A 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

• Register: EUCTR
• Last refreshed on: 13 November 2017
• Main ID: EUCTR2011-000860-90-IE
• Date of registration: 10/04/2014
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A 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
• Scientific title: 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
• Date of first enrolment: 05/06/2014
• Target sample size: 355
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-000860-90
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belgium, Canada, Colombia, Denmark, Germany, Greece, Hungary, Ireland, Italy, Japan, Korea, Republic of, Netherlands, Russian Federation, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States

Key inclusion & exclusion criteria

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:
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.
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.
c. Prior or concurrent use of vagal nerve stimulator (VNS) is allowed. If the patient is using VNS, device stimulator parameters must remain constant throughout the study.
d. Prior epilepsy surgery is allowed if performed at least 12 months before study entry.
5. Must be receiving one, two, or three AEDs at a stable dose for at least 4 weeks at the start of the 8-week prospective Baseline phase, remain on the same regimen throughout the Baseline phase, and intend to continue the same regimen throughout the 18-week double blind Core phase (rescue medications are permitted).
6. If female of child bearing potential, documentation of negative pregnancy test at time of informed consent and must use highly effective contraception during the study and for 8 weeks after stopping treatment
7. Sexually active males must use a condom during intercourse while taking study drug, and for 8 weeks after stopping study treatment
8. Hepatic, renal and blood laboratory values within the following range at screening:
a. AST and ALT levels < 2.5 x ULN
b. serum bilirubin <1.5 × ULN (this limit does not apply to patients with an elevated indirect bilirubin, if they have Gilbert’s Syndrome)
c. serum creatinine < 1.5 x ULN
d. hemoglobin = 9 g/dL
e. platelets = 80,000/mm3
f. absolute neutrophil count = 1,000/mm3
9. Written informed consent. Subjects or their legal guardians must have the ability to comprehend the informed consent form and be willing to provide informed consent.
10. Patient or caregiver must be able to reliably record seizures and keep a daily diary and recall adverse events.
Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 72
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
1. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder or drug abuse or current seizures related to an acute medical illness
2. Presence of only non-motor partial seizures (NOT APPLICABLE per Amendment 2)
3. Patients with TSC who have SEGA in need of immediate surgical intervention
4. Patients under 2 years of age with untreated infantile spasms
5. Within 52 weeks prior to study entry, an episode of status epilepticus as defined in the protocol
6. Patients with history of seizure clusters (where individual seizures cannot be accurately counted
according to the judgment of the investigator) occurring within 26 weeks prior to study entry
7. Patients who require rescue medication during the Baseline phase for more than 6 days
8. Patients with non-TSC related progressive encephalopathy
9. Patients who weigh less than 12 kg
10. Patients with coexisting malignancies within the 3 years prior to randomization, except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
11. Patients with any severe and/or uncontrolled medical conditions at randomization such as:
a. Symptomatic congestive heart failure of New York Heart Association Class III or IV, history of left ventricular ejection fraction (LVEF) <50%, QTc interval >460ms, congenital QT syndrome, unstable angina pectoris, myocardial infarction within 6 months of study entry, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
b. Significant symptomatic deterioration of lung function
c. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, malabsorption syndrome or small bowel resection)
d. liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis
e. Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN
f. Active skin, mucosa, ocular or GI disorders of Grade > 1.
g. Active (acute or chronic) or uncontrolled severe infections
h. A known history of HIV seropositivity or other active viral infections
12. Patients with an active, bleeding diathesis
13. Patient with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL OR >7.75 mmol/L AND fasting triglycerides > 2.5 x ULN
14. Patients who have had a major surgery or significant traumatic injury within 4 weeks of study entry.
15. Patients with a prior history of organ transplant
16. Patients receiving more than 3 antiepileptic drugs at any time in the baseline phase or at randomization or who change the dose of the AEDs during 4 weeks before screening or during the baseline period
17. Patients being treated with felbamate, unless treatment has been continuous for = 1 years
18. Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of study entry (including chemotherapy, radiation therapy, antibody based therapy, etc.)
19. Prior treatment with any investigational drug within the preceding 4 weeks prior to study entry.
20. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent at study entry. Topical or inhaled corticosteroids are allowed.
21. Patients who have received prior treatment with a systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus) within 24 months of study entry. Patients who have received prior tr

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Refractory partial-onset seizures associated with tuberous sclerosis complex (TSC)
MedDRA version: 17.1 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]

Intervention(s)

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

Primary Outcome(s)

Primary end point(s): EMA: Response rate
FDA: Percentage reduction in partial onset seizure frequency

Timepoint(s) of evaluation of this end point: Baseline, Week 6 to Week 12 (during maintenance period of core study)

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

Secondary Objective: Please refer to the protocol for all secondary objectives

Secondary Outcome(s)

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)

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

Secondary ID(s)

2011-000860-90-ES

CRAD001M2304

Source(s) of Monetary Support

Novartis Pharma Services AG