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Tuberous SclerosisPhase 3EXIST-1NCT00789828

Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1)

A Phase 3 study testing Everolimus in people with Tuberous Sclerosis and Subependymal Giant Cell Astrocytoma, run by Novartis Pharmaceuticals at 24 sites in 10 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study evaluated the efficacy and safety of Everolimus in treating patients with Subependymal Giant Cell Astrocytomas associated with Tuberous Sclerosis Complex. Read more about this study

Who is it for?
Any age
What is being tested?
Everolimus
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
117 participants
Where
24 sitesin 10 countries
Study dates
Aug 2009to Oct 2014
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 Any age
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 15Show fewer
  • 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

Trial locations and contacts

24 sites in 10 countries.

24 sites in 10 countries

United States12 sites

  • Children's Healthcare of Atlanta

    Atlanta, Georgia, 30342

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35294

  • Massachusetts General Hospital Mass General

    Boston, Massachusetts, 02114

  • Children's Hospital Boston SC-1

    Boston, Massachusetts, 02115

  • University of CHicago Comer Children's Hospital

    Chicago, Illinois, 60637-1470

  • Cincinnati Children's Hospital Medical Center Cincinnati Children's Hosp

    Cincinnati, Ohio, 45229-3039

  • Texas Scottish Rite Hospital for Children

    Dallas, Texas, 75219

  • Children's Regional Outpatients Center SC

    Fairfax, Virginia, 22031

  • University of California at Los Angeles

    Los Angeles, California, 90048

  • Children's Hospital Oakland Hematology/Oncology Dept

    Oakland, California, 94609-1809

  • Barrow Tuberous Sclerosis Center

    Phoenix, Arizona, 85013

  • Minnesota Epilepsy Group - PA

    Saint Paul, Minnesota, 55102-2383

Other trials in United States

Canada2 sites

  • Novartis Investigative Site

    Québec, H3T IC5

  • Novartis Investigative Site

    Toronto, Ontario, M5G 1X8

Other trials in Canada

Germany2 sites

  • Novartis Investigative Site

    Berlin, 13353

  • Novartis Investigative Site

    Heidelberg, 69120

Other trials in Germany

Italy2 sites

  • Novartis Investigative Site

    Genova, GE, 16147

  • Novartis Investigative Site

    Roma, 00137

Other trials in Italy

Australia1 site

  • Novartis Investigative Site

    Randwick, New South Wales, 2130

Other trials in Australia

Belgium1 site

  • Novartis Investigative Site

    Brussels, 1090

Other trials in Belgium

Netherlands1 site

  • Novartis Investigative Site

    Utrecht, Netherlands, 3584CX

Other trials in Netherlands

Poland1 site

  • Novartis Investigative Site

    Warsaw, 04-730

Other trials in Poland

Russia1 site

  • Novartis Investigative Site

    Moscow, 127412

Other trials in Russia

United Kingdom1 site

  • Novartis Investigative Site

    Bristol, BS1 3NU

Other trials in United Kingdom

About this study

Official 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)

This study evaluated the efficacy and safety of Everolimus in treating patients with Subependymal Giant Cell Astrocytomas associated with Tuberous Sclerosis Complex.

Being tested
Everolimus, Placebo
Keywords
SEGA, Tuberous Sclerosis, Subependymal Giant Cell Astrocytoma, mTOR, RAD001, Mamalian Target Rapamycin, Everolimus, TSC
Medical subject headings
Tuberous Sclerosis, Astrocytoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EverolimusDrug

    Also called RAD001

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

  • PlaceboDrug

    Placebo was provided as a matching tablet and was blisterpacked under aluminum foil in units of 10.

Study groups in NCT00789828
Study groupRoleWhat they receive
EverolimusExperimentalEverolimus 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.
Receives: Drug: Everolimus
PlaceboPlacebo comparatorMatching Placebo administered orally.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response

    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.

    Measured: End of core period (Week 48), and end of extension period (up to 4 years)

Secondary outcomes (10)

  1. Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period

    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.

    Measured: 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)

  2. Time to SEGA Progression

    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.

    Measured: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

  3. Time to SEGA Response

    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.

    Measured: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

  4. Duration of SEGA Response

    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.

    Measured: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

  5. Time to SEGA Worsening

    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).

    Measured: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

  6. Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score

    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.

    Measured: End of core period (Week 48), and end of extension period (up to 4 years)

  7. Duration of Skin Lesion Response in Everolimus Treated Participants

    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.

    Measured: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

  8. Everolimus Blood Concentration (C2h) at 2 Hours Post Dose

    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.

    Measured: 2 hours post dose on Week 6, Week 24, Week 48, Week 96, Week 144, and Week 240

  9. Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose

    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.

    Measured: 24 hours post dose on Week 6, Week 24, Week 48, Week 72, Week 96, Week 144, and Week 240

  10. Percentage of Participants With Renal Impairment During Core Period

    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.

    Measured: Day 1 up to 28 days after end of treatment (Core period)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Nov 2008 (estimated)
  2. Study startAug 2009
  3. Primary completionMar 2011
  4. Study completionOct 2014

Resources

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
117 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00789828
Sponsor's protocol ID
CRAD001M2301
Other IDs
2007-006997-27
Acronym
EXIST-1
Status last verified
Jan 2016
First submitted
12 Nov 2008
Last updated
3 Feb 2016

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.

    PubMed 30053159

  • 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.

    PubMed 29023494

  • 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.

    PubMed 27351628

  • 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.

    PubMed 26858193

  • 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.

    PubMed 25682485

  • 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.

    PubMed 25456370

  • 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.

    PubMed 24729041

  • 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.

    PubMed 23733802

  • 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.

    PubMed 23158522

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Everolimus in people with Tuberous Sclerosis and Subependymal Giant Cell Astrocytoma, run by Novartis Pharmaceuticals at 24 sites in 10 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 6 inclusion and 15 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 3 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in United States, Canada, Germany, Italy, Australia and 5 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 1 May 2012). 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?

Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response (time frame: End of core period (Week 48), and end of extension period (up to 4 years)). 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 NCT00789828, which also lists 9 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 3 Feb 2016.

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