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

NCT01713946 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: CRAD001M23042011-000860-90
• Study Type: interventional
• Target: 366
• Locations: 25 countries
• Sites: 104

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 \[from end of Extension phase to end of study\].

Conditions

Tuberous Sclerosis Complex-associated Refractory Seizures

Keywords

TSC seizures; TSC epilepsy; mTOR inhibitor; RAD001; Everolimus

Outcome Measures

Primary Outcomes (2)

• Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate

  Comparison of response rates in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm. Response means at least a 50% reduction from baseline in partial-onset seizure frequency during the maintenance period of the core phase.

  Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)

• Core Phase: Food & Drug Administration (FDA): Percentage Change From Baseline in Partial Onset-seizure Frequency

  Comparison of median percent change from baseline in weekly seizure frequency in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm during maintenance period of the core phase. Percentage change from baseline in average weekly seizure frequency during the maintenance period of the Core phase (SFcfb) = 100 × (SFB - SFM) ÷ SFB where: SFB is the average weekly seizure frequency in the Baseline phase SFM is the average weekly seizure frequency in the maintenance period of the Core phase A positive percentage change from baseline (SFcfb) means a reduction in seizure frequency whereas a negative percentage change from baseline (SFcfb) means an increase in seizure frequency.

  Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)

Secondary Outcomes (20)

• Percentage of Seizure-free Patients During the Maintenance Period of the Core Phase

  Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)

• Core Phase: Percentage of Patients With at Least a 25% Reduction in Seizure Frequency

  Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)

• Core Phase: Distribution of Reduction From Baseline in Seizure Frequency

  Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)

• Core Phase: Changes From Baseline in Number of Seizure-free Days

  Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)

• Core Phase: Probability That a Patient Remains On-treatment up to a Specified Time Point

  Week 6, Week 12, Week 18

Study Arms (3)

Everolimus LT target of 3 - 7 ng/mL

EXPERIMENTAL

Participants received everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL plus 1 to 3 antiepileptic drugs.

Drug: RAD001; Drug: Antiepileptic drug (1 to 3 only); Drug: open label RAD001 (only used for post-extension phase)

Everolimus HT target of 9 -15 ng/mL

EXPERIMENTAL

Participants received everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL plus 1 to 3 antiepileptic drugs.

Drug: RAD001; Drug: Antiepileptic drug (1 to 3 only); Drug: open label RAD001 (only used for post-extension phase)

Placebo

PLACEBO COMPARATOR

Participants received placebo plus 1 to 3 antiepileptic drugs.

Drug: Placebo; Drug: Antiepileptic drug (1 to 3 only); Drug: open label RAD001 (only used for post-extension phase)

Interventions

RAD001 DRUG

Everolimus tablets for oral suspension (dispersible tablets) were packaged as 2 mg tablets in blister packs and placed in boxes with color-coded labels, color 1 or color 2.

Also known as: everolimus

Everolimus HT target of 9 -15 ng/mL; Everolimus LT target of 3 - 7 ng/mL

Placebo DRUG

Placebo tablets for oral suspension (dispersible tablets) were packaged as 2 mg tablets in blister packs and placed in boxes with color-coded labels, color 1 or color 2.

Placebo

Antiepileptic drug (1 to 3 only) DRUG

no more than any 3 of the listed antiepileptic drugs could be taken with the study drug or placebo. List of allowed antiepileptic drugs were: valporic acid, carbamazepine, clobazam, N-desmethylclobazam, topiramate,TRI477, TRI476, clonazepam, zonisamide, phenobarbital, phenytoin

Everolimus HT target of 9 -15 ng/mL; Everolimus LT target of 3 - 7 ng/mL; Placebo

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

everolimus tablets for oral suspension (dispersible tablets) were packaged as 2 mg tablets in blister backs in boxes with open label design and were taken during the Post-Extension phase, where all the participants, including those who were previously on placebo, took the 2mg tablets.

Also known as: open label everolimus

Everolimus HT target of 9 -15 ng/mL; Everolimus LT target of 3 - 7 ng/mL; Placebo

Eligibility Criteria

• Age: 2 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Male or female between the ages of 2 and 65 years (except in Europe where minimum age will be 1).
• \. 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.
• \. Uncontrolled partial-onset seizures; must meet the following:
• 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.
• 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.
• 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.
• Prior epilepsy surgery is allowed if performed at least 12 months before study entry.
• \. 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).
• \. 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 :
• <!-- -->
• AST and ALT levels \< 2.5 x ULN
• serum bilirubin \<1.5 × ULN (this limit does not apply to patients with an elevated indirect bilirubin, if they have Gilbert's Syndrome),
• serum creatinine \< 1.5 x ULN
• hemoglobin ≥ 9 g/dL
• platelets ≥ 80,000/mm3

You may not qualify if:

• \. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder or drug abuse or current seizures related to an acute medical illness.
• \. 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.
• \. 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.
• \. 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.
• \. Patients with any severe and/or uncontrolled medical conditions at randomization such as:
• 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.
• Significant symptomatic deterioration of lung function
• 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).
• liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis
• Uncontrolled diabetes as defined by fasting serum glucose \> 1.5 × ULN.
• Active skin, mucosa, ocular or GI disorders of Grade \> 1.
• Active (acute or chronic) or uncontrolled severe infections.
• 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.
• \. Patients who have had a major surgery or significant traumatic injury within 4 weeks of study entry.
• \. 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (104)

University of Alabama at Birmingham SC

Birmingham, Alabama, 35294, United States

Location

TGen/APNNA

Phoenix, Arizona, 85012, United States

Location

University of California at Los Angeles SC

Los Angeles, California, 90095, United States

Location

Children's Hospital Oakland SC

Oakland, California, 94609, United States

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Children's Hospital of Orange County SC

Orange, California, 92868-3874, United States

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Rady Children's Hospital SC

San Diego, California, 92123, United States

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Children's Hospital Colorado

Aurora, Colorado, 80045, United States

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Connecticut Childrens Medical Center SC

Hartford, Connecticut, 06106, United States

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University of Chicago SC - 2

Chicago, Illinois, 60637, United States

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Kennedy Krieger Institute SC

Baltimore, Maryland, 21205, United States

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Children's Hospital Boston SC

Boston, Massachusetts, 02115, United States

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Minnesota Epilepsy Group - PA SC

Saint Paul, Minnesota, 55102-2383, United States

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Washington University School of Medicine SC-2

St Louis, Missouri, 63110, United States

Location

Morristown Memorial Hospital SC-2

Morristown, New Jersey, 07962, United States

Location

New York University Medical Center SC-3

New York, New York, 10016, United States

Location

Cincinnati Children's Hospital Medical Center SC

Cincinnati, Ohio, 45229-3039, United States

Location

Oregon Health and Science University SC - 3

Portland, Oregon, 97239, United States

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Children's Hospital of Philadelphia SC

Philadelphia, Pennsylvania, 19104-4399, United States

Location

LeBonheur Childrens Medical Group SC

Memphis, Tennessee, 38103, United States

Location

Texas Scottish Rite Hospital for Children Texas Scottish

Dallas, Texas, 75219, United States

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Texas Children s Hospital SC

Houston, Texas, 77030, United States

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The University of Texas Medical School-Houston SC

Houston, Texas, 77030, United States

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CABA, Buenos Aires, C1428AQK, Argentina

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Córdoba, X5000JJS, Argentina

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Randwick, New South Wales, 2031, Australia

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Parkville, Victoria, 3052, Australia

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Perth, Western Australia, 6840, Australia

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Jette, Brussels Capital, 1090, Belgium

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Brussels, 1070, Belgium

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Brussels, 1200, Belgium

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Ghent, 9000, Belgium

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Leuven, 3000, Belgium

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Vancouver, British Columbia, V6H 3V4, Canada

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Montreal, Quebec, H3T 1C5, Canada

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Cali, Valle del Cauca Department, Colombia

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Bogotá, Colombia

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Medellín, Colombia

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Aarhus, 8000 C, Denmark

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Amiens, 80054, France

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Angers, 49933, France

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Bron, 69677, France

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Lille, 59037, France

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Strasbourg, F-67098, France

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Berlin, 12351, Germany

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Bielefeld, 33617, Germany

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Kehl-Kork, 77694, Germany

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Kiel, 24105, Germany

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Ioannina, GR, 455 00, Greece

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Athens, 15236, Greece

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Budapest, 1145, Hungary

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Kaposvár, 7400, Hungary

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Nyíregyháza, 4400, Hungary

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Dublin, 12, Ireland

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Bari, BA, 70124, Italy

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Bologna, BO, 40133, Italy

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Catania, CT, 95100, Italy

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Genova, GE, 16147, Italy

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Milan, MI, 20142, Italy

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Pavia, PV, 27100, Italy

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Roma, RM, 00161, Italy

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Siena, SI, 53100, Italy

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Okayama, Okayama-ken, 700-8558, Japan

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Izumi, Osaka, 594-1101, Japan

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Suita, Osaka, 565 0871, Japan

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Shizuoka, Shizuoka, 420-8688, Japan

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Setagaya-ku, Tokyo, 157-8535, Japan

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Osaka, 534-0021, Japan

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Guadalajara, Jalisco, 44280, Mexico

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Heeze, 5591 VE, Netherlands

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Rotterdam, 3015 CN, Netherlands

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Utrecht, 3584CX, Netherlands

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Oslo, 0424, Norway

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Warsaw, 04 730, Poland

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Samara, Samara Oblast, 443095, Russia

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Voronezh, Voronezh Oblast, 394024, Russia

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Moscow, 119991, Russia

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Moscow, 127412, Russia

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Seoul, Korea, 03080, South Korea

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Seoul, Korea, 05505, South Korea

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Seoul, Korea, 06351, South Korea

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Seoul, 03722, South Korea

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Seville, Andalusia, 41013, Spain

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Donostia / San Sebastian, Basque Country, 20080, Spain

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Barcelona, Catalonia, 08035, Spain

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Valencia, Valencia, 46026, Spain

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Madrid, 28009, Spain

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Tainan, Taiwan ROC, 70421, Taiwan

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Kaohsiung City, 83301, Taiwan

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Taipei, 10002, Taiwan

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Bangkok, 10330, Thailand

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Bangkok, 10400, Thailand

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Bangkok, 10700, Thailand

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Ankara, 06100, Turkey (Türkiye)

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Ankara, 06500, Turkey (Türkiye)

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Istanbul, 34093, Turkey (Türkiye)

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Birmingham, B15 2WB, United Kingdom

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Buckinghamshire, SL9 0RJ, United Kingdom

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Cambridge, CB2 2QQ, United Kingdom

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Liverpool, L12 2AP, United Kingdom

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London, SW17 0QT, United Kingdom

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London, WC1N 3JH, United Kingdom

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Related Publications (3)

• 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.

  PMID: 30169322 DERIVED

• 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.

  PMID: 27613521 DERIVED

• 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.

  PMID: 25682485 DERIVED

MeSH Terms

Interventions

Everolimus; Anticonvulsants

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Central Nervous System Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Results Point of Contact

• Title: Clinical Disclosure Office
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2012
• First Posted: October 25, 2012
• Study Start: April 29, 2013
• Primary Completion: October 25, 2017
• Study Completion: October 25, 2017
• Last Updated: November 7, 2018
• Results First Posted: November 7, 2018

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will share

Locations

TU (3); HU (3); US (22); BE (5); CA (2); DE (4); JP (6); AU (3); ME (1); GB (8); AR (2); NO (1); PL (1); FR (6); ES (5); CO (3); KR (4); DK (1); IE (1); NL (3); IT (8); RU (4); TH (3); TW (3); GR (2)