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| ID | Type | Description | Link |
|---|---|---|---|
| R01NS074409 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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Pediatric cerebral malaria (CM) affects more than 3 million children each year killing ~20% and leaving one third of survivors with long term neurologic and psychiatric sequelae. Seizures occur commonly with CM and are associated with an increased risk of death and neuropsychiatric disabilities. In this Malawi-based, safety and feasibility study of enteral levetiracetam in pediatric CM, the investigators will lay the groundwork for future efficacy studies aimed at improving seizure control and ultimately decreasing the neurologic morbidity of pediatric CM.
Cerebral malaria (CM) affects ~3 million children each year, primarily in sub-Saharan Africa. Antimalarial medications can rapidly clear P. falciparum parasites, but mortality rates remain high (12-25%). Survivors do not escape unscathed--~30% experience neurologic sequelae including epilepsy, behavioral disorders and gross neurologic deficits. Acute seizures occur commonly in CM and are associated with higher neurologic morbidity and mortality. Seizure management in malaria endemic regions is challenging because the available antiepileptic drugs (AED) induce respiratory suppression and assisted ventilation is unavailable. More optimal seizure control may improve neurologic outcomes in pediatric CM survivors, especially if the medication used is affordable and can be delivered safely and easily in resource limited settings. The investigators conducted a dose- escalation study detailed elsewhere (NCT01660672) to determine the optimal dose for use in this safety and feasibility study of enteral levetiracetam (LVT) for seizure control in children with CM and seizures admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Enteral LVT given via nasogastric tube (NGT) rather than an intravenous (IV) formulation will be used since LVT has excellent enteral bioavailability and IV formations are not affordable in most malaria-endemic regions. LVT 40mg/kg followed by 30mg per kg Q12 hourly. Children admitted with cerebral malaria and seizures will be randomized to LVT vs. standard of care with phenobarbital as needed comparing seizure control, safety, and neurological outcomes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Oral Levetiracetam | Experimental | Oral Levetiracetam administered by NG tube. |
|
| Standard AED | Active Comparator | Standard AED regimen |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Oral Levetiracetam | Drug | liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Minutes With Seizure on EEG | Comparing LVT to standard AED the number of minutes spent in seizure per cEEG in the 72 hours after treatment allocation. | 72 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Required Additional AED | Additional AEDs required (including for breakthrough seizures in LVT group) during admission for seizure control (yes/no) | 7 days |
| Mean Time From Admission to BCS >/= 4 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gretchen L Birbeck, M.D. | University of Rochester | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Queen Elizabeth Central Hospital | Blantyre | 3 | Malawi |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31672143 | Derived | Birbeck GL, Herman ST, Capparelli EV, Dzinjalamala FK, Abdel Baki SG, Mallewa M, Toto NM, Postels DG, Gardiner JC, Taylor TE, Seydel KB. A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria. BMC Pediatr. 2019 Nov 1;19(1):399. doi: 10.1186/s12887-019-1766-2. |
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After the finding have been published, the de-identified study data will be available to other researchers on request pending a review of their plans for using the data.
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Randomized consecutive, eligible consented children with cerebral malaria during two recruitment periods--January to June 2014 and 2015,
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| ID | Title | Description |
|---|---|---|
| FG000 | Oral Levetiracetam | Oral Levetiracetam administered by NG tube. Oral Levetiracetam: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days |
| FG001 | Comparison Group | 2014: Children randomized to routine care who then recieved 20mg/kg phenobarbital with additional doses at the managing clinicians discretion 2015: Children randomized to routine care will phenobarbital given at the discretion of the managing clinician but with a max od 20mg/kg load |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Oral Levetiracetam | Oral Levetiracetam administered by NG tube. Oral Levetiracetam: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days |
| BG001 | Standard AED |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Minutes With Seizure on EEG | Comparing LVT to standard AED the number of minutes spent in seizure per cEEG in the 72 hours after treatment allocation. | Posted | Mean | Standard Deviation | minutes with seizure | 72 hours |
|
1 month post enrollment
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Oral Levetiracetam | Oral Levetiracetam administered by NG tube. Oral Levetiracetam: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| death | Nervous system disorders | Grade 5 | Systematic Assessment | Died with respiratory then cardiac failure as is typical of death in pediatric cerebral malaria |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| myoclonus | Nervous system disorders | Grade 1-5 | Systematic Assessment | myoclonic jerks while fully awake |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Gretchen L. Birbeck | University of Rochester | 585-273-4265 | gretchen_birbeck@urmc.rochester.edu |
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| ID | Term |
|---|---|
| D012640 | Seizures |
| D004827 | Epilepsy |
| D016779 | Malaria, Cerebral |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000077287 | Levetiracetam |
| ID | Term |
|---|---|
| D000081 | Acetamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000085 | Acetates |
| D000144 |
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| Standard AED | Drug | Active comparitor, Standard AED |
|
|
The mean time in hours from admission until the subject reaches Blantyre Coma Scale of greater than or equal to 4. Participants who died are excluded from this analysis.
The Blantyre Coma Score has ranges from 0-5 based upon the a sum of the following 3 domains- Eye movement
1 - Watches or follows 0 - Fails to watch or follow
Best motor response 2 - Localizes painful stimulus 1 - Withdraws limb from painful stimulus 0 - No response or inappropriate response
Best verbal response 2 - Cries appropriately with pain, or, if verbal, speaks
1 - Moan or abnormal cry with pain 0 - No vocal response to pain
| 7 days |
| Sequelae | Neurologic outcome in 3 categories--
| 7 days |
Standard AED regimen
Standard AED: Active comparitor, Standard AED
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | months |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Everyone in this Malawian study population was a black African | Number | participants |
|
| cerebral malaria retinopathy (present) | Number | participants |
|
|
|
| Secondary | Required Additional AED | Additional AEDs required (including for breakthrough seizures in LVT group) during admission for seizure control (yes/no) | Posted | Number | Participants requiring additional AEDs | 7 days |
|
|
|
| Secondary | Mean Time From Admission to BCS >/= 4 | The mean time in hours from admission until the subject reaches Blantyre Coma Scale of greater than or equal to 4. Participants who died are excluded from this analysis. The Blantyre Coma Score has ranges from 0-5 based upon the a sum of the following 3 domains- Eye movement 1 - Watches or follows 0 - Fails to watch or follow Best motor response 2 - Localizes painful stimulus 1 - Withdraws limb from painful stimulus 0 - No response or inappropriate response Best verbal response 2 - Cries appropriately with pain, or, if verbal, speaks 1 - Moan or abnormal cry with pain 0 - No vocal response to pain | Comparing mean time to coma resolution in hours among survivors | Posted | Mean | Standard Deviation | hours of coma from admission | 7 days |
|
|
|
| Secondary | Sequelae | Neurologic outcome in 3 categories--
| Posted | Number | participants | 7 days |
|
|
|
| 5 |
| 23 |
| 15 |
| 23 |
| EG001 | Comparison Group | 2014: Children randomized to routine care who then recieved 20mg/kg phenobarbital with additional doses at the managing clinicians discretion 2015: Children randomized to routine care will phenobarbital given at the discretion of the managing clinician but with a max od 20mg/kg load | 8 | 21 | 18 | 21 |
|
| elevated AST | Hepatobiliary disorders | Grade 1-5 | Systematic Assessment | laboratory assessment at 24 hours, 7 days and 1 month post randomization |
|
| thrombocytopenia | Blood and lymphatic system disorders | Grade 1-5 | Systematic Assessment | Persistent or worsening thrombocytopenia |
|
| hyperkalemia | Metabolism and nutrition disorders | Grade 1-5 | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | Grade 1-5 | Systematic Assessment | Based upon creatinine |
|
| respiratory suppression or aspiration | Respiratory, thoracic and mediastinal disorders | Grade 1-5 | Systematic Assessment |
|
| Anemia (persistent) | Blood and lymphatic system disorders | Grade 1-5 | Systematic Assessment |
|
| elevated ALT | Hepatobiliary disorders | Grade 1-5 | Systematic Assessment | laboratory assessment at 24 hours, 7 days and 1 month post randomization |
|
| elevated alkaline phosphatase | Hepatobiliary disorders | Grade 1-5 | Systematic Assessment | laboratory assessment at 24 hours, 7 days and 1 month post randomization |
|
|
| Anemia with persistent low retics | Blood and lymphatic system disorders | Grade 1-5 | Systematic Assessment | At 30 days post d/c |
|
| Increased AST | Hepatobiliary disorders | Grade 1-5 | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Grade 1-5 | Systematic Assessment |
|
| elevated platelet count | Blood and lymphatic system disorders | Grade 1-5 | Systematic Assessment |
|
| Decreased reticulocyte count | Blood and lymphatic system disorders | Grade 1-5 | Systematic Assessment |
|
| Abnormal ECG | Cardiac disorders | Grade 1-5 | Systematic Assessment |
|
| Excess sedation | Nervous system disorders | Grade 1-5 | Systematic Assessment |
|
| Increased ALT | Hepatobiliary disorders | Grade 1-5 | Systematic Assessment |
|
| Increased alkaline phosphotase | Hepatobiliary disorders | Grade 1-5 | Systematic Assessment |
|
| Increased potassium | Metabolism and nutrition disorders | Grade 1-5 | Systematic Assessment |
|
| Increased chloride | Metabolism and nutrition disorders | Grade 1-5 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Grade 1-5 | Systematic Assessment |
|
| increased phosphate | Metabolism and nutrition disorders | Grade 1-5 | Systematic Assessment |
|
| increased calcium | Metabolism and nutrition disorders | Grade 1-5 | Systematic Assessment |
|
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| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D020808 | Central Nervous System Protozoal Infections |
| D020807 | Central Nervous System Parasitic Infections |
| D002494 | Central Nervous System Infections |
| D007239 | Infections |
| D010272 | Parasitic Diseases |
| D008288 | Malaria |
| D011528 | Protozoan Infections |
| D000096724 | Mosquito-Borne Diseases |
| D000079426 | Vector Borne Diseases |
| Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Died during admission |
|