An MRI Ancillary Study of a Malaria Fever Investigation

Malaria Clinical Trial

— MRIA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05746819
• Other study ID #: RSRB_STUDY00005384
• Secondary ID: R01NS111057
• Status: Completed
• Start date: January 2, 2021
• Est. completion date: March 31, 2024

Study information

• Verified date: April 2024
• Source: University of Rochester
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 181
• Est. completion date: March 31, 2024
• Est. primary completion date: August 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 12 Years

Eligibility

Inclusion criteria

1. All children enrolled in the parent Malaria RCT study are eligible

2. Signed parental consent is required

3. CNS symptoms associated with malaria.

Exclusion criteria

1. Circulatory failure (cold extremities, capillary refill > 3 seconds, sunken eyes, ? skin turgor)

2. Vomiting in the past 2 hours

3. Serum Cr > 1.2 mg/dL

4. A history of liver disease

5. Jaundice or a total bilirubin of >3.0mg/dL

6. A history of gastric ulcers or gastrointestinal bleeding

7. A history of thrombocytopenia or other primary hematologic disorder

8. Petechiae or other clinical indications of bleeding abnormalities

9. A known allergy to ibuprofen, acetaminophen, aspirin or any non-steroidal medication

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

Related Conditions & MeSH terms

• Behavior Problem
• Brain Injuries
• Chronic Kidney Diseases
• Kidney Diseases
• Malaria
• MRI Imaging
• Problem Behavior
• Renal Insufficiency, Chronic

Intervention

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.

Locations

Country	Name	City	State
Malawi	Queen Elizabeth Central Hospital	Blantyre	Southern
Zambia	Chipata Central Hospital	Chipata	Eastern

Sponsors (2)

Lead Sponsor	Collaborator
University of Rochester	National Institute of Neurological Disorders and Stroke (NINDS)

Countries where clinical trial is conducted

Malawi,  Zambia, 

References & Publications (68)

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* Note: There are 68 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Safety assessment: bleeding	Where GRE imaging is available, we will compare presence/absence of evidence of GRE positive findings	at 1-month
Secondary	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