Aggressive Antipyretics for Fever Reduction in CNS Malaria

NCT03399318 | Completed Phase 2 Results DMC

• 2 other identifiers: RSRB00067717R01NS102176
• Study Type: interventional
• Target: 256
• Locations: 2 countries
• Sites: 3

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.

Conditions

Malaria; Seizures; Coma; Parasitemia; Hyperpyrexia; Fever

Keywords

HRP2

Outcome Measures

Primary Outcomes (2)

• 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

Secondary Outcomes (2)

• Parasite Clearance

  72 hours

• Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best)

  72 hours

Study Arms (2)

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.

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.

Drug: placebo for acetaminophen; Drug: placebo for ibuprofen

Interventions

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

Also known as: Paracetamol

Aggressive Antipyretics

Ibuprofen DRUG

10 mg/kg Q6 hours for the Aggressive Antipyretic Arm

Also known as: Brufen

Aggressive Antipyretics

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

Also known as: Placebo

Usual Care

placebo for ibuprofen DRUG

placebo for ibuprofen

Also known as: Placebo

Usual Care

Eligibility Criteria

• Age: 2 Years - 11 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Rochester: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (3)

Pediatric Research Ward at Queen Elizabeth Central Hospital

Blantyre, Malawi

Location

Chipata Central Hospital

Chipata, Eastern Province, Zambia

Location

University Teaching Hospital's Lusaka Childrens Hospital

Lusaka, Zambia

Location

Related Publications (2)

• 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.

  PMID: 38857015 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.

  PMID: 36316704 DERIVED

MeSH Terms

Conditions

Malaria; Seizures; Coma; Parasitemia; Hyperthermia; Fever

Interventions

Acetaminophen; Ibuprofen

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Unconsciousness; Consciousness Disorders; Neurobehavioral Manifestations; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Body Temperature Changes; Heat Stress Disorders; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids

Results Point of Contact

• Title: Professor Gretchen L. Birbeck
• Organization: University of Rochester

gretchen_birbeck@urmc.rochester.edu

+ 1(517) 505-0283

Study Officials

• Gretchen L Birbeck, MD

  University of Rochester

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 17, 2017
• First Posted: January 16, 2018
• Study Start: January 7, 2019
• Primary Completion: December 2, 2022
• Study Completion: December 2, 2022
• Last Updated: March 5, 2024
• Results First Posted: March 5, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (2); MA (1)