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

Phase 1

• Conditions: Refractory partial-onset seizures associated with tuberous sclerosis complex (TSC); MedDRA version: 17.0Level: PTClassification code 10045138Term: Tuberous sclerosisSystem Organ Class: 10010331 - Congenital, familial and genetic disorders; Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

• Registration Number: EUCTR2011-000860-90-BE
• Lead Sponsor: ovartis Pharma Services AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2013-06-05
• Last Update Posted: 13 November 2017

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 355

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) yes
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 treat

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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;Primary end point(s): EMA: Response rate<br>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)