Protocol No: ECCT/21/03/02 Date of Protocol: 11-01-2021

Study Title:

Pancreatic Enzymes and Bile Acids: A Non-Antibiotic approach to Treat Intestinal Dysbiosis in Acutely Ill Severely Malnourished Children.

Study Objectives:

Primary objective
To determine whether treatment with pancreatic enzymes or bile acids reduce mortality in acutely ill hospitalized children with severe malnutrition compared to placebo.

Secondary objectives
To determine:
1.    Rate and type of SAEs (including readmissions to hospital)
2.    Safety: rate of grade 3 or 4 toxicity events whilst receiving investigational products
3.    Intestinal function: number of days with diarrhoea during admission.
4.    Use of second and third-line antibiotics during admission and readmission
5.    Number of days from enrolment to discharge during admission
6.    Growth: (MUAC, weight-for-length, length-for-age) to day 60.


Laymans Summary:

Lay Title
Controlling intestinal bacteria in sick children with malnutrition.

What is the problem?
Children with severe malnutrition who are sick and admitted to hospitals have high mortality, usually because of infection. Malnourished children have more potentially harmful bacteria in their upper intestines than well-nourished children and this may contribute to inflammation in the gut and whole body. These bacteria may cross from the intestines to the bloodstream causing life-threatening infection. Another abnormality among malnourished children is reduction in the digestive enzymes made by the pancreas and the liver. Apart from helping with digestion of food, these enzymes are important in controlling bacteria in the intestines. It is therefore possible that treatment with digestive enzymes could help reduce the burden of harmful bacteria and thus lower inflammation and risk of serious infection. One study conducted in Malawi has shown that children with severe malnutrition who were supplemented with pancreatic enzymes had a lower risk of dying. However, this was a small study and although promising, requires validation. No studies of supplementation with bile acids have been done among severely malnourished children. However, bile acids are commonly used to manage patients with cholestatic liver diseases, something that malnourished children suffer from as well.

What questions are we trying to answer?
We want to find out if giving special salts, which are enzymes that help in digestion (pancreatic enzymes and bile acids), in addition to the standard of care, for ill children with severe acute malnutrition is safe and reduces the risk of death, deterioration or readmission to hospital. We will also assess the costs associated with the interventions to patients and health providers.

Where is the study taking place, how many people does it involve and how are they selected?
The study is being carried out by the CHAIN Network ( a network of doctors and scientists committed to improving the lives of sick and undernourished children. We will carry out the study in hospitals in Kenya, Malawi, Uganda and Bangladesh that are CHAIN Network sites. We will ask parents and guardians of children between the ages of 2 months to 59 months who are admitted to hospital with severe malnutrition and clinical signs of severe illness to participate.

The trial will be conducted in 3 stages. In the first stage, we will enrol 200 children with severe malnutrition admitted to hospital with severe illness across all sites. This will be followed by an interim analysis focused on confirming safety. Then which a further 200 children across all sites will be enrolled in stage 2. A second interim analysis will then be done and if the study results suggest one or both interventions are safe and potentially effective, then a further 800 children across all sites will be enrolled in the third stage resulting in a total of 1,200 children enrolled.

What does the study involve for those who are in it?
After obtaining informed consent, a study clinician will examine the child and the special salts that help in digestion or similar looking placebo products without active ingredients will be randomly allocated. Children will receive the study medications by mouth or nasogastric tube (if an NG tube is sited for feeding) before feeds for 21 days (both in hospital and at home if discharged early) and will be followed up at 21 and 60 days from enrolment. Pancreatic enzymes are in form of powdered granules which will be given by sprinkling over normal food or with therapeutic milk feeds. Bile acids are in form of oral syrup. In addition to the study medication(s) and/or placebo, all children enrolled in the study will also receive the standard treatments for severe malnutrition (for example, empiric antibiotics), as provided by the local admitting hospital.

3 ml of blood (about half a tablespoon), rectal swabs, and a faecal sample will be taken together with the routine tests for care at enrolment to the trial, then at 21 days after enrolment. Blood sample for research will not exceed 1ml/kg while total volume collected at enrolment will vary according to tests required at admission. Rectal swabs and a faecal sample will also be collected at hospital discharge and at 60 days after enrolment. In addition, Kilifi participants will have a finger-prick blood sample taken once each day for 5 days after enrolment to measure salts, oxygen and lactate in the child’s blood as they continue to receive treatment. If blood for routine care tests is being taken, then a drop will be used instead of a finger-prick.

Children will be reviewed daily by the study team while in hospital. Study staff will work together with hospital staff to provide the highest quality of care available to all children. Follow up visits will involve a health questionnaire, measuring growth and the collection of rectal swabs (D21 and D60), a faecal sample (D21 and D60), and a 3ml blood sample (D21 only). Parents will be advised to contact the study team and bring the child to the hospital if he/she becomes unwell. If readmitted, 3ml of blood (about half a tablespoon), rectal swabs, and a faecal sample will be taken with routine tests for research. All results of blood tests that are available in real-time will be fed back to the clinical team to assist in care. Some parents, caregivers and health providers will also be interviewed about costs incurred for treatment.

What are the benefits and risks/costs of the study for those involved?  
Training and staffing will be enhanced for all paediatric ward staff on the treatment of sick and malnourished children. The sites involved are already in the CHAIN Network which has standardised care according to World Health Organisation and National guidelines and has ongoing monitoring of care. Pancreatic enzymes and bile acids have a good safety profile. However, any evidence of harm will be carefully assessed, and appropriate management provided. Drawing a blood sample carries risks of discomfort and damage to the vein or infection; careful procedures including cleaning the skin will help prevent these. Performance of rectal swabs and faeces collection entails minimal risk. Travel costs and out of pocket allowances associated with scheduled follow up visits will be reimbursed according to local institutional policies.
During the study, appropriate precautions will be taken to protect participants and staff from COVID-19 infection through training and provision of personal protective equipment and hand sanitisation facilities. Participants’ carers will be given surgical facemasks and appropriate hand hygiene. Where possible, face to face contact and home visits will be minimised according to local institutional procedures.
How will the study benefit society?  
Knowing how to better treat ill malnourished children when they are admitted to hospital will help inform the development of optimal interventions to improve child health and survival. The findings from this research will directly inform policy and program management decisions related to the care of the sick child.

When does the study start and finish?
The study aims to start as soon as scientific and ethical approval is granted and the COVID-19 pandemic situation permits research to take place. We will undertake two interim analyses after 200 then 400 participants (expected after about 1 to 1.5 years) to assess safety and the likelihood of effectiveness before enrolling the full sample size. One or both study medications may be discontinued at these interim analyses if they are unlikely to be of benefit, or the final sample size may be adjusted if needed. The trial will require approximately 3 to 4 years of enrolment and 5 years to complete from the start to the end of analysis.


Abstract of Study:

Severely malnourished children who present with an acute illness have a high risk of mortality. Severe malnutrition is associated with intestinal inflammation and changes in the faecal microbiome (‘dysbiosis’). Apart from the large intestine, this dysbiosis is also present in the small intestine, where increased bacterial density and altered microbial composition can contribute to intestinal inflammation and intestinal dysfunction which may ultimately contribute to the development of sepsis and death. The bacterial density and composition in the small intestine can be reduced and altered, respectively, using antibiotics. However, apart from side effects, antibiotic use contributes to the development of antibiotic resistance, which is very common in hospitalized malnourished patients and can pose a threat to both individual and public health. In addition to intestinal dysbiosis and intestinal inflammation, children with severe malnutrition suffer from impaired exocrine pancreatic and hepatobiliary function, which are important for nutrient digestion and absorption. We recently reported that treating children with severe malnutrition with pancreatic enzymes led to a reduction in mortality in a pilot trial which was not powered for mortality. Importantly, enzymes and bile acids produced by the pancreas and liver affect bacteria that reside in the intestinal lumen. We hypothesize that providing these enzymes exogenously to severely malnourished children will improve their clinical outcome by reducing dysbiosis, intestinal inflammation and sepsis.

The objective of this study is to determine whether treating ill severely malnourished children with pancreatic enzymes or bile acids, in addition to standard therapies including empiric antibiotics, improves mortality. We will conduct a double blind, randomized clinical trial in a 2x2 factorial design in hospitalized severely malnourished children. We will treat participants with paediatric formulations of pancreatic enzymes, bile acids, both or placebo for 21 days. Participants will be followed up daily during their hospital stay, and on day 21 and 60 after enrolment. We will conduct this trial in three stages to allow for careful interim evaluations to assess safety and study progress. In the first and second stage, we will conduct interim analyses to assess safety and likelihood of benefit before enrolling the full sample size to assess mortality as the primary outcome. Secondary outcomes include adverse events, length of hospital stay, and growth. Exploratory outcomes will examine intestinal and systemic inflammation and metabolic changes to examine mechanisms affected by the interventions, and costs. Two sub-studies will also be conducted. In Kenya and Bangladesh, a substudy examining daily blood gases, lactate and biochemistry during the first 5 days of enrolment to assess early clinical progress will be performed. In Malawi and Uganda, hydrogen breath testing performed within 72hr of enrolment and on day 21 following enrolment, will be used to evaluate impact of the intervention on upper small intestinal bacterial overgrowth.

Overall, this trial will determine whether a non-antibiotic, bactericidal intervention given in additional to standard of care management reduces mortality in acutely ill severely malnourished children.