Condition category
Infections and Infestations
Date applied
04/05/2017
Date assigned
09/05/2017
Last edited
18/07/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Children with severe malnutrition who are admitted to hospitals have a high mortality (death rate), usually due to 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 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. The study also aims to find out how often children carry bacteria that are resistant to antibiotics in their intestines and the effects of different antibiotics on the ability for bacteria to resist antibiotic treatment and the costs to hospitals and to families of treating malnourished children with the different antibiotics.

Who can participate?
Children aged 2 months to 13 years old with severe malnutrition who are admitted to the hospital.

What does the study involve?
Participants are randomly allocated to receiving one of two intravenous (IV) antibiotic treatments and are randomised again to one of two oral antibiotic treatments. Those who are allocated to the first IV antibiotic treatment group receive ceftriaxone (80 mg/kg) once per day during their hospitalisation. Those in the second group receive the standard antibiotics. Those who are allocated to the first group oral antibiotic treatment group receive metronidazole (10 to 16 mg/kg taken by mouth) for seven days. Those in the second antibiotic treatment group receive a placebo (a dummy medication) which is taken by mouth for seven days. Participants provide blood and faecal samples before they take the antibiotics, while they are taking them and when they leave the hospital. They are followed up for 90 days with three follow up visits which include a health questionnaire, measurements and faecal samples. Parents and carers may be interviewed about the costs of their child’s healthcare.

What are the possible benefits and risks of participating?
Participants may benefit from close observation, appropriate nutritional and clinical care. Communities may benefit from the additional clinical care staff and the additional training about managing severely ill children, antimicrobial usage and infection control. Participants may benefit from the costs of care, consultant and investigation being covered by the study. There are risks with participating in this study. The medications provided have common side effects such as skin rashes, abdominal discomfort, and headache, loss of appetite, nausea and vomiting. There is a risk of drug allergies, therefore history of drug allergies are taken from participants. Participants may experience discomfort from blood tests and rectal swabbing.

Where is the study run from?
This study is being run by the KEMRI/Wellcome Trust Research Programme (Kenya) and takes place in three hospitals in Kenya and one in Uganda.

When is the study starting and how long is it expected to run for?
September 2013 to December 2019

Who is funding the study?
Global Health Trials Scheme [Department for International Development, Medical Research Council & Wellcome Trust] (UK)

Who is the main contact?
Professor James Berkley

Trial website

Contact information

Type

Scientific

Primary contact

Prof James Berkley

ORCID ID

http://orcid.org/0000-0002-1236-849X

Contact details

KEMRI/Wellcome Trust Research Programme
P.O Box 230-80108
Kilifi
80108
Kenya

Type

Public

Additional contact

Miss Nancy Kagwanja

ORCID ID

Contact details

Clinical Trials Facility
KEMRI/Wellcome Trust Research Programme
P.O Box 230-80108
Kilifi
80108
Kenya

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

KEMRI/SERU/CGMR-C/063/3399

Study information

Scientific title

First Line Antimicrobials in Children with Complicated Severe Acute Malnutrition

Acronym

FLACSAM

Study hypothesis

Mortality amongst children admitted to hospital with complicated severe acute malnutrition (SAM) is not altered by administration of intravenous ceftriaxone or metronidazole as first line agents compared to penicillin plus gentamicin.

Ethics approval

1. KEMRI Scientific Ethics Review Unit (SERU), 20/01/2017, ref: KEMRI/SERU/CGMR-C/0063/3399
2. Oxford Tropical Research Ethics Committee (OxTREC), Oxford: 06/02/2017, ref: OxTREC 1-17

Study design

Randomized controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

See additional files

Condition

Invasive bacterial infection, Severe acute malnutrition

Intervention

This study is testing two interventions. Participants are randomised to receive either one of two intravenous antimicrobial treatment arms and then are randomised again to one of two oral antimicrobial treatment arms.

Intervention 1:
Participants are randomly allocated to one of two groups:
Arm 1 IV Ceftriaxone: Participants in this group receive 80mg/kg IV ceftriaxone once a day. IV ceftriaxone is given for a minimum of 48 hours and a usual maximum of seven days. If a child receiving IV ceftriaxone is feeding well and no longer has any signs of infection or complications after two days and before seven days, they are prescribed standard care for uncomplicated SAM with oral amoxicillin (40mg/kg every 12 hours) to complete a total of seven days of antibiotics, as per WHO guidance. If a participant has a specific and documented indication to continue ceftriaxone beyond seven days (e.g. proven bacterial meningitis), ceftriaxone is continued beyond those seven days.

Arm 2 IV Benzyl penicillin plus gentamicin (usual care): Participants in this group receive 50 000 U/kg IV benzyl penicillin every six hours. In the usual care arm, as per WHO guidelines, IV benzyl penicillin plus gentamicin is given for a minimum of two days and a maximum of seven days. If a child receiving IV penicillin and gentamicin is feeding well and no longer has any signs of infection or complications after two days and before seven days, they are prescribed standard care for uncomplicated severe acute malnutrition (SAM) with oral amoxicillin (40mg/kg every 12 hours) to complete a total of seven days of antibiotics, as per WHO guidance.

Participants in both treatment arms who are discharged before seven days are prescribed oral amoxicillin to take home to complete a total of seven days of antimicrobial therapy, as per WHO guidance. First line antimicrobial treatment in hospital may be changed on the basis of confirmed antimicrobial susceptibility results from an admission blood culture, this is recorded in the case report form (CRF), along with the reason. Children with specific and documented clinical indications for second or third line antimicrobials, deterioration after at least 48 hours may change antimicrobials for clinical care according to study standard operating procedures aimed at ensuring optimum care. This is recorded in the CRF, along with the reason.

Intervention 2:
Arm 1 Metronidazole: Participants receive 10 to 16 mg/kg oral metronidazole twice a day for seven days.
Arm 2 Placebo: Participants receive a placebo dose to match that for Metronidazole oral twice a day for seven days.

Any early discontinuation of metronidazole or placebo will be recorded in the CRF, along with the reason. Children discharged before seven days will be prescribed oral metronidazole or placebo to complete a total of seven days of therapy.

All participants provide a small volume of blood and a faecal sample in addition to the routine tests for care at admission before antibiotic administration, and again at discharge. Participants are reviewed daily by the study team, working together with the hospital staff to provide the best care available in the hospital. Participants are followed up for 90 days from enrolment with three scheduled follow up visits which include a health questionnaire, measurements and the collection of a faecal sample at two of the visits. The levels of the antibiotics being used are checked in the blood of 120 participants at Kenyan sites whilst in hospital. Parents and carers of participants at each site may also be interviewed about any costs they have met as a result of the child needing healthcare. If a participant requires readmission to hospital, a small volume of blood is drawn to try and determine the cause. Results of blood tests will be fed back to the clinical team to assist in care. For non-severely malnourished children, a rectal swab will be taken at admission and discharge, and information collected during admission, but with no additional samples or further follow up.

Intervention type

Drug

Phase

Phase III

Drug names

Ceftriaxone, benzyl penicillin, gentamicin and metronidazole

Primary outcome measures

Mortality is measured using source documents from medical records, verbal autopsy, or death or burial certificates in the community from enrolment to 90 days after enrolment.

Secondary outcome measures

1. Grade 4 toxicity events are measured according to the Division of AIDS Tables for Grading the Severity of Adverse Events using medical records from enrolment to end of the study
2. Serious adverse events are measured using inpatient and outpatient medical records from enrolment to 90 days after enrolment
3. Mortality within the first 48 hours after enrolment, by day 7 and until discharge from the index hospitalisation, is measured using inpatient records from enrolment to discharge from hospital
4. Mortality occurring after discharge from the index hospital admission is measured using source documents from inpatient medical records, verbal autopsy, or death or burial certificates in the community from discharge to 90 days after enrolment
5. Causes of death, as determined by an endpoint review committee from enrolment to 90 days after enrolment
6. 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 the index admission to 90 days after enrolment
7. Causes of re-admission, as determined by the admitting study clinician from discharge from the index admission to 90 days after enrolment
8. Total duration of hospitalisation is measured in days using inpatient records at the start and end of each admission to hospital from enrolment to 90 days after enrolment
9. Total duration of administration of antibiotics in hospital is measured using inpatient records at the start and end of each admission to hospital from enrolment to 90 days after enrolment
10. Change in nutritional status is measured using mid-upper arm circumference, weight-for-length, weight-for-age and length-for-age at enrolment, 14, 45 and 90 days after enrolment
11. Aetiology of invasive infections are measured using microbial culture and sensitivity testing of blood, cerebrospinal fluid, urine or other sterile site samples taken for clinical investigation from enrolment to 90 days after enrolment
12. Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL) is measured using microbial culture and sensitivity testing of rectal swabs taken at enrolment, discharge from the index admission, day 45 and day 90 after enrolment

Overall trial start date

01/09/2013

Overall trial end date

31/12/2019

Reason abandoned

Eligibility

Participant inclusion criteria

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

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

2000

Participant exclusion criteria

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

Recruitment start date

20/07/2017

Recruitment end date

01/10/2019

Locations

Countries of recruitment

Kenya, Uganda

Trial participating centre

KEMRI/Wellcome Trust Research Programme
Clinical Trials Facility P.O Box 230-80108
Kilifi
80108
Kenya

Trial participating centre

Mbale Clinical Research Institute
Mbale Regional Referral Hospital P.O. Box 1966
Mbale
256
Uganda

Trial participating centre

Coast General Hospital
P.O Box P.O. Box 90231-80100
Mombasa
80100
Kenya

Trial participating centre

Mbagathi Hospital
P.O Box 20725
Nairobi
0202
Kenya

Sponsor information

Organisation

University of Oxford

Sponsor details

Wellington Square
Oxford
OX1 2JD
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Charity

Funder name

Joint Global Health Trials Scheme of the Department for International Development (DFID)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Wellcome Trust

Alternative name(s)

Wellcome

Funding Body Type

private sector organisation

Funding Body Subtype

international

Location

United Kingdom

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal.

IPD sharing plan:
The datasets generated during and/or analysed during the current study will be available upon request from: DGC@kemri-wellcome.org

Intention to publish date

31/12/2020

Participant level data

Available on request

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

18/07/2017: Overall trial start date changed from 01/06/2016 to 01/09/2013. Recruitment start date changed from 22/05/2017 to 20/07/2017. 11/05/2017: The participant information sheet has been uploaded.