| Protocol No: | ECCT/20/04/02 | Date of Protocol: | 15-01-2020 |
| Study Title: | A 4-arm, open-label, individually randomized, controlled, phase-2, study of a probiotic and two synbiotics in young children in western Kenya. |
Summary and reasons for the proposed amendments
Impact of the amendment on the original study objectivesNone
Impact of the amendments on the study endpoints and data generated.
None
Impact of the proposed amendments on the safety and wellbeing of study participants
None
Please find attached copies of the following documents in support of this application:
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| Study Objectives: |
PRIMARY OBJECTIVE
SECONDARY OBJECTIVES
To determine:
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| Laymans Summary: |
Anyone exposed to poor sanitation and hygiene develops an unhealthy gut. This is called “environmental enteric dysfunction” (EED). In EED, the breakdown of food and absorption of nutrients into the body are compromised. In addition, the gut wall becomes leaky making it easier for harmful bacteria that live in the gut to cross into the body. Therefore, EED in young children impairs weight gain and growth and increases infections.
EED results from harmful bacteria and other microbes damaging the gut. This can occur as early as age 6 weeks and occurs even in babies that are only breast fed.
“Friendly” bacteria that live in a healthy gut are one of the important defences against harmful microbes. Babies acquire these friendly bacteria naturally during a normal delivery and also during the first few months of life through breastfeeding. However, there are many factors that prevent young babies acquiring these healthy bacteria in the gut.
In this study, we want to see whether boosting the friendly bacteria in babies improves their gut health. The main types of friendly bacteria in healthy, breastfed babies are Bifidobacteria and Lactobacilli. These are given as dietary supplements and often called “probiotics”. Probiotics have been tested in many people, including very small babies, and found to be safe. Another approach is to give the special sugars that support the growth of friendly bacteria – called “prebiotics”. The benefit might be greatest when a probiotic and a prebiotic are combined - called a “synbiotic”.
We will invite the mothers/carers of newborn babies in Kisumu, Kenya to participate in this study. Newborn babies will be allocated by chance to receive one of two synbiotics, a probiotic alone or usual care without any dietary supplement. The probiotic and synbiotics are prepared as a small amount of powder in capsules. The powder can be given directly into the mouth before a feed or mixed in a clean container with a small amount of expressed breast milk, or infant formula milk if the baby is not breastfed. They will be started after the newborn baby has taken a feed well and given daily for 10 days and then weekly to age 6 months.
The health of the baby’s gut will be assessed by measuring in the laboratory biomarkers in small volume heel/finger prick blood samples and stool samples. This will be done at ages 6 weeks and 3, 6 and 12 months. We will also measure growth and record episodes of illness such as diarrhoea and pneumonia. We will follow-up the babies until age 2 years to document any longer-term effects of the dietary supplements. We will also ask parents/carers how they are trying to keep their baby away from infections and what they think about the dietary supplements. We will estimate “real-world” costs of delivery.
If this initial study shows that the dietary supplements seem to improve gut health, are acceptable to mothers/carers and are affordable, then we would plan a larger, follow-on study to confirm these findings.
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| 3 | Anyone exposed to poor sanitation and hygiene develops an unhealthy gut. This is called “environmental enteric dysfunction” (EED). In EED, the breakdown of food and absorption of nutrients into the body are compromised. In addition, the gut wall becomes leaky making it easier for harmful bacteria that live in the gut to cross into the body. Therefore, EED in young children impairs weight gain and growth and increases infections. EED results from harmful bacteria and other microbes damaging the gut. This can occur as early as age 6 weeks and occurs even in babies that are only breast fed. “Friendly” bacteria that live in a healthy gut are one of the important defences against harmful microbes. Babies acquire these friendly bacteria naturally during a normal delivery and also during the first few months of life through breastfeeding. However, there are many factors that prevent young babies acquiring these healthy bacteria in the gut. In this study, we want to see whether boosting the friendly bacteria in babies improves their gut health. The main types of friendly bacteria in healthy, breastfed babies are Bifidobacteria and Lactobacilli. These are given as dietary supplements and often called “probiotics”. Probiotics have been tested in many people, including very small babies, and found to be safe. Another approach is to give the special sugars that support the growth of friendly bacteria – called “prebiotics”. The benefit might be greatest when a probiotic and a prebiotic are combined - called a “synbiotic”. We will invite the mothers/carers of newborn babies in Western, Kenya to participate in this study. Newborn babies will be allocated by chance to receive one of two synbiotics, a probiotic alone or usual care without any dietary supplement. The probiotic and synbiotics are prepared as a small amount of powder in capsules. The powder can be given directly into the mouth before a feed or mixed in a clean container with a small amount of expressed breast milk, or infant formula milk if the baby is not breastfed. They will be started after the newborn baby has taken a feed well and given daily for 10 days and then weekly to age 6 months. The health of the baby’s gut will be assessed by measuring in the laboratory biomarkers in small volume heel/finger prick blood samples and stool samples. This will be done at ages 6 weeks and 3, 6 and 12 months. We will also measure growth and record episodes of illness such as diarrhoea and pneumonia. We will follow-up the babies until age 2 years to document any longer-term effects of the dietary supplements. We will also ask parents/carers how they are trying to keep their baby away from infections and what they think about the dietary supplements. We will estimate “real-world” costs of delivery. If this initial study shows that the dietary supplements seem to improve gut health, are acceptable to mothers/carers and are affordable, then we would plan a larger, follow-on study to confirm these findings. |
| 4 | Anyone exposed to poor sanitation and hygiene develops an unhealthy gut. This is called “environmental enteric dysfunction” (EED). In EED, the breakdown of food and absorption of nutrients into the body are compromised. In addition, the gut wall becomes leaky making it easier for harmful bacteria that live in the gut to cross into the body. Therefore, EED in young children impairs weight gain and growth and increases infections. EED results from harmful bacteria and other microbes damaging the gut. This can occur as early as age 6 weeks and occurs even in babies that are only breast fed. “Friendly” bacteria that live in a healthy gut are one of the important defences against harmful microbes. Babies acquire these friendly bacteria naturally during a normal delivery and also during the first few months of life through breastfeeding. However, there are many factors that prevent young babies acquiring these healthy bacteria in the gut. In this study, we want to see whether boosting the friendly bacteria in babies improves their gut health. The main types of friendly bacteria in healthy, breastfed babies are Bifidobacteria and Lactobacilli. These are given as dietary supplements and often called “probiotics”. Probiotics have been tested in many people, including very small babies, and found to be safe. Another approach is to give the special sugars that support the growth of friendly bacteria – called “prebiotics”. The benefit might be greatest when a probiotic and a prebiotic are combined - called a “synbiotic”. We will invite the mothers/carers of newborn babies in Western, Kenya to participate in this study. Newborn babies will be allocated by chance to receive one of two synbiotics, a probiotic alone or usual care without any dietary supplement. The probiotic and synbiotics are prepared as a small amount of powder in capsules. The powder can be given directly into the mouth before a feed or mixed in a clean container with a small amount of expressed breast milk, or sterile water. They will be started after the newborn baby has taken a feed well and given daily for 10 days and then weekly to age 6 months. The health of the baby’s gut will be assessed by measuring in the laboratory biomarkers in small volume heel/finger prick blood samples and stool samples. This will be done at ages 6 weeks and 3, 6 and 12 months. We will also measure growth and record episodes of illness such as diarrhoea and pneumonia. We will follow-up the babies until age 2 years to document any longer-term effects of the dietary supplements. We will also ask parents/carers how they are trying to keep their baby away from infections and what they think about the dietary supplements. We will estimate “real-world” costs of delivery. If this initial study shows that the dietary supplements seem to improve gut health, are acceptable to mothers/carers and are affordable, then we would plan a larger, follow-on study to confirm these findings |
| 5 | Anyone exposed to poor sanitation and hygiene develops an unhealthy gut. This is called “environmental enteric dysfunction” (EED). In EED, the breakdown of food and absorption of nutrients into the body are compromised. In addition, the gut wall becomes leaky making it easier for harmful bacteria that live in the gut to cross into the body. Therefore, EED in young children impairs weight gain and growth and increases infections. EED results from harmful bacteria and other microbes damaging the gut. This can occur as early as age 6 weeks and occurs even in babies that are only breast fed. “Friendly” bacteria that live in a healthy gut are one of the important defences against harmful microbes. Babies acquire these friendly bacteria naturally during a normal delivery and also during the first few months of life through breastfeeding. However, there are many factors that prevent young babies acquiring these healthy bacteria in the gut. In this study, we want to see whether boosting the friendly bacteria in babies improves their gut health. The main types of friendly bacteria in healthy, breastfed babies are Bifidobacteria and Lactobacilli. These are given as dietary supplements and often called “probiotics”. Probiotics have been tested in many people, including very small babies, and found to be safe. Another approach is to give the special sugars that support the growth of friendly bacteria – called “prebiotics”. The benefit might be greatest when a probiotic and a prebiotic are combined - called a “synbiotic”. We will invite the mothers/carers of newborn babies in Western, Kenya to participate in this study. Newborn babies will be allocated by chance to receive one of two synbiotics, a probiotic alone or usual care without any dietary supplement. The probiotic and synbiotics are prepared as a small amount of powder in capsules. The powder can be given directly into the mouth before a feed or mixed in a clean container with a small amount of expressed breast milk, or sterile water. They will be started after the newborn baby has taken a feed well and given daily for 10 days and then weekly to age 6 months. The health of the baby’s gut will be assessed by measuring in the laboratory biomarkers in small volume heel/finger prick blood samples and stool samples. This will be done at ages 6 weeks and 3, 6 and 12 months. We will also measure growth and record episodes of illness such as diarrhoea and pneumonia. We will follow-up the babies until age 2 years to document any longer-term effects of the dietary supplements. We will also ask parents/carers how they are trying to keep their baby away from infections and what they think about the dietary supplements. We will estimate “realworld” costs of delivery. If this initial study shows that the dietary supplements seem to improve gut health, are acceptable to mothers/carers and are affordable, then we would plan a larger, follow-on study to confirm these findings. |
| Abstract of Study: | People exposed to poor sanitation and hygiene develop a gut disorder called “environmental enteric dysfunction” (EED). EED is characterised by abnormal histopathology, mucosal permeability defects, and inflammation. In young children, EED contributes significantly to poor growth through reduced digestion and absorption of nutrients, increased susceptibility to infections and systemic inflammation that directly inhibits growth hormones. Apart from impaired growth, EED is largely sub-clinical. EED may already be apparent by age six weeks, and growth faltering occurs within the first few months of life highlighting the need for early intervention. Previous studies have highlighted the role of pathogenic microbes in colonising the gut in young children resulting in EED. Measures such as exclusive breastfeeding and improved hygiene are often insufficient to prevent transmission of pathogens to young infants. The gut microbiome in healthy, exclusively breastfed infants is characterised by a predominance of Bifidobacterium and Lactobacillus genera. A healthy gut microbiome may provide a last line of defence against ingested gut pathogens through “colonisation resistance”. However, multiple environmental factors threaten the development of a healthy gut microbiome including delivery by Caesarean section, faulty feeding practices, poor hygiene and sanitation and exposure to antibiotics. Dietary supplements of prebiotics or synbiotics may provide resilience to the developing gut microbiome against these adverse environmental factors. Prebiotics are non-digestible compounds that encourage the growth of healthy gut bacteria. Synbiotics are prebiotics combined with live beneficial bacteria such as bifidobacteria and lactobacilli (“probiotics”). In a 52-month pilot project, we plan to administer prebiotics or synbiotics to infants in Western Kenya over the first 0-5 months. We will assess whether the interventions improve gut health and reduce inflammation by measuring biomarkers in blood and stool samples during infancy with follow-up to 2 years. We will also record growth and episodes of illness. We will compare the infants in the intervention arms with controls who receive standard care but no dietary supplements. We expect that infants in the intervention arms of the project will have better gut health, reduced inflammation and better growth as assessed by biomarkers. If proof-of-concept, feasibility, acceptability and affordability are confirmed, the findings from this initial project will directly inform the design of a subsequent larger study. The information generated will allow us to refine the intervention and estimate the number of infants needed to show a significant effect on important health outcomes such as growth and prevention of common illnesses.
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| 5 | Summary and reasons for the proposed amendments
Impact of the amendment on the original study objectivesNone
Impact of the amendments on the study endpoints and data generated.
None
Impact of the proposed amendments on the safety and wellbeing of study participants
None
Please find attached copies of the following documents in support of this application:
|