A study to compare antibiotics used to treat children with severe acute malnutrition
| ISRCTN | ISRCTN18051843 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN18051843 |
| Secondary identifying numbers | KEMRI/SERU/CGMR-C/063/3399 |
- Submission date
- 04/05/2017
- Registration date
- 09/05/2017
- Last edited
- 23/05/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
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 July 2020
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
Contact information
Scientific
KEMRI/Wellcome Trust Research Programme
P.O Box 230-80108
Kilifi
80108
Kenya
 ORCID ID |
0000-0002-1236-849X |
|---|
Public
Clinical Trials Facility
KEMRI/Wellcome Trust Research Programme
P.O Box 230-80108
Kilifi
80108
Kenya
| Phone | +254 709 983 859 |
|---|---|
| injagi@kemri-wellcome.org |
Study information
| Study design | Randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN18051843_PIS_12Jan17_V1.docx |
| Scientific title | First Line Antimicrobials in Children with Complicated Severe Acute Malnutrition |
| Study 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(s) | 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 |
| 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Ceftriaxone, benzyl penicillin, gentamicin and metronidazole |
| Primary outcome measure | 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 study start date | 01/09/2013 |
| Overall study end date | 31/07/2020 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 2 Months |
| Upper age limit | 13 Years |
| Sex | Both |
| Target number of participants | 2000 |
| Total final enrolment | 1872 |
| 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 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 | 31/03/2020 |
Locations
Countries of recruitment
- Kenya
- Uganda
Study participating centres
PO Box 230-80108
Kilifi
80108
Kenya
PO Box 1966
Mbale
256
Uganda
Mombasa
80100
Kenya
Nairobi
0202
Kenya
Sponsor information
University/education
Wellington Square
Oxford
OX1 2JD
England
United Kingdom
"ROR" |
https://ror.org/052gg0110 |
|---|
Funders
Funder type
Charity
No information available
Private sector organisation / International organizations
- Location
- United Kingdom
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/09/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| 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 |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version V1 | 12/01/2017 | 11/05/2017 | No | Yes |
| Protocol file | version 1.04 | 20/03/2019 | 12/08/2022 | No | No |
Additional files
- ISRCTN18051843_PIS_12Jan17_V1.docx
- Uploaded 11/05/2017
- 33600 FLACSAM Protocol V1.04 20Mar2019.pdf
Editorial Notes
23/05/2024: The intention to publish date was changed from 31/03/2024 to 30/09/2024.
17/08/2023: The intention to publish date has been changed from 31/08/2023 to 31/03/2024.
15/12/2022: The intention to publish date has been changed from 31/12/2022 to 31/08/2023.
18/08/2022: The intention to publish date has been changed from 31/08/2022 to 31/12/2022.
12/08/2022: Uploaded protocol (not peer-reviewed) as an additional file.
15/02/2022: The following changes were made to the trial record:
1. The overall end date was changed from 31/01/2021 to 31/07/2020.
2. The intention to publish date was changed from 31/12/2021 to 31/08/2022.
3. The public contact was changed.
4. The plain English summary was updated to reflect these changes.
16/06/2020: The following changes were made to the trial record:
1. The overall end date was changed from 31/07/2020 to 31/01/2021 and the plain English summary has been updated to reflect this change.
2. The intention to publish date was changed from 31/12/2020 to 31/12/2021.
11/06/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/05/2020 to 31/03/2020.
2. The overall end date was changed from 30/09/2020 to 31/07/2020.
3. The total final enrolment was added.
02/08/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/10/2019 to 31/05/2020.
2. The overall trial end date was changed from 31/12/2019 to 30/09/2020.
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.
