Clinical trial NCT01713946: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberous Sclerosis Complex-associated Refractory Seizures
Keywords: TSC seizures
TSC epilepsy
mTOR inhibitor
RAD001
Everolimus
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-10-25
Enrollment: 366
Sex: ALL
Minimum age (years): 2
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluated the efficacy and safety of two trough-ranges of everolimus given as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who had refractory partial-onset seizures.

The study consisted 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 \[from Week 18 (V11) until 48 weeks after the last patient had completed the core phase\] and Post Extension phase \[from end of Extension phase to end of study\].


Eligibility 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

Primary outcomes:
measure: Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate
timeFrame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
measure: Core Phase: Food & Drug Administration (FDA): Percentage Change From Baseline in Partial Onset-seizure Frequency
timeFrame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Secondary outcomes:
measure: Percentage of Seizure-free Patients During the Maintenance Period of the Core Phase
timeFrame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
measure: Core Phase: Percentage of Patients With at Least a 25% Reduction in Seizure Frequency
timeFrame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
measure: Core Phase: Distribution of Reduction From Baseline in Seizure Frequency
timeFrame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
measure: Core Phase: Changes From Baseline in Number of Seizure-free Days
timeFrame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
measure: Core Phase: Probability That a Patient Remains On-treatment up to a Specified Time Point
timeFrame: Week 6, Week 12, Week 18
measure: Core Phase: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years
timeFrame: Baseline, Week 18
measure: Core Phase: Change From Baseline in the QOLIE-AD-48 Overall Quality-of-life Score for Patients >=11 to 18 Years
timeFrame: Baseline, Week 18
measure: Core Phase: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years
timeFrame: Baseline, Week 18
measure: Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score
timeFrame: Baseline, 18 weeks
measure: Long Term Evaluation: Effect of Everolimus Over Time in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score
timeFrame: Baseline, Weeks 18, 42, 66 and 90
measure: Core Phase: Change From Baseline in Wechsler Nonverbal Composite Score
timeFrame: Baseline, Week 18
measure: Long Term Evaluation: Effect of Everolimus Over Time in the Overall Wechsler Nonverbal Composite Score
timeFrame: Baseline, Weeks 18, 42, 66 and 90
measure: Core Phase: Response Rate in Seizure Frequency by Time Normalized Minimum Concentration
timeFrame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
measure: Core Phase: Median Percentage Change From Baseline in Seizure Frequency by Time Normalized Minimum Concentration
timeFrame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
measure: Long Term Evaluation: Relationship Between Seizure Frequency and Time-normalized Everolimus Concentration at Trough (Cmin,TN) - Repeated Measures Analysis
timeFrame: During everolimus treatment from start of everolimus up to the end of the extension phase, an average of 1.7 year
measure: Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations
timeFrame: Baseline, Weeks 1 & 3
measure: Long Term Evaluation: Percentage Change From Start of Everolimus in Seizure Frequency by Time Window
timeFrame: Baseline (8-week period before start of everolimus), Week 7 to 18, Week 19 to 30, and 12 weeks thereafter up to Week 102
measure: Seizure Free Rates by Time Window
timeFrame: Weeks 18, 30, 42, 54, 66, 78, 90 & 102
measure: Core Phase: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes
timeFrame: Baseline, Week 18
measure: Long Term Evaluation: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes
timeFrame: During everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham SC
state: Alabama
city: Phoenix
country: United States
facility: TGen/APNNA
state: Arizona
city: Los Angeles
country: United States
facility: University of California at Los Angeles SC
state: California
city: Oakland
country: United States
facility: Children's Hospital Oakland SC
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County SC
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital SC
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Hartford
country: United States
facility: Connecticut Childrens Medical Center SC
state: Connecticut
city: Chicago
country: United States
facility: University of Chicago SC - 2
state: Illinois
city: Baltimore
country: United States
facility: Kennedy Krieger Institute SC
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston SC
state: Massachusetts
city: Saint Paul
country: United States
facility: Minnesota Epilepsy Group - PA SC
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine SC-2
state: Missouri
city: Morristown
country: United States
facility: Morristown Memorial Hospital SC-2
state: New Jersey
city: New York
country: United States
facility: New York University Medical Center SC-3
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center SC
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University SC - 3
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia SC
state: Pennsylvania
city: Memphis
country: United States
facility: LeBonheur Childrens Medical Group SC
state: Tennessee
city: Dallas
country: United States
facility: Texas Scottish Rite Hospital for Children Texas Scottish
state: Texas
city: Houston
country: United States
facility: Texas Children s Hospital SC
state: Texas
city: Houston
country: United States
facility: The University of Texas Medical School-Houston SC
state: Texas
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Randwick
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Perth
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Jette
country: Belgium
facility: Novartis Investigative Site
state: Brussel
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Cali
country: Colombia
facility: Novartis Investigative Site
state: Valle Del Cauca
city: Bogotá
country: Colombia
facility: Novartis Investigative Site
city: Medellín
country: Colombia
facility: Novartis Investigative Site
city: Aarhus
country: Denmark
facility: Novartis Investigative Site
city: Amiens Cedex 1
country: France
facility: Novartis Investigative Site
city: Angers cedex 09
country: France
facility: Novartis Investigative Site
city: Bron Cedex
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bielefeld
country: Germany
facility: Novartis Investigative Site
city: Kehl-Kork
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Ioannina
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Kaposvar
country: Hungary
facility: Novartis Investigative Site
city: Nyiregyhaza
country: Hungary
facility: Novartis Investigative Site
city: Dublin
country: Ireland
facility: Novartis Investigative Site
city: Bari
country: Italy
facility: Novartis Investigative Site
state: BA
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Catania
country: Italy
facility: Novartis Investigative Site
state: CT
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Pavia
country: Italy
facility: Novartis Investigative Site
state: PV
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Siena
country: Italy
facility: Novartis Investigative Site
state: SI
city: Okayama-city
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: Izumi-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Suita-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Shizuoka-city
country: Japan
facility: Novartis Investigative Site
state: Shizuoka
city: Setagaya-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Guadalajara
country: Mexico
facility: Novartis Investigative Site
state: Jalisco
city: Heeze
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Samara
country: Russian Federation
facility: Novartis Investigative Site
state: Samara Region
city: Voronezh
country: Russian Federation
facility: Novartis Investigative Site
state: Voronezh Region
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucía
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: San Sebastian
country: Spain
facility: Novartis Investigative Site
state: Pais Vasco
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan ROC
city: Kaohsiung City
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Buckinghamshire
country: United Kingdom
facility: Novartis Investigative Site
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Sheffield
country: United Kingdom
facility: Novartis Investigative Site
city: York
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Curatolo P, Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, de Vries PJ, Dlugos DJ, Fan J, Ridolfi A, Pelov D, Voi M, French JA. Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc Health. 2018 Jul;2(7):495-504. doi: 10.1016/S2352-4642(18)30099-3. Epub 2018 May 24.
citation: French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Berkowitz N, Voi M, Peyrard S, Pelov D, Franz DN. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Oct 29;388(10056):2153-2163. doi: 10.1016/S0140-6736(16)31419-2. Epub 2016 Sep 6.
citation: Goyer I, Dahdah N, Major P. Use of mTOR inhibitor everolimus in three neonates for treatment of tumors associated with tuberous sclerosis complex. Pediatr Neurol. 2015 Apr;52(4):450-3. doi: 10.1016/j.pediatrneurol.2015.01.004. Epub 2015 Jan 14.