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)
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ClinicalTrials.gov Identifier: NCT00790400 |
Recruitment Status
:
Completed
First Posted
: November 13, 2008
Results First Posted
: August 28, 2012
Last Update Posted
: February 17, 2017
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Condition or disease | Intervention/treatment | Phase |
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Tuberous Sclerosis Complex (TSC) Lymphangioleiomyomatosis (LAM) | Drug: Everolimus (RAD001) Drug: Everolimus Placebo | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 118 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 RAD0001 in the Treatment of Angiomyolipoma in Patients With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) |
Study Start Date : | April 2009 |
Actual Primary Completion Date : | June 2011 |
Actual Study Completion Date : | November 2015 |

Arm | Intervention/treatment |
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Experimental: Everolimus
Study drug was given by continuous oral daily dosing of two 5 mg tablets.
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Drug: Everolimus (RAD001)
Everolimus is used in 5 mg strength tablets, blister-packed under aluminum foil in units of ten tablets and dosed on a daily basis. 10mg daily dosing throughout the trial.
Other Name: RAD001
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Placebo Comparator: Placebo
Placebo was given by continuous oral daily dosing of two 5 mg tablets.
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Drug: Everolimus Placebo
Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.
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- Angiomyolipoma Response Rate as Per Central Radiology Review [ 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 up to 5.7 years ]
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.
For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.
- Time to Angiomyolipoma Progression as Per Central Radiology Review [ 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 up to about 5.7 years ]
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.
For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma progression is defined starting from the start of everolimus. The baseline means the latest value on or before starting everolimus.
- 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 up to 5.7 years ]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). A complete clinical response (CCR) requires a grading of 0 indicating the absence of disease (histological confirmation is not required). Grades 1, 2, and 3 constitute partial response, indicating improvement of at least 50 percent, but less than 100 percent improvement. For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.
- Percentage of Participants With Renal Impairment [ Time Frame: Day 1 up to 28 days after end of treatment ]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. Severe renal impairment was defined as a GFR of <30ml/min/1.73m2.
- Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker [ Time Frame: 4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks ]Blood samples for biomarker assessment were collected immediately prior to study administration. On-treatment samples was compared to baseline samples with the change from baseline.
- Everolimus Trough Concentrations (Cmin) [ Time Frame: Prior to dosing at weeks 2, 4, 12, 24, 48 ]Cmin values collected prior to dose administration on the same study day and at 20-28 hours after previous dose, at steady state, and patient did not vomit within 4 hours of previous dose. Samples collected during the first 4 days of dosing were excluded from all analyses.
- Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose [ Time Frame: 2 hours post-dose administration at Weeks 2, 4, 12, 24, 48 ]C2h values collected 1-3 hours after dose administration on the same study day, at steady state, and patient did not vomit between taking previous dose and blood collection. Samples collected during the first 4 days of dosing will be excluded from all analyses.
- Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response [ 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 up to 5.7 years ]
Time to angiomyolipoma response was defined as the time from the date of randomization until the date of the first documented angiomyolipoma response. 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; no kidney increases in volume > 20% from nadir; no angiomyolipoma-related bleeding of ≥ grade 2.
For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma response is from the start of everolimus. The baseline in the response definition means the latest value on or before starting everolimus.
- Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response [ 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 up to about 5.7 years ]Duration of angiomyolipoma response was defined as the time from the date of the first documented angiomyolipoma response until the date of the first documented angiomyolipoma progression . Angiomyolipoma response was 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.
- Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of 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 up to about 5.7 years ]Duration of skin lesion response is defined as the time from the date of the first skin lesion response until the date of the first skin lesion progression, according to the PGA (physician's global assessment of clinical condition). A progression is when the disease is worse than at baseline evaluation by >=25% or more.

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Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Male or Female 18 years or older
- Clinically definite diagnosis of Tuberous Sclerosis Complex according to the modified Gomez criteria or sporadic LAM (biopsy-proven or compatible chest CT scan)
- Clinically definite diagnosis of renal angiomyolipoma
- At least one Angiomyolipoma of ≥ 3 cm in its longest diameter using CT or MRI
- Females of child bearing potential must use birth control and have documentation of negative pregnancy test
- Written informed consent according to local guidelines
Exclusion Criteria:
- Recent heart attack, cardiac related chest pain or stroke
- Severely impaired lung function
- Bleeding related to angiomyolipoma or embolization during 6 months prior to randomization
- Clinically significant chylous ascites
- Clinically significant hematological or hepatic abnormality
- 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
- Recent use of an investigational drug
- Bleeding diathesis or on oral anti-vitamin K medication
- Uncontrolled high cholesterol
- Uncontrolled diabetes
- HIV
- Inability to attend scheduled clinic visits
- Patients with metal implants thus prohibiting MRI evaluations
- Angiomyolipoma which requires surgery at the time of randomization
- History of malignancy
- Severe or uncontrolled medical conditions which would cause an unacceptable safety risk or compromise compliance with the protocol

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00790400

United States, Alabama | |
University of Alabama at Birmingham | |
Birmingham, Alabama, United States, 35294 | |
United States, Arizona | |
Barrow Tuberous Sclerosis Center | |
Phoenix, Arizona, United States, 85013 | |
United States, Massachusetts | |
Massachusetts General Hospital Massachussetts General Hospita | |
Boston, Massachusetts, United States, 02114 | |
United States, Minnesota | |
Minnesota Epilepsy Group | |
St. Paul, Minnesota, United States, 55102-2383 | |
United States, Ohio | |
Cincinnati Children's Hospital Medical Center | |
Cincinnati, Ohio, United States, 45229-3039 | |
United States, Tennessee | |
LeBonheur Childrens Medical Group SC-2 | |
Memphis, Tennessee, United States, 38103 | |
Canada, Ontario | |
Novartis Investigative Site | |
Torono, Ontario, Canada, M5G 2C4 | |
France | |
Novartis Investigative Site | |
Lyon, France, 69003 | |
Germany | |
Novartis Investigative Site | |
Berlin, Germany, 10098 | |
Novartis Investigative Site | |
München, Germany, 80336 | |
Italy | |
Novartis Investigative Site | |
Siena, SI, Italy, 53100 | |
Novartis Investigative Site | |
Torino, TO, Italy, 10126 | |
Novartis Investigative Site | |
Roma, Italy, 00137 | |
Japan | |
Novartis Investigative Site | |
Sapporo-city, Hokkaido, Japan, 060-8648 | |
Novartis Investigative Site | |
Suita-city, Osaka, Japan, 565-0871 | |
Novartis Investigative Site | |
Yamagata, Japan, 990-9585 | |
Netherlands | |
Novartis Investigative Site | |
Utrecht, Netherlands, 3584CX | |
Poland | |
Novartis Investigative Site | |
Warszawa, Poland, 01138 | |
Novartis Investigative Site | |
Warszawa, Poland, 04-730 | |
Russian Federation | |
Novartis Investigative Site | |
Moscow, Russian Federation, 127412 | |
Spain | |
Novartis Investigative Site | |
Barcelona, Catalunya, Spain, 08025 | |
United Kingdom | |
Novartis Investigative Site | |
Brighton, East Sussex, United Kingdom, BN2 5BE | |
Novartis Investigative Site | |
Craigavon, Northern Ireland, United Kingdom, BT63 5QQ | |
Novartis Investigative Site | |
Cardiff, Wales, United Kingdom, CF14 4XN | |
Novartis Investigative Site | |
London, United Kingdom, SW17 0QT |
Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | Novartis Pharmaceuticals |
ClinicalTrials.gov Identifier: | NCT00790400 History of Changes |
Other Study ID Numbers: |
CRAD001M2302 2008-002113-48 ( EudraCT Number ) |
First Posted: | November 13, 2008 Key Record Dates |
Results First Posted: | August 28, 2012 |
Last Update Posted: | February 17, 2017 |
Last Verified: | January 2017 |
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Angiomyolipoma AML Tuberous Sclerosis Complex TSC mTOR RAD001 Mammalian Target of Rapamycin Everolimus Afinitor SEGA Subependymal Giant Cell Astrocytoma Seizures Tuberous sclerosis complex (TSC) Tuberous sclerosis |
benign tumors of brain kidney heart eyes lungs skinTSC1 TSC2 hamaratin tuberin, tumor growth suppressors gyri tubers Sporadic Lymphangioleiomyomatosis. Lymphangioleiomyomatosis (LAM) rare lung disease |
Additional relevant MeSH terms:
Sclerosis Tuberous Sclerosis Lymphangioleiomyomatosis Angiomyolipoma Pathologic Processes Hamartoma Neoplasms Neoplasms, Multiple Primary Neoplastic Syndromes, Hereditary Malformations of Cortical Development, Group I Malformations of Cortical Development Nervous System Malformations Nervous System Diseases Neurocutaneous Syndromes Heredodegenerative Disorders, Nervous System |
Neurodegenerative Diseases Congenital Abnormalities Genetic Diseases, Inborn Lymphangiomyoma Lymphatic Vessel Tumors Neoplasms by Histologic Type Perivascular Epithelioid Cell Neoplasms Neoplasms, Connective and Soft Tissue Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Neoplasms, Adipose Tissue Everolimus Sirolimus |