Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex

Study Overview
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Brief Summary
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Study design is a Phase IIb prospective multi-center, randomized, placebo-controlled, double-blind clinical trial. The goal will be to enroll 80 infants with Tuberous Sclerosis Complex who are less than 6 months of age prior to the onset of their first seizure

Detailed Description
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The central hypothesis of this Phase IIb trial is that early identification of electroencephalography (EEG) biomarkers and early treatment versus delayed treatment with vigabatrin in infants with tuberous sclerosis complex (TSC) will have a positive impact on developmental outcomes at 24 months of age. It would also prevent or lower the risk of developing infantile spasms and refractory seizures. This preventative approach would be expected to result in more favorable long-term cognitive, behavioral, developmental and psychiatric outcomes and significantly improve overall quality of life. It is a randomized, double-blind, placebo-controlled clinical trial design. Successful completion of this trial will also advance the field by demonstrating the value of systematic surveillance with EEG in asymptomatic infants with TSC.

Official Title
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Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex (PREVeNT Trial) A Randomized, Double-blind, Placebo-controlled Seizure Prevention Clinical Trial for Infants With TSC

Conditions
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Tuberous Sclerosis Complex

Intervention / Treatment
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* Drug: Vigabatrin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: less than or equal to 6 months of age No history of seizures or infantile spasms, or evidence of subclinical electrographic seizures on a previous video EEG Meet genetic or clinical diagnostic criteria for TSC, the latter based on current recommendations for diagnostic evaluation, such as physical exam, neuroimaging, echocardiogram Exclusion Criteria: Is greater than 6 months of age Has not been diagnosed with TSC History of seizures or infantile spasms, or evidence of subclinical electrographic seizures on a previous video EEG Has received any anticonvulsant medication including vigabatrin, other anti-seizure therapeutic agent including cannabidiol Has received an oral mTOR inhibitor such as everolimus or sirolimus Has taken an investigational drug, including but not limited to cannabidiol, as part of a research study 30 days prior to enrollment, or plans on taking an investigational drug at any time during the duration of the study Is currently enrolled, or plans on enrolling at any time during the duration of the study, in an experimental behavioral early intervention study Has a history of being born prematurely (born less than <30 weeks gestation at the time of delivery)

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vigabatrin or Placebo<br>Vigabatrin or Placebo is given for administration, the entire content of one sachet (500 mg active drug) is dissolved in 10 ml water for oral administration that is dosed according to body weight 50-150 mg/kg/day divided BID. Dosing will follow established recommended guidelines (50 mg/kg/day and increased as needed by 50 mg/kg/day every 3 days up to a maximum dose of 150 mg/kg/day, divided BID). | Drug: Vigabatrin<br>* Subjects randomized to vigabatrin in Arm A will be treated with vigabatrin 100mg/kg/day until 24 months of age or until they show evidence of clinical seizures or electrographic seizures on video EEG. If electrographic or clinical seizures occur while on study drug, they will transition into the Open label phase of the study (Arm B) and continue to be followed until 36 months of age.<br>* Other names: Sabril;Drug: Placebo<br>* Subjects randomized to placebo in Arm A will be treated with matching placebo at 100mg/kg/day until 24 months of age or until they show evidence of clinical seizures or electrographic seizures on video EEG. If electrographic or clinical seizures occur while on study drug, they will transition into the Open label phase of the study (Arm B) and continue to be followed until 36 months of age.<br>|
| Other: Vigabatrin<br>Vigabatrin open label is given for administration, the entire content of one sachet (500 mg active drug) is dissolved in 10 ml water for oral administration that is dosed according to body weight 50-150 mg/kg/day divided BID. Dosing will follow established recommended guidelines (50 mg/kg/day and increased as needed by 50 mg/kg/day every 3 days up to a maximum dose of 150 mg/kg/day, divided BID). | Drug: Vigabatrin<br>* Subjects randomized to vigabatrin in Arm A will be treated with vigabatrin 100mg/kg/day until 24 months of age or until they show evidence of clinical seizures or electrographic seizures on video EEG. If electrographic or clinical seizures occur while on study drug, they will transition into the Open label phase of the study (Arm B) and continue to be followed until 36 months of age.<br>* Other names: Sabril;|
| No Intervention: Control Group<br>Enrolled subjects who never develop EEG abnormalities or clinical seizures | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Assessment Scores and Developmental Impact | The primary outcome measure will be the cognitive assessment scores on the Bayley Scales of Infant and Toddler Development at 24 months. The Bayley Scales of Infant and Toddler Development at 24 months will be used for the data analysis and compare the developmental impact of early versus delayed treatment with vigabatrin. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects that develop seizures when treated with vigabatrin | Evaluate the number of subjects that develop seizures when treated with vigabatrin as a seizure prevention. | 24 months | 
| Time to the Subject's First Clinical Seizure | Time to the subject's first clinical seizure will be measured for both subjects on placebo and vigabatrin. | 24 months | 
| Prevalence of Drug Resistant Epilepsy | The prevalence of drug resistant epilepsy. | 24 months | 
| Evaluate Vineland II Scores and Impact of Early Versus Late Treatment | Evaluate Vineland II scores and the impact of early versus late treatment with vigabatrin at 12, 24, and 36 months. | 12 months, 24 months and 36 months | 
| Evaluate Autism Diagnostic Observation Schedule 2nd Edition (ADOS2) Scores and Impact of Early Versus Late Treatment | Evaluate ADOS2 scores and the impact of early versus late treatment at 24 and 36 months. | 24 months and 36 months | 
| Number of Subjects with Vigabatrin Related Adverse Events and Severe Adverse Events | Number of subjects with vigabatrin related adverse events, severe adverse events as assessed by CTCAE v4.0 and risk evaluation and mitigation strategy (REMS) measures as required by the FDA. | 24 months | 
| EEG Biomarker for Developing Epilepsy | Feasibility of the routine 1 hour video EEG in determining the EEG biomarker for developing epilepsy | 24 months |