Tuberous Sclerosis Complex
Conditions
Brief summary
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
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.
Interventions
DRUGEarly 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.
DRUGDelayed 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.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Martina Bebin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Days to 6 Months
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Assessment Scores and Developmental Impact | 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to the Subject's First Clinical Seizure From Randomization | 24 months | Time to the subject's first clinical seizure will be measured for both subjects on placebo and vigabatrin. |
| Count of Participants With Drug Resistant Epilepsy at 24 Months of Age. | 24 months | 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). |
| Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 12 months, 24 months and 36 months | 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. |
| Number of Subjects That Develop Seizures When Treated With Study Drug During the Randomized Phase of the Study. | 24 months | Evaluate the number of subjects that develop seizures when treated with vigabatrin or placebo as a seizure prevention. |
| Number of Subjects With Vigabatrin Related Adverse Events and Severe Adverse Events | 24 months | 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. |
| EEG Biomarker for Developing Epilepsy | 24 months | 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). |
| Evaluate Autism Diagnostic Observation Schedule 2nd Edition (ADOS2) Scores and Impact of Early Versus Late Treatment | 24 months and 36 months | Evaluate ADOS2 scores and the impact of early versus late treatment at 24 and 36 months. |
Countries
United States
Participant flow
Recruitment details
The PREVeNT clinical trial was conducted at 12 TSC Clinics in the U.S. with the first participant enrolled in December 2016 and last participant enrolled in March 2020. The study enrolled 84 TSC infants who were 6 months of age or younger and met the diagnostic criteria for TSC, with no history of seizures nor evidence of subclinical electrographic seizures on EEG. Participants were excluded if they were born prematurely, received any anti-seizure medication (ASM), or an mTOR inhibitor.
Participants by arm
| Arm | Count |
|---|---|
| Delayed Vigabatrin (Placebo) Study drug (in this case, placebo) is given for administration, the entire content of one sachet (500 mg placebo) 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).
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. | 27 |
| Early Vigabatrin Study drug (in this case, vigabatrin) is given for administration, the entire content of one sachet (500 mg vigabatrin) 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).
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. | 29 |
| 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. | 12 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Enrolled, Pre-randomized Period | Excluded prior to randomization due to discovery of exclusion criteria, e.g. prenatal mTOR inhibitor | 0 | 0 | 12 | 0 |
Baseline characteristics
| Characteristic | Delayed Vigabatrin (Placebo) | Early Vigabatrin | Watchful Waiting (Control Group) | Total |
|---|---|---|---|---|
| Age, Continuous | 1.9 Months STANDARD_DEVIATION 1.3 | 2.3 Months STANDARD_DEVIATION 1.4 | 4.4 Months STANDARD_DEVIATION 2.1 | 2.5 Months STANDARD_DEVIATION 1.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 28 Participants | 10 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 15 Participants | 16 Participants | 3 Participants | 34 Participants |
| Sex: Female, Male Male | 12 Participants | 13 Participants | 9 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 29 | 0 / 27 | 0 / 29 | 0 / 12 | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 4 / 27 | 4 / 29 | 15 / 27 | 17 / 29 | 7 / 12 | 3 / 4 | 3 / 4 |
| serious Total, serious adverse events | 3 / 27 | 2 / 29 | 14 / 27 | 15 / 29 | 1 / 12 | 2 / 4 | 2 / 4 |
Outcome results
Primary
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.
Time frame: 24 months
Population: The analysis population was the intent to treat population. Three participants withdrew prior to 24 months of age, and one participant did not complete the Bayley assessment at 24 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Delayed Vigabatrin (Placebo) | Cognitive Assessment Scores and Developmental Impact | 83.9 score on a scale | Standard Deviation 17.3 |
| Early Vigabatrin | Cognitive Assessment Scores and Developmental Impact | 80.9 score on a scale | Standard Deviation 15.6 |
| Watchful Waiting (Control Group) | Cognitive Assessment Scores and Developmental Impact | 97.3 score on a scale | Standard Deviation 16.9 |
| Watchful Waiting (Open Label Vigabatrin) | Cognitive Assessment Scores and Developmental Impact | 85.0 score on a scale | Standard Deviation 21.6 |
p-value: 0.868195% CI: [-8.5567, 7.2436]Mixed Models Analysis
Secondary
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).
Time frame: 24 months
Population: Three participants in the Delayed Vigabatrin group withdrew prior to age 24 months and could therefore not be classified as has having drug resistant epilepsy or not at age 24 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delayed Vigabatrin (Placebo) | Count of Participants With Drug Resistant Epilepsy at 24 Months of Age. | 14 Participants |
| Early Vigabatrin | Count of Participants With Drug Resistant Epilepsy at 24 Months of Age. | 14 Participants |
p-value: 0.4653Chi-squared
Secondary
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).
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delayed Vigabatrin (Placebo) | EEG Biomarker for Developing Epilepsy | 19 Participants |
| Early Vigabatrin | EEG Biomarker for Developing Epilepsy | 20 Participants |
| Watchful Waiting (Control Group) | EEG Biomarker for Developing Epilepsy | 0 Participants |
| Watchful Waiting (Open Label Vigabatrin) | EEG Biomarker for Developing Epilepsy | 4 Participants |
Secondary
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.
Time frame: 24 months and 36 months
Population: This outcome was not assessed because it required an in-person evaluation that could not be performed while wearing a face mask, which would have invalidated the assessment, and was thus eliminated as an outcome measure at the start of the COVID-19 pandemic.
Secondary
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.
Time frame: 12 months, 24 months and 36 months
Population: The analysis population was the intent to treat population. Three participants withdrew prior to 24 months of age, and 2 withdrew prior to 12 months of age.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Delayed Vigabatrin (Placebo) | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 12 months | 86.9 score on a scale | Standard Deviation 13.1 |
| Delayed Vigabatrin (Placebo) | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 36 months | 86.2 score on a scale | Standard Deviation 17.5 |
| Delayed Vigabatrin (Placebo) | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 24 months | 90.6 score on a scale | Standard Deviation 14.3 |
| Early Vigabatrin | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 12 months | 86.0 score on a scale | Standard Deviation 9.8 |
| Early Vigabatrin | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 36 months | 78.6 score on a scale | Standard Deviation 14 |
| Early Vigabatrin | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 24 months | 84.9 score on a scale | Standard Deviation 11.9 |
| Watchful Waiting (Control Group) | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 24 months | 96.3 score on a scale | Standard Deviation 5.8 |
| Watchful Waiting (Control Group) | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 12 months | 97.8 score on a scale | Standard Deviation 14.2 |
| Watchful Waiting (Control Group) | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 36 months | 93.6 score on a scale | Standard Deviation 8.8 |
| Watchful Waiting (Open Label Vigabatrin) | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 12 months | 86.3 score on a scale | Standard Deviation 7 |
| Watchful Waiting (Open Label Vigabatrin) | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 36 months | 76.8 score on a scale | Standard Deviation 14.4 |
| Watchful Waiting (Open Label Vigabatrin) | Evaluate Vineland II ABC Scores and Impact of Early Versus Late Treatment | 24 months | 85.3 score on a scale | Standard Deviation 10.7 |
p-value: 0.169795% CI: [-10.8346, 1.9562]Mixed Models Analysis
Secondary
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.
Time frame: 24 months
Population: One participant in the Delayed Vigabatrin group withdrew prior to 24 months and prior to the development of any seizures. They were therefore excluded from count endpoints and from cognitive assessments at 24 months, although they were included in time to event analyses (censored at drop-out).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delayed Vigabatrin (Placebo) | Number of Subjects That Develop Seizures When Treated With Study Drug During the Randomized Phase of the Study. | 19 Participants |
| Early Vigabatrin | Number of Subjects That Develop Seizures When Treated With Study Drug During the Randomized Phase of the Study. | 20 Participants |
p-value: 0.7375Chi-squared
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delayed Vigabatrin (Placebo) | Number of Subjects With Vigabatrin Related Adverse Events and Severe Adverse Events | 6 Participants |
| Early Vigabatrin | Number of Subjects With Vigabatrin Related Adverse Events and Severe Adverse Events | 2 Participants |
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Delayed Vigabatrin (Placebo) | Time to the Subject's First Clinical Seizure From Randomization | 2.77 Months from randomization |
| Early Vigabatrin | Time to the Subject's First Clinical Seizure From Randomization | 9.47 Months from randomization |
p-value: 0.117495% CI: [0.309, 1.14]Regression, Cox