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

Novartis Pharmaceuticals118 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

118

Conditions

Tuberous Sclerosis Complex (TSC)Lymphangioleiomyomatosis (LAM)

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.

Everolimus PlaceboDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (25)

University of Alabama at Birmingham

Birmingham, Alabama, United States

Outcomes

Primary Outcomes

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.

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

Secondary Outcomes

Time to Angiomyolipoma Progression as Per Central Radiology Review

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.

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

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

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.

Data from ClinicalTrials.gov

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Barrow Tuberous Sclerosis Center

Phoenix, Arizona, United States

Massachusetts General Hospital Massachussetts General Hospita

Boston, Massachusetts, United States

Minnesota Epilepsy Group

Saint Paul, Minnesota, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

LeBonheur Childrens Medical Group SC-2

Memphis, Tennessee, United States

Novartis Investigative Site

Torono, Ontario, Canada

Novartis Investigative Site

Lyon, France, France

Novartis Investigative Site

Berlin, Germany

Novartis Investigative Site

München, Germany

...and 15 more locations

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

Percentage of Participants With Renal Impairment

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.

Time frame: Day 1 up to 28 days after end of treatment

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

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.

Time frame: 4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks

Everolimus Trough Concentrations (Cmin)

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.

Time frame: Prior to dosing at weeks 2, 4, 12, 24, 48

Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose

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 frame: 2 hours post-dose administration at Weeks 2, 4, 12, 24, 48

Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response

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.

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

Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response

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)

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.