Cerebral Malaria, Epilepsy, Seizure
Conditions
Brief summary
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.
Detailed description
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.
Interventions
liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days
DRUGStandard AED
Active comparitor, Standard AED
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
24 Months to 83 Months
Healthy volunteers
No
Inclusion criteria
* Comatose with Blantyre Comas Score ≤ 2 * P. falciparum parasitemia via thick blood film or rapid diagnostic test * Active seizure in past 24 hours
Exclusion criteria
* Serum creatinine \> 2mg/dL * Pre-admission/concomitant treatment with antiretroviral medications for HIV (ARVs), antituberculous treatments(ATTs), or chronic use of any other enzyme-inducing medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Minutes With Seizure on EEG | 72 hours | Comparing LVT to standard AED the number of minutes spent in seizure per cEEG in the 72 hours after treatment allocation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Required Additional AED | 7 days | Additional AEDs required (including for breakthrough seizures in LVT group) during admission for seizure control (yes/no) |
| Mean Time From Admission to BCS >/= 4 | 7 days | 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 |
| Sequelae | 7 days | Neurologic outcome in 3 categories-- 1. Neurologically intact at discharge 2. Neurologic sequelae at discharge--specifically new sensory or motor deficits, ongoing seizures, or behavioral abnormalities based upon a physician examination at discharge 3. Died during admission, never discharged |
Countries
Malawi
Participant flow
Recruitment details
Randomized consecutive, eligible consented children with cerebral malaria during two recruitment periods--January to June 2014 and 2015,
Participants by arm
| Arm | Count |
|---|---|
| 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 | 23 |
| Standard AED Standard AED regimen
Standard AED: Active comparitor, Standard AED | 21 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 5 |
| Overall Study | Death | 1 | 5 |
Baseline characteristics
| Characteristic | Oral Levetiracetam | Standard AED | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 23 Participants | 21 Participants | 44 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 41.4 months STANDARD_DEVIATION 10.6 | 41.8 months STANDARD_DEVIATION 16.7 | 41.6 months STANDARD_DEVIATION 13.7 |
| cerebral malaria retinopathy (present) retinopathy negative | 7 participants | 9 participants | 16 participants |
| cerebral malaria retinopathy (present) retinopathy positive | 16 participants | 12 participants | 28 participants |
| Race/Ethnicity, Customized African | 23 participants | 21 participants | 44 participants |
| Sex: Female, Male Female | 10 Participants | 14 Participants | 24 Participants |
| Sex: Female, Male Male | 13 Participants | 7 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 23 | 18 / 21 |
| serious Total, serious adverse events | 5 / 23 | 8 / 21 |
Outcome results
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.
Time frame: 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Levetiracetam | Minutes With Seizure on EEG | 165.2 minutes with seizure | Standard Deviation 265.9 |
| Comparison Group | Minutes With Seizure on EEG | 464.8 minutes with seizure | Standard Deviation 639.3 |
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
Time frame: 7 days
Population: Comparing mean time to coma resolution in hours among survivors
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Levetiracetam | Mean Time From Admission to BCS >/= 4 | 35.4 hours of coma from admission | Standard Deviation 29 |
| Comparison Group | Mean Time From Admission to BCS >/= 4 | 34.6 hours of coma from admission | Standard Deviation 27.8 |
Secondary
Required Additional AED
Additional AEDs required (including for breakthrough seizures in LVT group) during admission for seizure control (yes/no)
Time frame: 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Levetiracetam | Required Additional AED | 18 Participants requiring additional AEDs |
| Comparison Group | Required Additional AED | 18 Participants requiring additional AEDs |
Secondary
Sequelae
Neurologic outcome in 3 categories-- 1. Neurologically intact at discharge 2. Neurologic sequelae at discharge--specifically new sensory or motor deficits, ongoing seizures, or behavioral abnormalities based upon a physician examination at discharge 3. Died during admission, never discharged
Time frame: 7 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oral Levetiracetam | Sequelae | Died during admission | 1 participants |
| Oral Levetiracetam | Sequelae | Neurologically intact at discharge | 19 participants |
| Oral Levetiracetam | Sequelae | Neurologic sequelae at discharge | 3 participants |
| Comparison Group | Sequelae | Neurologically intact at discharge | 14 participants |
| Comparison Group | Sequelae | Neurologic sequelae at discharge | 2 participants |
| Comparison Group | Sequelae | Died during admission | 5 participants |