Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria
Maneno muhimu
Kikemikali
Maelezo
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 propose to conduct a dose- escalation, 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 will be escalated based upon efficacy and toxicity endpoints with efficacy defined as seizure freedom in 75% of children during the 24 hours post LVT administration. Generally, only ~20% of children admitted with CM and seizures who receive standard AED treatment remain seizure free during the first 24 hours after admission. Safety assessments will include monitoring for problems related to NGT placement and medication delivery, laboratory parameters at 24 hours and 7 days post LVT, and overall case fatality rates. If efficacy endpoints are not met but enteral LVT is otherwise tolerated, LVT doses of ~3 times the standard dose used for other seizure-related conditions will be assessed. Pharmacokinetic (Pk) data on the absorption and elimination of LVT in CM will be obtained since enteral formulations are not typically used in critically ill children and malaria has been shown to impact drug absorption and elimination for some other medications. The safety, feasibility, Pk, optimal dosing and preliminary efficacy data from this proposed work will provide the information needed to determine whether to proceed with a randomized clinical trial of LVT in pediatric CM patients which would include acute seizure control as well as long term neurologic outcomes as critical endpoints. Since enteral LVT is relatively affordable for short-term use and could be feasibly delivered in resource limited settings, this therapy could potentially be scaled up for broad use throughout malaria endemic African countries
Tarehe
| Imethibitishwa Mwisho: | 07/31/2016 |
| Iliyowasilishwa Kwanza: | 07/18/2012 |
| Uandikishaji uliokadiriwa Uliwasilishwa: | 08/05/2012 |
| Iliyotumwa Kwanza: | 08/08/2012 |
| Sasisho la Mwisho Liliwasilishwa: | 08/02/2016 |
| Sasisho la Mwisho Lilichapishwa: | 09/14/2016 |
| Tarehe ya matokeo ya kwanza yaliyowasilishwa: | 08/10/2014 |
| Tarehe ya matokeo ya kwanza ya QC yaliyowasilishwa: | 10/15/2014 |
| Tarehe ya matokeo ya kwanza kuchapishwa: | 10/16/2014 |
| Tarehe halisi ya kuanza kwa masomo: | 12/31/2012 |
| Tarehe ya Kukamilisha Msingi iliyokadiriwa: | 06/30/2013 |
| Tarehe ya Kukamilisha Utafiti: | 06/30/2013 |
Hali au ugonjwa
Uingiliaji / matibabu
Drug: LEVETIRACETAM
Awamu
Vikundi vya Arm
| Mkono | Uingiliaji / matibabu |
|---|---|
| Other: LEVETIRACETAM Open label, dose escalation to optimal dose. | Drug: LEVETIRACETAM liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. If primary outcome is not reached, dose escalation to 150, 225, and 300% standard, as needed, will be conducted. |
Vigezo vya Kustahiki
| Zama zinazostahiki Kujifunza | 2 Years Kwa 2 Years |
| Jinsia Inastahiki Kujifunza | All |
| Hupokea Wajitolea wa Afya | Ndio |
| Vigezo | Inclusion Criteria: - Comatose with Blantyre Comas Score ≤ 3 - P. falciparum parasitemia - Active seizure 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 |
Matokeo
Hatua za Matokeo ya Msingi
1. Freedom From Seizure [24 hours]
Hatua za Matokeo ya Sekondari
1. Toxicity Related to LVT [1 week]
2. Range of Plasma Concentration of LVT Across All Individuals [72 hours]
Hatua Nyingine za Matokeo
1. Number of Participants With Neurologic Sequelae at Discharge [day 7]
2. Number of Subjects With Retinopathy at Enrollment [Upon admission]
3. Number of Subjects Exposed to Phenobarbitone Prior to Enrollment [0 hour]
4. Number of Participants Requiring AED During Admission [7 days]
5. Mean Time to Return to a BCS Score Greater Than or Equal to 4 [7 days]
