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)

January 3, 2017 updated by: Novartis Pharmaceuticals

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)

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

118

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Torono, Ontario, Canada, M5G 2C4
        • Novartis Investigative Site
  • France
      • Lyon, France, 69003
        • Novartis Investigative Site
  • Germany
      • Berlin, Germany, 10098
        • Novartis Investigative Site
      • München, Germany, 80336
        • Novartis Investigative Site
  • Italy
      • Roma, Italy, 00137
        • Novartis Investigative Site
    • SI
      • Siena, SI, Italy, 53100
        • Novartis Investigative Site
    • TO
      • Torino, TO, Italy, 10126
        • Novartis Investigative Site
  • Japan
      • Yamagata, Japan, 990-9585
        • Novartis Investigative Site
    • Hokkaido
      • Sapporo-city, Hokkaido, Japan, 060-8648
        • Novartis Investigative Site
    • Osaka
      • Suita-city, Osaka, Japan, 565-0871
        • Novartis Investigative Site
  • Netherlands
      • Utrecht, Netherlands, 3584CX
        • Novartis Investigative Site
  • Poland
      • Warszawa, Poland, 04-730
        • Novartis Investigative Site
      • Warszawa, Poland, 01138
        • Novartis Investigative Site
  • Russian Federation
      • Moscow, Russian Federation, 127412
        • Novartis Investigative Site
  • Spain
    • Catalunya
      • Barcelona, Catalunya, Spain, 08025
        • Novartis Investigative Site
  • United Kingdom
      • London, United Kingdom, SW17 0QT
        • Novartis Investigative Site
    • East Sussex
      • Brighton, East Sussex, United Kingdom, BN2 5BE
        • Novartis Investigative Site
    • Northern Ireland
      • Craigavon, Northern Ireland, United Kingdom, BT63 5QQ
        • Novartis Investigative Site
    • Wales
      • Cardiff, Wales, United Kingdom, CF14 4XN
        • Novartis Investigative Site
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • University of Alabama at Birmingham
    • Arizona
      • Phoenix, Arizona, United States, 85013
        • Barrow Tuberous Sclerosis Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital Massachussetts General Hospita
    • Minnesota
      • St. Paul, Minnesota, United States, 55102-2383
        • Minnesota Epilepsy Group
    • Ohio
      • Cincinnati, Ohio, United States, 45229-3039
        • Cincinnati Children's Hospital Medical Center
    • Tennessee
      • Memphis, Tennessee, United States, 38103
        • LeBonheur Childrens Medical Group SC-2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / 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 Names:
  • 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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)
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.
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
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.
Day 1 up to 28 days after end of treatment
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.
4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks
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.
Prior to dosing at weeks 2, 4, 12, 24, 48
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.
2 hours post-dose administration at Weeks 2, 4, 12, 24, 48
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.
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
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.
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 - 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.
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2009

Primary Completion (ACTUAL)

June 1, 2011

Study Completion (ACTUAL)

November 1, 2015

Study Registration Dates

First Submitted

November 10, 2008

First Submitted That Met QC Criteria

November 12, 2008

First Posted (ESTIMATE)

November 13, 2008

Study Record Updates

Last Update Posted (ACTUAL)

February 17, 2017

Last Update Submitted That Met QC Criteria

January 3, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CRAD001M2302
  • 2008-002113-48 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Subscribe