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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00789828




Registration number
NCT00789828
Ethics application status
Date submitted
12/11/2008
Date registered
13/11/2008
Date last updated
3/02/2016

Titles & IDs
Public title
Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1)
Scientific title
A Randomized, Double-blind, Placebo-controlled Study of Everolimus in the Treatment of Patients With Subependymal Giant Cell Astrocytomas (SEGA) Associated With Tuberous Sclerosis Complex (TSC)
Secondary ID [1] 0 0
2007-006997-27
Secondary ID [2] 0 0
CRAD001M2301
Universal Trial Number (UTN)
Trial acronym
EXIST-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tuberous Sclerosis 0 0
Subependymal Giant Cell Astrocytoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain
Cancer 0 0 0 0
Children's - Brain
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Everolimus
Treatment: Drugs - Placebo

Experimental: Everolimus - Everolimus was administered orally at a starting dose of 4.5mg/m\^2 daily and subsequently titrated to attain whole blood trough concentration of 5 to 15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.

Placebo comparator: Placebo - Matching Placebo administered orally.


Treatment: Drugs: Everolimus
Everolimus was formulated as tablets of 1.0-mg strength and was blisterpacked under aluminum foil in units of 10 tablets.

Treatment: Drugs: Placebo
Placebo was provided as a matching tablet and was blisterpacked under aluminum foil in units of 10.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response
Timepoint [1] 0 0
End of core period (Week 48), and end of extension period (up to 4 years)
Secondary outcome [1] 0 0
Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period
Timepoint [1] 0 0
Baseline (Core period) to Week 24 (Core period), Baseline (Extension period, Week 24 post-core baseline) to Week 24 (Extension period, Week 48 post-core baseline)
Secondary outcome [2] 0 0
Time to SEGA Progression
Timepoint [2] 0 0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Secondary outcome [3] 0 0
Time to SEGA Response
Timepoint [3] 0 0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Secondary outcome [4] 0 0
Duration of SEGA Response
Timepoint [4] 0 0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Secondary outcome [5] 0 0
Time to SEGA Worsening
Timepoint [5] 0 0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Secondary outcome [6] 0 0
Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score
Timepoint [6] 0 0
End of core period (Week 48), and end of extension period (up to 4 years)
Secondary outcome [7] 0 0
Duration of Skin Lesion Response in Everolimus Treated Participants
Timepoint [7] 0 0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Secondary outcome [8] 0 0
Everolimus Blood Concentration (C2h) at 2 Hours Post Dose
Timepoint [8] 0 0
2 hours post dose on Week 6, Week 24, Week 48, Week 96, Week 144, and Week 240
Secondary outcome [9] 0 0
Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose
Timepoint [9] 0 0
24 hours post dose on Week 6, Week 24, Week 48, Week 72, Week 96, Week 144, and Week 240
Secondary outcome [10] 0 0
Percentage of Participants With Renal Impairment During Core Period
Timepoint [10] 0 0
Day 1 up to 28 days after end of treatment (Core period)

Eligibility
Key inclusion criteria
* All Ages
* Definite diagnosis of Tuberous Sclerosis according to the modified Gomez criteria
* At least one Subependymal Giant Cell Astrocytoma of at least 1 cm in diameter
* Evidence of SEGA worsening as compared to prior MRI scans
* Females of child bearing potential must use birth control
* Written informed consent
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* SEGA related surgery is likely to be required in the opinion of the investigator
* Recent heart attack, cardiac related chest pain or stroke
* Severely impaired lung function
* Severe liver dysfunction
* Severe kidney dysfunction
* Pregnancy or breast feeding
* Current infection
* History of organ transplant
* Surgery within two months prior to study enrollment
* Prior therapy with a medication in the same class as Everolimus
* Uncontrolled high cholesterol
* Uncontrolled diabetes
* HIV
* Patients with metal implants thus prohibiting MRI evaluations

Other protocol-defined inclusion/exclusion criteria may apply

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
1/08/2009
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/10/2014
Sample size
Target
Accrual to date
Final
117
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Novartis Investigative Site - Randwick
Recruitment postcode(s) [1] 0 0
2130 - Randwick
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
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Massachusetts
Country [7] 0 0
United States of America
State/province [7] 0 0
Minnesota
Country [8] 0 0
United States of America
State/province [8] 0 0
Ohio
Country [9] 0 0
United States of America
State/province [9] 0 0
Texas
Country [10] 0 0
United States of America
State/province [10] 0 0
Virginia
Country [11] 0 0
Belgium
State/province [11] 0 0
Brussel
Country [12] 0 0
Canada
State/province [12] 0 0
Ontario
Country [13] 0 0
Canada
State/province [13] 0 0
Quebec
Country [14] 0 0
Germany
State/province [14] 0 0
Berlin
Country [15] 0 0
Germany
State/province [15] 0 0
Heidelberg
Country [16] 0 0
Italy
State/province [16] 0 0
GE
Country [17] 0 0
Italy
State/province [17] 0 0
Roma
Country [18] 0 0
Netherlands
State/province [18] 0 0
Utrecht
Country [19] 0 0
Poland
State/province [19] 0 0
Warszawa
Country [20] 0 0
Russian Federation
State/province [20] 0 0
Moscow
Country [21] 0 0
United Kingdom
State/province [21] 0 0
Bristol

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 Everolimus in treating patients with Subependymal Giant Cell Astrocytomas associated with Tuberous Sclerosis Complex.
Trial website
https://clinicaltrials.gov/study/NCT00789828
Trial related presentations / publications
Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, Belousova E, Berkowitz N, Ridolfi A, Christopher Kingswood J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2. Nephrol Dial Transplant. 2019 Jun 1;34(6):1000-1008. doi: 10.1093/ndt/gfy132.
Sparagana S, Franz DN, Krueger DA, Bissler JJ, Berkowitz N, Burock K, Kingswood JC. Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex. PLoS One. 2017 Oct 12;12(10):e0186235. doi: 10.1371/journal.pone.0186235. eCollection 2017.
Franz DN, Belousova E, Sparagana S, Bebin EM, Frost MD, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Berkowitz N, Niolat J, Jozwiak S. Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study. PLoS One. 2016 Jun 28;11(6):e0158476. doi: 10.1371/journal.pone.0158476. eCollection 2016.
Jozwiak S, Kotulska K, Berkowitz N, Brechenmacher T, Franz DN. Safety of Everolimus in Patients Younger than 3 Years of Age: Results from EXIST-1, a Randomized, Controlled Clinical Trial. J Pediatr. 2016 May;172:151-155.e1. doi: 10.1016/j.jpeds.2016.01.027. Epub 2016 Feb 6.
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.
Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Berkowitz N, Anak O, Niolat J, Jozwiak S. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol. 2014 Dec;15(13):1513-1520. doi: 10.1016/S1470-2045(14)70489-9. Epub 2014 Nov 10.
Kingswood JC, Jozwiak S, Belousova ED, Frost MD, Kuperman RA, Bebin EM, Korf BR, Flamini JR, Kohrman MH, Sparagana SP, Wu JY, Brechenmacher T, Stein K, Berkowitz N, Bissler JJ, Franz DN. The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1. Nephrol Dial Transplant. 2014 Jun;29(6):1203-10. doi: 10.1093/ndt/gfu013. Epub 2014 Apr 11.
Kotulska K, Borkowska J, Jozwiak S. Possible prevention of tuberous sclerosis complex lesions. Pediatrics. 2013 Jul;132(1):e239-42. doi: 10.1542/peds.2012-3607. Epub 2013 Jun 3.
Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013 Jan 12;381(9861):125-32. doi: 10.1016/S0140-6736(12)61134-9. Epub 2012 Nov 14. Erratum In: Lancet. 2013 Jan 12;381(9861):116.
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticlas
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/study/NCT00789828