The pharmacology of azithromycin in severe malaria bacterial co-infection in African children
| ISRCTN | ISRCTN49726849 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN49726849 |
| Protocol serial number | WMNP_P66265 |
| Sponsor | Imperial College, London |
| Funder | Medical Research Council |
- Submission date
- 24/10/2017
- Registration date
- 27/10/2017
- Last edited
- 07/11/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
Malaria is a tropical disease spread by mosquitoes that causes high temperature, sweats and chills, headaches, vomiting, muscle pains and diarrhea. Severe malaria killed an estimated 475,000 African children in 2013. Fast-acting effective antimalarial drugs are now used in most hospitals, but a large number of children still die (around one in every ten). To reduce this number, there is a need to find better ways to manage these sick children. Some children with severe malaria infection also have a higher chance of also having infections caused by bacteria (bugs) at the same time. These bacterial infections increase the risk of children with severe malaria dying in hospital even more (to around a one in four chance). Around one-third of all severe malaria deaths in African children are thought to be due to these bacterial infections. The problem is that most African hospitals are not able to grow the bacteria from blood to work out which children really have these bacterial infections. So there are two options: no one gets antibiotics, or everyone gets antibiotics. The problem with giving all these children antibiotics is that most of them don’t need them, and using antibiotics for all children can increase the risk of resistance in the community (meaning antibiotics stop working for people who really need them). There is no agreement on which antibiotics, at what dose or for how long, they should be used in children with severe malaria. The main bacteria responsible for these infections come from the gut, because the gut becomes ‘leaky’ in severe malaria so these bugs can cross over into the blood. These bacteria are frequently resistant to, or are not treated by, currently recommended and commonly available antimicrobials. The aim of this study is to examine one of the antibiotics that can be given by mouth (specifically azithromycin) which has the potential to treat most common causes of infections and to find out what is the correct dose to give (to treat infections) in order to progress to the next step which will be a larger trial comparing different types of antibiotics to improve both short term and longer term outcomes.
Who can participate?
Children aged six months to 12 years old who are admitted to the hospital with malaria.
What does the study involve?
Participants are randomly allocated to one of three groups. Those in the first group receive a 10 mg/kg dose of azithromycin. Those in the second group receive a 15 mg/kg dose of azithromycin . Those in the last group receive the 20 mg/kg dose of azithromycin. The medication is taken once daily over five days. Participants are followed up at day seven, day 28 and day 90 to assess their treatment and how well the medication is working.
What are the possible benefits and risks of participating?
Participants may benefit from regular assessment of by doctors/nurses to enable carers to make important changes to your child’s treatment in hospital, if these are needed. Researchers help supply routine medical supplies and treatments for participants to the hospital, so that carers will not have to buy any treatments. This means that there will be no delay to starting treatment. The medical tests performed during this illness are also paid for by the study. Participants are asked back for follow up visit(s), therefore transport from hospital to your home and back to the clinic are paid for. During the follow up visit(s), we will treat any illnesses we find, or arrange referral to appropriate hospital. The trial will be recruiting patients with severe illness and likely a high mortality rate. At the start of the trial, all sites will receive emergency care training, including triage of those at highest risk. All patients will be closely monitored so that clinical deteriorations can be identified at the earliest opportunity. GCP-compliant adverse event data collection and reporting procedures will be adopted. Azithromycin is an approved drug for use in children and risk is therefore very low.
Where is the study run from?
Mbale Regional Referral Hospital (Uganda)
When is the study starting and how long is it expected to run for?
July 2017 to November 2019
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Professor Kathryn Maitland
Contact information
Scientific
Wellcome Centre for Clinical Tropical Medicine
Room 232, 2nd Floor, Medical School Building
St Mary's Campus
Norfolk Place
London
W21PG
United Kingdom
 ORCID ID |
0000-0002-0007-0645 |
|---|
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Phase I/II trial randomised single centre study |
| Secondary study design | Randomised parallel trial |
| Study type | Participant information sheet |
| Scientific title | Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children |
| Study acronym | TABS-PKPD |
| Study objectives | Hypotheses: 1. Azithromycin (an antibiotic) given to children once-daily for 5 days in addition to standard treatment of severe malaria (including anti-malarials) can provide adequate dosing in children admitted to hospital with severe malaria 2. Children severe malaria with culture-proven bacteraemia can be accurately identified using clinical criteria alone or in combination with a rapid diagnostic biomarker tests, in comparison with a control cohort of children hospitalized with severe malaria but not meeting Teule criteria, at low risk of bacterial co-infection |
| Ethics approval(s) | 1. Imperial College Research Ethics Committee (ICREC), 10/11/2017, ref: 17IC3965 2. Mbale Regional Referral Hospital Research Ethics Committee, Mbale Uganda Preliminary, 27/10/2017 |
| Health condition(s) or problem(s) studied | Severe Malaria |
| Intervention | Children are randomised (1:1:1) to compare three doses of azithromycin: 10, 15 and 20 mg/kg (based on weight-bands) taken orally once daily over five days in order to optimize dose and study pharmacokinetics and their relation with treatment outcome. Randomisation lists are generated and kept at the MRC CTU at UCL, London. The randomisation envelopes are prepared before the trial at the Clinical trials facilty, KWTRP, Kilifi. These contain the actual allocation visible only once opened. Children are randomised (1:1:1) to receive 10, 15 or 20 mg/kg azithromycin (based on weight-bands). The cards will be numbered consecutively and opened in numerical order. Children are followed up at day seven, day 28 and day 90 to study the medication pharmacokinetics and their relation with treatment outcome. |
| Intervention type | Drug |
| Phase | Phase I/II |
| Drug / device / biological / vaccine name(s) | Azithromycin |
| Primary outcome measure(s) |
Sepsis markers are measured using the c-reactive protein tests using blood samples at baseline to 72 hours (continuous) and microbiological cure (7-day). |
| Key secondary outcome measure(s) |
1. Mortality is measured using dedicated case report forms at clinical visit or telephone interviews at 48 days and 90 days |
| Completion date | 30/12/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 6 Months |
| Upper age limit | 12 Years |
| Sex | All |
| Target sample size at registration | 105 |
| Total final enrolment | 105 |
| Key inclusion criteria | 1. Children aged 6 months to 12 years at admission to hospital with Plasmodium falciparum malaria (on either blood film or ParacheckTM rapid diagnostic test) 2. Axillary temperature >380C or <360C 3. ‘Teule’ severity criteria: any one of the following: prostration; respiratory distress; severe anaemia (haemoglobin<5g/dL) or HIV infection 4. Parents willing/able to provide consent |
| Key exclusion criteria | 1. Major contraindications to azithromycin, eg strong existing clinical diagnosis of QT-prolongation 2. Concomitant use of interacting drugs: drugs that may cause QT-prolongation or drugs that may cause a pharmacokinetic interaction with azithromycin, like strong CYP3A/P-GP inducers and concomitantly administered antacids |
| Date of first enrolment | 01/09/2020 |
| Date of final enrolment | 01/04/2022 |
Locations
Countries of recruitment
- Uganda
Study participating centre
Mbale
PO Box 92
Uganda
Results and Publications
| Individual participant data (IPD) Intention to share | No |
|---|---|
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| IPD sharing plan | The current data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | 06/11/2024 | 07/11/2024 | Yes | No | |
| Protocol article | 10/01/2023 | 31/07/2023 | Yes | No | |
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
| Statistical Analysis Plan | version 1.0 | 20/05/2021 | 26/02/2024 | No | No |
Additional files
- ISRCTN49726849_SAP_v1.0_20May2021.pdf
- Statistical Analysis Plan
Editorial Notes
07/11/2024: Publication reference and total final enrolment added.
26/02/2024: Statistical analysis plan added.
31/07/2023: Publication reference added.
12/08/2020: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/01/2019 to 01/09/2020.
2. The recruitment end date was changed from 01/08/2020 to 01/04/2022.
3. The overall end date was changed from 30/11/2021 to 30/12/2022.
4. The plain English summary was updated to reflect these changes.
16/04/2020: Due to current public health guidance, recruitment for this study has been paused.
08/10/2018: The following updates were made:
1. The recruitment start date was updated from 01/12/2017 to 01/01/2019
2. The recruitment end date was updated from 01/08/2018 to 01/08/2020
3. The overall trial end date was updated from 30/11/2019 to 30/11/2021
10/11/2017: Ethics approval information has been added.,
