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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00789828
• Collaborator: (none)
• Enrollment: 117
• Locations: 24
• Arms: 2
• Duration (Months): 62
• Patients Per Site: 4.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Tuberous Sclerosis; Subependymal Giant Cell Astrocytoma	Drug: Everolimus; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 117 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Everolimus; Everolimus was formulated as tablets of 1.0-mg strength and was blisterpacked under aluminum foil in units of 10 tablets.; Other Names: RAD001
Placebo Comparator: Placebo Matching Placebo administered orally.	Drug: Placebo; Placebo was provided as a matching tablet and was blisterpacked under aluminum foil in units of 10.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response [End of core period (Week 48), and end of extension period (up to 4 years)]

   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.

Secondary Outcome Measures

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

   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.

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

   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.

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

   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.

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

   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.

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

   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).

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

   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.

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

   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.

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

   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.

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

   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.

10. Percentage of Participants With Renal Impairment During Core Period [Day 1 up to 28 days after end of treatment (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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Barrow Tuberous Sclerosis Center	Phoenix	Arizona	United States	85013
3	University of California at Los Angeles	Los Angeles	California	United States	90048
4	Children's Hospital Oakland Hematology/Oncology Dept	Oakland	California	United States	94609-1809
5	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30342
6	University of CHicago Comer Children's Hospital	Chicago	Illinois	United States	60637-1470
7	Massachusetts General Hospital Mass General	Boston	Massachusetts	United States	02114
8	Children's Hospital Boston SC-1	Boston	Massachusetts	United States	02115
9	Minnesota Epilepsy Group - PA	St. Paul	Minnesota	United States	55102-2383
10	Cincinnati Children's Hospital Medical Center Cincinnati Children's Hosp	Cincinnati	Ohio	United States	45229-3039
11	Texas Scottish Rite Hospital for Children	Dallas	Texas	United States	75219
12	Children's Regional Outpatients Center SC	Fairfax	Virginia	United States	22031
13	Novartis Investigative Site	Randwick	New South Wales	Australia	2130
14	Novartis Investigative Site	Brussel		Belgium	1090
15	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1X8
16	Novartis Investigative Site	Quebec		Canada	H3T IC5
17	Novartis Investigative Site	Berlin		Germany	13353
18	Novartis Investigative Site	Heidelberg		Germany	69120
19	Novartis Investigative Site	Genova	GE	Italy	16147
20	Novartis Investigative Site	Roma		Italy	00137
21	Novartis Investigative Site	Utrecht		Netherlands	3584CX
22	Novartis Investigative Site	Warszawa		Poland	04-730
23	Novartis Investigative Site	Moscow		Russian Federation	127412
24	Novartis Investigative Site	Bristol		United Kingdom	BS1 3NU

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticlas, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Visit EXIST-1 NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00789828
• Other Study ID Numbers: CRAD001M2301; 2007-006997-27
• First Posted: Nov 13, 2008
• Last Update Posted: Feb 3, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by Novartis Pharmaceuticals: SEGA; Tuberous Sclerosis; Subependymal Giant Cell Astrocytoma; mTOR; RAD001; Mamalian Target Rapamycin; Everolimus; TSC
• Additional relevant MeSH terms: Astrocytoma; Tuberous Sclerosis; Sclerosis; Everolimus

Study Results

Participant Flow

Recruitment Details	The study was conducted at 24 centers in 10 countries.
Pre-assignment Detail	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.

Arm/Group Title	Everolimus	Placebo
Arm/Group Description	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.	Participants received oral dose of placebo matching to everolimus daily.
Period Title: Core Period (48 Weeks)
STARTED	78	39
COMPLETED	78	33
NOT COMPLETED	0	6
Period Title: Core Period (48 Weeks)
STARTED	111	0
COMPLETED	82	0
NOT COMPLETED	29	0

Baseline Characteristics

Arm/Group Title	Everolimus (Core Period)	Placebo (Core Period)	Total
Arm/Group Description	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.	Participants received oral dose of placebo matching to everolimus daily.	Total of all reporting groups
Overall Participants	78	39	117
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.1 (5.9)	10.3 (7.3)	10.2 (6.4)
Age, Customized (Number) [Number]
<3 years	13 16.7%	7 17.9%	20 17.1%
3-18 years	55 70.5%	26 66.7%	81 69.2%
≥18 years	10 12.8%	6 15.4%	16 13.7%
Sex: Female, Male (Count of Participants)
Female	29 37.2%	21 53.8%	50 42.7%
Male	49 62.8%	18 46.2%	67 57.3%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Everolimus (Core Period)	Placebo (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	Participants received oral dose of placebo matching to everolimus daily.	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.
Measure Participants	78	39	111
Number (95% Confidence Interval) [Percentage of participants]	34.6 44.4%	0.0 0%	57.7 49.3%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the FAS population. Missing values were imputed using last observation carried forward approach for core period while raw count for extension period.

Arm/Group Title	Everolimus (Core Period)	Placebo (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	Participants received oral dose of placebo matching to everolimus daily.	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.
Measure Participants	78	39	34
Mean (Standard Deviation) [Seizure frequency]	-1.24 (6.12)	-0.24 (5.7)	-6.07 (9.719)

3. Secondary Outcome

Title	Time to SEGA Progression
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Everolimus (Core Period)	Placebo (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	Participants received oral dose of placebo matching to everolimus daily.	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.
Measure Participants	78	39	111
Median (95% Confidence Interval) [months]	NA	NA	NA

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the FAS population.

Arm/Group Title	Everolimus (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	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.
Measure Participants	27	64
Median (95% Confidence Interval) [months]	2.99	5.32

5. Secondary Outcome

Title	Duration of SEGA Response
Description	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.
Time Frame	Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Everolimus (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	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.
Measure Participants	27	64
Median (95% Confidence Interval) [months]	NA	NA

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Everolimus (Core Period)	Placebo (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	Participants received oral dose of placebo matching to everolimus daily.	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.
Measure Participants	78	39	111
Median (95% Confidence Interval) [months]	NA	NA	55.72

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the FAS population. Here, "Number of participants analysed" signifies the participants assessed for skin lesion response during the study for each arm, respectively.

Arm/Group Title	Everolimus (Core Period)	Placebo (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	Participants received oral dose of placebo matching to everolimus daily.	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.
Measure Participants	72	38	105
Number (95% Confidence Interval) [Percentage of participants]	41.7 53.5%	10.5 26.9%	58.1 49.7%

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the FAS population. Here, "Number of participants analysed" signifies everolimus treated responders with best overall skin lesion response during the core and extension period, respectively.

Arm/Group Title	Everolimus (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	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.
Measure Participants	30	61
Median (95% Confidence Interval) [months]	NA	NA

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the Safety Set population (Only evaluable PK Samples), defined as participants who received at least one dose of the double-blind study drug, with a valid post baseline assessment. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

Arm/Group Title	Everolimus (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	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.
Measure Participants	78	111
Week 6 (n= 37, 47)	27.52 (15.24)	27.74 (16.202)
Week 24 (n= 11, 13)	38.7 (15.76)	39.25 (14.662)
Week 48 (n= 1, 3)	23.2 (NA)	49.73 (28.884)
Week 96 (n= 0, 6)	NA (NA)	31.63 (21.902)
Week 144 (n= 0, 6)	NA (NA)	26.33 (11.908)
Week 240 (n= 0, 0)	NA (NA)	NA (NA)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis was performed in the Safety Set population. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

Arm/Group Title	Everolimus (Core Period)	Everolimus (Extension Period)
Arm/Group Description	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.	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.
Measure Participants	78	111
Week 6 (n= 64, 94)	5.8 (3.68)	6.09 (3.708)
Week 24 (n= 64, 89)	6.59 (3.43)	6.86 (3.504)
Week 48 (n= 23, 86)	7.28 (3.11)	7.07 (3.214)
Week 72 (n= 4, 92)	6.08 (2.19)	7.25 (3.66)
Week 96 (n= 0, 83)	NA (NA)	7.09 (3.697)
Week 144 (n= 0, 69)	NA (NA)	7.28 (3.35)
Week 240 (n= 0, 13)	NA (NA)	5.85 (2.507)

11. Secondary Outcome

Title	Percentage of Participants With Renal Impairment During Core Period
Description	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.
Time Frame	Day 1 up to 28 days after end of treatment (Core period)

Outcome Measure Data

Analysis Population Description

The analysis was performed in the SAF population. Here, "Number of participants analysed" signifies the participants assessed for renal function during the study for each arm, respectively.

Arm/Group Title	Everolimus (Core Period)	Placebo (Core Period)
Arm/Group Description	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.	Participants received oral dose of placebo matching to everolimus daily.
Measure Participants	78	39
Grade 3 or 4	0 0%	0 0%
Grade 1 or 2	3.8 4.9%	0 0%
Grade 0	96.2 123.3%	100 256.4%

Adverse Events

Time Frame	Serious Adverse Events were monitored from date of First Participant First Visit (FPFV) until Last Participant Last Visit (LPLV), 48 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) until LPLV, up to 4 years.
Adverse Event Reporting Description	For safety, the reporting arms have been created on the basis of actual exposure to study treatment
Arm/Group Title	Everolimus Treated (Core and Extension Period)		Placebo (Core) Then Everolimus Treated (Extension Period)		Placebo Treated (Core Period)
Arm/Group Description	Participants who received everolimus treatment in core period and continued to receive evrolimus treatment in extension period.		Participants who received placebo in core period and then received evrolimus treatment in extension period.		Participants who received placebo in core period.
All Cause Mortality
	Everolimus Treated (Core and Extension Period)		Placebo (Core) Then Everolimus Treated (Extension Period)		Placebo Treated (Core Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Everolimus Treated (Core and Extension Period)		Placebo (Core) Then Everolimus Treated (Extension Period)		Placebo Treated (Core Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/78 (42.3%)		17/33 (51.5%)		3/6 (50%)
Blood and lymphatic system disorders
Anaemia	0/78 (0%)		1/33 (3%)		0/6 (0%)
Lymphadenopathy	0/78 (0%)		1/33 (3%)		0/6 (0%)
Gastrointestinal disorders
Abdominal pain	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Dysphagia	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Gastrooesophageal reflux disease	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Large intestinal ulcer	0/78 (0%)		1/33 (3%)		0/6 (0%)
Mouth ulceration	0/78 (0%)		1/33 (3%)		0/6 (0%)
Small intestinal obstruction	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Umbilical hernia	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Vomiting	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
General disorders
Pyrexia	3/78 (3.8%)		2/33 (6.1%)		1/6 (16.7%)
Immune system disorders
Hypersensitivity	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Infections and infestations
Acinetobacter bacteraemia	0/78 (0%)		1/33 (3%)		0/6 (0%)
Adenovirus infection	2/78 (2.6%)		0/33 (0%)		0/6 (0%)
Bronchitis	3/78 (3.8%)		1/33 (3%)		0/6 (0%)
Bronchopneumonia	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Cellulitis	2/78 (2.6%)		1/33 (3%)		0/6 (0%)
Croup infectious	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Ear infection bacterial	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Epstein-Barr virus infection	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Febrile infection	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Gastroenteritis	4/78 (5.1%)		0/33 (0%)		0/6 (0%)
Gastroenteritis viral	3/78 (3.8%)		0/33 (0%)		0/6 (0%)
Gastrointestinal infection	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Herpes zoster	0/78 (0%)		1/33 (3%)		0/6 (0%)
Infected bites	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Influenza	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Laryngitis	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Mastoiditis	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Meningitis viral	0/78 (0%)		1/33 (3%)		0/6 (0%)
Nasopharyngitis	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Otitis media	2/78 (2.6%)		0/33 (0%)		0/6 (0%)
Parainfluenzae virus infection	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Pertussis	0/78 (0%)		1/33 (3%)		0/6 (0%)
Pneumonia	11/78 (14.1%)		5/33 (15.2%)		1/6 (16.7%)
Respiratory tract infection viral	1/78 (1.3%)		1/33 (3%)		0/6 (0%)
Sinusitis	0/78 (0%)		1/33 (3%)		0/6 (0%)
Tonsillitis	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Tooth abscess	0/78 (0%)		1/33 (3%)		0/6 (0%)
Upper respiratory tract infection	2/78 (2.6%)		1/33 (3%)		0/6 (0%)
Urinary tract infection	1/78 (1.3%)		2/33 (6.1%)		0/6 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Foreign body aspiration	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Procedural pain	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Investigations
Blood alkaline phosphatase increased	0/78 (0%)		1/33 (3%)		0/6 (0%)
Metabolism and nutrition disorders
Dehydration	3/78 (3.8%)		1/33 (3%)		0/6 (0%)
Hyponatraemia	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Patellofemoral pain syndrome	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Temporomandibular joint syndrome	0/78 (0%)		1/33 (3%)		0/6 (0%)
Tendon disorder	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Nervous system disorders
Ataxia	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Complex partial seizures	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Convulsion	4/78 (5.1%)		1/33 (3%)		2/6 (33.3%)
Drooling	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Epilepsy	2/78 (2.6%)		0/33 (0%)		0/6 (0%)
Febrile convulsion	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Grand mal convulsion	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Headache	0/78 (0%)		1/33 (3%)		0/6 (0%)
Partial seizures	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Status epilepticus	2/78 (2.6%)		1/33 (3%)		0/6 (0%)
Psychiatric disorders
Affective disorder	1/78 (1.3%)		1/33 (3%)		0/6 (0%)
Agitation	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Renal and urinary disorders
Focal segmental glomerulosclerosis	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Asphyxia	0/78 (0%)		1/33 (3%)		0/6 (0%)
Pneumonia aspiration	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Pneumothorax	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Pulmonary pneumatocele	0/78 (0%)		1/33 (3%)		0/6 (0%)
Tonsillar hypertrophy	1/78 (1.3%)		0/33 (0%)		0/6 (0%)
Vascular disorders
Raynaud's phenomenon	0/78 (0%)		0/33 (0%)		1/6 (16.7%)
Other (Not Including Serious) Adverse Events
	Everolimus Treated (Core and Extension Period)		Placebo (Core) Then Everolimus Treated (Extension Period)		Placebo Treated (Core Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/78 (98.7%)		33/33 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anaemia	6/78 (7.7%)		1/33 (3%)		0/6 (0%)
Neutropenia	8/78 (10.3%)		3/33 (9.1%)		0/6 (0%)
Ear and labyrinth disorders
Ear pain	2/78 (2.6%)		2/33 (6.1%)		0/6 (0%)
Vertigo	0/78 (0%)		0/33 (0%)		1/6 (16.7%)
Endocrine disorders
Hypothyroidism	0/78 (0%)		0/33 (0%)		1/6 (16.7%)
Gastrointestinal disorders
Abdominal pain	5/78 (6.4%)		0/33 (0%)		1/6 (16.7%)
Abdominal pain upper	5/78 (6.4%)		3/33 (9.1%)		0/6 (0%)
Constipation	11/78 (14.1%)		2/33 (6.1%)		0/6 (0%)
Dental caries	5/78 (6.4%)		2/33 (6.1%)		0/6 (0%)
Diarrhoea	21/78 (26.9%)		7/33 (21.2%)		0/6 (0%)
Enteritis	2/78 (2.6%)		0/33 (0%)		1/6 (16.7%)
Mouth ulceration	33/78 (42.3%)		6/33 (18.2%)		0/6 (0%)
Nausea	7/78 (9%)		1/33 (3%)		0/6 (0%)
Oral pain	4/78 (5.1%)		1/33 (3%)		0/6 (0%)
Stomatitis	29/78 (37.2%)		21/33 (63.6%)		1/6 (16.7%)
Toothache	1/78 (1.3%)		2/33 (6.1%)		0/6 (0%)
Vomiting	24/78 (30.8%)		6/33 (18.2%)		1/6 (16.7%)
General disorders
Asthenia	0/78 (0%)		2/33 (6.1%)		0/6 (0%)
Fatigue	16/78 (20.5%)		2/33 (6.1%)		0/6 (0%)
Pyrexia	25/78 (32.1%)		7/33 (21.2%)		2/6 (33.3%)
Immune system disorders
Seasonal allergy	5/78 (6.4%)		5/33 (15.2%)		0/6 (0%)
Infections and infestations
Abscess	0/78 (0%)		0/33 (0%)		1/6 (16.7%)
Body tinea	0/78 (0%)		2/33 (6.1%)		0/6 (0%)
Bronchitis	14/78 (17.9%)		5/33 (15.2%)		1/6 (16.7%)
Cellulitis	4/78 (5.1%)		0/33 (0%)		0/6 (0%)
Conjunctivitis	7/78 (9%)		5/33 (15.2%)		0/6 (0%)
Croup infectious	4/78 (5.1%)		0/33 (0%)		0/6 (0%)
Ear infection	14/78 (17.9%)		4/33 (12.1%)		0/6 (0%)
Fungal infection	0/78 (0%)		3/33 (9.1%)		0/6 (0%)
Gastroenteritis	4/78 (5.1%)		2/33 (6.1%)		0/6 (0%)
Gastroenteritis viral	9/78 (11.5%)		4/33 (12.1%)		0/6 (0%)
Gastrointestinal infection	1/78 (1.3%)		2/33 (6.1%)		0/6 (0%)
Gastrointestinal viral infection	4/78 (5.1%)		1/33 (3%)		0/6 (0%)
Influenza	6/78 (7.7%)		2/33 (6.1%)		0/6 (0%)
Laryngitis	4/78 (5.1%)		0/33 (0%)		0/6 (0%)
Nasopharyngitis	30/78 (38.5%)		15/33 (45.5%)		1/6 (16.7%)
Oral candidiasis	2/78 (2.6%)		0/33 (0%)		1/6 (16.7%)
Otitis media	16/78 (20.5%)		5/33 (15.2%)		0/6 (0%)
Pharyngitis	12/78 (15.4%)		7/33 (21.2%)		0/6 (0%)
Pharyngitis streptococcal	15/78 (19.2%)		2/33 (6.1%)		1/6 (16.7%)
Pneumonia	12/78 (15.4%)		3/33 (9.1%)		1/6 (16.7%)
Respiratory tract infection	6/78 (7.7%)		1/33 (3%)		0/6 (0%)
Respiratory tract infection viral	7/78 (9%)		3/33 (9.1%)		0/6 (0%)
Rhinitis	8/78 (10.3%)		2/33 (6.1%)		0/6 (0%)
Sinusitis	17/78 (21.8%)		4/33 (12.1%)		1/6 (16.7%)
Tracheitis	0/78 (0%)		0/33 (0%)		1/6 (16.7%)
Upper respiratory tract infection	23/78 (29.5%)		7/33 (21.2%)		3/6 (50%)
Urinary tract infection	7/78 (9%)		1/33 (3%)		0/6 (0%)
Varicella	4/78 (5.1%)		0/33 (0%)		0/6 (0%)
Viral infection	6/78 (7.7%)		3/33 (9.1%)		0/6 (0%)
Vulvovaginal mycotic infection	1/78 (1.3%)		1/33 (3%)		1/6 (16.7%)
Injury, poisoning and procedural complications
Arthropod bite	3/78 (3.8%)		4/33 (12.1%)		0/6 (0%)
Excoriation	4/78 (5.1%)		0/33 (0%)		0/6 (0%)
Fall	2/78 (2.6%)		0/33 (0%)		2/6 (33.3%)
Hand fracture	0/78 (0%)		0/33 (0%)		1/6 (16.7%)
Laceration	2/78 (2.6%)		2/33 (6.1%)		0/6 (0%)
Limb injury	2/78 (2.6%)		1/33 (3%)		1/6 (16.7%)
Lip injury	0/78 (0%)		1/33 (3%)		1/6 (16.7%)
Investigations
Activated partial thromboplastin time prolonged	4/78 (5.1%)		1/33 (3%)		0/6 (0%)
Blood cholesterol increased	11/78 (14.1%)		3/33 (9.1%)		1/6 (16.7%)
Blood fibrinogen decreased	5/78 (6.4%)		6/33 (18.2%)		0/6 (0%)
Blood glucose increased	0/78 (0%)		0/33 (0%)		1/6 (16.7%)
Blood lactate dehydrogenase increased	6/78 (7.7%)		0/33 (0%)		0/6 (0%)
Blood triglycerides increased	7/78 (9%)		0/33 (0%)		0/6 (0%)
Carbon dioxide decreased	4/78 (5.1%)		0/33 (0%)		0/6 (0%)
Cardiac murmur	0/78 (0%)		0/33 (0%)		1/6 (16.7%)
International normalised ratio increased	4/78 (5.1%)		1/33 (3%)		0/6 (0%)
Low density lipoprotein increased	6/78 (7.7%)		2/33 (6.1%)		1/6 (16.7%)
Neutrophil count decreased	6/78 (7.7%)		1/33 (3%)		0/6 (0%)
Weight decreased	5/78 (6.4%)		1/33 (3%)		0/6 (0%)
Metabolism and nutrition disorders
Decreased appetite	12/78 (15.4%)		6/33 (18.2%)		0/6 (0%)
Dehydration	2/78 (2.6%)		1/33 (3%)		2/6 (33.3%)
Hypercholesterolaemia	11/78 (14.1%)		3/33 (9.1%)		0/6 (0%)
Hyperlipidaemia	6/78 (7.7%)		0/33 (0%)		0/6 (0%)
Hypertriglyceridaemia	4/78 (5.1%)		2/33 (6.1%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	6/78 (7.7%)		0/33 (0%)		0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	3/78 (3.8%)		0/33 (0%)		1/6 (16.7%)
Nervous system disorders
Convulsion	31/78 (39.7%)		13/33 (39.4%)		4/6 (66.7%)
Dizziness	6/78 (7.7%)		3/33 (9.1%)		0/6 (0%)
Epilepsy	3/78 (3.8%)		2/33 (6.1%)		1/6 (16.7%)
Headache	13/78 (16.7%)		6/33 (18.2%)		1/6 (16.7%)
Migraine with aura	0/78 (0%)		0/33 (0%)		1/6 (16.7%)
Psychiatric disorders
Abnormal behaviour	6/78 (7.7%)		0/33 (0%)		0/6 (0%)
Aggression	10/78 (12.8%)		3/33 (9.1%)		0/6 (0%)
Agitation	6/78 (7.7%)		1/33 (3%)		0/6 (0%)
Anxiety	10/78 (12.8%)		3/33 (9.1%)		0/6 (0%)
Insomnia	11/78 (14.1%)		4/33 (12.1%)		0/6 (0%)
Irritability	5/78 (6.4%)		1/33 (3%)		0/6 (0%)
Obsessive-compulsive disorder	5/78 (6.4%)		0/33 (0%)		0/6 (0%)
Sleep disorder	1/78 (1.3%)		3/33 (9.1%)		0/6 (0%)
Reproductive system and breast disorders
Amenorrhoea	5/78 (6.4%)		0/33 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	23/78 (29.5%)		10/33 (30.3%)		1/6 (16.7%)
Epistaxis	4/78 (5.1%)		3/33 (9.1%)		0/6 (0%)
Nasal congestion	2/78 (2.6%)		2/33 (6.1%)		0/6 (0%)
Oropharyngeal pain	6/78 (7.7%)		1/33 (3%)		0/6 (0%)
Rhinorrhoea	4/78 (5.1%)		2/33 (6.1%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Acne	18/78 (23.1%)		4/33 (12.1%)		0/6 (0%)
Dermatitis	1/78 (1.3%)		2/33 (6.1%)		0/6 (0%)
Dry skin	4/78 (5.1%)		1/33 (3%)		0/6 (0%)
Eczema	5/78 (6.4%)		0/33 (0%)		0/6 (0%)
Rash	12/78 (15.4%)		2/33 (6.1%)		0/6 (0%)
Vascular disorders
Hypertension	11/78 (14.1%)		1/33 (3%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Principal Investigators are NOT employed by the organization sponsoring the study. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.