Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) (EXIST-2)

This study is ongoing, but not recruiting participants.

Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

ClinicalTrials.gov Identifier:

NCT00790400

First received: November 10, 2008

Last updated: February 25, 2013

Last verified: February 2013

History of Changes

Results First Received: May 23, 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 Complex (TSC) Lymphangioleiomyomatosis (LAM)
Interventions:	Drug: Everolimus (RAD001) Other: 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
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Everolimus	Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo	Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Participant Flow: Overall Study

	Everolimus	Placebo
STARTED	79	39
COMPLETED	7 ^[1]	13
NOT COMPLETED	72	26
Ongoing in Double-blind	72	26

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

Baseline Characteristics

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Reporting Groups

	Description
Everolimus	Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo	Placebo was given by continuous oral daily dosing of two 5 mg tablets.
Total	Total of all reporting groups

Baseline Measures

	Everolimus	Placebo	Total
Number of Participants [units: participants]	79	39	118
Age [units: years] Mean ± Standard Deviation	32.5 ± 10.37	31.0 ± 9.64	32.0 ± 10.12
Age, Customized [units: Participants]
<30 years	35	20	55
≥ 30 years	44	19	63
Gender [units: participants]
Female	52	26	78
Male	27	13	40

Outcome Measures

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1. Primary:

Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period) [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or analysis cut-off date (30-June-2011). ]

Measure Type	Primary
Measure Title	Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period)
Measure Description	Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later)• No new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified.• There were no kidney increases in volume > 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2
Time Frame	From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or analysis cut-off date (30-June-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) is defined according to the Intention-to-Treat principle and consists of all randomized patients. Patients were to be analyzed according to the treatment that they were assigned to at randomization.

Reporting Groups

	Description
Everolimus	Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo	Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Measured Values

	Everolimus	Placebo
Number of Participants Analyzed [units: participants]	79	39
Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period) [units: Percentage of Participants] Number ( 95% Confidence Interval )	41.8 ( 30.8 to 53.4 )	0 ( 0.0 to 9.0 )

No statistical analysis provided for Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period)

2. Secondary:

Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period) [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or analysis cut-off date (30-June-2011). ]

Measure Type	Secondary
Measure Title	Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)
Measure Description	Time to angiomyolipoma progression (TTAP) is defined as time from date of randomization to date of first documented angiomyolipoma progression. Angiomyolipoma progression was defined as one or more of the following: • Increase from nadir of ≥ 25% in angiomyolipoma volume to value greater than baseline • The appearance of a new angiomyolipoma ≥ 1.0 cm in longest diameter •An increase from nadir of 20% or more in the volume of either kidney to a value greater than baseline •Angiomyolipoma-related bleeding grade ≥ 2
Time Frame	From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or analysis cut-off date (30-June-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) is defined according to the Intention-to-Treat principle and consists of all randomized patients. Patients were to be analyzed according to the treatment that they were assigned at randomization.

Reporting Groups

	Description
Everolimus	Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo	Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Measured Values

	Everolimus	Placebo
Number of Participants Analyzed [units: participants]	79	39
Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period) [units: months] Median ( 95% Confidence Interval )	NA ( NA to NA ) ^[1]	11.37 ( 11.07 to NA ) ^[2]

[1]	The median time to Angiomyolipoma Progression could not be estimated because <50% of patients had an Angiomyolipoma Progression during the time period.
[2]	The upper limit was not estimable in the study as it is longer than the estimated time period till data cut-off date (30-June-2011)

No statistical analysis provided for Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)

3. Secondary:

Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline) [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or analysis cut-off date (30-June-2011). ]

Measure Type	Secondary
Measure Title	Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)
Measure Description	Skin lesion response rate in the double-blind period was determined only among patients with at least one skin lesion at baseline, and is the percentage of this group of patients with a best overall skin lesion response on the Physician’s Global Assessment of Clinical Condition (PGA) of either complete clinical response (CCR) or partial response (PR).
Time Frame	From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or analysis cut-off date (30-June-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) is defined according to the Intention-to-Treat principle and consists of all randomized patients. Patients were to be analyzed according to the treatment that they were assigned at randomization.

Reporting Groups

	Description
Everolimus	Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo	Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Measured Values

	Everolimus	Placebo
Number of Participants Analyzed [units: participants]	77	37
Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline) [units: Percentage of participants] Number ( 95% Confidence Interval )	26 ( 16.6 to 37.2 )	0 ( 0.0 to 9.5 )

No statistical analysis provided for Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)

4. Secondary:

Percentage of Participants With Renal Impairment [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or analysis cut-off date (30-June-2011). ]

Measure Type	Secondary
Measure Title	Percentage of Participants With Renal Impairment
Measure Description	Renal Impairment was measured by glomerular filtration rate which was calculated using the Modification of Diet in Renal Disease formula. Percentage of participants with renal impairment was reported.
Time Frame	From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or analysis cut-off date (30-June-2011).
Safety Issue	Yes

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 safety set consists of all patients who received at least one dose of the double-blind study drug with a valid post-baseline assessment.

Reporting Groups

	Description
Everolimus	Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo	Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Measured Values

	Everolimus	Placebo
Number of Participants Analyzed [units: participants]	79	39
Percentage of Participants With Renal Impairment [units: Percentage of Participants]
Glomerular filtration rate <30 ml/min/1.73m^2	2.5	7.7
Glomerular filtration rate≥ 30 ml/min/1.73m^2	97.5	92.3

No statistical analysis provided for Percentage of Participants With Renal Impairment

5. Secondary:

Change From Baseline in Plasma Angiogenic Molecules [ Time Frame: Baseline, 12 Months ]

Results not yet posted. Anticipated Posting Date: 12/2014 Safety Issue: No

Serious Adverse Events

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Other Adverse Events

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Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Everolimus	Everolimus
Placebo	Placebo

Other Adverse Events

	Everolimus	Placebo
Total, other (not including serious) adverse events
# participants affected / at risk	78/79	36/39
Blood and lymphatic system disorders
Anaemia ^{† 1}
# participants affected / at risk	10/79 (12.66%)	1/39 (2.56%)
Leukopenia ^{† 1}
# participants affected / at risk	8/79 (10.13%)	3/39 (7.69%)
Lymphopenia ^{† 1}
# participants affected / at risk	5/79 (6.33%)	3/39 (7.69%)
Neutropenia ^{† 1}
# participants affected / at risk	5/79 (6.33%)	4/39 (10.26%)
Thrombocytopenia ^{† 1}
# participants affected / at risk	6/79 (7.59%)	0/39 (0.00%)
Ear and labyrinth disorders
Vertigo ^{† 1}
# participants affected / at risk	1/79 (1.27%)	2/39 (5.13%)
Gastrointestinal disorders
Abdominal pain ^{† 1}
# participants affected / at risk	9/79 (11.39%)	3/39 (7.69%)
Abdominal pain upper ^{† 1}
# participants affected / at risk	1/79 (1.27%)	2/39 (5.13%)
Aphthous stomatitis ^{† 1}
# participants affected / at risk	15/79 (18.99%)	4/39 (10.26%)
Constipation ^{† 1}
# participants affected / at risk	6/79 (7.59%)	1/39 (2.56%)
Diarrhoea ^{† 1}
# participants affected / at risk	10/79 (12.66%)	2/39 (5.13%)
Flatulence ^{† 1}
# participants affected / at risk	5/79 (6.33%)	0/39 (0.00%)
Mouth ulceration ^{† 1}
# participants affected / at risk	13/79 (16.46%)	2/39 (5.13%)
Nausea ^{† 1}
# participants affected / at risk	13/79 (16.46%)	5/39 (12.82%)
Stomatitis ^{† 1}
# participants affected / at risk	38/79 (48.10%)	3/39 (7.69%)
Vomiting ^{† 1}
# participants affected / at risk	12/79 (15.19%)	2/39 (5.13%)
General disorders
Fatigue ^{† 1}
# participants affected / at risk	13/79 (16.46%)	7/39 (17.95%)
Influenza like illness ^{† 1}
# participants affected / at risk	1/79 (1.27%)	4/39 (10.26%)
Oedema peripheral ^{† 1}
# participants affected / at risk	7/79 (8.86%)	3/39 (7.69%)
Pyrexia ^{† 1}
# participants affected / at risk	6/79 (7.59%)	3/39 (7.69%)
Infections and infestations
Bronchitis ^{† 1}
# participants affected / at risk	4/79 (5.06%)	5/39 (12.82%)
Cellulitis ^{† 1}
# participants affected / at risk	1/79 (1.27%)	3/39 (7.69%)
Influenza ^{† 1}
# participants affected / at risk	2/79 (2.53%)	3/39 (7.69%)
Nasopharyngitis ^{† 1}
# participants affected / at risk	19/79 (24.05%)	12/39 (30.77%)
Otitis media ^{† 1}
# participants affected / at risk	4/79 (5.06%)	0/39 (0.00%)
Rash pustular ^{† 1}
# participants affected / at risk	5/79 (6.33%)	0/39 (0.00%)
Rhinitis ^{† 1}
# participants affected / at risk	6/79 (7.59%)	5/39 (12.82%)
Sinusitis ^{† 1}
# participants affected / at risk	4/79 (5.06%)	1/39 (2.56%)
Upper respiratory tract infection ^{† 1}
# participants affected / at risk	8/79 (10.13%)	2/39 (5.13%)
Urinary tract infection ^{† 1}
# participants affected / at risk	12/79 (15.19%)	6/39 (15.38%)
Injury, poisoning and procedural complications
Procedural pain ^{† 1}
# participants affected / at risk	1/79 (1.27%)	2/39 (5.13%)
Investigations
Activated partial thromboplastin time prolonged ^{† 1}
# participants affected / at risk	1/79 (1.27%)	2/39 (5.13%)
Alanine aminotransferase increased ^{† 1}
# participants affected / at risk	3/79 (3.80%)	2/39 (5.13%)
Blood alkaline phosphatase increased ^{† 1}
# participants affected / at risk	6/79 (7.59%)	0/39 (0.00%)
Blood creatine phosphokinase increased ^{† 1}
# participants affected / at risk	3/79 (3.80%)	2/39 (5.13%)
Blood creatinine increased ^{† 1}
# participants affected / at risk	1/79 (1.27%)	3/39 (7.69%)
Blood lactate dehydrogenase increased ^{† 1}
# participants affected / at risk	9/79 (11.39%)	2/39 (5.13%)
Blood phosphorus decreased ^{† 1}
# participants affected / at risk	4/79 (5.06%)	0/39 (0.00%)
Carbon monoxide diffusing capacity decreased ^{† 1}
# participants affected / at risk	7/79 (8.86%)	0/39 (0.00%)
Gamma-glutamyltransferase increased ^{† 1}
# participants affected / at risk	4/79 (5.06%)	0/39 (0.00%)
Metabolism and nutrition disorders
Decreased appetite ^{† 1}
# participants affected / at risk	5/79 (6.33%)	0/39 (0.00%)
Hypercholesterolaemia ^{† 1}
# participants affected / at risk	16/79 (20.25%)	1/39 (2.56%)
Hyperlipidaemia ^{† 1}
# participants affected / at risk	6/79 (7.59%)	0/39 (0.00%)
Hypophosphataemia ^{† 1}
# participants affected / at risk	9/79 (11.39%)	0/39 (0.00%)
Iron deficiency ^{† 1}
# participants affected / at risk	4/79 (5.06%)	1/39 (2.56%)
Musculoskeletal and connective tissue disorders
Arthralgia ^{† 1}
# participants affected / at risk	10/79 (12.66%)	2/39 (5.13%)
Back pain ^{† 1}
# participants affected / at risk	5/79 (6.33%)	5/39 (12.82%)
Flank pain ^{† 1}
# participants affected / at risk	3/79 (3.80%)	5/39 (12.82%)
Musculoskeletal chest pain ^{† 1}
# participants affected / at risk	1/79 (1.27%)	2/39 (5.13%)
Myalgia ^{† 1}
# participants affected / at risk	5/79 (6.33%)	1/39 (2.56%)
Pain in extremity ^{† 1}
# participants affected / at risk	2/79 (2.53%)	3/39 (7.69%)
Nervous system disorders
Convulsion ^{† 1}
# participants affected / at risk	2/79 (2.53%)	4/39 (10.26%)
Dizziness ^{† 1}
# participants affected / at risk	6/79 (7.59%)	3/39 (7.69%)
Headache ^{† 1}
# participants affected / at risk	17/79 (21.52%)	7/39 (17.95%)
Migraine ^{† 1}
# participants affected / at risk	4/79 (5.06%)	0/39 (0.00%)
Psychiatric disorders
Affective disorder ^{† 1}
# participants affected / at risk	0/79 (0.00%)	2/39 (5.13%)
Depression ^{† 1}
# participants affected / at risk	4/79 (5.06%)	0/39 (0.00%)
Renal and urinary disorders
Haematuria ^{† 1}
# participants affected / at risk	1/79 (1.27%)	3/39 (7.69%)
Leukocyturia ^{† 1}
# participants affected / at risk	0/79 (0.00%)	2/39 (5.13%)
Proteinuria ^{† 1}
# participants affected / at risk	3/79 (3.80%)	3/39 (7.69%)
Reproductive system and breast disorders
Amenorrhoea ^{† 1}
# participants affected / at risk	7/79 (8.86%)	1/39 (2.56%)
Menorrhagia ^{† 1}
# participants affected / at risk	4/79 (5.06%)	0/39 (0.00%)
Menstruation irregular ^{† 1}
# participants affected / at risk	4/79 (5.06%)	0/39 (0.00%)
Vaginal haemorrhage ^{† 1}
# participants affected / at risk	4/79 (5.06%)	0/39 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough ^{† 1}
# participants affected / at risk	16/79 (20.25%)	5/39 (12.82%)
Epistaxis ^{† 1}
# participants affected / at risk	7/79 (8.86%)	1/39 (2.56%)
Oropharyngeal pain ^{† 1}
# participants affected / at risk	8/79 (10.13%)	4/39 (10.26%)
Skin and subcutaneous tissue disorders
Acne ^{† 1}
# participants affected / at risk	17/79 (21.52%)	2/39 (5.13%)
Dermatitis acneiform ^{† 1}
# participants affected / at risk	6/79 (7.59%)	0/39 (0.00%)
Dry skin ^{† 1}
# participants affected / at risk	7/79 (8.86%)	2/39 (5.13%)
Eczema ^{† 1}
# participants affected / at risk	8/79 (10.13%)	3/39 (7.69%)
Papule ^{† 1}
# participants affected / at risk	4/79 (5.06%)	1/39 (2.56%)
Vascular disorders
Haematoma ^{† 1}
# participants affected / at risk	1/79 (1.27%)	2/39 (5.13%)
Hypertension ^{† 1}
# participants affected / at risk	7/79 (8.86%)	4/39 (10.26%)

†	Events were collected by systematic assessment
1	Term from vocabulary, 14.0

More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

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
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Results Point of Contact:

Name/Title: Novartis Pharmaceuticals
Organization: Novartis Pharmaceuticals
phone: 862-778-8300

No publications provided

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT00790400 History of Changes
Other Study ID Numbers:	CRAD001M2302, 2008-002113-48
Study First Received:	November 10, 2008
Results First Received:	May 23, 2012
Last Updated:	February 25, 2013
Health Authority:	United States: Food and Drug Administration Canada: Health Canada France: Ministry of Health Germany: Federal Institute for Drugs and Medical Devices Italy: Ministry of Health Japan: Ministry of Health, Labour and Welfare, Pharmaceutical and Medical Safety Bureau Netherlands: Medical Ethics Review Committee (METC) Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Russia: Federal Service on Surveillance in Healthcare and Social Development of Russian Federation Spain: Ministerio de Sanidad y Politica Social United Kingdom: Medicines and Healthcare Products Regulatory Agency

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