Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| R01NS102176 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
Not provided
Not provided
Not provided
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Aggressive Antipyretics | Experimental | 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. |
|
| Usual Care | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acetaminophen | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 72 hours |
| Seizure Severity | Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome. | 72 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Parasite Clearance | Parasite clearance was based upon AUC for plasma HRP2 concentration every six hours | 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 |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Gretchen L Birbeck, MD | University of Rochester | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pediatric Research Ward at Queen Elizabeth Central Hospital | Blantyre | Malawi | ||||
| Chipata Central Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38857015 | Derived | Birbeck GL, Seydel KB, Mwanza S, Tembo D, Chilombe M, Watts A, Ume-Ezeoke I, Mathews M, Patel AA, Mwenechanya M, Pensulo P, McDermott MP. Acetaminophen and Ibuprofen in Pediatric Central Nervous System Malaria: A Randomized Clinical Trial. JAMA Neurol. 2024 Aug 1;81(8):857-865. doi: 10.1001/jamaneurol.2024.1677. | |
| 36316704 | Derived | Tembo D, Mwanza S, Mwaba C, Dallah I, Wa Somwe S, Seydel KB, Birbeck GL. Risk factors for acute kidney injury at presentation among children with CNS malaria: a case control study. Malar J. 2022 Nov 1;21(1):310. doi: 10.1186/s12936-022-04327-y. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | 95% Confidence Interval | degrees of Celsius | 72 hours |
|
72 hours
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | General disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Any bleeding | Vascular disorders | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Professor Gretchen L. Birbeck | University of Rochester | + 1(517) 505-0283 | gretchen_birbeck@urmc.rochester.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 21, 2021 | Jun 14, 2021 | Prot_SAP_003.pdf |
| ICF | No | No | Yes | Informed Consent Form: Zambian Consent Form | Dec 8, 2020 | Jun 14, 2021 | ICF_004.pdf |
| ICF | No | No | Yes | Informed Consent Form: Malawian Consent Form | Dec 8, 2020 | Jun 14, 2021 | ICF_005.pdf |
Not provided
| ID | Term |
|---|---|
| D008288 | Malaria |
| D012640 | Seizures |
| D003128 | Coma |
| D018512 | Parasitemia |
| D000084462 | Hyperthermia |
| D005334 | Fever |
| ID | Term |
|---|---|
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D000096724 | Mosquito-Borne Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| D007052 | Ibuprofen |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Ibuprofen | Drug | 10 mg/kg Q6 hours for the Aggressive Antipyretic Arm |
|
|
| placebo for acetaminophen | Drug | 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 |
|
|
| placebo for ibuprofen | Drug | placebo for ibuprofen |
|
|
| 72 hours |
| Chipata |
| Eastern Province |
| Zambia |
| University Teaching Hospital's Lusaka Childrens Hospital | Lusaka | Zambia |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Weight | Mean | Standard Deviation | units on a scale - kg |
|
| Admission temperature | Mean | Standard Deviation | degrees of Celsius (°C) |
|
| Cerebral malaria | Count of Participants | Participants |
|
| Blantyre Coma Score | BSC is ordinal 0-5 with 0 being worst and 5 being best (i.e. normal) | Count of Participants | Participants |
|
| Seizures | Seizures were captured by bedside convulsion charts and a 30-minute EEG obtained daily until return to consciousness. Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome. | One research file was lost and these data were not otherwise recoverable. | Number | participants |
|
| Had received antipyretics | Number | participants |
|
| Had received anticonvulsant | Count of Participants | Participants |
|
| Quantative parasite count | Quantitative counts are only applicable to participants who had parasite in their blood. Those who were smear negative on enrolment due to rapid antimalairal administration were not included in the analysis. These individuals had their diagnosis confirmed by a rapid diagnostic test | Geometric Mean | Inter-Quartile Range | parasite per microliter |
|
| HRP2-(ng/ml) | Geometric Mean | Inter-Quartile Range | ng/ml |
|
| Packed Cell Volume | The packed cell volume (PCV) is a measurement of the proportion of blood that is made up of cells | Mean | Standard Deviation | percent - % |
|
| Creatinine | Mean | Standard Deviation | units on a scale - mg/dL |
|
| HIV Positive | Count of Participants | Participants |
|
| OG001 | 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. |
|
|
|
| Primary | Seizure Severity | Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome. | One research file was lost and these data were not otherwise recoverable | Posted | Count of Participants | Participants | 72 hours |
|
|
|
|
| Secondary | Parasite Clearance | Parasite clearance was based upon AUC for plasma HRP2 concentration every six hours | Exclusion of 38 children with missing data | Posted | Median | 95% Confidence Interval | ng*hr/mL | 72 hours |
|
|
|
|
| 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 | Posted | Count of Participants | Participants | 72 hours |
|
|
|
|
| 3 |
| 128 |
| 15 |
| 128 |
| 102 |
| 128 |
| EG001 | 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. | 10 | 128 | 25 | 128 | 87 | 128 |
| Any bleeding | Vascular disorders | Systematic Assessment |
|
| Clinical signs of bleeding | Vascular disorders | Systematic Assessment |
|
| Creatinine increase | Renal and urinary disorders | Systematic Assessment |
|
| Neurologic deficits at discharge | Nervous system disorders | Systematic Assessment |
|
| Shock | General disorders | Systematic Assessment |
|
| Shock with necrotic digits | Vascular disorders | Systematic Assessment |
|
| Status epilepticus and prolonged apnea | Nervous system disorders | Systematic Assessment |
|
| Clinical signs of bleeding | Vascular disorders | Systematic Assessment |
|
| Creatinine increase | Renal and urinary disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Elevated lactate | Metabolism and nutrition disorders | Systematic Assessment |
|
| Fell from bed | General disorders | Systematic Assessment |
|
| Hyperbilirubinemia | Hepatobiliary disorders | Systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Misc. lab change | General disorders | Systematic Assessment |
|
| Nasogastric tube injury | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Bleeding occult | Blood and lymphatic system disorders | Systematic Assessment |
|
| Drop in level of consciousness | General disorders | Systematic Assessment | Participant level of consciousness dropped from BCS 5/5 to BCS 4/5. |
|
| Prolonged hospitalization. | Nervous system disorders | Systematic Assessment |
|
| Systemic allergic reaction | General disorders | Systematic Assessment |
|
| Urticaria | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Vomiting | General disorders | Systematic Assessment |
|
Not provided
Not provided
| D000079426 |
| Vector Borne Diseases |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D014474 | Unconsciousness |
| D003244 | Consciousness Disorders |
| D019954 | Neurobehavioral Manifestations |
| D018805 | Sepsis |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D001832 | Body Temperature Changes |
| D018882 | Heat Stress Disorders |
| D014947 | Wounds and Injuries |
| Aniline Compounds |
| D000588 | Amines |
| D010666 | Phenylpropionates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Multiple or Prolonged |
|
The adjusted treatment group difference in mean area 233 under the log10(HRP2 level) × time curve was estimated using appropriate contrasts among the 234 treatment group means over time that quantify this comparison.
| Superiority |
The model included terms for treatment group, country, and disease severity. |
| ≥ 2 |
|
| Superiority |