Use of paracetamol in resolving acute kidney injury in severe malaria
| ISRCTN | ISRCTN84974248 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN84974248 |
| ClinicalTrials.gov (NCT) | Nil known |
| Clinical Trials Information System (CTIS) | Nil known |
| Protocol serial number | Version 1; 13/08/2018 |
| Sponsor | European & Developing Countries Clinical Trials Partnership |
| Funder | European and Developing Countries Clinical Trials Partnership |
- Submission date
- 16/11/2020
- Registration date
- 08/12/2020
- Last edited
- 01/08/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
The global burden of malaria remains very high and there is a very high rate of death among patients presenting with malaria. The rate of death is even higher in sub Saharan Africa where 9/10 of those deaths occur in children especially those aged below 5 years. Even with the widespread implementation of fast acting antimalarial drugs, death among the children admitted with malaria is unacceptably high (about 1/10) and will not improve without better supportive treatments. Children with malaria complicated by hemoglobinuria (passing dark colored urine) have a higher rate of in hospital and post discharge deaths. In east Africa malaria is a very common cause of admissions and black water fever (passing dark colored urine) is a common feature in severe malaria. Other research studies done have shown that black water fever is associated with acute kidney injury in malarial illnesses.
The aim of this study is to gather enough information on a possible way of controlling Acute Kidney Injury and to check if using paracetamol, which is a cheap, affordable and readily available drug, will be helpful in resolving acute kidney injury in malaria which will help us improve on the management of complications in severe malaria. This will further decrease the rate of death among patients admitted with severe malaria.
Who can participate?
Children aged between 6month and 12 years admitted to the paediatric ward with confirmed severe malaria complicated by passing dark urine (haemoglobinuria)
What does the study involve?
Children will have a rapid structured assessment; conscious level, vital signs (heart rate, oxygen saturation, respiratory rate, axillary temperature, blood pressure), malaria Rapid Diagnostic Test and history of passing dark urine (hemoglobinuria) in the current illness will be carried out to see whether the child is potentially eligible for suspected Acute Kidney Injury. The child will have the usual daily assessments and an extra quick test to determine BUN levels to confirm whether the child is suitable for the study. Participants will be treated following the national guidelines. However, for the purposes of the study participants will be randomly allocated to oral paracetamol (also commonly referred to as Panadol) at 20 mg/kg or no paracetamol. A sample of about 5 ml (about 1 teaspoonful) of venous blood (volume varies - according to age) will be collected and taken for the following investigations: rapid test to determine Blood Urea Nitrogen (BUN) levels, lactate, glucose, malaria status, HIV test, cross match and a sample of blood will be stored for subsequent parasitological and genetic profiling (for sickle cell). Children will be asked to return 28 days, 90 and 180 from the first of admission. This is for a check-up and some tests.
What are the possible benefits and risks of participating?
There are no direct benefits from this study. However, children will get close observation and be reviewed at the follow-up visit. This will enable us to make important changes to their treatment if needed and treat any illnesses found. Routine medicines and medical tests will be performed during the study and will be paid for by the study. It will also help improve the care of children with haemoglobinuria in future. The study drug (Panadol) and tests are widely used/done in children and are safe. The total amount of blood taken during the study will not harm the health of the children. There are very few risks in this study and children will be monitored throughout their time in hospital.
Where is the study run from?
Mbale regional referral hospital paediatric Acute Care Unit (Uganda)
When is the study starting and how long is it expected to run for?
May 2018 to April 2024
Who is funding the study?
European and Developing Countries Clinical Trials Partnership (EDCTP) (Netherlands)
Who is the main contact
Prof. Peter Olupot-Olupot
ed@mcri.ac.ug
Contact information
Scientific
PO Box 1966
Mbale
-
Uganda
 ORCID ID |
0000-0002-5757-609X |
|---|---|
| Phone | +256 (0)772 457 217 |
| ed@mcri.ac.ug |
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Single-centre randomized controlled trial |
| Secondary study design | Randomised controlled trial |
| Study type | Participant information sheet |
| Scientific title | Paracetamol for Acute Renal Injury in Severe Malaria Trial (PARIST) |
| Study acronym | PARIST |
| Study objectives | 1. To conduct pharmacokinetic studies of paracetamol in patients with acute kidney injury in severe malaria 2. To assess the feasibility of conducting AKI in severe malaria in Eastern Uganda 3. To conduct safety and preliminary effectiveness study for use of paracetamol in ameliorating AKI in severe malaria |
| Ethics approval(s) | Approved 08/01/2019; renewal: 19/08/2021, Mbale Regional Referral Hospital Regulatory Ethics Committee (PO Box, 921 Mbale, Uganda; +256 (0)393280584; mrrhrec@gmail.com), ref: MRRHREC- OUT 002/2019 |
| Health condition(s) or problem(s) studied | Preventing cell-free haemoglobin renal toxicity and ameliorating Acute Kidney Injury (AKI) in children with haemoglobinuric severe malaria |
| Intervention | A. Paracetamol intervention dose arm: research nurses will administer paracetamol 20 mg/kg orally 6-hourly for 48 h. Patients unable to swallow will receive paracetamol by nasogastric tube. If the patient vomits within 30 min of paracetamol administration, a further dose will be given. B. Control arm: Patients in the control arm will receive standard of care for temperature control. That is, fever of 37.5°C – 39.4°C will be tepid sponged and fanned. The children whose temperature ≥39.5°C will have paracetamol 10 mg/kg as stated in the standard of care in the Uganda Clinical Guidelines 2016. Randomization process; After screening, the patients that qualify will be assigned study numbers which correspond to those assigned in envelopes which are arranged consecutively in sealed opaque envelopes, each assigned across the seal. These numbers are randomly assigned prior to the start of the study by a statistician using the "randomizeR" package of the statistical software R, which allows simple randomization and adaptive assignment through minimization procedure. Minimization allocates patients to best maintain balance in the treatment group by calculating an imbalance score at each randomization. It then assigns with higher probability each patient to the treatment that will reduce the imbalance. The allocation will be on 1:1 ratio to paracetamol (A) and no paracetamol (B). Those on paracetamol (A) are further randomized in the ratio of 1:1 to A1 or A2 according to different pK sampling schedules. A1 will be those sampled at time intervals 1, 2, 4, 6, 12, 18 and 24 h while the A2 will be sampled at time intervals 0.5, 1.5, 2.5, 5, 12, 18 and 24 h. During enrolment, the study staff will pick the cards consecutively and open it. Each envelope will have a card that shows which arm the participant is in (A or B). Arm B (n = 20), those not receiving paracetamol immediately, but if their temperature is ≥39.5°C they will receive 10 mg/kg; will further be randomised to B1 or B2 in a 1:1 ratio to different sampling schedules as follows; B1 (n = 10), will be sampled at 1, 2, 4, 6 h post randomisation. Thereafter, sampling will continue once every 6 hours for 24 h. B2 (n = 10) will be sampled at 0.5, 1.5, 2.5, 5 h post randomisation. Thereafter, sampling will continue once every 6 hours for 24 h. Study participants randomised to PK sampling will have an extra card which indicates which PK sampling scheduling the participant will follow (A1 vs A2 or B1 vs B2). Participants are followed up to 28 days post-randomization, day 90 and day 180 for survival and resolution of acute kidney injury. |
| Intervention type | Drug |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Paracetamol |
| Primary outcome measure(s) |
Correction of AKI at 48 hours, as indicated by BUN (<20 mmol/L), creatinine level (<80 mmol/L), normal glomerular filtration index (based on Schwartz criteria), plasma creatinine, BUN, urinary-plasma creatinine ratio, serum urea-creatinine ratio, urinary osmolality, urinary-plasma osmolality ratio and urine microscopy. |
| Key secondary outcome measure(s) |
1. Survival measured using mortality outcome at 48 h and day 28 |
| Completion date | 30/04/2024 |
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 | 40 |
| Key inclusion criteria | 1. Children aged >6 months to <12 years 2. Positive RDT for P. falciparum malaria at admission 3. One of the following features of severe malaria confirmed haemoglobinuria, impaired consciousness and/or severe respiratory distress 4. Guardian or parent willing and able to provide consent |
| Key exclusion criteria | 1. Surgery 2. Acute trauma or burns 3. Known allergy to paracetamol 4. Impaired liver function tests 5. Known chronic renal failure or suspected non-malarial causes of renal impairment 6. Refusal to consent |
| Date of first enrolment | 15/05/2021 |
| Date of final enrolment | 15/06/2023 |
Locations
Countries of recruitment
- Uganda
Study participating centre
Plot 29-33, Pallisa Road
Mbale
-
Uganda
Results and Publications
| Individual participant data (IPD) Intention to share | Yes |
|---|---|
| IPD sharing plan summary | Available on request |
| IPD sharing plan | The primary participant dataset will be held at Mbale clinical research institute database (www.mcri.ac.ug) and will only be available upon request. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 31/07/2023 | 01/08/2023 | Yes | No | |
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
Editorial Notes
01/08/2023: Publication reference added.
06/12/2022: The following changes were made to the trial record:
1. The overall end date was changed from 30/04/2023 to 30/04/2024.
2. The recruitment end date was changed from 15/11/2022 to 15/06/2023.
3. The plain English summary was updated to reflect these changes.
02/11/2022: The ethics approval was updated.
02/12/2020: Trial's existence confirmed by Mbale Regional Referral Hospital Regulatory Ethics Committee.
