Efficacy and Safety of Rapamycin Versus Vigabatrin in the Prevention of Tuberous Sclerosis Complex Symptoms in Infants

This is a two-arm, randomized, double-blind and double-dummy, placebo controlled study to evaluate the efficacy, tolerability, and safety of vigabatrin versus rapamycin as a preventive treatment in infants with TSC. The study consists of 3 phases for each patient: screening, core blinded phase, and open-label follow-up phase. Patients who meet the eligibility criteria will be randomized to receive vigabatrin or rapamycin. The randomization ratio is 1:1. Randomization will be stratified by the sex and the presence of epileptiform activity on baseline videoEEG (video electroencephalography) recording (yes versus no). Approximately 60 infants are planned to be enrolled in the study.

• Vigabatrin (Drug): Vigabatrin in capsules administered orally, initially (between V1 and V2) once daily in the evening,and starting from V2 administered two times daily.
• Rapamycin (Drug): Rapamycin in liquid administered orally, in the morning, every other day or daily depending on the patient's body weight. The starting dose of rapamycin will be calculated according to the body weight of the patient measured at V1.
• Placebo (Drug), also known as Placebo in liquid: Placebo in liquid administered orally, once daily, in the morning. The starting dose of placebo in liquid will be calculated according to the body weight of the patient measured at V1.
• Placebo (Drug), also known as Placebo in granules: Placebo in granules administered orally, initially once daily in the evening,and after reaching the targeted dose administered two times daily.

Primary outcomes

• Occurrence of clinical seizures in the blinded phase of the study, [730 days]
• Summarized volume of TSC-associated tumors ≥ 125% of initial value within the blinded phase of the study [730 days]

Secondary outcomes

• Total volume of TSC-associated tumors within the blinded phase and the whole study [730 days]
• The risk for high risk of autism assessed with psychological test at 6, 12, 18, 24 months [6, 12, 18, 24 months]
• The risk for low developmental quotient (< 70 points in Bayley Scales of Infant Development, measured at the end of the blinded phase and at the end of the entire study) at the end of the study [730 days]
• The risk of drug-resistant epilepsy at any point of the study [730 days]
• Occurrence of adverse events within the blinded phase of the study [730 days]
• Number of adverse events across the whole study [730 days]
• Parameters of physical development (weight gain history) across the whole study [730 days]
• Parameters of physical development (height gain history) across the whole study [730 days]

Sex: All, ages: 4 Weeks to 16 Weeks

Inclusion Criteria:

* Male or female aged from 4 up to 16 weeks (44-56 weeks of gestational age) at the day of randomization
* Parents/caregivers are willing to and able to give informed consent form for the participation in the study
* Parents/caregivers are willing to and able to comply with all study requirements
* Definite diagnosis of TSC according to the Consensus criteria (Northrup,2013)
* At least 1 focus of cortical dysplasia disclosed on brain MRI

Exclusion Criteria:

* history of seizures prior to randomization,
* history of antiepileptic treatment,
* history of treatment with mTOR (mammalian Target of Rapamycin) inhibitor,
* gestational age below 44 weeks at the day of randomization,
* body weight lower than 3 kg at the day of randomization,
* SEGA (Subependymal Giant Cell Astrocytoma) or other TSC-associated lesion requiring urgent surgical intervention
* recent surgery within 1 month prior to the randomization
* intercurrent infection at the date of randomization
* known history of HIV seropositivity
* live vaccination within 1 month prior to randomization*
* lack of first TBC and hepatitis B vaccinations
* Any significant clinical, laboratory , ECG or other abnormalities, comorbidity or concomitant treatment which, in the opinion of the investigator, may either put a patient at significant risk associated with the participation in the study or may influence the results of the study.
* Use of an investigational drug within 1 month prior to randomization.

• Katarzyna Kotulska-Jozwiak, Principal investigator, The Children's Memorial Health Institute