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Aggressive Antipyretics for Fever Reduction in CNS Malaria

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03399318
Recruitment Status : Recruiting
First Posted : January 16, 2018
Last Update Posted : June 11, 2020
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Gretchen Birbeck, University of Rochester

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.

Condition or disease Intervention/treatment Phase
Malaria Seizures Coma Parasitemia Hyperpyrexia Drug: Acetaminophen Drug: Ibuprofen Drug: placebo for acetaminophen Drug: placebo for ibuprofen Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 284 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Aggressive Antipyretics in CNS Malaria: A Randomized-Controlled Trial Assessing Antipyretic Efficacy and Parasite Clearance Effects
Actual Study Start Date : July 2, 2018
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fever Malaria

Arm Intervention/treatment
Experimental: Aggressive Antipyretics
regardless of temperature, children allocated to this arm will receive acetaminophen (30mg/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
30 mg/kg load then 15mg/kg
Other Name: Paracetamol

Drug: Ibuprofen
10 mg/kg
Other Name: Brufen

Placebo Comparator: Usual Care
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
placebo for acetaminophen
Other Name: Placebo

Drug: placebo for ibuprofen
placebo for ibuprofen
Other Name: Placebo




Primary Outcome Measures :
  1. 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 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.



Secondary Outcome Measures :
  1. Seizures [ Time Frame: 72 hours ]
    Seizures detected clinically or on daily EEG

  2. Parasite burden [ Time Frame: 72 hours ]
    based upon HRP2 levels and quantitative blood film Q6 hourly until aparasitemic on thick blood smear

  3. Area-under-the-curve of fever [ Time Frame: 72 hours ]
    AUC fever for temperatures above 37.5 degrees Celsius based upon continuous temperature monitoring



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 11 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Evidence of P. falciparum malaria infection by peripheral blood smear or rapid diagnostic test
  • CNS symptoms associated with malaria. CEREBRAL MALARIA: 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 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 medica-tion
  • Any contraindication for nasogastric tube (NGT) placement and/or delivery of enteral medications

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03399318


Contacts
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Contact: Phillip Thesing, DO +260962121455 Phillip_Thesing@urmc.rochester.edu
Contact: Karl B Seydel, MD PhD +265999452989 seydel@msu.edu

Locations
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Malawi
Pediatric Research Ward at Queen Elizabeth Central Hospital Recruiting
Blantyre, Malawi
Contact: Karl B Seydel, MD PhD    +265999452989    seydel@msu.edu   
Contact: Gretchen L Birbeck, MD    +265995008069    gretchen_birbeck@urmc.rochester.edu   
Zambia
Chipata Central Hospital Not yet recruiting
Chipata, Eastern, Zambia
Contact: Suzanna Mwanza, MMED (Peds)    +260 (977) 674471    mwanzasue@yahoo.co.uk   
Contact: Mbinga Mbinga    +260 (977) 480413    dr.mbinga@gmail.com   
University Teaching Hospital's Lusaka Childrens Hospital Recruiting
Lusaka, Zambia
Contact: Phillip Thesing, DO    +260962121455    phillip_thesing@urmc.rochester.edu   
Contact: Gretchen L Birbeck, MD    +260978086957    gretchen_birbeck@urmc.rochester.edu   
Sponsors and Collaborators
University of Rochester
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: Gretchen L Birbeck, MD University of Rochester
  Study Documents (Full-Text)

Documents provided by Gretchen Birbeck, University of Rochester:
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Responsible Party: Gretchen Birbeck, Professor, University of Rochester
ClinicalTrials.gov Identifier: NCT03399318    
Other Study ID Numbers: RSRB00067717
R01NS102176 ( U.S. NIH Grant/Contract )
First Posted: January 16, 2018    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Gretchen Birbeck, University of Rochester:
HRP2
Additional relevant MeSH terms:
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Malaria
Parasitemia
Seizures
Protozoan Infections
Parasitic Diseases
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Acetaminophen
Ibuprofen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action