Please note that the copy function is not enabled for this field.
If you wish to
modify
existing outcomes, please copy and paste the current outcome text into the Update field.
LOGIN
CREATE ACCOUNT
LOGIN
CREATE ACCOUNT
MY TRIALS
REGISTER TRIAL
FAQs
HINTS AND TIPS
DEFINITIONS
Trial Review
The ANZCTR website will be unavailable from 1pm until 3pm (AEDT) on Wednesday the 30th of October for website maintenance. Please be sure to log out of the system in order to avoid any loss of data.
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
Download to PDF
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)
Query!
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)
Query!
Secondary ID [1]
0
0
2007-006997-27
Query!
Secondary ID [2]
0
0
CRAD001M2301
Query!
Universal Trial Number (UTN)
Query!
Trial acronym
EXIST-1
Query!
Linked study record
Query!
Health condition
Health condition(s) or problem(s) studied:
Tuberous Sclerosis
0
0
Query!
Subependymal Giant Cell Astrocytoma
0
0
Query!
Condition category
Condition code
Cancer
0
0
0
0
Query!
Brain
Query!
Cancer
0
0
0
0
Query!
Children's - Brain
Query!
Human Genetics and Inherited Disorders
0
0
0
0
Query!
Other human genetics and inherited disorders
Query!
Neurological
0
0
0
0
Query!
Other neurological disorders
Query!
Intervention/exposure
Study type
Interventional
Query!
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.
Query!
Intervention code [1]
0
0
Treatment: Drugs
Query!
Comparator / control treatment
Query!
Control group
Query!
Outcomes
Primary outcome [1]
0
0
Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response
Query!
Assessment method [1]
0
0
Participants were assessed for SEGA response, defined as 50% reduction from baseline in SEGA volume (where SEGA volume was the sum of the volumes of all target SEGA lesions identified at baseline, and confirmed with a second scan performed approximately 12 weeks later), no unequivocal worsening of non-target SEGA lesions, no new SEGA lesions (= 1 cm in longest diameter), and no new or worsening hydrocephalus. Multi-phase brain MRI was utilized to identify SEGA lesions. SEGA response rate was defined as the percentage of participants whose best overall status was SEGA response as determined by Independent Central Radiology Review. The Kaplan-Meier estimate was used for determining time to SEGA response.
Query!
Timepoint [1]
0
0
End of core period (Week 48), and end of extension period (up to 4 years)
Query!
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
Query!
Assessment method [1]
0
0
Seizure frequency per 24 hours was defined as the number of seizures in the electroencephalography (EEG) divided by the number of hours in the EEG, multiplied by 24. Seizure frequency was evaluated using a 24-hour video-EEG. Seizure frequency was listed as missing if the actual EEG recording duration was \< 18 hours.
Query!
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)
Query!
Secondary outcome [2]
0
0
Time to SEGA Progression
Query!
Assessment method [2]
0
0
Time to SEGA progression was defined as time between randomisation to time to first SEGA progression. SEGA progression was defined as either one or more of the following criteria: 1. increase from nadir of = 25% in SEGA volume to a value greater than baseline SEGA volume (where SEGA volume is the sum of the volumes of all target SEGA lesions identified at baseline, and nadir is the lowest SEGA volume obtained for the participant previously in the trial), 2. unequivocal worsening of non-target SEGA lesions, 3. appearance of new SEGA lesion = 1.0 cm in longest diameter, 4. new or worsening hydrocephalus. The median TTSP based on central radiology review was not reached in any treatment arms; Only 6 events of SEGA progressions were observed in the placebo group of core period.
Query!
Timepoint [2]
0
0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Query!
Secondary outcome [3]
0
0
Time to SEGA Response
Query!
Assessment method [3]
0
0
Participants were assessed for time to SEGA response, defined as 50% reduction from baseline in SEGA volume (where SEGA volume was the sum of the volumes of all target SEGA lesions identified at baseline, and confirmed with a second scan performed approximately 12 weeks later), no unequivocal worsening of non-target SEGA lesions, no new SEGA lesions (= 1 cm in longest diameter), and no new or worsening hydrocephalus. Multi-phase brain MRI was utilised to identify SEGA lesions. SEGA response rate was defined as the percentage of participants whose best overall status was SEGA response as determined by Independent Central Radiology Review. The Kaplan-Meier estimate was used for determining time to SEGA response.
Query!
Timepoint [3]
0
0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Query!
Secondary outcome [4]
0
0
Duration of SEGA Response
Query!
Assessment method [4]
0
0
Duration of SEGA response was defined as time from the date of the first documented SEGA response until the date of the first documented SEGA progression. Duration of SEGA response was evaluated only for participants who achieved a SEGA response. The time to SEGA progression was censored if SEGA progression was not observed before the first to occur out of (i) analysis cut-off date (ii) the date when systemic anti-SEGA medication is started, (iii) the date of a SEGA-related surgery or (iv) the date of death. Since, no case of SEGA progression was observed in core study which resulted in censored duration of SEGA response. Only 5 SEGA responders experienced a SEGA progression in extension period.
Query!
Timepoint [4]
0
0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Query!
Secondary outcome [5]
0
0
Time to SEGA Worsening
Query!
Assessment method [5]
0
0
Time to SEGA worsening was defined as the time from the start of everolimus to date of the first SEGA worsening. SEGA worsening was defined as either; increase from nadir of = 25% in SEGA volume or unequivocal worsening of non-target SEGA lesions, or appearance of new SEGA lesion = 1.0 cm in longest diameter, or new or worsening hydrocephalus. The median value was not reached in either treatment arm of core period as SEGA worsening was observed in less participants (everolimus - 7 and placebo - 8).
Query!
Timepoint [5]
0
0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Query!
Secondary outcome [6]
0
0
Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score
Query!
Assessment method [6]
0
0
Skin lesions included hypomelanotic macules, the shagreen patch, periungual or subungual fibromas, facial angiofibromas and/or forehead plaques. Response was evaluated using the Physician's Global Assessment of Clinical Condition (PGA) on a 7-point scale: Grade 0 = complete clinical response, indicated absence of disease, Grade 1, 2, and 3 = partial response, indicated improvements of = 50% but \< 100%, Grade 4, 5 = stable disease, indicated some or no improvements of 25% - \< 50% and 6 = progressive disease, indicated worse than at baseline evaluation by \> 25%. Response rate was determined for participants with = 1 skin lesion at baseline, defined as the percentage of participants with overall status as complete clinical response or partial response.
Query!
Timepoint [6]
0
0
End of core period (Week 48), and end of extension period (up to 4 years)
Query!
Secondary outcome [7]
0
0
Duration of Skin Lesion Response in Everolimus Treated Participants
Query!
Assessment method [7]
0
0
Duration of skin lesion response was defined as the time from the first skin lesion response until the first skin lesion progression, defined as worsening of lesion by \> 25% or more from baseline.
Query!
Timepoint [7]
0
0
Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
Query!
Secondary outcome [8]
0
0
Everolimus Blood Concentration (C2h) at 2 Hours Post Dose
Query!
Assessment method [8]
0
0
The participants were assessed for everolimus blood concentration at 2 hours time point after dose administration on the same day, if the participant did not vomit between previous dose and blood sample collection. Tandem liquid chromatography-mass spectrometry method was used for evaluation. C2h values were categorized as \< 20 ng/mL, 20-50 ng/mL, and \> 50 ng/mL, concentrations below the lower limit of quantification were entered as 0 ng/mL.
Query!
Timepoint [8]
0
0
2 hours post dose on Week 6, Week 24, Week 48, Week 96, Week 144, and Week 240
Query!
Secondary outcome [9]
0
0
Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose
Query!
Assessment method [9]
0
0
The participants were assessed for everolimus trough concentration (Cmin) at 24 hours time point after previous dose administration, at a steady state following 5 days of consistent dosing, if the participant did not vomit within 4 hours of previous dose. Tandem liquid chromatography-mass spectrometry method was used for evaluation. Cmin values were categorized as \<5 ng/mL, 5-10 ng/mL, and \>10 ng/mL, concentrations below the lower limit of quantification were entered as 0 ng/mL.
Query!
Timepoint [9]
0
0
24 hours post dose on Week 6, Week 24, Week 48, Week 72, Week 96, Week 144, and Week 240
Query!
Secondary outcome [10]
0
0
Percentage of Participants With Renal Impairment During Core Period
Query!
Assessment method [10]
0
0
Renal function was assessed using glomerular filtration rate (GFR) based on age measure; Modification of Diet in Renal Disease (MDRD) formula for participants aged 18 years or older, defined as GFR equal to 32788\*(serum creatinine (micromol/L)\^-1.154)\*(age\^-0.203 )\*(0.742, if female)\*(1.210, if black), and Schwartz formula for participants less than 18 years defined as GFR equal to 0.41\*height (cm)/ Serum creatinine (mg/dL). Participants with severe renal impairment defined as GFR \< 30 mL/min/1.73 m\^2 and participants with National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 3/4 serum creatinine were reported.
Query!
Timepoint [10]
0
0
Day 1 up to 28 days after end of treatment (Core period)
Query!
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
Query!
Minimum age
No limit
Query!
Query!
Maximum age
No limit
Query!
Query!
Sex
Both males and females
Query!
Can healthy volunteers participate?
No
Query!
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
Query!
Study design
Purpose of the study
Treatment
Query!
Allocation to intervention
Randomised controlled trial
Query!
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Query!
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Query!
Masking / blinding
Blinded (masking used)
Query!
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
Query!
Query!
Query!
Query!
Intervention assignment
Parallel
Query!
Other design features
Query!
Phase
Phase 3
Query!
Type of endpoint/s
Query!
Statistical methods / analysis
Query!
Recruitment
Recruitment status
Completed
Query!
Data analysis
Query!
Reason for early stopping/withdrawal
Query!
Other reasons
Query!
Date of first participant enrolment
Anticipated
Query!
Actual
1/08/2009
Query!
Date of last participant enrolment
Anticipated
Query!
Actual
Query!
Date of last data collection
Anticipated
Query!
Actual
1/10/2014
Query!
Sample size
Target
Query!
Accrual to date
Query!
Final
117
Query!
Recruitment in Australia
Recruitment state(s)
NSW
Query!
Recruitment hospital [1]
0
0
Novartis Investigative Site - Randwick
Query!
Recruitment postcode(s) [1]
0
0
2130 - Randwick
Query!
Recruitment outside Australia
Country [1]
0
0
United States of America
Query!
State/province [1]
0
0
Alabama
Query!
Country [2]
0
0
United States of America
Query!
State/province [2]
0
0
Arizona
Query!
Country [3]
0
0
United States of America
Query!
State/province [3]
0
0
California
Query!
Country [4]
0
0
United States of America
Query!
State/province [4]
0
0
Georgia
Query!
Country [5]
0
0
United States of America
Query!
State/province [5]
0
0
Illinois
Query!
Country [6]
0
0
United States of America
Query!
State/province [6]
0
0
Massachusetts
Query!
Country [7]
0
0
United States of America
Query!
State/province [7]
0
0
Minnesota
Query!
Country [8]
0
0
United States of America
Query!
State/province [8]
0
0
Ohio
Query!
Country [9]
0
0
United States of America
Query!
State/province [9]
0
0
Texas
Query!
Country [10]
0
0
United States of America
Query!
State/province [10]
0
0
Virginia
Query!
Country [11]
0
0
Belgium
Query!
State/province [11]
0
0
Brussel
Query!
Country [12]
0
0
Canada
Query!
State/province [12]
0
0
Ontario
Query!
Country [13]
0
0
Canada
Query!
State/province [13]
0
0
Quebec
Query!
Country [14]
0
0
Germany
Query!
State/province [14]
0
0
Berlin
Query!
Country [15]
0
0
Germany
Query!
State/province [15]
0
0
Heidelberg
Query!
Country [16]
0
0
Italy
Query!
State/province [16]
0
0
GE
Query!
Country [17]
0
0
Italy
Query!
State/province [17]
0
0
Roma
Query!
Country [18]
0
0
Netherlands
Query!
State/province [18]
0
0
Utrecht
Query!
Country [19]
0
0
Poland
Query!
State/province [19]
0
0
Warszawa
Query!
Country [20]
0
0
Russian Federation
Query!
State/province [20]
0
0
Moscow
Query!
Country [21]
0
0
United Kingdom
Query!
State/province [21]
0
0
Bristol
Query!
Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Query!
Name
Novartis Pharmaceuticals
Query!
Address
Query!
Country
Query!
Ethics approval
Ethics application status
Query!
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.
Query!
Trial website
https://clinicaltrials.gov/study/NCT00789828
Query!
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.
Query!
Public notes
Query!
Contacts
Principal investigator
Name
0
0
Novartis Pharmaceuticlas
Query!
Address
0
0
Novartis Pharmaceuticals
Query!
Country
0
0
Query!
Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
Query!
Contact person for public queries
Name
0
0
Query!
Address
0
0
Query!
Country
0
0
Query!
Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
Query!
Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT00789828
Download to PDF