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

Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This study will evaluate the safety and efficacy of RAD001 in treating patients with Angiomyolipoma associated with Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis.

Condition or disease	Intervention/treatment	Phase
Tuberous Sclerosis Complex (TSC) Lymphangioleiomyomatosis (LAM)	Drug: Everolimus (RAD001) Drug: Everolimus Placebo	Phase 3

Study Design


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

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Lymphangioleiomyomatosis Tuberous sclerosis complex

MedlinePlus related topics: Tuberous Sclerosis

Drug Information available for: Sirolimus Everolimus Temsirolimus

Genetic and Rare Diseases Information Center resources: Tuberous Sclerosis Bourneville Syndrome Lymphangioleiomyomatosis Subependymal Giant Cell Astrocytoma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Everolimus Study drug was given by continuous oral daily dosing of two 5 mg tablets.	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
Placebo Comparator: Placebo Placebo was given by continuous oral daily dosing of two 5 mg tablets.	Drug: Everolimus Placebo Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.

Outcome Measures

Primary Outcome Measures :

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.

Secondary Outcome Measures :

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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Information from the National Library of Medicine

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

Hide Study Locations

Locations


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

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators


Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

Publications:

Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2013 Mar 9;381(9869):817-24.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Sparagana S, Franz DN, Krueger DA, Bissler JJ, Berkowitz N, Burock K, Kingswood JC. Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex. PLoS One. 2017 Oct 12;12(10):e0186235. doi: 10.1371/journal.pone.0186235. eCollection 2017.

Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Berkowitz N, Miao S, Segal S, Peyrard S, Budde K. Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol Dial Transplant. 2016 Jan;31(1):111-9. doi: 10.1093/ndt/gfv249. Epub 2015 Jul 8.


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

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