Pancreatic Enzymes and Bile Acids in Acutely Ill Severely Malnourished Children

NCT04542473 | Unknown Phase 2 DMC

• 1 other identifier: OxTREC 43-20
• Study Type: interventional
• Target: 400
• Locations: 4 countries
• Sites: 4

Brief Summary

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 infections. A related 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 helping the body control bacteria in the upper intestines. It is therefore possible that treatment with digestive enzymes could help reduce the burden of harmful bacteria and thus lower inflammation and the 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 liver function abnormalities, something that malnourished children suffer from as well. The investigators want to find out if supplementing these pancreatic enzymes and bile acids among ill children with severe acute malnutrition is safe and reduces the risk of death, deterioration or readmission to hospital.

Conditions

SEPSIS; MALNUTRITION, CHILD

Keywords

"small intestinal bacterial overgrowth"; "severe malnutrition"; "factorial"; "pancreatic enzymes"; "bile acids"; "bacterial"; "translocation"; "dysbiosis"; "inflammation"

Outcome Measures

Primary Outcomes (1)

• Mortality

  Death

  60 days

Secondary Outcomes (9)

• Rate of SAEs

  60 days

• Rate of toxicity events

  21 days

• Intestinal function

  60 days

• Antimicrobials

  60 days

• Hospitalisation duration

  60 days

Study Arms (4)

Pancreatic Enzymes (PE)

ACTIVE COMPARATOR

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

Drug: Pancreatic Enzyme

Placebo-PE

PLACEBO COMPARATOR

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

Other: Pancreatic Enzyme placebo

Ursodeoxycholic acid (UA)

ACTIVE COMPARATOR

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.

Drug: Ursodeoxycholic acid

Placebo-UA

PLACEBO COMPARATOR

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.

Other: Ursodeoxycholic acid placebo

Interventions

Pancreatic Enzyme DRUG

CREON micro 5000

Also known as: CREON

Pancreatic Enzymes (PE)

Ursodeoxycholic acid DRUG

Ursodiol C24H40O4 suspension

Also known as: UDCAMENT

Ursodeoxycholic acid (UA)

Pancreatic Enzyme placebo OTHER

Microcrystalline Cellulose,Macrogel 4000, Iron Oxide Yellow, Iron Oxide Red, Activated Charcoal.

Also known as: Placebo-PE

Placebo-PE

Ursodeoxycholic acid placebo OTHER

Sodium Citrate Dihydrate, Aspartame, Carboxymethylcellulose Sodium, Citric Acid Monohydrate, Dispersible Cellulose, Glycerol, Polysorbate-80, Saccharin Sodium,Sodium Benzoate, Sodium Methylparaben, Sodium Propylparaben

Also known as: Placebo-UA

Placebo-UA

Eligibility Criteria

• Age: 2 Months - 59 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

Sponsors & Collaborators

• University of Oxford: lead
• University of Amsterdam: collaborator
• University of Toronto: collaborator
• University of Washington: collaborator
• Oregon Health and Science University: collaborator
• Kenya Medical Research Institute: collaborator
• Queen Elizabeth Central Hospital, Blantyre, Malawi: collaborator
• Makerere University: collaborator
• KEMRI-Wellcome Trust Collaborative Research Program: collaborator
• International Centre for Diarrhoeal Disease Research, Bangladesh: collaborator

Study Sites (4)

ICDDR,B Dhaka Hospital

Dhaka, Bangladesh

Location

KEMRI WT Clinical Trials Facility

Kilifi, 80800, Kenya

Location

Queen Elizabeth Central Hospital

Blantyre, Malawi

Location

Mulago Hospital

Kampala, Uganda

Location

Related Publications (4)

• 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.

  PMID: 27163928 BACKGROUND

• 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.

  PMID: 28912050 BACKGROUND

• 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.

  PMID: 30979939 BACKGROUND

• 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.

  PMID: 27655441 BACKGROUND

Related Links

• The CHAIN Network

MeSH Terms

Conditions

Sepsis; Child Nutrition Disorders; Malnutrition; Dysbiosis; Inflammation

Interventions

Pancrelipase; Ursodeoxycholic Acid

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Nutrition Disorders; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Lipase; Carboxylic Ester Hydrolases; Esterases; Hydrolases; Enzymes; Enzymes and Coenzymes; Pancreatic Extracts; Tissue Extracts; Complex Mixtures; Deoxycholic Acid; Cholic Acids; Bile Acids and Salts; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Cholanes

Study Officials

• James A Berkley, MD

  University of Oxford

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Sequential study numbers will be computer generated according to a blocked randomization list of random block sizes allocated to each site before the study begins. Identical study investigation medical product (IMP) packs will be labelled with sequential study numbers according to a prepared blocked randomization list before the trial begins. An independent off-site trial-pharmacist will implement labeling of the IMP with unique study numbers according to the randomization list. Study numbers will be issued in consecutive order at each site.
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Double-blind, randomized clinical trial 2x2 factorial design in 3 stages: In stage 1, (200 participants). Then the Data \& Safety Monitoring Committee (DSMC) will review data for likelihood major safety signals/harm (non-inferior to placebo) based on a composite endpoint of toxicity, serious adverse events (SAEs) and deaths. In stage 2, (200 more participants, total 400 participants). Then the DSMC will review data on a composite endpoint of SAEs and deaths and results of modeled simulations for the likelihood of superiority over placebo for mortality. Interventions with less than 80% probability of efficacy will be discontinued. Sample size for stage 3 may be adjusted. In stage 3, (800 more participants, total target sample size 1,200) across all sites, based on a hazard ratio of 0.66 (a 33% reduction in mortality) from a baseline mortality of 24% to 16% with 90% power, 20% inflation for the factorial design and 5% loss to follow up.

Study Record Dates

• First Submitted: August 6, 2020
• First Posted: September 9, 2020
• Study Start: July 1, 2021
• Primary Completion: October 31, 2023
• Study Completion: June 30, 2024
• Last Updated: February 24, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

BA (1); KE (1); MA (1); UG (1)