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

NCT00790400 | Completed Phase 3 Results DMC

• 2 other identifiers: CRAD001M23022008-002113-48
• Study Type: interventional
• Target: 118
• Locations: 11 countries
• Sites: 25

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.

Conditions

Tuberous Sclerosis Complex (TSC); Lymphangioleiomyomatosis (LAM)

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Angiomyolipoma Response Rate as Per Central Radiology Review

  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.

  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

Secondary Outcomes (9)

• Time to Angiomyolipoma Progression as Per Central Radiology Review

  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

• Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)

  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

• Percentage of Participants With Renal Impairment

  Day 1 up to 28 days after end of treatment

• Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker

  4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks

• Everolimus Trough Concentrations (Cmin)

  Prior to dosing at weeks 2, 4, 12, 24, 48

Study Arms (2)

Everolimus

EXPERIMENTAL

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

Drug: Everolimus (RAD001)

Placebo

PLACEBO COMPARATOR

Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Drug: Everolimus Placebo

Interventions

Everolimus (RAD001) DRUG

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.

Also known as: RAD001

Everolimus

Everolimus Placebo DRUG

Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (25)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Barrow Tuberous Sclerosis Center

Phoenix, Arizona, 85013, United States

Location

Massachusetts General Hospital Massachussetts General Hospita

Boston, Massachusetts, 02114, United States

Location

Minnesota Epilepsy Group

Saint Paul, Minnesota, 55102-2383, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

LeBonheur Childrens Medical Group SC-2

Memphis, Tennessee, 38103, United States

Location

Novartis Investigative Site

Torono, Ontario, M5G 2C4, Canada

Location

Novartis Investigative Site

Lyon, France, 69003, France

Location

Novartis Investigative Site

Berlin, 10098, Germany

Location

Novartis Investigative Site

München, 80336, Germany

Location

Novartis Investigative Site

Siena, SI, 53100, Italy

Location

Novartis Investigative Site

Torino, TO, 10126, Italy

Location

Novartis Investigative Site

Roma, 00137, Italy

Location

Novartis Investigative Site

Sapporo, Hokkaido, 060-8648, Japan

Location

Novartis Investigative Site

Suita, Osaka, 565-0871, Japan

Location

Novartis Investigative Site

Yamagata, Yamagata, 990-9585, Japan

Location

Novartis Investigative Site

Utrecht, Netherlands, 3584CX, Netherlands

Location

Novartis Investigative Site

Warsaw, 01138, Poland

Location

Novartis Investigative Site

Warsaw, 04-730, Poland

Location

Novartis Investigative Site

Moscow, 127412, Russia

Location

Novartis Investigative Site

Barcelona, Catalonia, 08025, Spain

Location

Novartis Investigative Site

Brighton, East Sussex, BN2 5BE, United Kingdom

Location

Novartis Investigative Site

Craigavon, Northern Ireland, BT63 5QQ, United Kingdom

Location

Novartis Investigative Site

Cardiff, Wales, CF14 4XN, United Kingdom

Location

Novartis Investigative Site

London, SW17 0QT, United Kingdom

Location

Related Publications (5)

• 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. doi: 10.1016/S0140-6736(12)61767-X.

  PMID: 23312829 BACKGROUND

• Bissler JJ, Nonomura N, Budde K, Zonnenberg BA, Fischereder M, Voi M, Louveau AL, Herbst F, Bebin EM, Curatolo P, Zonta A, Belousova E. Angiomyolipoma rebound tumor growth after discontinuation of everolimus in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. PLoS One. 2018 Sep 7;13(9):e0201005. doi: 10.1371/journal.pone.0201005. eCollection 2018.

  PMID: 30192751 DERIVED

• Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, Belousova E, Berkowitz N, Ridolfi A, Christopher Kingswood J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2. Nephrol Dial Transplant. 2019 Jun 1;34(6):1000-1008. doi: 10.1093/ndt/gfy132.

  PMID: 30053159 DERIVED

• 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.

  PMID: 29023494 DERIVED

• 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.

  PMID: 26156073 DERIVED

Related Links

• Visit EXIST-2 NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

MeSH Terms

Conditions

Tuberous Sclerosis; Lymphangioleiomyomatosis; Angiomyolipoma; Hereditary Sensory and Autonomic Neuropathies; Astrocytoma; Seizures; Tuberous Sclerosis 2

Interventions

Everolimus

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Lymphangiomyoma; Neoplasm, Lymphatic Tissue; Neoplasms by Histologic Type; Perivascular Epithelioid Cell Neoplasms; Neoplasms, Connective and Soft Tissue; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Adipose Tissue; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Novartis Pharmaceuticals
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 10, 2008
• First Posted: November 13, 2008
• Study Start: April 1, 2009
• Primary Completion: June 1, 2011
• Study Completion: November 1, 2015
• Last Updated: February 17, 2017
• Results First Posted: August 28, 2012

Record last verified: 2017-01

Locations

ES (1); CA (1); RU (1); GB (4); NL (1); FR (1); PL (2); DE (2); US (6); IT (3); JP (3)