Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1) (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: January 4, 2016

Last verified: January 2016

History of Changes

Results First Received: March 1, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions:	Tuberous Sclerosis Subependymal Giant Cell Astrocytoma
Interventions:	Drug: Everolimus Drug: Placebo

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study was conducted at 24 centers in 10 countries.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 117 participants were enrolled and randomized into the core period. Only 111 participants completing the core period, continued in the open-label extension period of the study.

Reporting Groups

	Description
Everolimus	Participants received oral dose of everolimus 4.5 milligram/square meter (mg/m^2) daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 nanogram/millilitre (ng/mL). Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo	Participants received oral dose of placebo matching to everolimus daily.

Participant Flow for 2 periods

Period 1: Core Period (48 Weeks)

	Everolimus	Placebo
STARTED	78	39
COMPLETED	78	33
NOT COMPLETED	0	6
Administrative problems	0	1
Withdrawal by Subject	0	4
Lost to Follow-up	0	1

Period 2: Open-label Extension Period (4 Years)

	Everolimus	Placebo
STARTED	111 ^[1]	0 ^[2]
COMPLETED	82	0
NOT COMPLETED	29	0
Adverse Event	10	0
Withdrawal by Subject	6	0
Lost to Follow-up	3	0
Administrative problems	7	0
Death	1	0
Disease progression	1	0
New treatment for indication under study	1	0

^[1]	Of 117 participants only 111 completed the core period and continued in the extension period
^[2]	No participant received placebo.

Baseline Characteristics

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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.
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Reporting Groups

	Description
Everolimus (Core Period)	Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo (Core Period)	Participants received oral dose of placebo matching to everolimus daily.
Total	Total of all reporting groups

Baseline Measures

	Everolimus (Core Period)	Placebo (Core Period)	Total
Overall Participants Analyzed [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

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1. Primary:

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) ]

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Measure Type	Primary
Measure Title	Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response
Measure Description	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.
Time Frame	End of core period (Week 48), and end of extension period (up to 4 years)

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 primary analysis was performed in Full Analysis Set (FAS) population, defined as all randomized participants involved in the study.

Reporting Groups

	Description
Everolimus (Core Period)	Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo (Core Period)	Participants received oral dose of placebo matching to everolimus daily.
Everolimus (Extension Period)	Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain blood trough concentrations in range of 5-15 ng/mL.

Measured Values

	Everolimus (Core Period)	Placebo (Core Period)	Everolimus (Extension Period)
Participants Analyzed [Units: Participants]	78	39	111
Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response [Units: Percentage of participants] Number (95% Confidence Interval)	34.6 (24.2 to 46.2)	0.0 (0.0 to 9.0)	57.7 (47.9 to 67)

No statistical analysis provided for Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response

2. Secondary:

Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period [ Time Frame: 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) ]

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3. Secondary:

Time to SEGA Progression [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

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Measure Type	Secondary
Measure Title	Time to SEGA Progression
Measure Description	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.
Time Frame	Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

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 analysis was performed in the FAS population. Here "Number of participants analysed" signifies the participants assessed for time to SEGA progression during the study for each arm, respectively.

Reporting Groups

	Description
Everolimus (Core Period)	Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo (Core Period)	Participants received oral dose of placebo matching to everolimus daily.
Everolimus (Extension Period)	Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain blood trough concentrations in range of 5-15 ng/mL.

Measured Values

	Everolimus (Core Period)	Placebo (Core Period)	Everolimus (Extension Period)
Participants Analyzed [Units: Participants]	78	39	111
Time to SEGA Progression [Units: Months] Median (95% Confidence Interval)	NA ^[1]	NA ^[2]	NA ^[3]

[1]	Median was not reached as no participant experienced disease progression during core period.
[2]	Median was not reached as only 6 participants experienced disease progression during core period.
[3]	Median was not reached as no participant experienced disease progression during extension period.

No statistical analysis provided for Time to SEGA Progression

4. Secondary:

Time to SEGA Response [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

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5. Secondary:

Duration of SEGA Response [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

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6. Secondary:

Time to SEGA Worsening [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

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7. Secondary:

Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score [ Time Frame: End of core period (Week 48), and end of extension period (up to 4 years) ]

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8. Secondary:

Duration of Skin Lesion Response in Everolimus Treated Participants [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

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9. Secondary:

Everolimus Blood Concentration (C2h) at 2 Hours Post Dose [ Time Frame: 2 hours post dose on Week 6, Week 24, Week 48, Week 96, Week 144, and Week 240 ]

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10. Secondary:

Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose [ Time Frame: 24 hours post dose on Week 6, Week 24, Week 48, Week 72, Week 96, Week 144, and Week 240 ]

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11. Secondary:

Percentage of Participants With Renal Impairment During Core Period [ Time Frame: Day 1 up to 28 days after end of treatment (Core period) ]

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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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
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