First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition (FLACSAM)

May 15, 2020 updated by: University of Oxford
Children with severe malnutrition who are admitted sick to hospitals have a high mortality(death rate), usually because of infection. All children with severe malnutrition admitted to hospitals are treated with antibiotics(medication used to kill bacteria). However, the current antibiotics used in hospitals may not be the most effective. It is possible that the antibiotics that are currently used after initial antibiotics should be used first. No studies have been carried out to determine if the current antibiotics used for treating malnourished children who are sick and admitted in hospital are the most appropriate. The aim of this study is to find out if a changed antibiotic system for children with malnutrition is safe, reduces the risk of death and improves nutritional recovery.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Children with complicated severe acute malnutrition (SAM) admitted to hospital in sub-Saharan Africa have a case fatality(death rate) between 12% and more than 20%. Because children with SAM may not exhibit the usual signs of infection, WHO guidelines recommend routine antibiotics(medication used to kill bacteria). However, this is based on "low quality evidence". There is evidence that because of bacterial resistance to the currently recommended first-line antibiotics (gentamicin plus ampicillin or penicillin) could be less effective than potential alternatives. Some hospitals in Africa are already increasing use of ceftriaxone as a first-line treatment. However, this is not based on any data that ceftriaxone actually improves outcomes. Of concern is that ceftriaxone use may also lead to increased antimicrobial resistance, including inducing extended spectrum beta-lactamase (ESBL) and other classes of resistance.

A further area where evidence for policy is lacking is the use of metronidazole in severely malnourished children. The WHO guidelines recommend "Metronidazole 7.5 mg/kg every 8 h for 7 days may be given in addition to broad-spectrum antibiotics; however, the efficacy of this treatment has not been established in clinical trials." Metronidazole is effective against anaerobic bacteria, small bowel bacterial overgrowth, Clostridium difficile colitis and also Giardia, which is common amongst children with SAM. Small cohort studies of metronidazole usage suggest there may be benefits for nutritional recovery in malnourished children. However, metronidazole can cause nausea and anorexia, potentially impairing recovery from malnutrition and may also rarely cause liver and neurological toxicity.

This multi-centre clinical trial will assess the efficacy of two interventions, ceftriaxone and metronidazole, on mortality and nutritional recovery in sick, severely malnourished children in a 2x2 factorial design. There will also be an analysis of antimicrobial resistance and an economic analysis. To extend our understanding of metronidazole and ceftriaxone pharmacokinetics, additional pharmacokinetic data for the dosing schedule used in the trial will be collected from 120 participants in a sub-study. The trial will be conducted at Kilifi County Hospital, Coast General Hospital, Mbagathi Hospital in Kenya and Mbale Regional Referral Hospital in Uganda. The trial will assess antimicrobial resistance that is carried by children in their intestines and in invasive bacterial isolates. A further sub-study will examine the relative costs of care for SAM for health facilities and for families, including antimicrobial usage will also be assessed. Clear data on the benefits, risks and costs of these antimicrobials will influence policy on case management and antimicrobial stewardship in this vulnerable population.

Study Type

Interventional

Enrollment (Anticipated)

2000

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Kenya
      • Kilifi, Kenya, 80800
        • KEMRI WT Clinical Trials Facility
      • Kilifi, Kenya
        • Kilifi County Hospital
      • Mombasa, Kenya
        • Coast General Hospital - Study site
      • Nairobi, Kenya
        • Mbagathi District Hospital
      • Nairobi, Kenya
        • Mbagathi Hospital
    • Coast
      • Kilifi, Coast, Kenya, 80108
        • Kilifi County Hospital
    • Coast Province
      • Kilifi, Coast Province, Kenya, 80108
        • KEMRI Wellcome Trust Research Programme
  • Uganda
      • Mbale, Uganda
        • Mbale Regional Referral Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 9 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion:

  • Age 2 months to 13 years inclusive
  • Severe malnutrition defined as:
  • kwashiorkor at any age or:
  • for children between 2 to 5 months: MUAC <11cm or weight-for length Z score <-3
  • for children between 6 to 59 months: MUAC <11.5cm or weight-for length Z score <-3
  • for children between 5 to 13 years: MUAC <11.5cm or BMI-for-age Z score <-3
  • Admitted to hospital and eligible for intravenous antibiotics according to WHO guidelines
  • Planning to remain within the hospital catchment area and willing to come for specified visits during the 90 day follow up period
  • Informed consent provided by the parents/guardian

Exclusion:

  • Known allergy or contraindication to penicillin, gentamicin, ceftriaxone or metronidazole
  • A specific and documented clinical indication for another class of antibiotic
  • Previously enrolled in this study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ceftriaxone
Arm 1 IV Ceftriaxone: Participants in this group receive 80mg/kg IV ceftriaxone once a day for a minimum of 48 hours and a usual maximum of seven days.
Drug: Ceftriaxone
Ceftriaxone a third-generation cephalosporin. Ceftriaxone is active against a broad spectrum of Gram positive and Gram negative bacteria.
Active Comparator: Benzyl penicillin plus gentamicin
Arm 2 IV Benzyl penicillin plus gentamicin (usual care): Participants in this group receive 50 000 U/kg IV benzyl penicillin every six hours for a minimum of two days and a maximum of seven days.
Drug: Benzyl penicillin
The currently recommended first-line antibiotics for the treatment of severe acute malnutrition are gentamicin plus ampicillin or penicillin.
Drug: Gentamicin
The currently recommended first-line antibiotics for the treatment of severe acute malnutrition are gentamicin plus ampicillin or penicillin.
Experimental: Metronidazole
Arm 1 Metronidazole: Participants receive 10 to 16 mg/kg oral metronidazole twice a day for seven days.
Drug: Metronidazole
The WHO guidelines recommend that Metronidazole may be given in addition to broad-spectrum antibiotics, "however, the efficacy of this treatment has not been established in clinical trials."
Placebo Comparator: Placebo
Arm 2 Placebo: Participants receive an oral placebo dose to match that for Metronidazole twice a day for seven days.
Other: Placebo
Suspension manufactured to match metronidazole

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality
Time Frame: 90 days after enrolment.
Mortality is measured using source documents from medical records, verbal autopsy, or death or burial certificates in the community.
90 days after enrolment.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality during the first 7 days
Time Frame: 7 days
Mortality during the first 7 days
7 days
Mortality during the first 30 days
Time Frame: 7 days
Mortality during the first 30 days
7 days
Index admission inpatient mortality
Time Frame: Through index hospital admission, an average of 7 days.
Mortality during the index hospitalisation, measured using inpatient records.
Through index hospital admission, an average of 7 days.
Mortality after discharge from index admission.
Time Frame: 90 days after enrolment
Mortality occurring after discharge from the index hospital admission is measured using inpatient medical records, verbal autopsy, or death or burial certificates in the community.
90 days after enrolment
Grade 4 toxicity
Time Frame: Up to 7 days following enrolment
Grade 4 toxicity events are measured according to the Division of AIDS Tables for Grading the Severity of Adverse Events using medical records.
Up to 7 days following enrolment
Serious adverse events
Time Frame: 90 days after enrolment.
Serious adverse events are measured using inpatient and outpatient medical records.
90 days after enrolment.
Tolerability - relevant side effects during the first 7 day
Time Frame: 7 days
Vomiting, diarrhoea, NG tube in place and convulsions during the first 7 days
7 days
Causes of death.
Time Frame: 90 days after enrolment
Causes of death, as determined by an endpoint review committee.
90 days after enrolment
Re-admission to hospital.
Time Frame: From discharge from hospital to 90 days after enrolment
Re-admission to hospital defined as at least one overnight stay in a hospital or health facility are measured using inpatient records.
From discharge from hospital to 90 days after enrolment
Duration of hospitalisation.
Time Frame: 90 days after enrolment.
Total duration of hospitalisation is measured in days using inpatient records at the start and end of each admission to hospital.
90 days after enrolment.
Duration of administration of antibiotics.
Time Frame: 90 days after enrolment.
Duration of administration of intravenous antibiotics measured using inpatient records.
90 days after enrolment.
Change in nutritional status
Time Frame: 90 days after enrolment.
Change in nutritional status is measured using mid-upper arm circumference, weight-for-length, weight-for-age and length-for-age compared to at enrollment.
90 days after enrolment.
Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL)
Time Frame: Through study completion an average of 90 days.
Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL) is measured using microbial culture and sensitivity testing of rectal swabs.
Through study completion an average of 90 days.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oxford

Collaborators

London School of Hygiene and Tropical Medicine
University College, London
KEMRI-Wellcome Trust Collaborative Research Program
Kenya Medical Research Institute
Swansea Trials Unit

Investigators

  • Principal Investigator: James A Berkely, FRCPCH, KEMRI/Wellcome Trust Research Programme & University of Oxford

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 4, 2017

Primary Completion (Actual)

January 31, 2020

Study Completion (Anticipated)

December 31, 2020

Study Registration Dates

First Submitted

May 15, 2017

First Submitted That Met QC Criteria

May 30, 2017

First Posted (Actual)

June 2, 2017

Study Record Updates

Last Update Posted (Actual)

May 19, 2020

Last Update Submitted That Met QC Criteria

May 15, 2020

Last Verified

May 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KEMRI/SERU/CGMR-C/063/3399
  • 1-17 (Other Identifier: OxTREC)
  • 105431/Z/14/Z (Other Grant/Funding Number: Joint Global Health Trials, MRC/DfID/Wellcome Trust)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Data sharing will be considered by applying to the Data Governance Committee at CGMR,C Kilifi who will manage the process and ensure that appropriate ethical approval is in place and consent has been obtained for uses outside those given in this protocol:DGC@kemri-wellcome.org. Explanation of this eventuality will be included in the participant information and consent form. We intend to share anonymised data with the CHAIN network cohort study (KEMRI/SERU/CGMR-C /054/3318, OxTREC 34-16) which consists of institutions doing studies in malnourished children in Africa and South Asia; to upload anonymised bacterial and resistance sequences on recognised international repositories; and share anonymised bacterial sequence data relating to bacterial resistance with groups working an antimicrobial resistance in Africa and elsewhere.

IPD Sharing Time Frame

2 years after study end, no end date foreseen

IPD Sharing Access Criteria

Managed access. Apply to the Data Governance Committee: dgc@kemri-wellcome.org

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)
  • Clinical Study Report (CSR)
  • Analytic Code

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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