Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202102678743565 Date of Approval: 17/02/2021
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Controlling intestinal bacteria in severely ill children with malnutrition.
Official scientific title Pancreatic Enzymes and Bile Acids: A Non-Antibiotic approach to Treat Intestinal Dysbiosis in Acutely Ill Severely Malnourished Children (PB-SAM)
Brief summary describing the background and objectives of the trial 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.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) PB SAM
Disease(s) or condition(s) being studied Digestive System,Infections and Infestations,Nutritional, Metabolic, Endocrine,Paediatrics
Sub-Disease(s) or condition(s) being studied Sepsis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 14/03/2021
Actual trial start date
Anticipated date of last follow up 14/12/2025
Actual Last follow-up date
Anticipated target sample size (number of participants) 1200
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
NCT04542473 ClinicalTrials.gov
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously Randomised Permuted block randomization Sealed opaque envelopes Masking/blinding used Care giver/Provider,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Pancreatic enzymes Prescription will follow weight bands to allow a lower range of 2000 IU/kg/day and upper range of 4000 IU/kg/day 21 days Pancreatic exocrine replacement therapy (PERT) are enzymes and essential medications for patients with cystic fibrosis characterized by exocrine pancreas insufficiency and commonly used in these children. These enzymes act locally in the gastro-intestinal tract and after exerting their action, are digested themselves in the intestine and are not absorbed (See: https://www.medicines.org.uk/emc/product/5564/smpc). They have an excellent safety profile, although a potential long-term side effect after prolonged high dose use (i.e. several months of >2500 U lipase/kg/meal) is fibrosing colonopathy. 600
Control Group Placebo for pancreatic enzymes Prescription will follow weight bands to allow a lower range of 2000 IU/kg/day and upper range of 4000 IU/kg/day. 21 days The placebo matched in appearance and taste to pancreatic enzymes and produced according to GMP standards will be supplied from a licensed manufacturer. 600 Placebo
Experimental Group Bile acids The dose of ursodeoxycholic acid will be 10 mg/kg twice per day just prior to a feed, using a suspension of 50 mg/ml 21 days Ursodeoxycholic acid is a bile acid that is licensed for use in patients with primary biliary cirrhosis and used widely in other paediatric liver diseases such as primary sclerosing cholangitis, and biliary atresia among others. Its safety profile is excellent. However, diarrhoea has been reported as a potential side effect and there is a theoretical risk for hepatoxicity from accumulation of the toxic lithocholic acid metabolite, although no clinical reports have documented this. Although ursodeoxycholic acid is used as standard-of-care among young children with pediatric liver disease, ursodeoxycholic acid has not been licensed for use for management of severe malnutrition. 600
Control Group Placebo for bile acids The dose of placebo will be 10 mg/kg twice per day just prior to a feed, using a suspension of 50 mg/ml 21 days The placebo is matched in appearance and taste to bile acid and is produced according to GMP standards will be sourced from a supplied from a licensed manufacturer. 600 Placebo
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
• Age ≥2 to <59 months • Admitted to hospital with an acute, non-traumatic illness and within 72 hours of admission at the time of enrolment • Severe malnutrition (weight-for-height <-3 z scores of the median WHO growth standards and/or mid upper arm circumference <115mm (<110mm age below 6 months), or symmetrical oedema of at least the feet related to malnutrition (not related to a primary cardiac or renal disorder) • Presence of two or more features of severity as specified in the protocol and trial SOP. If a child meets two criteria, they may be enrolled before further criteria are assessed (e.g. a child may be eligible on clinical signs before the complete blood count results are known). • Accompanied by care provider who provides written informed consent • Primary caregiver plans to stay in the study area during the duration of the study. • Requires immediate cardiac/respiratory resuscitation (may be re-evaluated for study eligibility within 72h of admission) • Presence of terminal illness (other than severe acute malnutrition) likely to result in death within 6 months in the opinion of the recruitment team • Known congenital heart disease • Admission for traumatic or surgical indication • Known liver disorder or exocrine pancreatic disorder – e.g. biliary atresia, history of gallstones, cystic fibrosis or clinical jaundice • Known stomach or duodenal ulcer • Residence is outside the catchment area of study hospital • Primary caregiver declines to provide informed consent • Known intolerance or allergy to any study medication Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Child: 6 Year-12 Year,Infant: 13 Month(s)-24 Month(s),Middle Aged: 45 Year(s)-64 Year(s),Preschool Child: 2 Year-5 Year 2 Month(s) 59 Month(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 08/10/2020 Oxford Tropical Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
University of Oxford, Wellington Square, Oxford, OX1 2JD United Kingdom. Oxford OX1 2JD United Kingdom
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 26/11/2020 Scientific and Ethics Review Unit
Ethics Committee Address
Street address City Postal code Country
Kenya Medical Research Institute P.O. Box 54840 00200 Off Mbagathi Road. Nairobi, Kenya. Nairobi 00200 Kenya
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Death This will be assessed from study enrolment through day 60 of follow up.
Secondary Outcome Serious Adverse Events of any cause to day 60 This will be assessed from study enrolment through day 60 of follow up.
Secondary Outcome Safety: grade 3 or 4 toxicity events This will be assessed from enrolment to day 21
Secondary Outcome Number of days with diarrhoea and stool consistency during admission This will be assessed from enrolment till discharge during index admission
Secondary Outcome Number of days with clinical features of sepsis (fever, impaired circulation) during admission This will be assessed from enrolment till discharge during index admission
Secondary Outcome Usage of second and third-line antibiotics during index admission and readmission as recorded by the study team This will be assessed during index admission and during each readmission
Secondary Outcome Number of days from enrolment to discharge during the index admission This will be assessed during index admission
Secondary Outcome Change in MUAC, weight-for-length, length-for-age from enrolment to days 21 and 60 This will be assessed during index admission and follow up on days 21 and 60
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Kilifi County Hospital Bofa Road, P.O. BOX 9- 80108, Kilifi, Kenya. Kilifi 80108 Kenya
Coast General Hospital Kisauni Road, P.O. Box 90231-80100, Mombasa, Kenya. Mombasa 80100 Kenya
Mbagathi Hospital Kenyatta Market, P.O.Box 20725-00202 , Nairobi, Kenya Nairobi 00202 Kenya
Migori County Hospital P.O BOX 202-40400, Suna-Migori Migori 40400 Kenya
Ombo Mission Hospital P.O. Box 250 - 40400 Suna Migori Migori 40400 Kenya
Dhaka Hospital icddrb Mohakhali, Dhaka 1212, Bangladesh Dhaka 1000 Bangladesh
Mulago National Referral Hospital Lourdel Road, Nakasero Kampala 7272 Uganda
Queen Elizabeth Central Hospital Chipatala Blantyre 95 Malawi
FUNDING SOURCES
Name of source Street address City Postal code Country
Bill and Melinda Gates Foundation 500 5th Ave N, Seattle, WA 98109 Seattle WA 98109 United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor University of Oxford Wellington Square, Oxford, OX1 2JD United Kingdom. Oxford OX1 2JD United Kingdom University
COLLABORATORS
Name Street address City Postal code Country
University of Washington University of Washington 325 Ninth Avenue, Box 359909 Seattle, WA 98104 United States Seattle WA 98104 United States of America
Hospital for Sick Children The Hospital for Sick Children 555 University Avenue Toronto, Ontario Canada M5G 1X8 Toronto M5G 1X8 Canada
University of Malawi college of medicine Mahatma Gandhi Blantyre 360 Malawi
Mulago Hospital Lourdel Road, Nakasero Kampala 7272 Uganda
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Robert Bandsma robert.bandsma@sickkids.ca +14168131500 The Hospital for Sick Children 555 University Avenue Toronto, Ontario Canada M5G 1X8
City Postal code Country Position/Affiliation
Toronto M5G 1X8 Canada Associate Professor of Paediatrics
Role Name Email Phone Street address
Scientific Enquiries Caroline Ogwang COgwang@kemri-wellcome.org +254709983000 KEMRI Wellcome Trust Research Programme, P. O. Box 230 80108, Kilifi, Kenya.
City Postal code Country Position/Affiliation
Kilifi 80108 Kenya Clinical lead
Role Name Email Phone Street address
Public Enquiries Isaiah Njagi INjagi@kemri-wellcome.org +254730162110 KEMRI-Wellcome Trust Research Programme P.O Box 43640 00100, 197 Lenana Place, Off Lenana Road next to Cedars Restaurant Nairobi, Kenya
City Postal code Country Position/Affiliation
Nairobi 00100 Kenya Clinical Trials Coordinator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Data from the trial will be uploaded onto the KWTRP Research Data Repository. Study Protocol Within 12 months of the main publication The data will have managed access being governed by Data Governance Committee at KEMRI, Center for Geographic Medicine Research, Coast, Kilifi, Kenya.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
https://dataverse.harvard.edu/dataverse/kwtrp No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information