- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04542473
Pancreatic Enzymes and Bile Acids in Acutely Ill Severely Malnourished Children (PB-SAM)
Pancreatic Enzymes and Bile Acids: A Non-Antibiotic Approach to Treat Intestinal Dysbiosis in Acutely Ill Severely Malnourished Children
Study Overview
Status
Conditions
Detailed Description
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 fecal microbiome ('dysbiosis'). Apart from in the large intestine, dysbiosis is also present in the small (upper) 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 altered 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 to aid their recovery.
One previous pilot trial showed that treating children with severe malnutrition with pancreatic enzymes led to a reduction in mortality. The investigators hypothesize that supplementing 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 is safe and improves mortality. The investigators will conduct a double blind, randomized clinical trial in a 2x2 factorial design in hospitalized severely malnourished children. Participants will be treated with pediatric 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 enrollment.
This trial will be conducted in three stages to allow for careful interim evaluations to assess safety and study progress. After the first and second stage, interim analyses 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 be conducted. In Kenya and Bangladesh, daily blood gases, lactate and biochemistry for the first 5 days to assess early clinical progress. In Malawi and Uganda, hydrogen breath testing will be used to evaluate impact 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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Contact
- Name: Robert Bandsma, MD
- Phone Number: 309057 416-813-7654
- Email: robert.bandsma@sickkids.ca
Study Contact Backup
- Name: Wieger Voskiujl, MD
- Phone Number: +31 621297632
- Email: w.p.voskuijl@amsterdamumc.nl
Study Locations
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Dhaka, Bangladesh
- icddr,b Dhaka Hospital
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Contact:
- Jobayer Chisti, MBBS
- Email: chisti@icddrb.org
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Contact:
- Abu Sadat Md. Sayeem, MBBS
- Email: sayeem@icddrb.org
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Kilifi, Kenya, 80800
- KEMRI WT Clinical Trials Facility
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Contact:
- Johnstone Thitiri, MSc
- Phone Number: +254709983338
- Email: Jthitiri@kemri-wellcome.org
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Contact:
- Caroline Ogwang, MBBS
- Phone Number: +254709983115
- Email: COgwang@kemri-wellcome.org
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Blantyre, Malawi
- Queen Elizabeth Central Hospital
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Contact:
- Isabel Potani
- Email: isabelpotani@gmail.com
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Kampala, Uganda
- Mulago Hospital
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Contact:
- Ezekiel Mupere, MBBS
- Email: mupez@yahoo.com
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Sub-Investigator:
- Christina Lancioni, PhD
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 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)
- Able to feed orally in usual state of health.
- Accompanied by care provider who provides written informed consent
- Primary caregiver plans to stay in the study area during the duration of the study
- Presence of two or more features of severity as specified below. 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):
Respiratory distress "Subcostal indrawing" or "nasal flaring" or "head-nodding" Oxygenation "Central cyanosis" or SaO2 <90% Circulation Limb temperature gradient or capillary refill >3 seconds Conscious level AVPU < "A" Pulse > 180 per min Haemoglobin < 7g/dl Blood glucose < 3mmol/L White blood cells < 4 or > 17.5 x 109/L Temperature <36 or >38.5oC Very low MUAC MUAC <11cm
Exclusion Criteria:
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Factorial Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Pancreatic Enzymes (PE)
Pancreatic enzymes formulated as 5000 IE lipase, 3600 IE amylase and 200 IE protease per 100 mg of granules, packaged as sachets. The target dose is 3000 IU lipase/kg, twice daily (1440 IU/kg amylase/80 IU/kg protease), which is the dose used for children with cystic fibrosis and exocrine pancreas insufficiency. For oedematous malnutrition, weight for dosing is reduced by 10%. To be prescribed following enrolment and given just prior to or during a feed. Prescription will follow weight bands to allow a lower range of 2000 IU/kg/day and upper range of 4000 IU/kg/day: Weight from Weight to Dose Dose Upper range Lower range (Kg) (Kg) (sachets) (IU Lipase) (IU/kg/dose) (IU Lipase) ---------------------------------------------------------------------------------------------------------- 2.50 4.99 2 10000 4000 2000 5.00 7.49 4 20000 4000 2670 7.50 9.99 6 30000 4000 3000 10.0 15.0 8 40000 4000 2667 |
CREON micro 5000
Other Names:
|
Placebo Comparator: Placebo-PE
Oral/enteral placebo matching active Pancreatic Enzymes (PE). Dose presentation in whole sachets of 100mg of granules. For oedematous malnutrition, weight for dosing is reduced by a pragmatic 10%. To be prescribed following enrolment and given just prior to or during a feed. Prescription will follow weight bands: Weight from Weight to Dose Dose Upper range Lower range (Kg) (Kg) (sachets) (IU Lipase) (IU/kg/dose) (IU Lipase) ----------------------------------------------------------------------------------------------------------------------------------------- 2.50 4.99 2 Nil Nil Nil 5.00 7.49 4 Nil Nil Nil 7.50 9.99 6 Nil Nil Nil 10.0 15.0 8 Nil Nil Nil |
Microcrystalline Cellulose,Macrogel 4000, Iron Oxide Yellow, Iron Oxide Red, Activated Charcoal.
Other Names:
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Active Comparator: Ursodeoxycholic acid (UA)
The dose of ursodeoxycholic acid will be given at 10 mg/kg twice per day just prior to or during a feed, using a suspension of 50 mg/ml = 0.2 ml/kg.
For oedematous malnutrition participants, weight is pragmatically reduced by 10%.
To be prescribed and given following enrolment.
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Ursodiol C24H40O4 suspension
Other Names:
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Placebo Comparator: Placebo-UA
The dose of placebo will be given twice per day just prior to or during a feed at 0.2 ml/kg.
To be prescribed and given following enrolment.
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Sodium Citrate Dihydrate, Aspartame, Carboxymethylcellulose Sodium, Citric Acid Monohydrate, Dispersible Cellulose, Glycerol, Polysorbate-80, Saccharin Sodium,Sodium Benzoate, Sodium Methylparaben, Sodium Propylparaben
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Mortality
Time Frame: 60 days
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Death
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60 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rate of SAEs
Time Frame: 60 days
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All serious adverse events
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60 days
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Rate of toxicity events
Time Frame: 21 days
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Grade 3 or 4 toxicity events whilst receiving investigational products
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21 days
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Intestinal function
Time Frame: 60 days
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number of days with diarrhoea during index hospital admission
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60 days
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Antimicrobials
Time Frame: 60 days
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Days on second and third-line antibiotics during index admission and readmission
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60 days
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Hospitalisation duration
Time Frame: 60 days
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Number of days from enrolment to discharge during index admission
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60 days
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Growth - arm circumference cm
Time Frame: 60 Days
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Change in MUAC in cm between enrolment and 60 days later
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60 Days
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Growth - weight for age z score
Time Frame: 60 days
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Change in weight for age z score between enrolment and 60 days later
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60 days
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Growth - weight for length z score
Time Frame: 60 days
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Change in weight for length z score between enrolment and 60 days later
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60 days
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Growth - length for age z score
Time Frame: 60 days
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Change in length for age z score between enrolment and 60 days later
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60 days
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Chair: James A Berkley, MD, University of Oxford
Publications and helpful links
General Publications
- Zhang L, Voskuijl W, Mouzaki M, Groen AK, Alexander J, Bourdon C, Wang A, Versloot CJ, Di Giovanni V, Wanders RJ, Bandsma R. Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition. PLoS One. 2016 May 10;11(5):e0155143. doi: 10.1371/journal.pone.0155143. eCollection 2016.
- Bartels RH, Bourdon C, Potani I, Mhango B, van den Brink DA, Mponda JS, Muller Kobold AC, Bandsma RH, Boele van Hensbroek M, Voskuijl WP. Pancreatic Enzyme Replacement Therapy in Children with Severe Acute Malnutrition: A Randomized Controlled Trial. J Pediatr. 2017 Nov;190:85-92.e2. doi: 10.1016/j.jpeds.2017.07.013. Epub 2017 Sep 11.
- Njunge JM, Gwela A, Kibinge NK, Ngari M, Nyamako L, Nyatichi E, Thitiri J, Gonzales GB, Bandsma RHJ, Walson JL, Gitau EN, Berkley JA. Biomarkers of post-discharge mortality among children with complicated severe acute malnutrition. Sci Rep. 2019 Apr 12;9(1):5981. doi: 10.1038/s41598-019-42436-y.
- Attia S, Versloot CJ, Voskuijl W, van Vliet SJ, Di Giovanni V, Zhang L, Richardson S, Bourdon C, Netea MG, Berkley JA, van Rheenen PF, Bandsma RH. Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study. Am J Clin Nutr. 2016 Nov;104(5):1441-1449. doi: 10.3945/ajcn.116.130518. Epub 2016 Sep 21.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- OxTREC 43-20
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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