Treatment of Nodding Syndrome - A Randomized Blinded Placebo-Controlled Crossover Trial of Oral Pyridoxine and Conventional Anti-Epileptic Therapy, in Northern Uganda — 2012
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Purpose
Nodding Syndrome (NS) is a novel form of epilepsy seen predominantly among children aged 5-15 years and characterized by head nodding, progressively worsening seizures, and cognitive impairment. To date, the cause of NS remains unclear. A recent assessment by the Uganda Ministry of Health (MOH), World Health Organization (WHO), and US CDC conducted in Kitgum District in northern Uganda documented that the nodding episodes themselves resulted from atonic seizures, and that the children also exhibit multiple different seizure types, both clinically and electrographically. The investigation also found that there was significantly greater sero-positivity for onchocerciasis among children with NS compared with control children, and demonstrated low serum concentrations of vitamin B6 (pyridoxine) among both cases and controls. Vitamin B6 is involved in neurotransmission and has been an effective treatment of seizures for certain rare type of epileptic syndrome. Children with nodding syndrome in Kitgum have been episodically treated with multivitamins, ivermectin, and anti-epileptic medications including phenobarbital, phenytoin, carbamazepine, and valproate, but the possible beneficial or harmful effects of any of these medications for nodding syndrome has not been systematically assessed, and reports from parents and guardians about apparent effectiveness are varied.
The investigators propose a randomized blinded four group clinical trial with crossover design to study the effect and response to therapeutic doses of oral pyridoxine (vitamin B6) and treatment with currently used conventional anti-epileptics including phenytoin and sodium valproate, among children with nodding syndrome.
| Condition | Intervention | Phase |
|---|---|---|
|
Nodding Syndrome |
Drug: Pyridoxine Drug: Sodium Valproate Drug: Phenytoin Drug: Placebo |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Treatment of Nodding Syndrome - A Randomized Blinded Placebo-Controlled Crossover Trial of Oral Pyridoxine and Conventional Anti-Epileptic Therapy, in Northern Uganda — 2012 |
- Change in the frequency of observed head nodding and other seizure activity from baseline (which is the frequency at week 1) [ Time Frame: 1 week, 5 weeks, 7 weeks, 12 weeks ] [ Designated as safety issue: No ]Change (Reduction) in frequency of observed head nodding or other seizure activity episodes among children with NS
| Estimated Enrollment: | 80 |
| Study Start Date: | February 2013 |
| Estimated Study Completion Date: | September 2013 |
| Estimated Primary Completion Date: | September 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Pyridoxine (B6)
Oral pyridoxine, 30- 50 mg/kg/day in one daily dose (powder form)for a period of four weeks followed by cross-over to Phenytoin arm for another four weeks
|
Drug: Pyridoxine
Other Name: Vitamin B6
Drug: Phenytoin
|
|
Experimental: Phenytoin
Phenytoin Oral, 5 mg/kg/day in two equally divided doses(powder form)for a period of four weeks and then cross-over to Pyridoxine arm for another four weeks
|
Drug: Pyridoxine
Other Name: Vitamin B6
Drug: Phenytoin
|
|
Experimental: Sodium Valproate
Sodium valproate oral, 10 - 15 mg/kg/day once daily powder form)for a period of four weeks and then cross-over to placebo arm for another four weeks
|
Drug: Sodium Valproate Drug: Placebo |
|
Placebo Comparator: Placebo
Placebo will consist of an inert substance (e.g., gelatin) with an appearance similar to medication in similar dosage as the study arms for a period of 4 weeks and subsequent cross-over to Sodium Valproate arm
|
Drug: Sodium Valproate Drug: Placebo |
Show Detailed Description Eligibility| Ages Eligible for Study: | 5 Years to 17 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria: All children identified at clinic level and/or community level in the study region will be eligible to enter into the study if they meet the following inclusion criteria after completing the screening form (Appendix H):
- Clinical head nodding episodes with or without other types of seizure activity with a frequency of at least 1 per day (7 episodes per week). [The seizures must be frequent enough so that a change/decrease in that frequency is measurable.] Children will be stratified into those with high frequency or observed nodding (with 3 or more episodes daily), and lower frequency events (more than one but fewer than 3 episodes per day reported).
- Plan to remain in the study area/region for at least two months from the time of entry
- Are attended by a care giver who is/are able to understand and give informed consent
- Are at least 5 years old at the time of entry into the study and not more than 17 years
Exclusion Criteria: Children will not be eligible for registration (or will be excluded from the trial if already registered) if they are determined to meet any of the following exclusion criteria when screened initially or at the time of entry into study:
- Have a history of allergic reaction to any anti-epileptic medications
- Have severe acute malnutrition diagnosed based on anthropometric measurements
- Have known or suspected condition in which anti-epileptic medications or pyridoxine treatment is contraindicated
- Because both phenytoin and valproate have been associated with birth defects and adverse events on the developing fetus, pregnancy will be ruled out before inclusion of females reaching menarche. Pregnant females will not be included in the study.
Contacts and Locations| Contact: Sudhir Bunga, MD | 678-314-1380 | sbunga@cdc.gov |
| Contact: James Sejvar, MD | 404-536-4203 | zea3@cdc.gov |
| Uganda | |
| Kitgum Nodding Syndrome Treatment Center, Kitgum General Hospital | Not yet recruiting |
| Kitgum, Uganda | |
| Contact: RICHARD IDRO, MD +256-774274173 ridro1@gmail.com | |
| Contact: SUDHIR BUNGA, MD 678-314-1380 sbunga@cdc.gov | |
| Principal Investigator: SUDHIR BUNGA, MD | |
| Principal Investigator: RICHARD IDRO, MD | |
| Principal Investigator: | Scott Dowell, MD | Centers for Disease Control and Prevention |
| Principal Investigator: | JAMES SEJVAR, MD | Centers for Disease Control and Prevention |
| Principal Investigator: | SUDHIR BUNGA, MD | Centers for Disease Control and Prevention |
| Principal Investigator: | RICHARD IDRO, MD | Ministry of Health, Uganda |
More Information
No publications provided
| Responsible Party: | Centers for Disease Control and Prevention |
| ClinicalTrials.gov Identifier: | NCT01730313 History of Changes |
| Other Study ID Numbers: | CDC-CGH-6318 |
| Study First Received: | November 9, 2012 |
| Last Updated: | November 20, 2012 |
| Health Authority: | United States: Federal Government |
Keywords provided by Centers for Disease Control and Prevention:
|
Nodding syndrome |
Additional relevant MeSH terms:
|
Anticonvulsants Phenytoin Valproic Acid Pyridoxine Vitamin B 6 Pyridoxal Central Nervous System Agents Therapeutic Uses Pharmacologic Actions Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |
GABA Agents Neurotransmitter Agents Physiological Effects of Drugs Antimanic Agents Tranquilizing Agents Central Nervous System Depressants Psychotropic Drugs Vitamin B Complex Vitamins Micronutrients Growth Substances |
ClinicalTrials.gov processed this record on May 21, 2013