Aggressive Antipyretics for Fever Reduction in CNS Malaria

• ClinicalTrials.gov Identifier: NCT03399318
• Recruitment Status: Recruiting
• First Posted: January 16, 2018
• Last Update Posted: June 11, 2020
• Sponsor: University of Rochester
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Gretchen Birbeck, University of Rochester

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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

Contacts and Locations

Contacts

Contact: Phillip Thesing, DO; +260962121455; Phillip_Thesing@urmc.rochester.edu

Contact: Karl B Seydel, MD PhD; +265999452989; seydel@msu.edu

Locations

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

• Principal Investigator: Gretchen L Birbeck, MD; University of Rochester

  Study Documents (Full-Text)

Documents provided by Gretchen Birbeck, University of Rochester:

Informed Consent Form: Zambian consent form  [PDF] February 26, 2019

Study Protocol and Informed Consent Form: Only protocol  [PDF] October 11, 2019

More Information

• 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
• Last Update Posted: June 11, 2020
• Last Verified: June 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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