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: January 14, 2014
Last verified: January 2014
  Purpose

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


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

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
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)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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). ] [ Designated as safety issue: No ]

    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



Secondary Outcome Measures:
  • 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). ] [ Designated as safety issue: No ]
    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

  • 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). ] [ Designated as safety issue: No ]
    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).

  • 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). ] [ Designated as safety issue: Yes ]
    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.

  • Change From Baseline in Plasma Angiogenic Molecules [ Time Frame: Baseline, 12 Months ] [ Designated as safety issue: No ]

Enrollment: 118
Study Start Date: April 2009
Estimated Study Completion Date: January 2015
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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. (Placebo arm closed when study was unblinded and all patients transitioned to everolimus.)
Drug: Placebo
Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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

Non-interventional follow-up inclusion:

  • No angiomyolipoma progression at time of study treatment discontinuation and no plan to continue treating their angiomyolipoma(s) with systemic therapy
  • Non-interventional follow-up phase consent

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

Non-interventional follow-up phase exclusion:

  • Starting treatment with any mTOR inhibitor
  • Embolization immediately after discontinuing study treatment
  • Surgical resection of angiomyolipoma after discontinuing study treatment
  • Prior kidney CT/MRI already performed 1-year after discontinuation of everolimus

Other protocol-defined inclusion/exclusion criteria may apply

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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 - PA
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
Toronto, Ontario, Canada, M5G 2C4
France
Novartis Investigative Site
Lyon, France, 69003
Germany
Novartis Investigative Site
Berlin, Germany, 10098
Novartis Investigative Site
Muenchen, Germany, 80336
Italy
Novartis Investigative Site
Milano, MI, Italy, 20142
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

Additional Information:
Publications:
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: January 14, 2014
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 amd 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
Japan: Ministry of Health, Labour and Welfare, Pharmaceutical and Medical Safety Bureau

Keywords provided by Novartis:
Angiomyolipoma
AML
Tuberous Sclerosis Complex
TSC
mTOR
RAD001
Mammalian Target of Rapamycin
Everolimus
Afinitor
SEGA
Subependymal Giant Cell Astrocytoma
Seizures

Additional relevant MeSH terms:
Sclerosis
Tuberous Sclerosis
Angiomyolipoma
Lymphangioleiomyomatosis
Pathologic Processes
Hamartoma
Neoplasms
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Malformations of Cortical Development
Nervous System Malformations
Nervous System Diseases
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Neoplasms, Adipose Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Perivascular Epithelioid Cell Neoplasms
Lymphangiomyoma
Lymphatic Vessel Tumors
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Everolimus
Sirolimus
Immunosuppressive Agents

ClinicalTrials.gov processed this record on August 18, 2014