A Phase 2 interventional study of Acetaminophen and Ibuprofen in Malaria, Seizures and Coma, sponsored by University of Rochester. Completed at 3 sites in 2 countries. Open to participants aged 2 Years to 11 Years. Per ClinicalTrials.gov, last updated 2024-03-05.
Sponsored by University of Rochester · Phase 2, Interventional, and Treatment
The study will examine whether prophylactic and scheduled treatment with acetaminophen and ibuprofen can decrease the maximum temperature experienced during the acute illness in children with CNS malaria.
Despite ongoing eradication efforts, malaria remains a major public health challenge in Africa where annually, \~250,000 children with malaria experience a neurologic injury with subsequent neurodisability. In other central nervous system (CNS) disorders, fever is a recognized cause of worsening secondary neurologic injury and ex-tensive efforts are made to avoid hyperthermia or induce hypothermia for neuroprotection. Evidence indicates that among children with CNS malaria a higher temperature during the acute illness is a risk factor for post-infectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted, at least among children with complicated malaria who are at substantial risk of brain injury. Previous clinical trials conducted primarily in children with uncomplicated malaria and using only a single antipyretic medication have shown limited benefits in terms of fever reduction; however, no studies to date have examined malaria fever management using dual therapies. Enthusiasm for aggressive fever reduction measures among clinicians caring for children with malaria has been curbed by in vitro findings that malaria parasite replication slows at higher temperatures and a single clinical trial in which peripheral parasite clearance was slower in children receiving treatment for fever. However, the relationship between temperature and malaria parasite behavior is complex. Additional in vitro data suggest that at febrile temperatures uninfected red blood cells (RBCs) are more likely to adhere to infected RBCs, worsening the process of sequestration, increasing the parasite burden obstructing microvascular cerebral blood flow, and perhaps contributing to ongoing immunopathogenesis in CNS malaria. In this exploratory clinical trial of aggressive antipyretic therapy, children hospitalized with CNS malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5ºC) vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours. This proof-of-concept study will determine whether aggressive antipyretic therapy results in a lower mean maximum temperature relative to usual care. Serial quantitative levels of histidine rich protein 2 (HRP2), a P. falciparum-specific protein that facilitates estimates of whole body parasite burden and CNS parasite sequestration, will also be collected to clarify the relationship between antipyretic use and in vivo parasite behavior. Findings from this study will determine whether a Phase III clinical trial of aggressive antipyretics for neuroprotection in pediatric CNS malaria should be undertaken. This study will take place in Zambia and Malawi, where prior NIH-funded collaborations have assisted in developing the substantial infrastructure needed to undertake a clinical trial of this nature.
1,184 studies on the registry are indexed under Malaria; 79 are open to participants now.
This study's enrollment of 256 is close to the median of 252 across 937 interventional studies indexed under Malaria.
Browse Malaria studies →University of Rochester is the lead sponsor of 729 studies on the registry; 116 are open to participants now.
Of its 56 completed or terminated interventional studies of FDA-regulated products, 44 (79%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
regardless of temperature, children allocated to this arm will receive acetaminophen (30 milligrams (mg)/ kilogram (kg) load then 15mg/kg Q6 hours) and ibuprofen (10mg/kg Q 6 hours) for 72 hours. Pediatric syrup formulations of both agents will be administered orally or via nasogastric tube. For temperatures over 38.5 degrees Celsius, placebo will be added and if the fever persists, a cooling fan will be added.
Drug: Acetaminophen · Drug: Ibuprofen
will receive placebo for acetaminophen and placebo for ibuprofen. If they have a temperature over 38.5 degrees Celsius, they will receive acetaminophen (15mg/kg, Q6 hours), as needed. If the fever persists, a cooling fan will be added.
Drug: placebo for acetaminophen · Drug: placebo for ibuprofen
30 mg/kg load then 15mg/kg Q6 hours for the Aggressive Antipyretic Arm Acetaminophen is also given to children in the placebo arm when they have a fever over 38.5 degrees Celsius during scheduled clinical assessments
Also known as: Paracetamol
10 mg/kg Q6 hours for the Aggressive Antipyretic Arm
Also known as: Brufen
placebo for acetaminophen for children in the Usual Care arm For children in the Aggressive Antipyretic Arm, when they have a temperature over 38.5 degrees Celsius they are treated with a placebo
Also known as: Placebo
placebo for ibuprofen
Also known as: Placebo
Mean Maximum Temperature
Mean maximum temperature (Tmax). Tmax will be defined as the highest temperature during the study duration (72 hours) in degrees Celsius recorded by a continuous temperature monitor. The continuous temperature monitors are not magnetic resonance imaging (MRI) compatible. If TMAX is a clinical temperature obtained when continuous monitoring data is not available, the clinical TMAX will be used as the primary outcome.
Time frame: 72 hours
Seizure Severity
Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome.
Time frame: 72 hours
Parasite Clearance
Parasite clearance was based upon AUC for plasma HRP2 concentration every six hours
Time frame: 72 hours
Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best)
AUC fever for temperatures above 37.5 degrees Celsius based upon continuous temperature monitoring A secondary efficacy measure included fever exposure as measured by the area under the temperature × time curve for T≥38.5°C during the 72-hour follow-up period, categorized as 0, \> 0 and \< 2, and ≥ 2 degree-hours. An ordinal logistic regression model assuming proportional odds with terms for treatment group, country, and disease severity as covariates was used to derive the estimated adjusted treatment group odds ratio and associated 95% confidence interval. Sensitivity analyses with best-case and worst-case imputation were performed to accommodate missing data for the 12 participants with insufficient temperature data to determine the proper outcome category
Time frame: 72 hours
The trial was conducted in Malawi and Zambia from 2019 to 2022. In Malawi, enrolment occurred at Queen Elizabeth Central Hospital in Blantyre. In Zambia, the trial was conducted at the University Teaching Hospital in Lusaka and Chipata Central Hospital in the Eastern Province. This work was approved by the appropriate ethics review boards in Zambia and Malawi and at the University of Rochester in the United States.
| Milestone | Aggressive Antipyretics (AA) | Usual Care (UC). |
|---|---|---|
| Started | 128 | 128 |
| Completed | 128 | 128 |
| Not completed | 0 | 0 |
Mean maximum temperature (Tmax). Tmax will be defined as the highest temperature during the study duration (72 hours) in degrees Celsius recorded by a continuous temperature monitor. The continuous temperature monitors are not magnetic resonance imaging (MRI) compatible. If TMAX is a clinical temperature obtained when continuous monitoring data is not available, the clinical TMAX will be used as the primary outcome.
| degrees of Celsius | Aggressive Antipyretics (AA) | Usual Care (UC). |
|---|---|---|
| Mean Maximum Temperature | 38.6 (38.4 to 38.7) | 39.2 (39.1 to 39.3) |
Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome.
| Participants | Aggressive Antipyretics (AA) | Usual Care (UC). |
|---|---|---|
| None | 107 | 88 |
| Single and brief | 10 | 6 |
| Multiple or Prolonged | 10 | 34 |
Parasite clearance was based upon AUC for plasma HRP2 concentration every six hours
| ng*hr/mL | Aggressive Antipyretics (AA) | Usual Care (UC). |
|---|---|---|
| Parasite Clearance | 86.3 (78.2 to 94.4) | 80 (71.5 to 88.4) |
AUC fever for temperatures above 37.5 degrees Celsius based upon continuous temperature monitoring A secondary efficacy measure included fever exposure as measured by the area under the temperature × time curve for T≥38.5°C during the 72-hour follow-up period, categorized as 0, \> 0 and \< 2, and ≥ 2 degree-hours. An ordinal logistic regression model assuming proportional odds with terms for treatment group, country, and disease severity as covariates was used to derive the estimated adjusted treatment group odds ratio and associated 95% confidence interval. Sensitivity analyses with best-case and worst-case imputation were performed to accommodate missing data for the 12 participants with insufficient temperature data to determine the proper outcome category
| Participants | Aggressive Antipyretics (AA) | Usual Care (UC). |
|---|---|---|
| 0 | 67 | 37 |
| > 0 and < 2 | 47 | 54 |
| ≥ 2 | 14 | 37 |
Collected over 72 hours. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Aggressive Antipyretics (AA) | 3/128 (2.3%) | 15/128 (11.7%) | 102/128 (79.7%) |
| Usual Care (UC). | 10/128 (7.8%) | 25/128 (19.5%) | 87/128 (68%) |
| Event | Aggressive Antipyretics (AA) | Usual Care (UC). |
|---|---|---|
| DeathGeneral disorders | 3/128 | 10/128 |
| Neurologic deficits at dischargeNervous system disorders | 9/128 | 10/128 |
| Creatinine increaseRenal and urinary disorders | 3/128 | 0/128 |
| Any bleedingVascular disorders | 0/128 | 1/128 |
| Clinical signs of bleedingVascular disorders | 0/128 | 1/128 |
| ShockGeneral disorders | 0/128 | 1/128 |
| Shock with necrotic digitsVascular disorders | 0/128 | 1/128 |
| Status epilepticus and prolonged apneaNervous system disorders | 0/128 | 1/128 |
| Event | Aggressive Antipyretics (AA) | Usual Care (UC). |
|---|---|---|
| HyperbilirubinemiaHepatobiliary disorders | 64/128 | 66/128 |
| Creatinine increaseRenal and urinary disorders | 61/128 | 48/128 |
| Elevated lactateMetabolism and nutrition disorders | 12/128 | 19/128 |
| Any bleedingVascular disorders | 17/128 | 9/128 |
| Bleeding occultBlood and lymphatic system disorders | 12/128 | 7/128 |
| VomitingGeneral disorders | 10/128 | 9/128 |
| Clinical signs of bleedingVascular disorders | 5/128 | 2/128 |
| HypoglycemiaMetabolism and nutrition disorders | 0/128 | 3/128 |
| DiarrheaGastrointestinal disorders | 1/128 | 2/128 |
| Fell from bedGeneral disorders | 2/128 | 2/128 |
Eligible children were 24-132 months of age with evidence of P. falciparum infection, based upon a thick peripheral blood smear or rapid diagnostic test, and symptoms of CNS malaria including complicated seizures (multiple seizures, focal seizures or prolonged seizures lasting more than 15 minutes) or impaired consciousness
| Age, Continuous(years) | Aggressive Antipyretics (AA) | Usual Care (UC). | Total |
|---|---|---|---|
| Median | 4.4 (2.9 to 6.6) | 3.8 (2.8 to 5.1) | 4.1 (2.9 to 5.9) |
| Sex: Female, Male(Participants) | Aggressive Antipyretics (AA) | Usual Care (UC). | Total |
|---|---|---|---|
| Female | 59 | 56 | 115 |
| Male | 69 | 72 | 141 |
| Race (NIH/OMB)(Participants) | Aggressive Antipyretics (AA) | Usual Care (UC). | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 128 | 128 | 256 |
| White | 0 | 0 | 0 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(Participants) | Aggressive Antipyretics (AA) | Usual Care (UC). | Total |
|---|---|---|---|
| Malawi | 74 | 72 | 146 |
| Zambia | 54 | 56 | 110 |
| Weight(units on a scale - kg) | Aggressive Antipyretics (AA) | Usual Care (UC). | Total |
|---|---|---|---|
| Mean | 15.1 ± 4.4 | 14.0 ± 3.2 | 14.6 ± 3.8 |
| Admission temperature(degrees of Celsius (°C)) | Aggressive Antipyretics (AA) | Usual Care (UC). | Total |
|---|---|---|---|
| Mean | 38.1 ± 1.3 | 38.1 ± 1.3 | 38.1 ± 1.3 |
| Cerebral malaria(Participants) | Aggressive Antipyretics (AA) | Usual Care (UC). | Total |
|---|---|---|---|
| Count of participants | 83 | 72 | 155 |
| Blantyre Coma Score(Participants) | Aggressive Antipyretics (AA) | Usual Care (UC). | Total |
|---|---|---|---|
| 0 | 2 | 6 | 8 |
| 1 | 22 | 27 | 49 |
| 2 | 48 | 50 | 98 |
| 3 | 21 | 16 | 37 |
| 4 | 12 | 11 | 23 |
| 5 | 23 | 18 | 41 |
8 further baseline measures are reported on the registry.
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from Jan 2019 to primary completion in Dec 2022, 46 months.
Results were first posted in Mar 2024, 1 year 3 months after primary completion. A results delay was requested in Jun 2023.
Of 39 phase 2 interventional studies under Malaria, half reached primary completion within 16 months of starting (the median), counting those still running; a quarter within 10 and three quarters within 27. This study's 46 months is above that.
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Studies of the drugs tested here: Acetaminophen · Ibuprofen