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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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). ]

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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). ]

Show Outcome Measure 2

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). ]

Show Outcome Measure 3

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). ]

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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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