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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01713946
Recruitment Status : Completed
First Posted : October 25, 2012
Last Update Posted : February 1, 2018
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:

This study will evaluate the efficacy and safety of two trough-ranges of everolimus given as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures.

The study consists of 4 phases for each patient [Baseline phase: From Screening Week -8 (V1) to randomization visit at Week 0 (V2)], Core phase, from randomization at Week 0 (V2) to Week 18 (V11)], Extension phase from Week 18 (V11) until 48 weeks after the last patient has completed the core phase, and Post Extension Phase.

Condition or disease Intervention/treatment Phase
Tuberous Sclerosis Complex-associated Refractory Seizures Drug: RAD001 Drug: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 370 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : April 29, 2013
Actual Primary Completion Date : October 2, 2015
Actual Study Completion Date : October 25, 2017

Arm Intervention/treatment
Experimental: Everolimus low trough
everolimus titrated to 3 to 7 ng/mL
Drug: RAD001
Other Name: Afinitor, Votubia

Experimental: Everolimus high trough
everolimus titrated to 9 to 15 ng/mL
Drug: RAD001
Other Name: Afinitor, Votubia

Placebo Comparator: Placebo
Drug: Placebo

Primary Outcome Measures :
  1. European Medicine Agency (EMA): Response rate [ Time Frame: Baseline, Week 12 ]
    Response means at least a 50% reduction from baseline in partial-onset seizure frequency

  2. Food & Drug Administration (FDA): Percentage reduction in partial onset seizure frequency [ Time Frame: Baseline, Week 12 ]
    Percentage reduction from baseline in partial onset seizure frequency during maintenance period of the core phase.

Secondary Outcome Measures :
  1. Seizure free rate [ Time Frame: Baseline, Week 6, Week 18 ]
    Seizure free means a 100% reduction in partial onset-seizure frequency

  2. Proportion of patients with at least a 25% reduction in partial onset seizure frequency [ Time Frame: Baseline, Week 6, Week 18 ]
  3. Categorical variable of six levels of reduction from baseline in partial-onset seizure frequency [ Time Frame: Baseline, Week 6 to 18 (during maintenance of core phase) ]
    Six levels of reduction: (≤ -25% (exacerbation); > -25% to < 25% (no change); ≥ 25% to < 50%; ≥ 50% to < 75%; ≥ 75% to < 100%; 100% (seizure-freedom)

  4. Frequency of seizure free days [ Time Frame: Week 6, Week 18 ]
  5. Treatment duration [ Time Frame: Week 0 (randomization), Week 18 ]
    Time from randomization until treatment discontinuation in the Core phase

  6. Overall Quality of Life global scores [ Time Frame: Baseline, Week 18, and End of Treatment (time when patient completes or leaves study. Range from 74 to 142 weeks) ]
    Taken from the 3 age-specific questionnaires

  7. Sub-test scores for neurocognitive, neurodevelopmental, and neurobehavioral tests [ Time Frame: Baseline, 18 weeks (End of Core), Every 6 months during Extension, End of Treatment Extension (time when patient completes or leaves study. Range from 74 to 142 weeks) ]
    Changes in the Vineland Adaptive Behavior Scales-II and the Wechsler Non-Verbal Scale of Ability

  8. Percentage reduction in seizure frequency/frequency of selected adverse events [ Time Frame: Baseline, end of study (if patient completes range from 74 to 142 weeks) ]
  9. Pre-dose concentrations of anti-epileptic drugs (AEDs) alone and post-baseline (AEDs plus everolimus) [ Time Frame: Baseline, Week 3 ]
  10. 50% response rate from Baseline by time interval over the extension phase [ Time Frame: Week 18 (start of Extension), End of Treatment Extension (time when patient completes or leaves study. Range from 74 to 142 weeks) ]
  11. Seizure free days in partial onsent seizure by time interval over the extension phase [ Time Frame: Week 18 (Start of Extension), End of Treatment Extension (time when patient completes or leaves study. Range from 74 to 142 weeks) ]
  12. Frequency of adverse events [ Time Frame: Baseline, End of Treatment Extension (time when patient completes or leaves study. Range from 74 to 142 weeks) ]
  13. Frequency of abnormal laboratory values [ Time Frame: Baseline, End of Treatment Extension (time when patient completes or leaves study. Range from 74 to 142 weeks) ]
  14. Frequency of Columbia Suicide Severity Rating Scale (C-SSRS) outcomes [ Time Frame: Week 8 (screening), End of Treatment Extension (time when patient completes or leaves study. Range from 74 to 142 weeks) ]
  15. Frequency of serious adverve events (SAEs) referring to a positive suicidal evaluation [ Time Frame: Week 8 (Screening), End of Treatment Extension (time when patient completes or leaves study. Range from 74 to 142 weeks) ]

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 inhibitor (sirolimus, temsirolimus, everolimus) within 4 weeks of study entry.

      22. Patients with a known hypersensitivity to everolimus or other rapamycin-analogues (sirolimus, temsirolimus) or to its excipients.

      23. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study 24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.

      25. Patients with a Score of 4 or 5 on the Suicidal Ideation item within 2 years of Screening, or any "yes" on the Suicidal Behavior item of the Columbia-Suicide Severity Rating Scale at Screening or Baseline , who upon follow up with a healthcare professional are found to be severely depressed or suicidal.

      26. Maintenance of a diet consisting of <40 g of carbohydrate per day within 3 months of screening

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01713946

  Show 103 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Novartis Pharmaceuticals Identifier: NCT01713946     History of Changes
Other Study ID Numbers: CRAD001M2304
2011-000860-90 ( EudraCT Number )
First Posted: October 25, 2012    Key Record Dates
Last Update Posted: February 1, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
TSC seizures,
TSC epilepsy,
mTOR inhibitor,

Additional relevant MeSH terms:
Tuberous Sclerosis
Pathologic Processes
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Malformations of Cortical Development, Group I
Malformations of Cortical Development
Nervous System Malformations
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents