Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex

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

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

Study Overview

• Status: Completed
• Conditions: Tuberous Sclerosis Complex
• Intervention / Treatment: Drug: Early Vigabatrin; Drug: Delayed Vigabatrin (Placebo)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Palo Alto, California, United States, 94304
      • Stanford University
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Boston Children's Hospital
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Children's Hospital
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Minnesota Epilepsy Group, PA
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
  • North Carolina
    • Durham, North Carolina, United States, 37710
      • Duke University
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati's Children Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77054
      • University of Texas Health Science Center at Houston
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 6 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. less than or equal to 6 months of age
2. No history of seizures or infantile spasms, or evidence of subclinical electrographic seizures on a previous video EEG
3. 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:

1. Is greater than 6 months of age
2. Has not been diagnosed with TSC
3. History of seizures or infantile spasms, or evidence of subclinical electrographic seizures on a previous video EEG
4. Has received any anticonvulsant medication including vigabatrin, other anti-seizure therapeutic agent including cannabidiol
5. Has received an oral mTOR inhibitor such as everolimus or sirolimus
6. 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
7. Is currently enrolled, or plans on enrolling at any time during the duration of the study, in an experimental behavioral early intervention study
8. Has a history of being born prematurely (born less than <30 weeks gestation at the time of delivery)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Delayed Vigabatrin (Placebo); Randomization will only occur after detection of epileptiform activity on EEG. Participants randomized to this arm will be treated with matching placebo 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 placebo, they will be eligible for Open label vigabatrin. Participants will be followed until 36 months of age.	Drug: Early Vigabatrin; Subjects randomized to vigabatrin 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 and continue to be followed until 36 months of age.; Other Names: Sabril; Drug: Delayed Vigabatrin (Placebo); Subjects randomized to placebo 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 and continue to be followed until 36 months of age.
Experimental: Early Vigabatrin; Randomization will only occur after detection of epileptiform activity on EEG. Participants randomized to this arm will be treated with vigabatrin 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 vigabatrin, they will be eligible for Open label vigabatrin. Participants will be followed until 36 months of age.	Drug: Early Vigabatrin; Subjects randomized to vigabatrin 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 and continue to be followed until 36 months of age.; Other Names: Sabril
No Intervention: Watchful Waiting (Control Group); Enrolled participants in this arm are those who never develop EEG abnormalities or clinical seizures during the length of the study. While all participants who enrolled in the study started in this group, participants were randomized upon development of EEG epileptiform activity. All participants who completed the study without developing EEG epileptiform activity or clinical seizures are reported in this group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Assessment Scores and Developmental Impact	The primary outcome measure will be the standardized Cognitive scale scores on the Bayley Scales of Infant and Toddler Development- Third Edition at 24 months. The Cognitive scale Composite score is a standard score derived from the observed and elicited performance of the child on cognitive assessment tasks, with a mean of 100 and standard deviation of 10. The range for the Cognitive scale Composite score is 55 to 145. The score is calculated using standard procedures available in the manual for this measure. A higher score is considered better performance. The Bayley Scales of Infant and Toddler Development at 24 months will be used for the data analysis and to compare the developmental impact of early versus delayed treatment with vigabatrin.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 That Develop Seizures When Treated With Study Drug During the Randomized Phase of the Study.	Evaluate the number of subjects that develop seizures when treated with vigabatrin or placebo as a seizure prevention.	24 months
Time to the Subject's First Clinical Seizure From Randomization	Time to the subject's first clinical seizure will be measured for both subjects on placebo and vigabatrin.	24 months
Count of Participants With Drug Resistant Epilepsy at 24 Months of Age.	The count of participants with drug resistant epilepsy. Drug resistant epilepsy classified according to International League Against Epilepsy (ILAE) definition, specifically defined as any participant on 2 or more anti-seizure medications experiencing persistent seizures (seizures occurring within 3 months of the 24 month participant visit).	24 months
Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment	The range for the Vineland-II Adaptive Behavior Composite is 20 to 160 The Vineland-II ABC standard score has a mean of 100 and standard deviation of 15, with higher scores indicating better overall adaptive functioning. The ABC standard score is a composite derived from obtained scores on the Communication, Daily Living Skills, Socialization, and Motor Skills domains on the Vineland-II and is calculated according to standardized procedures described in the Vineland-II manual.	12 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. Outcome was determined as the number of participants developing seizures amongst those developing the biomarker (epileptiform activity).	24 months

Collaborators and Investigators

• Sponsor: Martina Bebin
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Martina Bebin, MD, MPA, University of Alabama at Birmingham

Publications and helpful links

General Publications

• van der Poest Clement E, Jansen FE, Braun KPJ, Peters JM. Update on Drug Management of Refractory Epilepsy in Tuberous Sclerosis Complex. Paediatr Drugs. 2020 Feb;22(1):73-84. doi: 10.1007/s40272-019-00376-0.
• Bebin EM, Peters JM, Porter BE, McPherson TO, O'Kelley S, Sahin M, Taub KS, Rajaraman R, Randle SC, McClintock WM, Koenig MK, Frost MD, Northrup HA, Werner K, Nolan DA, Wong M, Krefting JL, Biasini F, Peri K, Cutter G, Krueger DA; PREVeNT Study Group. Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial. Ann Neurol. 2023 Aug 28:10.1002/ana.26778. doi: 10.1002/ana.26778. Online ahead of print.

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Actual): April 26, 2023
• Study Completion (Actual): May 5, 2023

Study Registration Dates

• First Submitted: July 13, 2016
• First Submitted That Met QC Criteria: July 28, 2016
• First Posted (Estimated): July 29, 2016

Study Record Updates

• Last Update Posted (Actual): August 19, 2024
• Last Update Submitted That Met QC Criteria: July 22, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Hamartoma; Neoplasms, Multiple Primary; Epilepsy; Sclerosis; Tuberous Sclerosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; GABA Agents; Anticonvulsants; Vigabatrin
• Other Study ID Numbers: PREVENT (Janssen Biotech Inc.); 1U01NS092595-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data will be shared with National Database for Autism Research (NDAR)