Tuberous Sclerosis Complex-associated Refractory SeizuresPhase 3EXIST-3NCT01713946
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
A Phase 3 study testing RAD001, Antiepileptic drug (1 to 3 only) and open label RAD001 (only used for post-extension phase) in people with Tuberous Sclerosis Complex-associated Refractory Seizures, run by Novartis Pharmaceuticals at 104 sites in 25 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 to 65 years
- Conditions the study is for
- Tuberous Sclerosis Complex-associated Refractory Seizures
- What is being tested?
- RAD001, Antiepileptic drug (1 to 3 only) and open label RAD001 (only used for post-extension phase)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 366 participants
- Where
- 104 sitesin 25 countries
- Study dates
- 29 Apr 2013to 25 Oct 2017
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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:
- 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.
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- 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 :
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- 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
- 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.
Who cannot join
- 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:
- 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.
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- 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.
- 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
Trial locations and contacts
104 sites in 25 countries.
104 sites in 25 countries
United States22 sites
Children's Hospital Colorado
Aurora, Colorado, 80045
Kennedy Krieger Institute SC
Baltimore, Maryland, 21205
University of Alabama at Birmingham SC
Birmingham, Alabama, 35294
Children's Hospital Boston SC
Boston, Massachusetts, 02115
University of Chicago SC - 2
Chicago, Illinois, 60637
Cincinnati Children's Hospital Medical Center SC
Cincinnati, Ohio, 45229-3039
Texas Scottish Rite Hospital for Children Texas Scottish
Dallas, Texas, 75219
Connecticut Childrens Medical Center SC
Hartford, Connecticut, 06106
Texas Children s Hospital SC
Houston, Texas, 77030
The University of Texas Medical School-Houston SC
Houston, Texas, 77030
University of California at Los Angeles SC
Los Angeles, California, 90095
LeBonheur Childrens Medical Group SC
Memphis, Tennessee, 38103
Morristown Memorial Hospital SC-2
Morristown, New Jersey, 07962
New York University Medical Center SC-3
New York, New York, 10016
Children's Hospital Oakland SC
Oakland, California, 94609
Children's Hospital of Orange County SC
Orange, California, 92868-3874
Children's Hospital of Philadelphia SC
Philadelphia, Pennsylvania, 19104-4399
TGen/APNNA
Phoenix, Arizona, 85012
Oregon Health and Science University SC - 3
Portland, Oregon, 97239
Minnesota Epilepsy Group - PA SC
Saint Paul, Minnesota, 55102-2383
Rady Children's Hospital SC
San Diego, California, 92123
Washington University School of Medicine SC-2
St Louis, Missouri, 63110
Italy8 sites
Novartis Investigative Site
Bari, BA, 70124
Novartis Investigative Site
Bologna, BO, 40133
Novartis Investigative Site
Catania, CT, 95100
Novartis Investigative Site
Genova, GE, 16147
Novartis Investigative Site
Milan, MI, 20142
Novartis Investigative Site
Pavia, PV, 27100
Novartis Investigative Site
Roma, RM, 00161
Novartis Investigative Site
Siena, SI, 53100
United Kingdom8 sites
Novartis Investigative Site
Birmingham, B15 2WB
Novartis Investigative Site
Buckinghamshire, SL9 0RJ
Novartis Investigative Site
Cambridge, CB2 2QQ
Novartis Investigative Site
Liverpool, L12 2AP
Novartis Investigative Site
London, SW17 0QT
Novartis Investigative Site
London, WC1N 3JH
Novartis Investigative Site
Sheffield, S10 2TH
Novartis Investigative Site
York, YO31 7EX
France6 sites
Novartis Investigative Site
Amiens, 80054
Novartis Investigative Site
Angers, 49933
Novartis Investigative Site
Bron, 69677
Novartis Investigative Site
Lille, 59037
Novartis Investigative Site
Marseille, 13385
Novartis Investigative Site
Strasbourg, F-67098
Japan6 sites
Novartis Investigative Site
Izumi, Osaka, 594-1101
Novartis Investigative Site
Okayama, Okayama-ken, 700-8558
Novartis Investigative Site
Osaka, 534-0021
Novartis Investigative Site
Setagaya-ku, Tokyo, 157-8535
Novartis Investigative Site
Shizuoka, Shizuoka, 420-8688
Novartis Investigative Site
Suita, Osaka, 565 0871
Belgium5 sites
Novartis Investigative Site
Brussels, 1070
Novartis Investigative Site
Brussels, 1200
Novartis Investigative Site
Ghent, 9000
Novartis Investigative Site
Jette, Brussels Capital, 1090
Novartis Investigative Site
Leuven, 3000
Spain5 sites
Novartis Investigative Site
Barcelona, Catalonia, 08035
Novartis Investigative Site
Donostia / San Sebastian, Basque Country, 20080
Novartis Investigative Site
Madrid, 28009
Novartis Investigative Site
Seville, Andalusia, 41013
Novartis Investigative Site
Valencia, Valencia, 46026
Germany4 sites
Novartis Investigative Site
Berlin, 12351
Novartis Investigative Site
Bielefeld, 33617
Novartis Investigative Site
Kehl-Kork, 77694
Novartis Investigative Site
Kiel, 24105
Russia4 sites
Novartis Investigative Site
Moscow, 119991
Novartis Investigative Site
Moscow, 127412
Novartis Investigative Site
Samara, Samara Oblast, 443095
Novartis Investigative Site
Voronezh, Voronezh Oblast, 394024
South Korea4 sites
Novartis Investigative Site
Seoul, Korea, 03080
Novartis Investigative Site
Seoul, Korea, 05505
Novartis Investigative Site
Seoul, Korea, 06351
Novartis Investigative Site
Seoul, 03722
Australia3 sites
Novartis Investigative Site
Parkville, Victoria, 3052
Novartis Investigative Site
Perth, Western Australia, 6840
Novartis Investigative Site
Randwick, New South Wales, 2031
Colombia3 sites
Novartis Investigative Site
Bogotá
Novartis Investigative Site
Cali, Valle del Cauca Department
Novartis Investigative Site
Medellín
Hungary3 sites
Novartis Investigative Site
Budapest, 1145
Novartis Investigative Site
Kaposvár, 7400
Novartis Investigative Site
Nyíregyháza, 4400
Netherlands3 sites
Novartis Investigative Site
Heeze, 5591 VE
Novartis Investigative Site
Rotterdam, 3015 CN
Novartis Investigative Site
Utrecht, 3584CX
Taiwan3 sites
Novartis Investigative Site
Kaohsiung City, 83301
Novartis Investigative Site
Tainan, Taiwan ROC, 70421
Novartis Investigative Site
Taipei, 10002
Thailand3 sites
Novartis Investigative Site
Bangkok, 10330
Novartis Investigative Site
Bangkok, 10400
Novartis Investigative Site
Bangkok, 10700
Turkey (Türkiye)3 sites
Novartis Investigative Site
Ankara, 06100
Novartis Investigative Site
Ankara, 06500
Novartis Investigative Site
Istanbul, 34093
Argentina2 sites
Novartis Investigative Site
CABA, Buenos Aires, C1428AQK
Novartis Investigative Site
Córdoba, X5000JJS
Canada2 sites
Novartis Investigative Site
Montreal, Quebec, H3T 1C5
Novartis Investigative Site
Vancouver, British Columbia, V6H 3V4
Greece2 sites
Novartis Investigative Site
Athens, 15236
Novartis Investigative Site
Ioannina, GR, 455 00
About this study
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
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].
- Being tested
- RAD001, Placebo, Antiepileptic drug (1 to 3 only), open label RAD001 (only used for post-extension phase)
- Keywords
- TSC seizures, TSC epilepsy, mTOR inhibitor, RAD001, Everolimus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RAD001Drug
Also called everolimus
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.
PlaceboDrug
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.
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
open label RAD001 (only used for post-extension phase)Drug
Also called open label everolimus
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Placebo; Drug: Antiepileptic drug (1 to 3 only); Drug: open label RAD001 (only used for post-extension phase) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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
Comparison of seizure freedom (100% reduction in 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. Seizure free means a 100% reduction from baseline in partial-onset seizure frequency during maintenance period of the core phase.
Measured: 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
Comparison of percentage of patients with at least ≥ 25% reduction in 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. At least 25% reduction from baseline in partial-onset seizure frequency during maintenance period of the core phase.
Measured: 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
Comparison of percentage of patients in six categories of seizure reduction from baseline (≤ -25% (exacerbation); > -25% to < 25% (no change); ≥ 25% to < 50%; ≥ 50% to < 75%; ≥ 75% to < 100%; 100% (seizure-freedom)) 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
Measured: 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
Comparison of seizure-free days relative to baseline 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
Measured: 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
Comparison of time to treatment discontinuation in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm during the core phase. Treatment duration is defined as the time from randomization until the date of permanent study treatment discontinuation (for any reason) at any time during the Core phase.
The percentage event-free probability estimate is the estimated probability that a patient will remain on-treatment up to a specified time point (Week 6, 12, 18)
Measured: Week 6, Week 12, Week 18
Core Phase: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years
Comparison of quality of life in the everolimus (from 3 age specific questionnaires) low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm at the end of the core phase. The Quality of Life Childhood Epilepsy (QOLCE) questionnaire, used for patients < 11 years at baseline, was completed by the patient's parent or caregiver. It consists of 16 subscales (13 multi-item scales and 3 single item scales) and one overall quality-of-life score. Scores range from 0-100, with higher scores corresponding to improved QoL. The Overall Quality of Life Score is computed by adding each subscale score for each individual and then dividing by 16.
Measured: Baseline, Week 18
Core Phase: Change From Baseline in the QOLIE-AD-48 Overall Quality-of-life Score for Patients >=11 to 18 Years
Comparison of quality of life (from 3 age specific questionnaires) in the everolimus low-trough treatment arm (3-7 ng/mL), hightrough treatment arm (9-15 ng/mL) and placebo arm at the end of the core phase. The Quality of Life in Epilepsy Inventory for Adolescents-48 (QOLIE-AD-48) is a survey of health-related quality of life for adolescents 11 to 18 years of age with epilepsy. The QOLIE-AD-48 is completed by the patient. It contains 48 items which assess 8 subscales. Scores range from 0-100, with higher scores corresponding to improved QoL. The overall quality of life score is obtained by summing a linear combination of the 8 subscale scores, where each subscale is multiplied by a relative weight that is provided in the original publication.
Measured: Baseline, Week 18
Core Phase: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years
Comparison of quality of life (from 3 age specific questionnaires) in the everolimus low-trough treatment arm (3-7 ng/mL), hightrough treatment arm (9-15 ng/mL) and placebo arm at the end of the core phase. The Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-P) is a survey of health-related quality of life for adults with epilepsy. The QOLIE-31-P is completed by the patient. It contains 39 items, of which a total of 30 are used to make up 7 different subscales. Scores range from 0-100, with higher scores indicating a greater level of functioning and QoL. The overall quality of life score is obtained by summing a linear combination of the 7 subscale scores, where each subscale is multiplied by a relative weight that is obtained from the patient's answer to 7 items of this questionnaire.
Measured: Baseline, Week 18
Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score
Comparison of adaptive functioning using the VABS-II composite score in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm. The Vineland II assesses an individual's development of personal independence \& social responsibility. The questionnaire contains 433 items which assess 15 subdomains organized into the five domains of Communication, Daily Living Skills, Socialization, Motor Skills and Maladaptive Behavior. The overall Adaptive Behavior Composite (ABC) score is obtained by summing the standard scores of the first four domain scores for patients aged less than 7 years, or the first 3 domain scores for patients aged 7 or older (the Maladaptive Behavior domain is optional). The ABC standard score ranges from 20 to 160 with a mean of 100 and a standard deviation of 15. Higher scores correspond to improved adaptive level. Note that 2 questionnaires with ABC scores<20 (data issues) were included in this analysis.
Measured: Baseline, 18 weeks
Long Term Evaluation: Effect of Everolimus Over Time in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score
Comparison of adaptive functioning using the VABS-II composite score in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm. The Vineland II assesses an individual's development of personal independence \& social responsibility. The questionnaire contains 433 items which assess 15 subdomains organized into the five domains of Communication, Daily Living Skills, Socialization, Motor Skills and Maladaptive Behavior. The overall Adaptive Behavior Composite (ABC) score is obtained by summing the standard scores of the first four domain scores for patients aged less than 7 years, or the first 3 domain scores for patients aged 7 or older (the Maladaptive Behavior domain is optional). The ABC standard score ranges from 20 to 160 with a mean of 100 and a standard deviation of 15. Higher scores correspond to improved adaptive level. Note that 2 questionnaires with ABC scores<20 (data issues) were included in this analysis.
Measured: Baseline, Weeks 18, 42, 66 and 90
Core Phase: Change From Baseline in Wechsler Nonverbal Composite Score
The brief version of the WNV consists of a 2-subtest battery: only Matrices and Recognition subtests for patients under 8, and Matrices and Spatial Span subtests for patients aged 8 to 21. Based on the raw scores obtained from the subtests, standardized z-scores were calculated for each subtest using the following formula: Zscore = (X - b)/Sb where X is the raw score of the subtest, b and Sb represent the mean and standard deviation respectively of the subtest score recorded at baseline for the study population. The composite WNV score was computed by summing up the Z-scores of the 3 subtests of the WNV (i.e. matrices, recognition, and coding for patients aged <8 years and matrices, spatial span, and coding for patients aged 8 to 21 years). The composite WNV score has no range.
Measured: Baseline, Week 18
Long Term Evaluation: Effect of Everolimus Over Time in the Overall Wechsler Nonverbal Composite Score
The brief version of the WNV consists of a 2-subtest battery: only Matrices and Recognition subtests for patients under 8, and Matrices and Spatial Span subtests for patients aged 8 to 21. Based on the raw scores obtained from the subtests, standardized z-scores were calculated for each subtest using the following formula: Zscore = (X - b)/Sb where X is the raw score of the subtest, b and Sb represent the mean and standard deviation respectively of the subtest score recorded at baseline for the study population. The composite WNV score was computed by summing up the Z-scores of the 3 subtests of the WNV (i.e. matrices, recognition, and coding for patients aged <8 years and matrices, spatial span, and coding for patients aged 8 to 21 years). The composite WNV score has no range
Measured: Baseline, Weeks 18, 42, 66 and 90
Core Phase: Response Rate in Seizure Frequency by Time Normalized Minimum Concentration
Comparison of response rate in seizure frequency for 5 categories of time-normalized minimum concentration (Cmin, TN) (< 3 ng/mL; 3-7 ng/mL; >7-<9 ng/mL; 9-15 ng/mL; >15 ng/mL). Response rate is the percentage of patients with ≥ 50% reduction from baseline in average weekly partial-onset seizure frequency during the maintenance period of the Core phase.
Measured: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Core Phase: Median Percentage Change From Baseline in Seizure Frequency by Time Normalized Minimum Concentration
Percentage change from baseline in average weekly seizure frequency during the maintenance period of the Core phase is calculated as follow: (SFcfb) = 100 × (SFB - SFM) ÷ SFB where SFB is the average weekly seizure frequency in the Baseline phase and 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.
Measured: 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
A repeated measures analysis considering fixed 2-week intervals and including the level of exposure (time-normalized Cmin values), the time on-treatment and the seizure frequency at baseline quantified the estimated percentage change over 2 weeks in seizure frequency associated with a double exposure to everolimus, 15 days more on treatment and half the seizure frequency at baseline. A positive percentage change means a reduction in seizure frequency whereas a negative percentage change means an increase in seizure frequency.
Measured: During everolimus treatment from start of everolimus up to the end of the extension phase, an average of 1.7 year
Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations
Impact of everolimus on AED concentrations at trough. Pre-dose plasma samples to measure AED concentrations were measured at at Visits 1 (Screening), 2 (Baseline), 3, and 5. Effects of everolimus on the exposure of antiepileptic drugs was assessed by comparing the anti-epileptic drug concentrations at Visits 1 and 2 (AEDs alone) and at Visits 3 and 5 (AEDs plus everolimus).
Measured: Baseline, Weeks 1 & 3
Long Term Evaluation: Percentage Change From Start of Everolimus in Seizure Frequency by Time Window
Percentage change from start of everolimus in average weekly seizure frequency (SFcfe) = 100 × (SFe - SFtw) ÷ SFe where:
SFe is the average weekly seizure frequency in the 8-week period before start of everolimus SFtw is the average weekly seizure frequency in a 12-week time window A positive percentage change from start of everolimus (SFcfe) means a reduction in seizure frequency whereas a negative percentage change from start of everolimus (SFcfe) means an increase in seizure frequency.
Measured: Baseline (8-week period before start of everolimus), Week 7 to 18, Week 19 to 30, and 12 weeks thereafter up to Week 102
Seizure Free Rates by Time Window
Percentage of seizure-free participants for each 12-week time window.
Measured: Weeks 18, 30, 42, 54, 66, 78, 90 & 102
Core Phase: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes
Comparison of suicidality using the C-SSRS in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm. The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide assessment developed by multiple institutions, including Columbia University, with NIMH support. The scale is evidence-supported and is part of a national and international public health initiative involving the assessment of suicidality. There are different scoring systems depending on the population. The important elements to note are that the higher the scores on the individual items and the more "yes" items, the higher the suicide risk.
Measured: 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
The C-SSRS was completed at each visit. The table below presents the number of patients who reported at least one completed suicide, one suicide attempt, one preparatory action toward imminent suicidal behavior, one suicidal ideation and one self-injurious behavior without suicidal intent at any time point after starting everolimus.
Measured: During everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Oct 2012 (estimated)
- Study start29 Apr 2013
- Primary completion25 Oct 2017
- Study completion25 Oct 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Tuberous Sclerosis Complex-associated Refractory SeizuresStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 366 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01713946
- Sponsor's protocol ID
- CRAD001M2304
- Other IDs
- 2011-000860-90
- Acronym
- EXIST-3
- Status last verified
- Nov 2018
- First submitted
- 9 Oct 2012
- Last updated
- 7 Nov 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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 www.clinicalstudydatarequest.com
Publications
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.
PubMed 30169322French 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.
PubMed 27613521Goyer 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.
PubMed 25682485
Study at a glance
From the registry record, last updated by the sponsor on 7 Nov 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01713946
- Acronym / sponsor ID
- EXIST-3 / CRAD001M2304
- Keywords
- TSC seizures, TSC epilepsy, mTOR inhibitor, RAD001, Everolimus
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 366 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 29 Apr 2013 (actual)
- Primary completion
- 25 Oct 2017 (actual)
- Study completion
- 25 Oct 2017 (actual)
- First posted
- 25 Oct 2012 (estimated)
- Results
- Posted 7 Nov 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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].
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Everolimus LT target of 3 - 7 ng/mL | Experimental | Drug: RAD001, Drug: Antiepileptic drug (1 to 3 only), Drug: open label RAD001 (only used for post-extension phase)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. |
| Everolimus HT target of 9 -15 ng/mL | Experimental | Drug: RAD001, Drug: Antiepileptic drug (1 to 3 only), Drug: open label RAD001 (only used for post-extension phase)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. |
| Placebo | Placebo comparator | Drug: Placebo, Drug: Antiepileptic drug (1 to 3 only), Drug: open label RAD001 (only used for post-extension phase)Participants received placebo plus 1 to 3 antiepileptic drugs. |
Who may qualify
- Ages
- 2 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (17 listed)
- 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.
- 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 :
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Key exclusion criteria (24 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RAD001Also: everolimusEverolimus 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. | Drug | Everolimus HT target of 9 -15 ng/mL, Everolimus LT target of 3 - 7 ng/mL |
| PlaceboPlacebo 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. | Drug | Placebo |
| Antiepileptic drug (1 to 3 only)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 | Drug | 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)Also: open label everolimuseverolimus 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. | Drug | Everolimus HT target of 9 -15 ng/mL, Everolimus LT target of 3 - 7 ng/mL, Placebo |
Primary outcome
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)
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.
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)
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.
20 secondary outcomes
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: 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)
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)
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: Probability That a Patient Remains On-treatment up to a Specified Time Point
Time frame: Week 6, Week 12, Week 18
Core Phase: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years
Time frame: Baseline, Week 18
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: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years
Time frame: Baseline, Week 18
Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score
Time frame: Baseline, 18 weeks
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: Change From Baseline in Wechsler Nonverbal Composite Score
Time frame: Baseline, Week 18
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: 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)
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)
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
Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations
Time frame: Baseline, Weeks 1 & 3
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
Seizure Free Rates by Time Window
Time frame: Weeks 18, 30, 42, 54, 66, 78, 90 & 102
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
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Nov 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 30169322Curatolo 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.
- Derived from this study: PubMed 27613521French 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.
- Derived from this study: PubMed 25682485Goyer 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.
- Individual participant dataSharing planned: Yes. 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 www.clinicalstudydatarequest.com
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
104 sites in 25 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing RAD001, Antiepileptic drug (1 to 3 only) and open label RAD001 (only used for post-extension phase) in people with Tuberous Sclerosis Complex-associated Refractory Seizures, run by Novartis Pharmaceuticals at 104 sites in 25 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 104 sites in United States, Italy, United Kingdom, France, Japan and 20 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 Nov 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01713946, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Nov 2018.