Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01713946




Registration number
NCT01713946
Ethics application status
Date submitted
9/10/2012
Date registered
25/10/2012
Date last updated
7/11/2018

Titles & IDs
Public title
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
Scientific 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
Secondary ID [1] 0 0
2011-000860-90
Secondary ID [2] 0 0
CRAD001M2304
Universal Trial Number (UTN)
Trial acronym
EXIST-3
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tuberous Sclerosis Complex-associated Refractory Seizures 0 0
Condition category
Condition code
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Neurological 0 0 0 0
Other neurological disorders
Neurological 0 0 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - RAD001
Treatment: Drugs - Placebo
Treatment: Drugs - Antiepileptic drug (1 to 3 only)
Treatment: Drugs - open label RAD001 (only used for post-extension phase)

Experimental: Everolimus LT target of 3 - 7 ng/mL - 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.

Experimental: Everolimus HT target of 9 -15 ng/mL - 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 Comparator: Placebo - Participants received placebo plus 1 to 3 antiepileptic drugs.


Treatment: Drugs: RAD001
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.

Treatment: Drugs: Placebo
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.

Treatment: Drugs: 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

Treatment: Drugs: open label RAD001 (only used for post-extension phase)
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate
Timepoint [1] 0 0
Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Primary outcome [2] 0 0
Core Phase: Food & Drug Administration (FDA): Percentage Change From Baseline in Partial Onset-seizure Frequency
Timepoint [2] 0 0
Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Secondary outcome [1] 0 0
Percentage of Seizure-free Patients During the Maintenance Period of the Core Phase
Timepoint [1] 0 0
Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Secondary outcome [2] 0 0
Core Phase: Percentage of Patients With at Least a 25% Reduction in Seizure Frequency
Timepoint [2] 0 0
Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Secondary outcome [3] 0 0
Core Phase: Distribution of Reduction From Baseline in Seizure Frequency
Timepoint [3] 0 0
Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Secondary outcome [4] 0 0
Core Phase: Changes From Baseline in Number of Seizure-free Days
Timepoint [4] 0 0
Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Secondary outcome [5] 0 0
Core Phase: Probability That a Patient Remains On-treatment up to a Specified Time Point
Timepoint [5] 0 0
Week 6, Week 12, Week 18
Secondary outcome [6] 0 0
Core Phase: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years
Timepoint [6] 0 0
Baseline, Week 18
Secondary outcome [7] 0 0
Core Phase: Change From Baseline in the QOLIE-AD-48 Overall Quality-of-life Score for Patients >=11 to 18 Years
Timepoint [7] 0 0
Baseline, Week 18
Secondary outcome [8] 0 0
Core Phase: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years
Timepoint [8] 0 0
Baseline, Week 18
Secondary outcome [9] 0 0
Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score
Timepoint [9] 0 0
Baseline, 18 weeks
Secondary outcome [10] 0 0
Long Term Evaluation: Effect of Everolimus Over Time in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score
Timepoint [10] 0 0
Baseline, Weeks 18, 42, 66 and 90
Secondary outcome [11] 0 0
Core Phase: Change From Baseline in Wechsler Nonverbal Composite Score
Timepoint [11] 0 0
Baseline, Week 18
Secondary outcome [12] 0 0
Long Term Evaluation: Effect of Everolimus Over Time in the Overall Wechsler Nonverbal Composite Score
Timepoint [12] 0 0
Baseline, Weeks 18, 42, 66 and 90
Secondary outcome [13] 0 0
Core Phase: Response Rate in Seizure Frequency by Time Normalized Minimum Concentration
Timepoint [13] 0 0
Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Secondary outcome [14] 0 0
Core Phase: Median Percentage Change From Baseline in Seizure Frequency by Time Normalized Minimum Concentration
Timepoint [14] 0 0
Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Secondary outcome [15] 0 0
Long Term Evaluation: Relationship Between Seizure Frequency and Time-normalized Everolimus Concentration at Trough (Cmin,TN) - Repeated Measures Analysis
Timepoint [15] 0 0
During everolimus treatment from start of everolimus up to the end of the extension phase, an average of 1.7 year
Secondary outcome [16] 0 0
Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations
Timepoint [16] 0 0
Baseline, Weeks 1 & 3
Secondary outcome [17] 0 0
Long Term Evaluation: Percentage Change From Start of Everolimus in Seizure Frequency by Time Window
Timepoint [17] 0 0
Baseline (8-week period before start of everolimus), Week 7 to 18, Week 19 to 30, and 12 weeks thereafter up to Week 102
Secondary outcome [18] 0 0
Seizure Free Rates by Time Window
Timepoint [18] 0 0
Weeks 18, 30, 42, 54, 66, 78, 90 & 102
Secondary outcome [19] 0 0
Core Phase: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes
Timepoint [19] 0 0
Baseline, Week 18
Secondary outcome [20] 0 0
Long Term Evaluation: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes
Timepoint [20] 0 0
During everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years

Eligibility
Key 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.
Minimum age
2 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
29/04/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
25/10/2017
Sample size
Target
Accrual to date
Final
366
Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Randwick
Recruitment hospital [2] 0 0
Novartis Investigative Site - Parkville
Recruitment hospital [3] 0 0
Novartis Investigative Site - Perth
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
3052 - Parkville
Recruitment postcode(s) [3] 0 0
6840 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Colorado
Country [5] 0 0
United States of America
State/province [5] 0 0
Connecticut
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Maryland
Country [8] 0 0
United States of America
State/province [8] 0 0
Massachusetts
Country [9] 0 0
United States of America
State/province [9] 0 0
Minnesota
Country [10] 0 0
United States of America
State/province [10] 0 0
Missouri
Country [11] 0 0
United States of America
State/province [11] 0 0
New Jersey
Country [12] 0 0
United States of America
State/province [12] 0 0
New York
Country [13] 0 0
United States of America
State/province [13] 0 0
Ohio
Country [14] 0 0
United States of America
State/province [14] 0 0
Oregon
Country [15] 0 0
United States of America
State/province [15] 0 0
Pennsylvania
Country [16] 0 0
United States of America
State/province [16] 0 0
Tennessee
Country [17] 0 0
United States of America
State/province [17] 0 0
Texas
Country [18] 0 0
Argentina
State/province [18] 0 0
Buenos Aires
Country [19] 0 0
Argentina
State/province [19] 0 0
Cordoba
Country [20] 0 0
Belgium
State/province [20] 0 0
Brussel
Country [21] 0 0
Belgium
State/province [21] 0 0
Bruxelles
Country [22] 0 0
Belgium
State/province [22] 0 0
Gent
Country [23] 0 0
Belgium
State/province [23] 0 0
Leuven
Country [24] 0 0
Canada
State/province [24] 0 0
British Columbia
Country [25] 0 0
Canada
State/province [25] 0 0
Quebec
Country [26] 0 0
Colombia
State/province [26] 0 0
Valle Del Cauca
Country [27] 0 0
Colombia
State/province [27] 0 0
Bogotá
Country [28] 0 0
Colombia
State/province [28] 0 0
Medellín
Country [29] 0 0
Denmark
State/province [29] 0 0
Aarhus
Country [30] 0 0
France
State/province [30] 0 0
Amiens Cedex 1
Country [31] 0 0
France
State/province [31] 0 0
Angers cedex 09
Country [32] 0 0
France
State/province [32] 0 0
Bron Cedex
Country [33] 0 0
France
State/province [33] 0 0
Lille Cedex
Country [34] 0 0
France
State/province [34] 0 0
Marseille
Country [35] 0 0
France
State/province [35] 0 0
Strasbourg Cedex
Country [36] 0 0
Germany
State/province [36] 0 0
Berlin
Country [37] 0 0
Germany
State/province [37] 0 0
Bielefeld
Country [38] 0 0
Germany
State/province [38] 0 0
Kehl-Kork
Country [39] 0 0
Germany
State/province [39] 0 0
Kiel
Country [40] 0 0
Greece
State/province [40] 0 0
GR
Country [41] 0 0
Greece
State/province [41] 0 0
Athens
Country [42] 0 0
Hungary
State/province [42] 0 0
Budapest
Country [43] 0 0
Hungary
State/province [43] 0 0
Kaposvar
Country [44] 0 0
Hungary
State/province [44] 0 0
Nyiregyhaza
Country [45] 0 0
Ireland
State/province [45] 0 0
Dublin
Country [46] 0 0
Italy
State/province [46] 0 0
BA
Country [47] 0 0
Italy
State/province [47] 0 0
BO
Country [48] 0 0
Italy
State/province [48] 0 0
CT
Country [49] 0 0
Italy
State/province [49] 0 0
GE
Country [50] 0 0
Italy
State/province [50] 0 0
MI
Country [51] 0 0
Italy
State/province [51] 0 0
PV
Country [52] 0 0
Italy
State/province [52] 0 0
RM
Country [53] 0 0
Italy
State/province [53] 0 0
SI
Country [54] 0 0
Japan
State/province [54] 0 0
Okayama
Country [55] 0 0
Japan
State/province [55] 0 0
Osaka
Country [56] 0 0
Japan
State/province [56] 0 0
Shizuoka
Country [57] 0 0
Japan
State/province [57] 0 0
Tokyo
Country [58] 0 0
Korea, Republic of
State/province [58] 0 0
Korea
Country [59] 0 0
Korea, Republic of
State/province [59] 0 0
Seoul
Country [60] 0 0
Mexico
State/province [60] 0 0
Jalisco
Country [61] 0 0
Netherlands
State/province [61] 0 0
Heeze
Country [62] 0 0
Netherlands
State/province [62] 0 0
Rotterdam
Country [63] 0 0
Netherlands
State/province [63] 0 0
Utrecht
Country [64] 0 0
Norway
State/province [64] 0 0
Oslo
Country [65] 0 0
Poland
State/province [65] 0 0
Warszawa
Country [66] 0 0
Russian Federation
State/province [66] 0 0
Samara Region
Country [67] 0 0
Russian Federation
State/province [67] 0 0
Voronezh Region
Country [68] 0 0
Russian Federation
State/province [68] 0 0
Moscow
Country [69] 0 0
Spain
State/province [69] 0 0
Andalucía
Country [70] 0 0
Spain
State/province [70] 0 0
Catalunya
Country [71] 0 0
Spain
State/province [71] 0 0
Comunidad Valenciana
Country [72] 0 0
Spain
State/province [72] 0 0
Pais Vasco
Country [73] 0 0
Spain
State/province [73] 0 0
Madrid
Country [74] 0 0
Taiwan
State/province [74] 0 0
Taiwan ROC
Country [75] 0 0
Taiwan
State/province [75] 0 0
Kaohsiung City
Country [76] 0 0
Taiwan
State/province [76] 0 0
Taipei
Country [77] 0 0
Thailand
State/province [77] 0 0
Bangkok
Country [78] 0 0
Turkey
State/province [78] 0 0
Ankara
Country [79] 0 0
Turkey
State/province [79] 0 0
Istanbul
Country [80] 0 0
United Kingdom
State/province [80] 0 0
Birmingham
Country [81] 0 0
United Kingdom
State/province [81] 0 0
Buckinghamshire
Country [82] 0 0
United Kingdom
State/province [82] 0 0
Cambridge
Country [83] 0 0
United Kingdom
State/province [83] 0 0
Liverpool
Country [84] 0 0
United Kingdom
State/province [84] 0 0
London
Country [85] 0 0
United Kingdom
State/province [85] 0 0
Sheffield
Country [86] 0 0
United Kingdom
State/province [86] 0 0
York

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
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].
Trial website
https://clinicaltrials.gov/ct2/show/NCT01713946
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01713946