Coma, Fever, Hyperpyrexia, Malaria, Parasitemia, Seizures
Conditions
Keywords
HRP2
Brief summary
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.
Detailed description
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.
Interventions
DRUGAcetaminophen
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
DRUGIbuprofen
10 mg/kg Q6 hours for the Aggressive Antipyretic Arm
DRUGplacebo for acetaminophen
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
DRUGplacebo for ibuprofen
placebo for ibuprofen
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Evidence of Plasmodium falciparum malaria infection by peripheral blood smear or rapid diagnostic test * Central nervous system (CNS) symptoms associated with malaria. CEREBRAL MALARIA (CM): Impaired consciousness with a Blantyre Coma Score (BCS)(73) ≤2 in children under 5 years or a Glasgow Coma score (GCS) ≤10 in children ≥5 years OR CNS MALARIA: Complicated seizure(s), meaning prolonged (\>15 minutes), focal or multiple; or impaired consciousness or other evidence of impaired consciousness (confusion, delirium) without frank coma (BCS\>2, GCS =11-14)
Exclusion criteria
* Circulatory failure (cold extremities, capillary refill \> 3 seconds, sunken eyes, ↓ skin turgor) * Vomiting in the past 2 hours * Serum creatinine (Cr) \> 1.2 mg/dL * A history of liver disease * Jaundice or a total bilirubin of \>3.0mg/dL * A history of gastric ulcers or gastrointestinal bleeding * A history of thrombocytopenia or other primary hematologic disorder * Petechiae or other clinical indications of bleeding abnormalities * A known allergy to ibuprofen, acetaminophen, aspirin or any non-steroidal medication * Any contraindication for nasogastric tube (NGT) placement and/or delivery of enteral medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Maximum Temperature | 72 hours | 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. |
| Seizure Severity | 72 hours | Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parasite Clearance | 72 hours | Parasite clearance was based upon AUC for plasma HRP2 concentration every six hours |
| Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best) | 72 hours | 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 |
Countries
Malawi, Zambia
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Aggressive Antipyretics (AA) AA children received a loading dose of acetaminophen (30 mg/kg) followed by 15 mg/kg every 6 hours regardless of clinical temperature for 72 hours. No loading dose was given if an antipyretic had been administered in the past 24 hours. In addition, AA children received ibuprofen 10mg/kg Q6 hours for 72 hours. A cooling fan was added for anyone with persistent fevers. When T≥38.5°C was detected, 15 mg/kg of placebo was added in the AA group. | 128 |
| Usual Care (UC). UC children received 15 mg/kg of acetaminophen as needed every 6 hours for T≥38.5°C based upon clinical axillary temperatures obtained every 2 hours in Malawi and every 6 hours in Zambia. No loading dose was given if an antipyretic had been administered in the past 24 hours. To maintain double-blinding, an initial loading dose of placebo and placebos for acetaminophen and ibuprofen were used in the UC group. | 128 |
| Total | 256 |
Baseline characteristics
| Characteristic | Aggressive Antipyretics (AA) | Total | Usual Care (UC). |
|---|---|---|---|
| Admission temperature | 38.1 degrees of Celsius (°C) STANDARD_DEVIATION 1.3 | 38.1 degrees of Celsius (°C) STANDARD_DEVIATION 1.3 | 38.1 degrees of Celsius (°C) STANDARD_DEVIATION 1.3 |
| Age, Continuous | 4.4 years | 4.1 years | 3.8 years |
| Blantyre Coma Score 0 | 2 Participants | 8 Participants | 6 Participants |
| Blantyre Coma Score 1 | 22 Participants | 49 Participants | 27 Participants |
| Blantyre Coma Score 2 | 48 Participants | 98 Participants | 50 Participants |
| Blantyre Coma Score 3 | 21 Participants | 37 Participants | 16 Participants |
| Blantyre Coma Score 4 | 12 Participants | 23 Participants | 11 Participants |
| Blantyre Coma Score 5 | 23 Participants | 41 Participants | 18 Participants |
| Cerebral malaria | 83 Participants | 155 Participants | 72 Participants |
| Creatinine | 0.64 units on a scale - mg/dL STANDARD_DEVIATION 0.23 | 0.64 units on a scale - mg/dL STANDARD_DEVIATION 0.22 | 0.63 units on a scale - mg/dL STANDARD_DEVIATION 0.2 |
| Had received anticonvulsant | 64 Participants | 133 Participants | 69 Participants |
| Had received antipyretics | 115 participants | 225 participants | 110 participants |
| HIV Positive | 3 Participants | 7 Participants | 4 Participants |
| HRP2-(ng/ml) | 123 ng/ml | 108 ng/ml | 86 ng/ml |
| Packed Cell Volume | 28 percent - % STANDARD_DEVIATION 7 | 29 percent - % STANDARD_DEVIATION 7 | 29 percent - % STANDARD_DEVIATION 7 |
| Quantative parasite count | 3281 parasite per microliter | 2100 parasite per microliter | 1890 parasite per microliter |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 128 Participants | 256 Participants | 128 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Malawi | 74 Participants | 146 Participants | 72 Participants |
| Region of Enrollment Zambia | 54 Participants | 110 Participants | 56 Participants |
| Seizures Multiple or prolonged | 88 participants | 186 participants | 98 participants |
| Seizures None | 23 participants | 43 participants | 20 participants |
| Seizures Single and brief | 16 participants | 26 participants | 10 participants |
| Sex: Female, Male Female | 59 Participants | 115 Participants | 56 Participants |
| Sex: Female, Male Male | 69 Participants | 141 Participants | 72 Participants |
| Weight | 15.1 units on a scale - kg STANDARD_DEVIATION 4.4 | 14.6 units on a scale - kg STANDARD_DEVIATION 3.8 | 14.0 units on a scale - kg STANDARD_DEVIATION 3.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 128 | 10 / 128 |
| other Total, other adverse events | 102 / 128 | 87 / 128 |
| serious Total, serious adverse events | 15 / 128 | 25 / 128 |
Outcome results
Primary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Aggressive Antipyretics (AA) | Mean Maximum Temperature | 38.6 degrees of Celsius |
| Usual Care (UC). | Mean Maximum Temperature | 39.2 degrees of Celsius |
Comparison: The analysis of the primary outcome variable, Tmax, involved fitting an analysis of 206 covariance model with treatment group as the factor of interest, country and disease severity 207 (CM=yes, no) as stratification factors, and admission temperature as a covariate. The estimated 208 treatment effect and associated 95% confidence interval, as well as a t-test for significance of the treatment effect, were derived from this model.p-value: <0.0001t-test, 2 sided
Primary
Seizure Severity
Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome.
Time frame: 72 hours
Population: One research file was lost and these data were not otherwise recoverable
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aggressive Antipyretics (AA) | Seizure Severity | None | 107 Participants |
| Aggressive Antipyretics (AA) | Seizure Severity | Single and brief | 10 Participants |
| Aggressive Antipyretics (AA) | Seizure Severity | Multiple or Prolonged | 10 Participants |
| Usual Care (UC). | Seizure Severity | None | 88 Participants |
| Usual Care (UC). | Seizure Severity | Single and brief | 6 Participants |
| Usual Care (UC). | Seizure Severity | Multiple or Prolonged | 34 Participants |
Comparison: Seizure occurrence defined as a three-level ordinal variable was analyzed using a 223 multinomial logistic regression model because there was evidence that the proportional odds 224 assumption did not hold. This model included treatment group as the factor of interest and 225 country and disease severity as stratification factors. The adjusted treatment group odds ratio, 226 and its associated 95% confidence interval were derived from this model.p-value: <0.0595% CI: [0.03, 0.27]Regression, Logistic
Secondary
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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aggressive Antipyretics (AA) | Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best) | 0 | 67 Participants |
| Aggressive Antipyretics (AA) | Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best) | > 0 and < 2 | 47 Participants |
| Aggressive Antipyretics (AA) | Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best) | ≥ 2 | 14 Participants |
| Usual Care (UC). | Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best) | 0 | 37 Participants |
| Usual Care (UC). | Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best) | > 0 and < 2 | 54 Participants |
| Usual Care (UC). | Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best) | ≥ 2 | 37 Participants |
Comparison: A secondary efficacy measure included fever exposure as measured by the area under 214 the temperature × time curve for T≥38.5°C during the 72-hour follow-up period, categorized as 215 0, \> 0 and \< 2, and ≥ 2 degree-hours.p-value: <0.0595% CI: [0.2, 0.52]Regression, Logistic
Secondary
Parasite Clearance
Parasite clearance was based upon AUC for plasma HRP2 concentration every six hours
Time frame: 72 hours
Population: Exclusion of 38 children with missing data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aggressive Antipyretics (AA) | Parasite Clearance | 86.3 ng*hr/mL |
| Usual Care (UC). | Parasite Clearance | 80 ng*hr/mL |
Comparison: Parasite clearance measured by log10 (HRP2 level) was analyzed with a repeated 228 measures analysis of covariance model (mixed model repeated measures)35 with terms for 229 treatment group, country, disease severity, log10(HRP2 level) at admission, time (treated as a 230 categorical variable), and interaction terms for admission log10(HRP2 level) and time, and for 231 treatment group and time.p-value: <0.0595% CI: [-5.1, 17.7]ANCOVA