An MRI Ancillary Study of a Malaria Fever Investigation (MRIA)

April 11, 2024 updated by: Gretchen Birbeck, University of Rochester

An MRI Ancillary Study of a Malaria Fever Randomized Controlled Trial (RCT)

This study will seek consent from parents of children enrolled in the Malaria FEVER study to obtain neuroimaging and 12-month neuropsychiatric outcomes data and kidney function on their child. The imaging and evaluations for this observational study will occur after the child has recovered from the acute malaria infection and has otherwise completed the RCT intervention and safety evaluations.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Other: Aggressive antipyretics therapy of fever vs usual care in the Malaria RCT study

Detailed Description

Despite eradication efforts, ~400,000 African children sustained brain injuries as a result of CNS malaria in 2016. A higher maximum temperature (Tmax) during the acute malaria infection is an established risk factor for neurologic sequelae and a randomized controlled trial (RCT) of aggressive antipyretic therapy with acetaminophen and ibuprofen conducted in Malawi and Zambia began enrollment in 2019 (R01NS102176). In that clinical trial, the primary outcome was Tmax during the acute infection. However, the antipyretic therapies used in this RCT may offer neuroprotective effects without affecting Tmax--for example, neuroprotection through anti-inflammatory mechanisms. In An MRI Ancillary Study of Malaria FEVER RCT, we propose to use neuroimaging in the context of the RCT to further evaluate the potential neuroprotective effects of aggressive antipyretic therapy for CNS malaria and explore possible mechanisms for these effects. Comparing children allocated to aggressive antipyretic therapy vs. usual care on the prevalence of structural brain abnormalities after recovery from CNS malaria will facilitate the evaluation of non-fever pathways for neuroprotection. Brain MRIs will be obtained in children enrolled in the RCT at 1- and 12-months post recovery. Analyses will be completed comparing the odds of having any structural injury based upon RCT treatment allocation and based upon (Tmax) stratified by treatment allocation to assess changes specifically related to response to therapy in terms of fever reduction. Potential mechanisms of aggressive antipyretic-related injury will be evaluated including assessments for treatment-related CNS bleeds. Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury including in pediatric CNS malaria. Adding this MRI ancillary study to our fever RCT may elucidate mechanisms of treatment-associated injury and allow for early identification of neuroprotection from aggressive antipyretic use that would otherwise require long-term follow-up for cognitive and behavioral assessments. This study will provide critical insights that could inform future neuroprotective studies of malaria that might incorporate imaging to optimize study design. It will also add to our understanding of the long term impact of severe malaria on chronic kidney disease risk in children.

Study Type

Observational

Enrollment (Actual)

181

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Malawi
- Southern
  - Blantyre, Southern, Malawi
    - Queen Elizabeth Central Hospital
Zambia
- Eastern
  - Chipata, Eastern, Zambia
    - Chipata Central Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 12 years (Child)

Accepts Healthy Volunteers

Sampling Method

Non-Probability Sample

Study Population

All children enrolled in the Malaria RCT who survive to discharge are eligible for enrollment.

Description

Inclusion criteria

All children enrolled in the parent Malaria RCT study are eligible
Signed parental consent is required
CNS symptoms associated with malaria.

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 medication
Any contraindication for nasogastric tube (NGT) placement and/or delivery of enteral medications

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI neuroimaging 1a Time Frame: at 1 month	Children in the RCT will undergo brain MRIs at 1 month after their acute malaria illness to check for any structural injury following CNS malaria. Two radiologists, blinded to treatment allocation, will independently review images and identify the presence or absence of any injury (present vs absent) For children who are unable to tolerate imaging, brain injury status will be determined by outcomes from age-specific neurocognitive and behavioral assessments.	at 1 month
MRI neuroimaging 1a Time Frame: at 12 months	Children in the RCT will undergo brain MRIs at 12 months after their acute malaria illness to check for any structural injury following CNS malaria. Two radiologists, blinded to treatment allocation, will independently review images and identify the presence or absence of any injury (present vs absent) For children who are unable to tolerate imaging, brain injury status will be determined by outcomes from age-specific neurocognitive and behavioral assessments.	at 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparing specific abnormalities in the two groups by allocation: Brain atrophy Time Frame: at 1 month post recovery	The Potchen volume score is 1-3 abnormal due to atrophy, 4-5 normal, 6-8 edema. And these are analyzed as three ordinal categories--atrophic, normal or edematous	at 1 month post recovery
Comparing specific abnormalities in the two groups by allocation: Brain atrophy Time Frame: at 12 months post recovery	The Potchen volume score is 1-3 abnormal due to atrophy, 4-5 normal, 6-8 edema. And these are analyzed as three ordinal categories--atrophic, normal or edematous	at 12 months post recovery
Comparing specific abnormalities in the two groups by allocation: Gliosis by Fazekas score Time Frame: 1 month post recovery	Gliosis by Fazekas score, which assesses white matter lesions on brain MRI scans. The scoring is from 0-3, with 0 = no lesion, 1 = mild, 2 = moderate and 3 = severe.	1 month post recovery
Comparing specific abnormalities in the two groups by allocation: Gliosis by Fazekas score Time Frame: 12 month post recovery	Gliosis by Fazekas score, which assesses white matter lesions on brain MRI scans. The scoring is from 0-3, with 0 = no lesion, 1 = mild, 2 = moderate and 3 = severe.	12 month post recovery
Comparing specific abnormalities in the two groups by allocation:The presence or absence of regional gliosis or atrophy in cortical region Time Frame: at 1 month post recovery	Comparing specific abnormalities in the two groups by allocation:The presence of regional gliosis or atrophy in cortical region	at 1 month post recovery
Comparing specific abnormalities in the two groups by allocation:The presence or absence of regional gliosis or atrophy in cortical region Time Frame: at 12 month post recovery	Comparing specific abnormalities in the two groups by allocation:The presence of regional gliosis or atrophy in cortical region	at 12 month post recovery
Comparing specific abnormalities in the two groups by allocation:The presence or absence of regional gliosis or atrophy in deep gray Time Frame: 1 month post recovery	Comparing specific abnormalities in the two groups by allocation:The presence of regional gliosis or atrophy in deep gray	1 month post recovery
Comparing specific abnormalities in the two groups by allocation:The presence or absence of regional gliosis or atrophy in deep gray Time Frame: 12 months post recovery	Comparing specific abnormalities in the two groups by allocation:The presence or absence of regional gliosis or atrophy in deep gray	12 months post recovery
Comparing specific abnormalities in the two groups by allocation:The presence or absence of regional gliosis or atrophy in corpus callosum Time Frame: 1 month post recovery	Comparing specific abnormalities in the two groups by allocation:The presence of regional gliosis or atrophy in corpus callosum	1 month post recovery
Comparing specific abnormalities in the two groups by allocation:The presence of or absence regional gliosis or atrophy in corpus callosum Time Frame: 12 months post recovery	Comparing specific abnormalities in the two groups by allocation:The presence of regional gliosis or atrophy in corpus callosum	12 months post recovery
Comparing specific abnormalities in the two groups by allocation:The presence or absence of regional gliosis or atrophy in posterior fossa Time Frame: 1 month post recovery	Comparing specific abnormalities in the two groups by allocation:The presence of regional gliosis or atrophy in posterior fossa	1 month post recovery
Comparing specific abnormalities in the two groups by allocation:The presence or absence of regional gliosis or atrophy in posterior fossa Time Frame: at 12 months post recovery	Comparing specific abnormalities in the two groups by allocation:The presence or absence of regional gliosis or atrophy in posterior fossa	at 12 months post recovery
Safety assessment: bleeding Time Frame: at 1-month	Where GRE imaging is available, we will compare presence/absence of evidence of GRE positive findings	at 1-month
Safety assessment: kidney Time Frame: At least 6 months post malaria	Compare incident chronic kidney disease based upon urine albumin:creatinine ratio with a cut off of ACR of 3	At least 6 months post malaria

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Rochester

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

Principal Investigator: Karl B Seydel, PhD, Michigan State University, USA

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 2, 2021

Primary Completion (Actual)

August 31, 2023

Study Completion (Actual)

March 31, 2024

Study Registration Dates

First Submitted

February 16, 2023

First Submitted That Met QC Criteria

February 16, 2023

First Posted (Actual)

February 28, 2023

Study Record Updates

Last Update Posted (Estimated)

April 15, 2024

Last Update Submitted That Met QC Criteria

April 11, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

RSRB_STUDY00005384
R01NS111057 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Research data that documents, supports and validates research findings will be made available after the main findings from the final research data set have been accepted for publication. Such research data will be redacted to prevent the disclosure of personal identifiers.

IPD Sharing Time Frame

1-year after study completion

IPD Sharing Access Criteria

reasonable written request

IPD Sharing Supporting Information Type

STUDY_PROTOCOL
SAP
ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Studies a U.S. FDA-regulated device product

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