A three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety of two trough-ranges of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures

INTERVENTION: Trade Name: Votubia Product Name: Everolimus Product Code: RAD001 Pharmaceutical Form: Dispersible tablet INN or Proposed INN: everolimus CAS Number: 159351‐69‐6 Current Sponsor code: RAD001 Other descriptive name: EVEROLIMUS Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2‐ Pharmaceutical form of the placebo: Dispersible tablet Route of administration of the placebo: Oral use CONDITION: Refractory partial‐onset seizures associated with tuberous sclerosis complex (TSC) ; MedDRA version: 17.0 Level: PT Classification code 10045138 Term: Tuberous sclerosis System Organ Class: 10010331 ‐ Congenital, familial and genetic disorders Therapeutic area: Diseases [C] ‐ Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] PRIMARY OUTCOME: Main Objective: To compare the reduction in frequency of partial‐onset seizures on each of two trough ranges of everolimus (3‐7 ng/mL and 9‐15 ng/mL) versus placebo in patients with TSC who are taking one to three AEDs Primary end point(s): EMA: Response rate; FDA: Percentage reduction in partial onset seizure frequency Secondary Objective: Please refer to the protocol for all secondary objectives Timepoint(s) of evaluation of this end point: Baseline, Week 6 to Week 12 (during maintenance period of core study) SECONDARY OUTCOME: Secondary end point(s): 1. Seizure free rate ; 2. Proportion of patients with at least a 25% reduction in partial onset seizure frequency ; 3. Categorical variable of six levels of reduction from baseline in partial‐onset seizure frequency ; 4. Frequency of seizure free days ; 5. Treatment duration ; 6. Overall Quality of Life global scores ; 7. Sub‐test scores for neurocognitive, neurodevelopmental, and neurobehavioral tests ; 8. Percentage reduction in seizure frequency/frequency of selected adverse events ; 9. Pre‐dose concentrations of antiepileptic drugs (AEDs) alone and post‐baseline (AEDs plus everolimus) ; 10. 50% response rate from Baseline by time interval over the extension phase ; 11. Seizure free days in partial onsent seizure by time interval over the extension phase ; 12. Frequency of adverse events ; 13. Frequency of abnormal laboratory values ; 14. Frequency of Columbia Suicide Severity Rating Scale (C‐SSRS) outcomes ; 15. Frequency of serious adverve events (SAEs) referring to a positive suicidal evaluation Timepoint(s) of evaluation of this end point: 1&2&4: Week 6 to 18 of treatment (during maintenance of core phase) ; 3.Baseline, Week 6 to 18 (during maintenance of core phase) ; 5.Randomization to Week 18 of treatment ; 6.Baseline, Week 18, End of Treatment* ; 7.Baseline, End of Core (18 weeks), Every 6 months during Extension, End of Treatment Extension* ; 8.Baseline,end of study (if patient completes range from 74 to 142 weeks) ; 9.Baseline,Week 5 ; 10&11:Start of Extension (Week 18) to End of Treatment Extension* ; 12.to 15.:Baseline to End of Treatment Extension* ; ; *(time when patient completes or leaves study.Range from 74 to 142 weeks) INCLUSION CRITERIA: 1. Male or female between the ages of 2 and 65 years (except in Europe where the minimum age will be 1 at the request of the EMA). 2. Clinically definite diagnosis of TSC per modified Gomez criteria 3. Diagnosis of partial‐onset epilepsy according to the classification of the International League Against Epilepsy (1989) and revised in 2009. 4. Uncontrolled partial‐onset seizures; must meet the following: b. Prior history of failure to control partial‐onset seizures despite having been treated with two or more sequential regimens of single or combined antiepileptic drugs. a. At least 16 reported quantifiable partial‐onset seizures over the Baseline period with no continuous 21‐day seizure‐free period between Visit 1 (Screening Visit) and Visit 2 (Randomization visit), as per data captured in daily seizure diaries. c. Prior or concurrent use of vagal nerve stimulator (VNS) is allowed. If the patient is using VNS, device sti