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

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

ClinicalTrials.gov Identifier:

NCT00789828

First received: November 12, 2008

Last updated: October 31, 2014

Last verified: October 2014

History of Changes

Results First Received: March 1, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions:	Tuberous Sclerosis Subependymal Giant Cell Astrocytoma
Interventions:	Drug: Everolimus Drug: Placebo

Participant Flow

Hide Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients in the study were randomized in a 2:1 ratio (Everolimus: Placebo).

Reporting Groups

	Description
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	Matching Placebo was administered orally.

Participant Flow: Overall Study

	Everolimus	Placebo
STARTED	78	39
COMPLETED	2 ^[1]	8
NOT COMPLETED	76	31
Ongoing in Double Blind	76	31

[1]	Completed means discontinued the double-blind treatment period.

Baseline Characteristics

Hide Baseline Characteristics

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
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	Matching Placebo was administered orally.
Total	Total of all reporting groups

Baseline Measures

	Everolimus	Placebo	Total
Number of Participants [units: participants]	78	39	117
Age [units: years] Mean ± Standard Deviation	10.1 ± 5.9	10.3 ± 7.3	10.2 ± 6.4
Age, Customized [units: Participants]
<3 years	13	7	20
3-18 years	55	26	81
≥18 years	10	6	16
Gender [units: participants]
Female	29	21	50
Male	49	18	67

Outcome Measures

Show All Outcome Measures

1. Primary:

Subependymal Giant Cell Astrocytomas (SEGA) Response Rate [ Time Frame: From date of randomization until the earliest date of first documented SEGA progression, date of further anti-SEGA medication (including open-label Everolimus)/surgery or analysis cut-off date (02-Mar-2011) ]

Hide Outcome Measure 1

Measure Type	Primary
Measure Title	Subependymal Giant Cell Astrocytomas (SEGA) Response Rate
Measure Description	Sega response Rate is defined as the percentage of patients whose best overall status is response as determined by Independent Central Radiology Review. SEGA response was defined as: (1) a ≥ 50% reduction in SEGA volume relative to baseline (where SEGA volume was the sum of all target SEGA lesion volumes identified at baseline); and (2) no unequivocal worsening of non-target SEGA lesions, no new SEGA lesions (≥ 1 cm in longest diameter), and no new or worsening hydrocephalus.
Time Frame	From date of randomization until the earliest date of first documented SEGA progression, date of further anti-SEGA medication (including open-label Everolimus)/surgery or analysis cut-off date (02-Mar-2011)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS) consisted of all randomized patients.

Reporting Groups

	Description
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	Matching Placebo was administered orally.

Measured Values

	Everolimus	Placebo
Number of Participants Analyzed [units: participants]	78	39
Subependymal Giant Cell Astrocytomas (SEGA) Response Rate [units: percentage of participants] Number ( 95% Confidence Interval )	34.6 ( 24.2 to 46.2 )	0.0 ( 0.0 to 9.0 )

No statistical analysis provided for Subependymal Giant Cell Astrocytomas (SEGA) Response Rate

2. Secondary:

Change From Baseline to Week 24 in Total Seizure Frequency Per 24 Hours From Video EEG as Per Central Reader. [ Time Frame: Baseline, Week 24 ]

Show Outcome Measure 2

3. Secondary:

Time to SEGA Progression Based on Independent Central Radiology Review [ Time Frame: From date of randomization until the earliest date of first documented SEGA progression, date of further anti-SEGA medication (including open-label Everolimus)/surgery or analysis cut-off date (02-Mar-2011) ]

Hide Outcome Measure 3

Measure Type	Secondary
Measure Title	Time to SEGA Progression Based on Independent Central Radiology Review
Measure Description	Time to SEGA progression was defined as time from date of randomization to date of first documented SEGA progression. SEGA progression was defined as one or more of: 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 where nadir is the lowest SEGA volume obtained for the patient previously in the trial) 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
Time Frame	From date of randomization until the earliest date of first documented SEGA progression, date of further anti-SEGA medication (including open-label Everolimus)/surgery or analysis cut-off date (02-Mar-2011)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS) consisted of all randomized patients.

Reporting Groups

	Description
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	Matching Placebo was administered orally.

Measured Values

	Everolimus	Placebo
Number of Participants Analyzed [units: participants]	78	39
Time to SEGA Progression Based on Independent Central Radiology Review [units: Months] Median ( 95% Confidence Interval )	NA ( NA to NA ) ^[1]	NA ( NA to NA ) ^[2]

[1]	NA = Median duration was not reached in either arm. Number of patients who had SEGA Progression was n=0 for Everolimus.
[2]	NA = Median duration was not reached in either arm. Number of patients who had SEGA Progression was n=6 for Placebo.

No statistical analysis provided for Time to SEGA Progression Based on Independent Central Radiology Review

4. Secondary:

Skin Lesion Response Rate as Per Investigator Assessment Using the Physician's Global Assessment of Clinical Condition (PGA) [ Time Frame: From date of randomization until the earliest date of first skin lesion progression, date of start of further therapy against skin lesions (including open-label Everolimus) or analysis cut-off date (02-Mar-2011) ]

Show Outcome Measure 4

5. Secondary:

Change From Baseline in Angiogenesis Biomarkers [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36 and Week 48 ]

Results not yet reported. Anticipated Reporting Date: 09/2014 Safety Issue: No

6. Secondary:

Changes in Renal Function Assessed Using Creatinine Clearance/Globerular Filtration Rate. [ Time Frame: From start of treatment and assessed on a continuous basis through the duration of the study ]

Results not yet reported. Anticipated Reporting Date: 09/2014 Safety Issue: Yes

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

Limitations and Caveats

Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

More Information

Show More Information

To Top