A Placebo-controlled Study of Efficacy & Safety of 2 Trough-ranges of Everolimus as Adjunctive Therapy in Patients With Tuberous Sclerosis Complex (TSC) & Refractory Partial-onset Seizures

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT01713946
• Date of registration: 09/10/2012
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharmaceuticals
• Public title: A Placebo-controlled Study of Efficacy & Safety of 2 Trough-ranges of Everolimus as Adjunctive Therapy in Patients With Tuberous Sclerosis Complex (TSC) & Refractory Partial-onset Seizures EXIST-3
• 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: April 29, 2013
• Target sample size: 366
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01713946
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 3

Countries of recruitment

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

Contacts

• Name: Novartis Pharmaceuticals
• Affiliation: Novartis Pharmaceuticals

Key inclusion & exclusion criteria

Inclusion Criteria:

- 1. Male or female between the ages of 2 and 65 years (except in Europe where minimum
age will be 1).

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:

1. 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.

2. 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.

3. 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.

4. 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 :

1. AST and ALT levels < 2.5 x ULN

2. serum bilirubin <1.5 × ULN (this limit does not apply to patients with an
elevated indirect bilirubin, if they have Gilbert's Syndrome),

3. serum creatinine < 1.5 x ULN

4. hemoglobin = 9 g/dL

5. platelets = 80,000/mm3

6. 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.

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:

1. 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.

2. Significant symptomatic deterioration of lung function

3. 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).

4. liver disease such as cirrhosis, decompensated liver disease, and chronic
hepatitis

5. Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN.

6. Active skin, mucosa, ocular or GI disorders of Grade > 1.

7. Active (acute or chronic) or uncontrolled severe infections.

8. 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 year.

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 treatment with a topical mTOR inhibito


Age minimum: 2 Years
Age maximum: 65 Years
Gender: All

Health Condition(s) or Problem(s) studied

Tuberous Sclerosis Complex-associated Refractory Seizures

Intervention(s)

Drug: open label RAD001 (only used for post-extension phase)

Drug: Placebo

Drug: RAD001

Drug: Antiepileptic drug (1 to 3 only)

Primary Outcome(s)

Core Phase: Food & Drug Administration (FDA): Percentage Change From Baseline in Partial Onset-seizure Frequency [Time Frame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)]

Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate [Time Frame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)]

Secondary Outcome(s)

Core Phase: Changes From Baseline in Number of Seizure-free Days [Time Frame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)]

Core Phase: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes [Time Frame: Baseline, Week 18]

Core Phase: Median Percentage Change From Baseline in Seizure Frequency by Time Normalized Minimum Concentration [Time Frame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)]

Core Phase: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years [Time Frame: Baseline, Week 18]

Long Term Evaluation: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes [Time Frame: During everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years]

Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score [Time Frame: Baseline, 18 weeks]

Core Phase: Change From Baseline in the QOLIE-AD-48 Overall Quality-of-life Score for Patients >=11 to 18 Years [Time Frame: Baseline, Week 18]

Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations [Time Frame: Baseline, Weeks 1 & 3]

Core Phase: Response Rate in Seizure Frequency by Time Normalized Minimum Concentration [Time Frame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)]

Long Term Evaluation: Effect of Everolimus Over Time in the Overall Wechsler Nonverbal Composite Score [Time Frame: Baseline, Weeks 18, 42, 66 and 90]

Core Phase: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years [Time Frame: Baseline, Week 18]

Core Phase: Distribution of Reduction From Baseline in Seizure Frequency [Time Frame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)]

Long Term Evaluation: Percentage Change From Start of Everolimus in Seizure Frequency by Time Window [Time Frame: Baseline (8-week period before start of everolimus), Week 7 to 18, Week 19 to 30, and 12 weeks thereafter up to Week 102]

Percentage of Seizure-free Patients During the Maintenance Period of the Core Phase [Time Frame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)]

Core Phase: Change From Baseline in Wechsler Nonverbal Composite Score [Time Frame: Baseline, Week 18]

Long Term Evaluation: Effect of Everolimus Over Time in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score [Time Frame: Baseline, Weeks 18, 42, 66 and 90]

Core Phase: Probability That a Patient Remains On-treatment up to a Specified Time Point [Time Frame: Week 6, Week 12, Week 18]

Core Phase: Percentage of Patients With at Least a 25% Reduction in Seizure Frequency [Time Frame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)]

Long Term Evaluation: Relationship Between Seizure Frequency and Time-normalized Everolimus Concentration at Trough (Cmin,TN) - Repeated Measures Analysis [Time Frame: During everolimus treatment from start of everolimus up to the end of the extension phase, an average of 1.7 year]

Seizure Free Rates by Time Window [Time Frame: Weeks 18, 30, 42, 54, 66, 78, 90 & 102]

Secondary ID(s)

2011-000860-90

CRAD001M2304

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 07/11/2018
• URL: https://clinicaltrials.gov/ct2/show/results/NCT01713946