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Trial record 1 of 1 for:    NCT00790400
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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 has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00790400
First received: November 10, 2008
Last updated: January 3, 2017
Last verified: January 2017
November 10, 2008
January 3, 2017
April 2009
June 2011   (Final data collection date for primary outcome measure)
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.

• Angiomyolipoma response rate through MRIs at screening, 12, 24 and 48 weeks and annually thereafter [ Time Frame: Screening, 12, 24, 48 weeks and annually for 4 years ]
Complete list of historical versions of study NCT00790400 on ClinicalTrials.gov Archive Site
  • 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.
  • • Time to angiomyolipoma progression through MRIs at screening, 12, 24 and 48 weeks and annually thereafter [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ]
  • • Skin lesion response rate tracked by digital photographs [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ]
  • • Change from baseline in biomarkers collected during the first years of study [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ]
  • • Changes in renal function by assessing creatinine clearance levels throughout the study [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ]
  • • Safety assessed on a continuous basis throughout study [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ]
Not Provided
Not Provided
 
Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
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.
Not Provided
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Tuberous Sclerosis Complex (TSC)
  • Lymphangioleiomyomatosis (LAM)
  • 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
  • Drug: Everolimus Placebo
    Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.
  • Experimental: Everolimus
    Study drug was given by continuous oral daily dosing of two 5 mg tablets.
    Intervention: Drug: Everolimus (RAD001)
  • Placebo Comparator: Placebo
    Placebo was given by continuous oral daily dosing of two 5 mg tablets.
    Intervention: Drug: Everolimus Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
118
November 2015
June 2011   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Canada,   France,   Germany,   Italy,   Japan,   Netherlands,   Poland,   Russian Federation,   Spain,   United Kingdom,   United States
 
 
NCT00790400
CRAD001M2302
2008-002113-48 ( EudraCT Number )
Yes
Not Provided
Not Provided
Novartis ( Novartis Pharmaceuticals )
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP