1   To assess and compare mortality among two groups of the study participants (i.e. 
probiotic and placebo group) in Haydom and surrounding area, Tanzania. 
2.2.2   To determine and compare episodes of infections (i.e. sepsis, diarrhea, etc) leading to 
hospitalization among the two groups of study participants in Haydom and 
surrounding area, Tanzania  
2.2.3 To determine and compare the prevalence of ESBL-E carriage between the two groups 
of study participants at six weeks and six months follow-up. 
2.2.4 To determine and compare the bacterial causes of sepsis, including antimicrobial 
susceptibility patterns, in and between the two groups of study participants. 
2.2.5 To assess and compare the effect of probiotics on growth between the two groups of 
study participants. 
2.2.6 To determine and compare the gut microbiota composition and diversity between the 
two groups of study participants. 
2.2.7 To determine the genetic characteristics of ESBL-E and other MDR isolates from 
carriage and clinical samples. 
2.2.8 To determine the bacterial causes of sepsis, including antimicrobial susceptibility 
patterns for all children under 6 months of age admitted with fever during the study 
period. 
2.2.9 To determine gut inflammatory markers from children at 6 month follow-ups 
 

 
 
 
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2.3 Study end point measures  
2.3.1 Primary end point 
• Prevalence of the composite outcome death and /or hospitalizations at six months of age.  
2.3.2 Secondary end points 
• Prevalence of ESBL-E carriage at six months of age.  
• Rates of hospitalizations up to six months of age. 
• Rates of confirmed sepsis episodes up to six months of age. 
• Growth monitored by height and weight up to six months of age. 
• Stool microbiota/metabolome composition including antibiotic resistome analysis 
(metagenome sequencing) at six weeks and six months of age.  
• Genetic characteristics of ESBL-E and other MDR isolates from carriage and clinical 
samples. 
• Characteristics of gut inflammatory markers  
 
 

 
 
 
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3.0 Methods  
3.1 Study design  
This will be a single-center randomized double-blinded controlled clinical trial (RCT) with 
two arms: 
Arm 1: The active group will receive the investigational product (IP); a commercially 
available multi-strain probiotic product (LaBiNIC® probiotic drops, Biofloratech Ltd, Surrey, 
UK. Five drops (0.2 ml) contain 1.8 x 109 CFU Lactobacillus acidophilus, Bifidobacterium 
infantis and Bifidobacterium bifidum (equal amount of all three strains). The product is 
already widely used in the UK (at hospitals in the National Health Service) and in other 
European countries (Robertson 2020, Klingenberg 2019). The product also recently received 
the Pharmacy Grade Certificate A-Grade by the South African Pharmacy Council, valid until 
31st of December 2021 (attached copy). 
LaBiNIC® probiotic drops can be stored at room temperature, provided this does not exceed 
25 ℃ for prolonged periods (a few hours at 30 ℃   causes no degradation). No refrigeration is 
needed for storage. The product is 100% dairy-, gluten-, egg-, soya- and allergen-free. It 
contains no animal products, no preservatives, no colouring products and/or no sweeteners. It 
is manufactured to GMP and GPP WHO standards. All batches are microbiologically tested 
for safety and composition. 
Arm 2: The placebo group will receive placebo drops; a MCT-oil and AEROSIL® 200 
Pharma (the latter is an additive for food and pharma products with a high quality standard, 
and with production processes based on quality concepts such as; ISO 9001, HACCP, FAMI-
QS and IPEC-GMP). The MCT-oil and AEROSIL® 200 Pharma are also constituents of the 
active IP. The placebo is produced by the same company that manufacture the IP 
(Biofloratech Ltd, Surrey, UK). The MCT-oil is used as a vehicle for the probiotic bacteria in 
the IP, and the taste and colour is identical, and it will be produced in identical bottles to the 
IP.   

 
 
 
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The drops for both arms will be dispensed in identical bottles. All infants will be given 5 
drops daily from inclusion and for a period of four weeks (“to bottle empty”). Previous 
studies in developing countries have used from 7 days (Panigrahi 2017 - India) to 60 days 
(Pernicia 2017 - Botswana) intervention with probiotic supplementation in infants.  
 
3.2 Study site 
This will be a single-centre study to be conducted at Haydom Lutheran Hospital (HLH) and 
surrounding area. HLH is located in the Mbulu district, at the western end of Manyara region 
in the North-Central Tanzania, about 300 km south-west from Arusha. The HLH catchment 
area consists of 4 administrative divisions, 3 districts and 2 regions. These are the Dongobesh 
and Haydom divisions in Mbulu District, the Basotu Division in Hanang District (Manyara 
Region), and the Nduguti Division in Mkalama District (Singida Region). The hospital serves 
more than 2 million population from five regions. HLH has strong and well-established 
research infrastructure, and over ten years has been involved in community research, which 
has built trust between the hospital and community around (Mduma, 2014). There are annualy 
more than 3900 deliveries and the neonatal mortality rate is around of 43/1000 live births.  
The hospital has a track record of conducting clinical trials, including the Early Life 
Intervention in Childhood growth and development (ELICIT), the Effectiveness of Quadruple 
Fortified Salt in Improving Hemoglobin Levels among Anemic Women of Reproductive Age 
(18-49 Years) in Rural Low Resource Setting (Salt study trial) and clinical trials on neonatal 
resuscitation evaluating the Helping Babies Breathe program. HLH has laboratory capacity 
with required equipment’s and trained staff to do clinical trials. 
 
3.3 Study setting and population 
Newborn infants delivered at HLH or outside hospital will be eligible for inclusion.  

 
 
 
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Mothers to potential eligible participants (newborn infants) will be approached and informed 
about the ProRIDE-study at home or when attending their last antenatal clinic visits before 
delivery. Those mothers who give written consent for potential participation of their future 
child will be recruited to participate in the study, and after giving birth the newborn will be 
screened for eligibility before being randomized in the study. We intend to include a total of 
2000 newborn infants to participate in the study, half of these i.e. 1000 will receive a multi-
strain probiotic product and the other 1000 will receive placebo.  
 
3.4 Research question and statistical power 
The research question is: Among term born healthy infants in Tanzania (P-population), will 
treatment with probiotics (I-intervention) compared to placebo (C-comparison) lead to a 40% 
reduction in hospitalizations and death, and in fecal carriage of ESBL-producing bacteria (O-
outcome)?  
Infant mortality rate in Tanzania was in 2017 reported at 4.4%. We do not have exact data for 
the Mbulu district, but we assume a similar rate. Serious infections leading to hospitalization 
are probably equally common, but hospitalization rates may depend on available access. In 
the Panigrahi study, the synbiotic product was given for only 7 days, and it reduced the 
composite outcome death and/or infection from 9.0% to 5.4% during the first 2 months of life. 
In our study, the intervention will continue for around 4 weeks and follow-up will continue 
until 6 months of life. We consider a similar reduction in the composite outcome death and 
infections leading to hospitalizations from 9.0% to 5.4%, as in the Panigrahi study, to be 
clinically relevant. To find this difference with a study power of 85% at 5% significance level 
we will need a sample size of minimum 924 cases in each arm; thus 1848 infants. In order to 
allow for drop-out we aim to include 1000 infants in each arm. We believe it is realistic to 
include this number of infants within a 12-month recruitment period.  

 
 
 
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With this number of infants, we will also have sufficient power to detect a minimum of 30% 
reduction in ESBL-carriage rate (from around 50% to 35%) at six months of age. 
 
3.5 Inclusion and exclusion criteria 
3.5.1 Inclusion criteria:  
• Healthy newborn infants with a birth weight equal or above 2.0 kg, will be included in the 
study between 0-3 days of life.  
• Newborn infants have to come from families who are long-term or permanent residents in 
the defined catchment area for this trial (30 km radius from HLH) in Tanzania.  
• Parents are able and willing to complete study visit (including required study procedures) 
schedules over the six months proposed follow-up, which also includes hospitalizations 
required for compliance of this study protocol.  
• Children less than 6 months of age admitted to hospital with suspected infection, not 
included in the RCT, will be included in a sub-study. A separate inclusion form is 
prepared for these children. 
3.5.2 Exclusion criteria:  
• Multiple Pregnancy 
• Birth weight below 2 kg 
• Other health problems/illness, obvious congenital malformations. 
• Parents not consenting 
 
3.6 Study period  
The study period is expected to last for 18 months, which will include recruitment period of 
one year and a six-month follow-up of all participants.  
 

 
 
 
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3.7 Investigational product (IP) 
3.7.1 Description and formulation 
The IP is a commercially available multi-strain probiotic product (LaBiNIC probiotic drops®, 
Biofloratech Ltd, Surrey, UK). The product is widely used in the UK (National Health 
Service) and other countries in Europe. The product also recently received the Pharmacy 
Grade Certificate A-Grade by the South African Pharmacy Council, valid until 31st of 
December 2021 (attached copy). 
The product is 100% dairy-, gluten-, egg-, soya- and allergen-free. It contains no animal 
products, no preservatives, no colourings or sweeteners. It is manufactured to GMP and GPP 
WHO Standards. All batches are microbiologically tested for safety and composition. 
3.7.2 Dose preparation and administration 
Five drops (0.2 ml) contain 1.8 x 109 CFU Lactobacillus acidophilus, Bifidobacterium 
infantis and Bifidobacterium bifidum (equal amount of all three strains) will be given by 
mouth once daily for 4 weeks to “bottle empty”. Bottle contains 5-5.5 ml. 
3.7.3. Storage and stability (shelf-life) 
Labinic probiotic drops can be stored at room temperature, provided this does not exceed      
25 ˚C for prolonged periods (a few hours at 30 ˚C causes no degradation). No refrigeration is 
needed for storage. 
3.7.4 Packaging and labelling 
Biofloratech Ltd will pack probiotic and placebo in identical packages, and number the 
packages according to the randomization list.  
3.7.5 Accountability 
The investigators will ensure that all investigational products (probiotic and placebo) are 
inventoried and stored as indicated by the manufacturer. Accurate records will be kept 
regarding the date manufactured, date received, lot number, expiry date and amount received.  
 

 
 
 
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3.8 Study procedures 
3.8.1 Recruitment of pregnant women and enrolment of study participants 
Pregnant women in their last trimester, visited at home or attending their last visit before 
delivery at HLH, will be informed about the study and asked for consent to let their future 
child participate in the study. A study research assistant will inform the woman about all 
aspects of the study, including the importance of performing such a study, and all procedures 
which will take place during the study period. A thorough explanation will also be given on 
how the IP/placebo will be administered orally once daily with 5 drops until bottle empty 
(four weeks). Finally, the importance of completing the dosage of the IP/placebo for the four 
week-intervention period will also be explained to the woman. Information will be given 
orally and by information included in a written informed consent form (ICF). If the woman, 
after this information, agrees for her child to participate in the ProRIDE-Trial, she will be 
asked to give written consent to screen and enroll the newborn baby in the study. The woman 
will receive a special information card developed for the ProRIDE-Trial, after delivery and 
inclusion. During and after delivery, the attending doctor/midwives will identify mothers who 
have consented to participation and inform the research assistant, who will help coordinate the 
study. After delivery the new-born baby will be screened for eligibility into the study, and if 
the baby fulfills the inclusion criteria of the study, the baby will be enrolled and allocated to 
the randomized product (active probiotics or placebo), which will be initiated on day 0-1 for 
hospital deliveries or day 0-3 for home deliveries. The mother will be explained and 
demonstrated how to administer the study product. 
3.8.2. Filling of the electronic CRF using RED cap 
Mothers who have given consent will be registered by name and address in the consent form. 
For enrolled babies, four different electronic case report forms (CRF) will be used for the 
study, three for the study visits and one for adverse events/unscheduled visits due to 
hospitalization/outpatient’s attendance for participants who fall sick during the study period.  

 
 
 
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Infant deaths, hospitalizations and sepsis episodes will also be recorded (Appendix 1-6). 
Tablet computers with RED cap® software will be provided to research assistants and 
investigators. Passwords will be created for each research assistant and investigator to get 
access to the study file in RED cap. Research assistants will have access only to fill in the 
respective CRF of the study participants they recruit at each visit and they will have no access 
to change any information entered in RED cap. Only study investigators will have access to 
change information filled in the RED cap when need arise. Infant’s deaths, hospitalisations 
and sepsis episodes will also be recorded.  
3.8.3 Randomization and blinding  
Before the start of the study, an independent researcher/statistician will generate a 
randomization list with the study identification number of patients, from 1 to 2000, and 
allocated investigational product or placebo. This randomization list will be sent to 
Biofloratech Ltd, Surrey, UK for labelling of the investigational product and placebo, which 
will be produced and labelled in identical bottles, numbered from 1 to 2000. Upon screening, 
the newborn infants will consecutively be allocated (randomized) to the next study 
identification number and given the corresponding investigational product/placebo.  
The main bias reducing technique in this RCT is randomization and blinding. A local 
pharmacist, who is not part of the study will be provided with the randomization list. Both 
study participants and investigators and care providers will be blinded for assignment of the 
intervention.  
3.8.4 Unmasking in emergency situations 
A pharmacist not involved in the study will have access to assignment list. Therefore, the 
study PI may request unblinding for treatment assignment if needed for medical care of a 
patient in an emergency situation. However, this is a very unlikely situation given the well-
known safety of probiotics in infants, and the lack of known interaction with other important 
drugs used for any other required therapy. 

 
 
 
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3.8.5 Visit schedule and follow-up activities  
The follow-up schedule is summarized in Table 1 below. After study randomization, 
participants will receive follow-up for six months. At enrollment the baby will be weighed 
and clinical data on mother and child will be entered in the CRF. The first visit after 
enrolment will be around 7 days after birth, the second at six weeks after initiation of 
intervention product, and the last visit at six months. During all study visits, the baby’s length, 
weight measurements, and clinical information will be recorded. Fecal samples and fecal 
swabs will also be taken according to the developed SOP.  
Table 1. Follow-up schedule visit for ProRIDE-trial 
Time  
Event  
Activity  
Day 0-3 after birth of the newborn  
Enrolment and randomization  - Filling of CRF-1 
- Giving the IP/placebo to the 
mother/caretaker of the baby  
Day 7 after initiation of 
investigational product 
Visit 1 
- Observe for the compliance 
- Discuss issues with care 
takers 
Six weeks after initiation of 
investigational product 
Visit 2 
 
-Observe if the bottle with 
IP/placebo is empty and 
return the bottle  
-First fecal and fecal swab 
sample will be taken  
-Filling of CRF-2 
Six months (25-27 weeks) after 
initiation of investigational product 
Visit 3 
-Second fecal and fecal 
swab will be taken 
- Filling of CRF-3 
 
 
3.9 Specimen collection and storage 
Standard Operating Procedures (SOP) which have been developed for the study will be used 
for specimen collection and processing. One fecal sample and one fecal swab sample will be 
collected at six weeks and six months visits, respectively. The fecal sample will be obtained 

 
 
 
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using a commercially available sampling kit (OMNIgen GUT kit, DNA Genotek, Ottawa, 
Canada) allowing storage of samples at ambient temperatures for up to 7-14 days before DNA 
extraction. These samples will be transported to HLH latest within 3 days after sampling and 
at HLH stored in -80 ℃ freezers. The fecal swab samples will be taken using eSwab (Copan 
Diagnostics, CA, USA) and frozen at -80 ℃ freezers until analysis.  
During unscheduled visits, when participants or other children below one year of age are 
hospitalized because of fever, Dr Museveni Justine who is the study physician will ensure 
blood specimens are collected using aseptic technique. The patient’s skin and the septum 
covering the blood culture vial will be disinfected with 70% alcohol (or 1-2% iodine tincture). 
Plastic gloves, sterile needles and syringes will be used. From the patient, one blood specimen 
will be collected from the same venipuncture. A total of 4-5 ml of blood will be drawn from 
the patient for blood culture to investigate for blood stream infections, C-reactive protein 
(CRP), and also malaria rapid test if clinically relevant. Furthermore, an additional fecal swab 
sample will be obtained from hospitalized children to investigate correlation between gut 
carriage of ESBL-E and ESBL-E as a cause for BSI. Caretakers of children <6 months, who 
are not included in the clinical trial, will be informed about the sepsis sub-study and asked to 
participate and sign a separate consent form. All children <6 months of age will receive the 
same diagnostics and treatment whether they are enrolled in the clinical trial, the sepsis sub-
study or none of the studies. 
 
3.10 Data collection and handling during the study period  
Clinical information as outlined in the CRFs will be recorded for each participant and will be 
kept confidential. The information will be recorded on electronic CRFs using the RED cap 
software; a software that globally is widely used for clinical trial purpose. Only informed 

 
 
 
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consents will be stored separately. Quality assessment of the data will be done by the internal 
clinical staffs and consent forms and eCRFs will be checked by external monitors.  
 
3.11 Microbiological methods 
3.11.1 Laboratory tests to be performed at Haydom Lutheran Hospital  
Blood specimens will be collected during unscheduled visits (hospitalization) of study 
participants and all children below 6 months of age (when they attend HLH to seek medical 
care) and analyzed at the laboratory facility in Haydom hospital. Results will be reported to 
the attending physician to assist patient treatment. Rapid malaria test (CareStart, USA) will be 
performed if relevant. CRP will be measured on all hospitalized children under one year with 
suspected infection to assist clinical evaluation of the infant. Blood cultures will be drawn 
from infants with fever or suspected infection. Blood culture bottles will be transported to the 
laboratory and will be incubated at 35°C in the BACTEC 9050® (Becton–Dickinson, Sparks, 
MD, USA) culture system for a maximum of 5 days unless flagged positive. Positive blood 
cultures will be sub-cultured on sheep-blood and chocolate agar using routine microbiological 
techniques. Furthermore, Gram stains will be made for all positive blood cultures. Antibiotic 
susceptibility testing (AST) will be performed on clinically relevant bacterial isolates using 
conventional methods (disk diffusion) following EUCAST guidelines 
(http://www.eucast.org/clinical_breakpoints/ ). All clinically relevant isolates (considered to 
cause infection) will be frozen at -80°C for subsequent genetic analysis (whole genome 
sequencing).  
3.11.2 Laboratory tests which to be performed at UiB/SUH/UNN 
Fecal samples and fecal swabs collected at six weeks and six months will be transported to 
Norway for the following analyses:  
• Fecal swab samples (n=4000) collected at six weeks and six months will be screened for 
ESBL-E using a selective ESBL-screening agar (ChromID ESBL and ChromID Carba, 

 
 
 
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BioMerieux). All samples will be plated on non-selective plates for growth control. 
ESBL-E isolates will be frozen for subsequent genetic analysis (whole genome 
sequencing and plasmid analysis).  
• Fecal samples (n=4000) collected at six weeks and six months will be subjected to gut 
microbiota/metabolome and antibiotic resistome analysis using state of the art methods. . 
This will be done on DNA or metabolites extracted from the feces sampled and stored in a 
commercially available sampling kit (OMNIgen GUT/MET kits). In addition, fecal 
samples collected at six months will be analyzed to determine the levels of gut 
inflammatory markers between the two groups.  
 

 
 
 
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4.0 Monitoring of the study  
Site monitoring will be conducted to ensure that the rights and well-being of study 
participants are protected. In addition, monitoring will verify that the reported clinical and 
laboratory data are accurate, complete and verifiable from source data. Site monitoring will 
also ensure that the conduct of the clinical trial is in compliance with the study protocol, good 
clinical practice (GCP) and good laboratory practice (GCLP) and applicable regulatory 
requirements. A data safety monitoring committee (DSMC) will be appointed and this DSMC 
will oversee that trial is conducted according to GCP and GCLP. 
 
Table 2 showing monitoring plan  
 
1st quarter 
2nd quarter 
4th quarter 
8th quarter 
Enrolment visit 
X 
 
 
 
Follow-up visit 
 
X 
X 
 
Close up 
 
 
 
X 
 
 
Table 3 showing key activities of the clinical monitor 
Site visits 
When 
Key activities 
Monitoring visit during 
enrolment 
One visit, four weeks since 
the start of enrolment.  
Perform monitoring visit, to check 
for: 
- Inspection of all ICH GCP 
certificates in place  
- Verification of Informed consent 
forms 
- Eligibility check 
- eCRF completion 
- Equipment, consumables, study 
material 
- Review laboratory sample 
management  
 

 
 
 
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Monitoring visit follow up 
-first 
One visit six months since 
the start of enrolment.  
 
Perform monitoring visit, in 
particular check for:  
- Specimen collection procedure 
- Eligibility check 
- eCRF completion 
- Eligibility of source documents 
- Source data verification 
- Review AE/SAE reporting  
 
Monitoring visit follow up 
-second 
One visit 12 months since 
the start of enrolment.  
 
Perform monitoring visit, in 
particular check for:  
- Specimen collection procedure 
- Eligibility check 
- eCRF completion 
- Eligibility of source documents 
- Source data verification 
- Review AE/SAE reporting  
 
Close up visit monitoring  
One visit 18 months since 
start of enrolment (end of 
study) 
Perform monitoring visit, in 
particular check for: 
- Last query resolution 
- Storage and archiving of 
documentation 
- Review, update and finalization of 
IF 
 
 
 

 
 
 
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5.0 Criteria for withdrawal of individual study participants  
Study participants will be discontinued from participation in the study if: 
• Any clinical adverse event (AE) during the four-week intervention, laboratory 
abnormality or other medical condition or situation occurs such that continued 
participation is not in the best interest of the participants  
• Participants wishes voluntary withdrawal.  
• Participants are free to withdraw from participating in the study at any time upon request.  
• In any case participants will be given appropriate care under medical supervision until the 
symptoms of any AE resolve or the participant’s condition becomes stable.  
 
 
 

 
 
 
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6.0 Ethical considerations  
6.1 Potential benefits and risks associated with the study 
The proposed intervention has shown beneficial effect on morbidity in very preterm infants 
below 32 weeks gestation. The large RCT from India also reported promising results 
regarding a potential reduction of death and severe infections in term infants. Participation in 
the study may thus be of potential benefit. 
No extra blood samples will be obtained by the included participants, only fecal samples. As 
such, no extra pain will be imposed on the participants. The intervention with administration 
of 5 droplets daily for 4 weeks is easy, and we consider it will not pose any significant extra 
burden on parents or participants. 
Included infants who may be sick and need hospitalization for any illnesses will receive 
standard care treatment at HLH, including optimal assessment of a potential infection with 
blood culture and CRP analyses. 
Identification of study participation may be perceived as a stigma, but we do not think this is a 
substantial risk with this study. 
 
6.2 Regulation statement, Ethical approval and Protocol registration  
This study will be conducted in accordance with the latest South Africa revision of the 
Declaration of Helsinki, Good clinical practice and local and international regulatory 
requirements.  
• Ethical approval of the ProRIDE Trial has been obtained from both i) the Regional 
Committee for Medical and Health Research Ethics Western Norway in 4th September 
2019 (REK Vest 2019/1025) and from ii) the National Institute of Medical Research 
(NIMR) approved the trial on 9th April 2020 reference No. NIMR/HQ/R.8a/Vol.IX/3398. 

 
 
 
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• The protocol is approved by the Tanzania Medicines and Medical Devices Authority 
(TMDA) on the 25th March 2021.  
• The study is registered in ClinicalTrials https://clinicaltrials.gov/ct2/show/NCT04172012) 
• The study protocol is also published: Kuwelker K, Langeland N, Löhr IH, Gidion J, 
Manyahi J, Moyo SJ, Blomberg B, Klingenberg C. Use of probiotics to reduce infections 
and death and prevent colonization with extended-spectrum beta-lactamase (ESBL)-
producing bacteria among newborn infants in Tanzania (ProRIDE Trial): study protocol 
for a randomized controlled clinical trial. Trials. 2021 Apr 29;22(1):312.  
 
6.3 Recruitment and consent 
Recruitment of study participants will start after receiving all appropriate ethical approvals 
and protocol registration. The proposed study involves infants who are not able to consent. 
Investigators will provide verbal and written information about the objectives of the study, 
procedures and the obligations of the parent/care taker of the study participant, during the last 
antenatal visit before delivery or during home visits. After being given all the information, the 
parent/caretaker of the future study participant will be given enough time to consider 
participation in the study for their newborn infants. When the parent/caretaker agrees to 
participate, written informed consent will be obtained. Participants parents/caretakers will be 
informed that they can withdraw their informed consent at any time during the study. 
 
6.4 Treatment during the study period 
All study participants, when they fall sick during the study period, will be treated according to 
existing standard of care at Haydom Lutheran Hospital. In addition, the study will provide 
CRP analysis, blood culture and antibiotic susceptibility testing of bacteria recovered from 
blood culture for all children under one year of age suspected of having sepsis. Malaria rapid 

 
 
 
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test will be performed if clinically indicated (Care Start, USA). Laboratory results will be 
given to the attending clinician responsible for the care of children to assist the patient 
management.  
 
6.5 Compensation for injury  
Even though the study products are not considered to be medicinal drugs, and studies have so 
far not revealed any serious adverse effects, study participants will be insured, if unforeseen 
side effects of the probiotics develop. Please find attached copy of the receipt of insurance 
cover.  
 
6.6 Transfer of Data and Biological Material  
Relevant Material Transfer agreement (MTA) and Data Transfer Agreement (DTA) approved 
by NIMR will be used in order to ship biological specimens to Norway for further analysis 
and share data.  
 
6.7 Data Safety Monitoring Body (DSMB) and schedule of work  
The DSMB consists of the following experts: 
• Ketil Størdal, MD, PhD. Head of committee. Størdal is an experienced paediatrician with 
a focus on global health issues, nutrition and care of sick newborns. He has worked for 
several years in Botswana and is leading research projects in Tanzania. He also has 
advanced skills in biostatistics making him a relevant and important member of the 
DSMB 
• Sven Gudmund Hinderaker MD, PhD, is a medical doctor with extensive experience in 
global health projects, with particular focus on projects in sub-Saharan Africa.  

 
 
 
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• Charles Makasi MD,MPH, is public health specialist , with experience on monitoring 
clinical trials as well as data management, he had  recently monitored WHO funded sepsis 
study in infants  at Haydom Global Health Research Centre 
• Blandina Mbaga MD,PhD, she is a professor of pediatric  and  Director of Kilimanjaro 
Christian Research Insititute(KCRI), Moshi Tanzania, she has vast experience in 
conducting and monitoring both clinical research and clinical trials. 
Schedule of work for the DSMB:  
The primary responsibilities of the DSMB are to 1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct and progress, and, when 
appropriate, efficacy, and 2) make recommendations to the ProRIDE study consortium 
concerning the continuation, modification, or termination of the trial.  
Prior to initiating any data review, the DSMB has defined these deliberative processes: 
• Event triggers that would call for an unscheduled review: Mortality rates which 
significantly exceed the expected rates in Tanzania. The national infant mortality rate 
in Tanzania is estimated to 36 per 1000 
live births (https://data.unicef.org/country/tza/). The survival of participants will be 
monitored continuously. A death rate of more than five deaths per 100 infants will 
prompt an unscheduled review. 
• Stopping procedures that are consistent with the protocol: If the proportions of deaths 
among study participant in the placebo-group and the probiotic-group at 6 weeks 
follow-up are significantly different at the level of p>0.05 by Chi square test 
after 500 and 1000 infants have been included and followed up for 6 months. 
• Unmasking (unblinding) of single patient’s treatment: Only if serious adverse events 
may be related to the event 
• Voting procedures: If disagreement the leader of the DMSB has two votes 

 
 
 
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The DSMB is also responsible for maintaining the confidentiality of its internal discussions 
and activities as well as the contents of reports provided to it. The DSMB have reviewed the 
protocol and not found any concern prior to implementation. During the trial, the DSMB will 
review cumulative study data to evaluate safety after 500 and 1000 infants have been 
recruited. Moreover, they will review study conduct, and scientific validity and integrity of 
the trial. As part of this responsibility, DSMB members must be satisfied that the timeliness, 
completeness, and accuracy of the data submitted to them for review are sufficient for 
evaluation of the safety and welfare of study participants. The DSMB will also assess the 
performance of overall study operations and any other relevant issues, as necessary. 
Items reviewed by the DSMB will include: 
• Interim/cumulative data for evidence of study-related adverse events: Deaths and 
admission to hospital 
• Data quality, completeness, and timeliness. 
• Adequacy of compliance with goals for recruitment and retention, including those related 
to the participation of women and minorities; 
• Adherence to the protocol. 
• Factors that might affect the study outcome or compromise the confidentiality of the trial 
data (such as protocol violations, unmasking, etc.) 
• Factors external to the study such as scientific or therapeutic developments that may 
impact participant safety or the ethics of the study. 
The DSMB will conclude each review with their recommendations to the ProRIDE study 
consortium as to whether the study should continue without change, be modified, or be 
terminated. Recommendations regarding modification of the design and conduct of the study 
could include: 

 
 
 
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• 
Modifications of the study protocol based upon the review of the safety data; 
• 
Suspension or early termination of the study or of one or more study arms because of 
serious concerns about subjects’ safety, inadequate performance, or rate of enrollment; 
• 
Suspension or early termination of the study because study objectives have been 
obtained according to pre-established statistical guidelines; 
• 
Optional approaches for the ProRIDE study consortium and investigators to consider 
when the DSMB determines that the incidence of primary study outcomes is 
substantially less than expected (such as recommendations to increase the number of 
trial centers or extend the recruitment period); and, 
• 
Corrective actions regarding if the study center’s  performance appears unsatisfactory 
or appears to raise questions regarding the conduct of the study. 
Confidentiality must always be maintained during all phases of DSMB review and 
deliberations. Usually, only voting members of the DSMB should have access to interim 
analyses of outcome data by treatment group. Exceptions may be made when the DSMB 
deems it appropriate. The reason and to whom the exceptions for access to interim analyses is 
granted will be documented in the Closed Session Report. DSMB members must maintain 
strict confidentiality concerning all privileged study results provided to them. The DSMB 
should review data only by masked study group (such as X vs. Y rather than experimental vs. 
control) unless or until the DSMB determines that the group identifiers are necessary for 
decision-making. Whenever masked data are presented to the DSMB, the key to the group 
coding must be available for immediate unmasking. 
7.0 Statistical analysis 
Comparisons of proportions will be done by Pearson’s chi-squared tests. Means will be 
compared by t-test or non-parametric tests as appropriate. Logistic regression analysis will be 
performed for assessment of the relative importance of risk factors for carriage of ESBL, 

 
 
 
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multidrug-resistant bacteria, infection episodes and mortality. Analysis will be performed in 
Stata 13 (Stata corporation, College Station, Texas). 
 
 

 
 
 
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8.0 Organization, collaboration and research environment 
Partners who are involved in this study are employed at: 
• Haydom Lutheran Hospital (HLH) 
• University of Bergen (UiB)/Haukeland University Hospital (HUH) 
• Stavanger University Hospital (SUH) 
• UiT-The Arctic University of Norway (UiT)/University Hospital of North Norway (UNN) 
• Muhimbili University of Health and Allied Sciences (MUHAS) 
The proposed project requires competencies in diverse but complementary scientific fields, 
including clinical medicine, pediatrics and microbiology and bioinformatics. Essential 
competencies among the partners include clinical studies in low-income settings (UiB, 
MUHAS, HLH), pediatrics (UiT/UNN, HLH), clinical microbiology (UiB/HUH, SUH, 
MUHAS), AMR research and specifically ESBL-resistance research (UiT/UNN, SUH, HUH, 
UiB, MUHAS), and bioinformatics (SUH, UiB, UiT).  
The group at UiB/HUH will coordinate the consortium. Professor Nina Langeland and 
Associate Professor Bjørn Blomberg have experience in clinical studies in low-income 
settings with particular focus on AMR and severe infections in children. Dr Sabrina Moyo has 
long experience in performing clinical studies on children in Tanzania. 
At SUH, Dr. Iren Löhr is a senior microbiologist and the coordinator of the Norwegian 
Research Council-funded Norwegian Klebsiella AMR-Network. Dr. Löhr has also experience 
and competence in Nanopore sequencing and the genetics behind the spread of ESBLs.  
At UiT/UNN, Professor Claus Klingenberg is an experienced pediatrician/neonatologist with 
experience from research on infections and use of antibiotics in neonates, and clinical work in 
Tanzania.  Klingenberg has recently completed a study using metagenome analyses of gut 
microbiota and resistome in stool samples from preterm infants. 

 
 
 
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At MUHAS, clinical microbiologist Dr J Manyahi has set up a well-functioning microbiology 
lab and is presently conducting two clinical studies. He will be the Tanzanian laboratory PI 
for the proposed RCT study.  
HLH (https://haydom.or.tz/) is a rural hospital with the experience of running clinical studies 
including being partner in Gates-funded multi-center studies. Located in a rural setting, HLH 
is an ideal institution for comparative studies on differences in AMR between rural and urban 
(MUHAS) settings. Dr. Joshua Gidion at the Pediatric Department is the HLH partner and 
local clinical PI. 
Leadership. The consortium will be led by Nina Langeland. She has ongoing collaboration 
with the other partners, and 15 years partnership in research and medical specialist training 
with MUHAS in Tanzania. Her group has performed outbreak investigations both in Norway 
and in Tanzania and has conducted large clinical studies as well as RCTs on AMR. She is 
presently funded by the Research Council of Norway and the Gates Foundation. 
 
 
 

 
 
 
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9.0 Budget 
The proposed budget (attached) covers the cost of running the study. Major costs involve 
probiotics/placebo, research assistants, coordination of the study in Tanzania, and laboratory 
costs including culture. Further cost covering microbiota analysis and whole genome 
sequencing is not included in the attached budget.  
 
Table 4. Budget Justification 
ACTIVITY 
RESPONSIBLE PARTY 
UNITS  TOTAL 
COST 
IN USD  
Ethical clearance 
NIMR  application  
1 
2000 
  
NMRI-extension 
1 
200 
  
TFDA 
1 
3000 
Study site 
preparations 
Initial trainings-for this trial most of the staff are 
going to be new and they have to be familiar with all 
the study procedures like protocol, GCP,GLP, ALL 
SOP etc., the budget will serve for stationaries and 
refreshments for days of training.  
 
 
1 
1000 
  
Community preparation/sensitization  meetings-this 
will includes local government leaders, religious 
leaders from where subjects recruitments will take 
place-the budget will cover for their transport fee, 
meeting allowances, stationaries, meals and 
refreshments 
1 
5378 
Human resource 
 
 
  
 
 
  
study coordinator -we expect to employ one medical 
doctor who will be paid 100%, will be responsible for 
all the regulatory issues, study coordination in all 
units, preparing and reporting to regulatory bodies i.e 
NIMR,TFDA,DSMB etc 
1 
21786 
  
 study site  PI- 
1 
12528 
  
Pharmacist -we intend to hire degree level pharmacist 
from Hospital who will oversee  the control of trial 
products, this will 10% of his time 
 
1 
651.6 

 
 
 
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Investigators-investigators will work on the project 
for 10% time contribution, and one will be a research 
doctor who  will be concerned with all AE during 
trial. 
3 
6894 
  
Research Nurse pharmacy (full time) responsible for 
the control and supply of study intervention, second 
nurse will be needed as backup for 20% time 
contribution see below for her budget. 
1 
3548.4 
  
Research Nurse pharmacy ( 20%) 
1 
990 
  
research Nurse (100%time contribution) will be 
responsible for overseeing  sample collection 
procedure, reporting on the progress of sample and 
availability of supplies in the hospital, the budget is 
for their full salary for entire period of project 
2 
6387.12 
  
community health workers to work 20% time, for 
attending and reporting any AE/SAE,  
20 
9396 
  
Field workers -responsible for daily follow-ups,to 
field on identification of potential participants, 
screening, recruitments, follow-ups visits and non-
invasive sample collection. 
10 
45078 
  
Laboratory personnel (20%of time)-we will need 2 
laboratory personnel to oversee lab supplies, sample 
processing, and reporting to study CRF. 
2 
6873.12 
  
IT person - we need for any trouble shooting of the 
data collection devices and back up of data locally 
and online communication,20% time will be 
appropriate. 
1 
1095 
Other logistics 
 
 
 
 
  
Stationaries - though in this study we intend  to utilize 
electronic CRFs, we still need significant paper work 
for ICFs for 2000 subjects, all regulatory documents, 
printers, cartridges, and files 
 
2000 
  
Communications-we expect extensive online 
communication, phone calls both locally and 
international. 
 
3000 
  
health insurance - as  in all clinical trial this required   
by both NIMR and TFDA for all participants  to be 
insured , here one insurance card will serve for 5 
participants, costing Tsh 30,000. 
One per 
year 
15000 

 
 
 
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life insurance  -the same as above  
One  per 
year  
2000 
Seeking permission 
from district and 
Regional authority  
Reporting to the all authorities in all regions and 
districts where participants will be recruited i.e 
Regional Medical officers, District Medical officers 
and Regional administrative secretaries, budget will 
be for travel, accommodation and PI DIEM. 
1 
130.43 
district authority  
1 
130.43 
Local onsite 
transportation  
Hiring a car for daily transportation of FW and other 
research  staff 1,500/km*80km/day /=120,000 
 
18750 
other expenses/unforeseen 5% 
 
 
Subtotal  
 
 
167816.1 
 
Institutional overhead (10%) 
1 
16782 
Grand Total  
 
184598.1 

 
 
 
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10.0 Time schedule 
Milestones 
2019 
2020 
2021 
2022 
2023 
Quarter of years  
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Protocol preparation 
x 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Protocol submission to 
ethical boards in Norway 
and Tanzania for clearance 
  
  
x 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Site preparation 
(community awareness, 
familiarization of protocol 
to study team) 
  
  
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Recruitment and enrolment 
of participants 
  
  
  
x 
x 
x 
x 
  
  
  
  
  
  
  
  
  
  
  
Follow-up and sample/data 
collection 
  
  
  
x 
x 
x 
x 
x 
x 
  
  
  
  
  
  
  
  
  
Laboratory analysis 
  
  
  
  
  
  
  
  
x 
x 
x 
  
  
  
  
  
  
  
Statistical data analysis 
  
  
  
  
  
  
  
  
  
  
  
x 
x 
x 
  
  
  
  
Ending trial and preparation 
of final report to regulatory 
authorities 
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
x 
x 
  
  
Prepare publication on trial 
results 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
x 
x 
x 
 
 
 

 
 
 
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11.0 End of study report 
The end of study is defined as the last study participants’ last visit. The Investigators will 
notify relevant IRBs of the end of the study within a period of three months. In case the study 
will end prematurely, the investigators will notify all relevant authorities and will also provide 
reasons why the study ends prematurely.  
 
 
 

 
 
 
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12.0 Plan for Dissemination of results  
The final report will be prepared by the Principal Investigator (PI) and Co-investigators. 
Study participants and local community where participants are recruited will be informed of 
the study results through local government authorities  with the aid of community health 
workers. The health care workers at HLH where study will be conducted will be informed of 
the results obtained. The results will also be made available to the Ministry of Health and 
Social Welfare. Study findings will also be published in international peer-reviewed journals, 
preferably in journals which are available free of charge, so that the information can be 
accessible to health professionals in the settings where the study will be conducted. In 
addition, results will be given to participating hospitals and to governmental bodies 
responsible for guidelines for infant treatment and prophylaxis.  
 
 
 

 
 
 
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13.0 Planned publications 
1. Main results of the study, data on hospitalization, survival and carriage of ESBL. 
2. Microbiota analysis in the two groups, including resistome analysis. 
3. Data on fever admissions and blood culture during the study period. Risk   factors for 
adverse outcome. 
4. Molecular epidemiology of bacteria causing fever among infants during the study period 
 
 
 

 
 
 
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14.0 User Involvement 
The end users of the results are caretakers/mothers of infants, health personnel and 
government officials responsible for national guidelines. All these levels of users will be 
involved in the study, and even more importantly in implementations of results if these have 
consequences for patient care.  
 

 
 
 
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15.0 References 
1. Agamennone V, et al. A practical guide for probiotics applied to the case of antibiotic-
associated diarrhea in The Netherlands. BMC Gastroenterol. 2018;18:103.  
2. AlFaleh K, et al. Probiotics for prevention of necrotizing enterocolitis in preterm infants. 
Cochrane Database of Systematic Reviews 2014 (4).CD005496.pub4. 
3. Arthur C, et al. Probiotic approach to prevent antibiotic resistance. Annals of Medicine 2016; 
48:4, 246-55, 
4. Blomberg B, et al. Antimicrobial resistance predicts death in Tanzanian children with 
bloodstream infections: a prospective cohort study. BMC Infect Dis. 2007;7: 43. 
5. Blomberg B, et al. High rate of fatal cases of pediatric septicemia caused by gram-negative 
bacteria with extended-spectrum beta-lactamases in Dar es Salaam, Tanzania. J Clin 
Microbiol. 2005; 43: 745-9. 
6. Chang HY, et al. Multiple strains probiotics appear to be the most effective probiotics in the 
prevention of necrotizing enterocolitis and mortality: An updated meta-analysis. PLoS One. 
2017;12:e0171579 
7. Deshpande G, et al. Benefits of probiotics in preterm neonates in low-income and medium-
income countries: a systematic review of randomised controlled trials. BMJ Open. 2017; 7: 
e017638.  
8. Esaiassen E, et al. Probiotic Supplementation and Preterm Infant Gut Microbiota and 
Antibiotic Resistome Development. Frontiers in Pediatrics 2018; 6: 347. 
9. Goenka A, et al. Development of immunity in early life. J Infect. 2015; 71 Suppl 1: S112-20 
10. Gutiérrez-Castrellón P, et al. Efficacy of Lactobacillus reuteri DSM 17938 for infantile colic: 
Systematic review with network meta-analysis. Medicine (Baltimore). 2017; 96:e9375 
11. Kipp AM, et al. Factors associated with declining under-five mortality rates from 2000 to 
2013: an ecological analysis of 46 African countries. BMJ Open. 2016; 6: e007675.  
12. Klingenberg C. Manual of Neonatal Medicine, Tromsø/Norway 6th Ed 2019 
13. Lenfestey MW, et al. Probiotics in Newborns and Children. Pediatr Clin North Am 2017; 64: 
1271-1289  

 
 
 
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14. Mduma ER, Gratz J, Patil C, Matson K, Dakay M, Liu S, et al. The Etiology, Risk Factors, 
and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health 
and Development Study (MAL-ED): Description of the Tanzanian Site.; 
15. Panigrahi, P. A randomized synbiotic trial to prevent sepsis among infants in rural India. 
Nature 2017; 548, 407-12.  
16. Pamer EG. Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. 
Science 2016; 352: 535-8. 
17. Pernica JM, et al. Rapid enteric testing to permit targeted antimicrobial therapy, with and 
without Lactobacillus reuteri probiotics, for paediatric acute diarrhoeal disease in Botswana: A 
pilot, randomized, factorial, controlled trial. PLoS One. 2018; 13: e0194957 
18. Rao SC, et al. Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-
analysis. Pediatrics 2016; 137: e20153684.   
19. Robertson C, et al. Incidence of necrotising enterocolitis before and after introducing routine 
Prophylactic Lactobacillus and Bifidobacterium probiotics. Arch Dis Child Fetal and Neonatal 
Ed. 2020 
20. Shane AL, et al. Neonatal sepsis. Lancet 2017; 390: 1770–80  
21. Tellevik MG, et al. High Prevalence of Faecal Carriage of ESBL-Producing 
Enterobacteriaceae among Children in Dar es Salaam, Tanzania. PLoS ONE 2016; 11: 
e0168024. 
22. Trial with 4,500 Babies in Odisha Finds Breakthrough Weapon Against Sepsis. The Wire 
23.08.17. https://thewire.in/health/sepsis-synbiotic-supplement-odisha-panigrahi-neonatal-
mortality 
23. Underwood MA, etal.Bifidobacterium longum subspecies infantis: champion colonizer of 
the infant gut. Pediatr Res. 2015; 77: 229-35 
24. Wang H and GBD 2016 Mortality Collaborators. Global, regional, and national under-5 
mortality, adult mortality, age-specific mortality, and life expectancy, 1970-2016: a systematic 
analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390: 1084-1150.  
25. WHO 2015. Global Action Plan on Antimicrobial Resistance. ISBN 978 92 4 150976 3 

 
 
 
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26. WHO 2018. Global priority list of antibiotic-resistant bacteria to guide research, discovery, 
and development of new antibiotics. http://www.who.int/medicines/publications/global-
priority-list-antibiotic-resistant-bacteria/en/ 
 
 

 
 
 
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16.0 Informed consent form 
 
INFORMED CONSENT FORM FOR PERMISSION TO PARTICIPATE IN A RESEARCH STUDY 
Title:  Use of Probiotics to Reduce Infections and Death and Prevent Colonization with Extended-
Spectrum beta-lactamase (ESBL) producing bacteria, among newborn infants in Haydom and 
surrounding area, Tanzania. 
Child’s Name………………………………………………………………………………. 
Principal investigator: Dr Joshua G. Gidabayda, Chief Paediatrician  
LOCATION: Haydom Lutheran Hospital (HLH) 
SPONSOR: Haydom Lutheran Hospital 
I am................................................  a clinical research assistant working for this project, and I would 
like to inform you about the project. You are asked to participate in this research study because you 
are expecting a child or have just given birth to one. Before you decide you can talk to anyone whom 
you feel free to discuss about the study. If there is anything you don’t understand, please ask me, and 
I can explain it. If you have any questions later, you may ask me or any employee in this study. 
INTRODUCTION 
Probiotics are safe live microorganisms that, when administered in adequate amounts, confer a 
benefit to human beings. Probiotics are currently widely used in newborns and children in developed 
world. They have proven beneficial effects in reducing incidence of gut inflammation and death of 
very preterm infants. The main purpose of this study is to evaluate whether use of probiotics among 
newborn infants can reduce carriage of resistant bacteria and thus reduce severe infections and 
death caused by these organisms. This study will take place in areas served by the Haydom Lutheran 
Hospital, which is Mbulu, Hanang and Mkalama district. The study will include a total of 2000 
newborns whose parents reside in the study area. 
 
PROCEDURES 
If you agree to participate in this study, we will first assess your child’s eligibility to participate in the 
study. You must be aged over 18 years and long-term residents of Hydom and willing to complete 
study visits schedules over six months follow-up, which also includes hospitalizations required for 
compliance of this study protocol. Your newborn baby must have a birth weight of ≥2.0 kg. If you 
have multiple pregnancy, you will not be eligible for the study. If you are willing to let your child 
participate in the study, we will ask you some questions about yourself during the pregnancy of this 
child, your age, previous history of illness and treatment. We will also give an identification card for 
this study, and you will show it to the doctor/nurse who will be attending you during childbirth. The 
attending doctor/midwives will inform the research assistant of the study about you. After delivery, 
your newborn baby will be screened for eligibility into the study, if eligible he/she will be enrolled 

 
 
 
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and allocated to the investigational product that will have to be used five drops once daily for four 
weeks when the bottle is empty. Some participants will receive the actual product under 
investigation, while others will receive a product called a placebo, that looks the same but does not 
contain probiotic. Whether your child gets the intervention, or the placebo is by chance. We do not 
know if the intervention works and therefore you are not necessarily “better off” to get the 
intervention or the placebo. We will also gather information about your baby and his/her health, and 
we will do a follow-up of your baby with three visits for six months. The first visit will be after one 
week, the second at six weeks and the third at six months. We will also take your baby’s stool 
specimen during 2 of the three visits i.e., 6 weeks and 6 months visit. A phone/tablet computer will 
be used to collect clinical and demographic information of your baby.  
 
SPECIMEN COLLECTION 
One fecal sample will be collected at six weeks and at six months’ visits. For storage and research 
purposes, the fecal sample will be divided into 3 portions by the research assistant collecting the 
specimen. Some of these specimens will be transported to Norway for further analysis. Laboratory 
results from these specimens will not be reported back to you because there is no evidence that these 
infections without symptoms need to be treated. If your child becomes ill and is hospitalized at 
Haydom Lutheran Hospital because of fever or presents with signs of infection, an additional stool 
sample will be obtained. 
 
POTENTIAL SIDE EFFECTS 
Dietary supplementation containing live enteric bacteria are usually well tolerated and there is no 
evidence of an increased risk resulting from probiotic use in healthy children. The side effects that may 
occur are a temporary increase in gas, bloating, and a change in frequency of stools. There is no need 
to stop the intervention when these minor side effects occur. 
 
ADVANTAGES 
There is no direct benefit for participating in this study. However, this research will increase our 
knowledge on how much probiotics can reduce carriage/presence of resistant bacteria, infections 
and death among newborn infants. In addition, the study will provide CRP analysis, and blood culture 
if the child has fever and malaria test. Laboratory results will be given to the attending clinician 
responsible for the care of children to assist in patient management. 
 
COMPENSATION 
There will be no compensation given for participation in this study, however, even though the study 
products are not considered to be medicinal drugs, and studies have so far not revealed any serious 
adverse effects, study participants will be insured, if unforeseen side effects of the probiotics 
develop.  
 
CONFIDENTIALITY 
We will only collect information directly relevant to this study, and all medical doctors and laboratory 
workers in this study have pledged secrecy. The data will be stored anonymously, meaning that no one 
can connect the information to you in-person, the study documents will not include your name or any 
identifier, but a unique number. If you sign this form, you have given us permission to allow the 
research staff to use and disclose health information about you to conduct this study. The information 
created about you may be shared with other institutions doing this study, data and safety monitoring 
boards, accrediting agencies, Government and local agencies (such as Tanzania National Institute for 
Medical Research (NIMR), Tanzania Medicine and Medical Devices Authority (TMDA)) overseeing this 
research.  

 
 
 
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PARTICIPATION AND RIGHT TO REFUSE OR WITHDRAW FROM THE STUDY 
You can decide not to participate in this study, and you can withdraw from participating at any time. 
Refusal to participate or withdrawal from this study will not interfere with the right of your baby to 
get medical care like any other patient in any hospital. Any information you provide will be kept 
confidential. 
 
WHO CAN I CONTACT WITH MORE QUESTIONS ABOUT THIS RESEARCH STUDY? 
For questions related to the study conduct,feel free to contact : Dr Joshua G. Gidabayda Department 
of Paediatrics at Haydom Lutheran Hospital, Phone:+255784995669, Email: joggs_2003@yahoo.com, 
Study 
Coordinator 
Dr. 
Museveni 
N 
Justine, 
Phone 
Number: 
+255621043779, 
Email: 
museveni.justine@gmail.com, Haydom Lutheran Hospital institution Phone number: +255 (0) 
272533194/5. Institution E-mail: post@haydom.co.tz 
WHO CAN I CONTACT WITH QUESTIONS ABOUT MY RIGHTS AS A RESEARCH SUBJECT? 
For questions related to your rights as a research participant, contact The National Institute for Medical 
Research (NIMR); 2448, Ocean Road, P.O.BOX 9653, Dar es salaam, Tanzania, Tel: +255-22-2121400. 
Email; hq@nimr.or.tz  
 
CONSENT: I have read and understand the information on this form. The information on this form 
was explained to me and I had a chance to ask questions about this research study and my questions 
have been answered to my satisfaction.  I also understand that participating in this study is 
completely voluntarily and have the right to withdraw at any time. I understand that when I sign my 
name below, I agree to participate in this research 
 
Name of participant/Pregnant woman 
……………………………………………………………. 
Signature or thumb print 
…………………………………………… 
Date 
…………………. 
Name of investigator/authorised 
…………………………………………………………….. 
Signature  
……………………………………………………………… 
Date 
…………………. 
Name of Parent/legal guardian of the child 
……………………………………………………………….. 
Signature or thumb print 
…………………………………………… 
Date 
…………………. 
Name of investigator/authorised 
…………………………………………………………….. 
Signature  
……………………………………………………………… 
Date 
…………………. 
      
Consent from Impartial Witness 
If this consent form is read to the subject because the subject is blind or illiterate, an impartial 
witness not affiliated with the research or researcher must be present for the consenting process 
and sign the following statement. The subject may place a thumb print on the Participant Signature 
line above. 
I agree the information in this informed consent form was presented orally in my presence to the 
identified individual(s) who has had the opportunity to ask any questions he/she had about the study. 
I also agree that the identified individual(s) freely gave their informed consent to participate in this 
trial.  
Please indicate with “X” in the box below for the identified individual: 
 Participating pregnant mother  
 Parent(s)/Legal Guardian of the subject 

 
 
 
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_______________________________ 
IMPARTIAL WITNESS 
(SIGNATURE) 
 
_____________________________ 
IMPARTIAL WITNESS 
(NAME(S)-CAPITAL LETTER PRINT) 
 
________ 
DATE