MalariaPhase 2NCT03399318
Aggressive Antipyretics for Fever Reduction in CNS Malaria
A Phase 2 study testing Acetaminophen and Ibuprofen in people with Malaria and Seizures, run by University of Rochester at 3 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 to 11 years
- What is being tested?
- Acetaminophen and Ibuprofen
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 256 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 7 Jan 2019to 2 Dec 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 11 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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)
Who cannot join
- 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
Show all 10Show fewer
- 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
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
Zambia2 sites
Chipata Central Hospital
Chipata, Eastern Province
University Teaching Hospital's Lusaka Childrens Hospital
Lusaka
Malawi1 site
Pediatric Research Ward at Queen Elizabeth Central Hospital
Blantyre
About this study
Official title: Aggressive Antipyretics in CNS Malaria: A Randomized-Controlled Trial Assessing Antipyretic Efficacy and Parasite Clearance Effects
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.
Read the 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.
- Conditions
- Malaria, Seizures, Coma, Parasitemia, Hyperpyrexia, Fever
- Being tested
- Acetaminophen, Ibuprofen, placebo for acetaminophen, placebo for ibuprofen
- Keywords
- HRP2
- Medical subject headings
- Malaria, Seizures, Coma, Parasitemia, Hyperthermia, Fever
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AcetaminophenDrug
Also called Paracetamol
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
IbuprofenDrug
Also called Brufen
10 mg/kg Q6 hours for the Aggressive Antipyretic Arm
placebo for acetaminophenDrug
Also called Placebo
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 ibuprofenDrug
Also called Placebo
placebo for ibuprofen
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Acetaminophen; Drug: Ibuprofen |
| 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. Receives: Drug: placebo for acetaminophen; Drug: placebo for ibuprofen |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 72 hours
Seizure Severity
Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome.
Measured: 72 hours
Secondary outcomes (2)
Parasite Clearance
Parasite clearance was based upon AUC for plasma HRP2 concentration every six hours
Measured: 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
Measured: 72 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jan 2018
- Study start7 Jan 2019
- Primary completion2 Dec 2022
- Study completion2 Dec 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 256 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Rochester
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS)
- Responsible party
- Principal investigator, Gretchen Birbeck, University of Rochester
- Investigators
- Gretchen L Birbeck, MD, Principal investigator, University of Rochester
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03399318
- Sponsor's protocol ID
- RSRB00067717
- Other IDs
- R01NS102176
- Status last verified
- Feb 2024
- First submitted
- 17 Oct 2017
- Last updated
- 5 Mar 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 38857015Chilombe MB, Seydel KB, Hammond CA, Mwanza S, Patel AA, Lungu F, Wa Somwe S, Kampondeni S, Potchen MJ, McDermott MP, Birbeck GL. Protocol for a magnetic resonance imaging study of participants in the fever RCT: Does fever control prevent brain injury in malaria? PLoS One. 2024 Apr 19;19(4):e0294823. doi: 10.1371/journal.pone.0294823. eCollection 2024.
PubMed 38640099Tembo 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.
PubMed 36316704
Study at a glance
From the registry record, last updated by the sponsor on 5 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Aggressive Antipyretics in CNS Malaria: A Randomized-Controlled Trial Assessing Antipyretic Efficacy and Parasite Clearance Effects
- ClinicalTrials.gov ID
- NCT03399318
- Acronym / sponsor ID
- RSRB00067717
- Conditions
- Malaria, Seizures, Coma, Parasitemia, Hyperpyrexia, Fever
- Keywords
- HRP2
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 256 participants (actual)
- Lead sponsor
- University of RochesterUniversity, hospital or other
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS)
- Study start
- 7 Jan 2019 (actual)
- Primary completion
- 2 Dec 2022 (actual)
- Study completion
- 2 Dec 2022 (actual)
- First posted
- 16 Jan 2018 (actual)
- Results
- Posted 5 Mar 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Aggressive Antipyretics | Experimental | Drug: Acetaminophen, Drug: Ibuprofenregardless 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 | Drug: placebo for acetaminophen, Drug: placebo for ibuprofenwill 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. |
Who may qualify
- Ages
- 2 to 11 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- 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)
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AcetaminophenAlso: Paracetamol30 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 | Drug | Aggressive Antipyretics |
| IbuprofenAlso: Brufen10 mg/kg Q6 hours for the Aggressive Antipyretic Arm | Drug | Aggressive Antipyretics |
| placebo for acetaminophenAlso: Placeboplacebo 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 | Drug | Usual Care |
| placebo for ibuprofenAlso: Placeboplacebo for ibuprofen | Drug | Usual Care |
Primary outcome
Mean Maximum Temperature
Time frame: 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
Time frame: 72 hours
Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome.
2 secondary outcomes
Parasite Clearance
Time frame: 72 hours
Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best)
Time frame: 72 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Mar 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38857015Birbeck 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.
- Derived from this study: PubMed 38640099Chilombe MB, Seydel KB, Hammond CA, Mwanza S, Patel AA, Lungu F, Wa Somwe S, Kampondeni S, Potchen MJ, McDermott MP, Birbeck GL. Protocol for a magnetic resonance imaging study of participants in the fever RCT: Does fever control prevent brain injury in malaria? PLoS One. 2024 Apr 19;19(4):e0294823. doi: 10.1371/journal.pone.0294823. eCollection 2024.
- Derived from this study: PubMed 36316704Tembo 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gretchen L Birbeck, MD principal investigator
University of Rochester
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Acetaminophen and Ibuprofen in people with Malaria and Seizures, run by University of Rochester at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Zambia, Malawi. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Mar 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean Maximum Temperature (time frame: 72 hours). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03399318, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Mar 2024.