An MRI Ancillary Study of a Malaria Fever Investigation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Brain Injuries, Malaria, MRI Imaging, Neurocognitive Deficits, Chronic Kidney Diseases, Behavior Problem

Intervention / Treatment
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* Other: Aggressive antipyretics therapy of fever vs usual care in the Malaria RCT study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: Aggressive antipyretics therapy of fever vs usual care in the Malaria RCT study|After clinical trial of the Malaria RCT study, this study will compare children allocated to aggressive antipyretic therapy vs. usual care on the prevalence of structural brain abnormalities after recovery from CNS malaria.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI neuroimaging 1a | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | Where GRE imaging is available, we will compare presence/absence of evidence of GRE positive findings | at 1-month | 
| Safety assessment: kidney | 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 |