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)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01713946
First received: October 9, 2012
Last updated: August 7, 2014
Last verified: August 2014
  Purpose

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 3 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)], and Extension phase from Week 18 (V11) until up to 48 weeks after the last patient has completed the core phase.


Condition Intervention Phase
Tuberous Sclerosis Complex-associated Refractory Seizures
Drug: RAD001
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • European Medicine Agency (EMA): Response rate [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
    Response means at least a 50% reduction from baseline in partial-onset seizure frequency

  • Food & Drug Administration (FDA): Percentage reduction in partial onset seizure frequency [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
    Percentage reduction from baseline in partial onset seizure frequency during maintenance period of the core phase.


Secondary Outcome Measures:
  • Seizure free rate [ Time Frame: Baseline, Week 6, Week 18 ] [ Designated as safety issue: No ]
    Seizure free means a 100% reduction in partial onset-seizure frequency

  • Proportion of patients with at least a 25% reduction in partial onset seizure frequency [ Time Frame: Baseline, Week 6, Week 18 ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
    Six levels of reduction: (≤ -25% (exacerbation); > -25% to < 25% (no change); ≥ 25% to < 50%; ≥ 50% to < 75%; ≥ 75% to < 100%; 100% (seizure-freedom)

  • Frequency of seizure free days [ Time Frame: Week 6, Week 18 ] [ Designated as safety issue: No ]
  • Treatment duration [ Time Frame: Week 0 (randomization), Week 18 ] [ Designated as safety issue: No ]
    Time from randomization until treatment discontinuation in the Core phase

  • 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) ] [ Designated as safety issue: Yes ]
    Taken from the 3 age-specific questionnaires

  • 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) ] [ Designated as safety issue: Yes ]
    Changes in the Vineland Adaptive Behavior Scales-II and the Wechsler Non-Verbal Scale of Ability

  • 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) ] [ Designated as safety issue: Yes ]
  • Pre-dose concentrations of anti-epileptic drugs (AEDs) alone and post-baseline (AEDs plus everolimus) [ Time Frame: Baseline, Week 3 ] [ Designated as safety issue: Yes ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • Frequency of adverse events [ Time Frame: Baseline, End of Treatment Extension (time when patient completes or leaves study. Range from 74 to 142 weeks) ] [ Designated as safety issue: Yes ]
  • 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) ] [ Designated as safety issue: Yes ]
  • 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) ] [ Designated as safety issue: Yes ]
  • 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) ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 355
Study Start Date: April 2013
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Placebo
Drug: Placebo

  Eligibility

Ages Eligible for Study:   1 Year to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01713946

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

  Show 138 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01713946     History of Changes
Other Study ID Numbers: CRAD001M2304, 2011-000860-90
Study First Received: October 9, 2012
Last Updated: August 7, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Novartis:
TSC seizures,
TSC epilepsy,
mTOR inhibitor,
RAD001,
Everolimus

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

ClinicalTrials.gov processed this record on September 18, 2014