A Study to Determine the Safety and Effectiveness of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis

Novartis Pharmaceuticals24 enrolled

Overview

This was an exploratory study to determine whether escalating doses of RAD001 (everolimus) were safe and effective in patients with Lymphangioleiomyomatosis

In addition to the data collected in this study, historical data from 43 patients treated with placebo from the multicenter trial of sirolimus in LAM (MILES) study (NCT00414648) were down weighted to an effective sample size of 18 for comparison of FEV1 and FVC endpoints. Reference to the publication of the MILES study has been provided under "Result Publication".

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Lymphangioleiomyomatosis

Interventions

EverolimusDRUG

Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Female aged \>/= 18 years with a diagnosis of LAM * Pulmonary function abnormalities as follows: * FEV1 of ≤ 80% of the predicted value following administration of a standard dose of a short acting β2-agonist (\*200 µg Salbutamol, measured between 10 and 15 minutes of inhalation) OR * FEV1 \< 90% of the predicted value of bronchodilator following administration of a standard dose of a short acting β2-agonist (\*200 µg Salbutamol, measured between 10 and 15 minutes of inhalation) and DLco (uncorrected) \<80% predicted. * Female patients including those of childbearing potential will be included in this study. * Negative pregnancy test at screening and baseline Exclusion Criteria: * FEV1\<50% of predicted post-bronchodilator. * Change in FVC (ml) \> ± 15% of screening value at baseline visit (not less than 14d after screening visit). * Use of any medicine containing estrogen in the 4 months prior to the screening visit and for the duration of the study * Significant hematologic, renal, hepatic laboratory abnormality or amylase \> 1.5x the upper limit of the normal range at the screening or baseline visits * Fasting blood glucose \> 126mg/dl or random blood glucose \>200mg/dl at screening and/or baseline * Recent surgery (involving entry into a body cavity or requiring sutures) within 2 months of the screening visit or any evidence of unhealed surgical wound. * Uncontrolled hyperlipidemia (defined as persistent elevation of total cholesterol or triglycerides \>6.5nM/L) or a history of clinical atherosclerotic disease including heart attack, angina, peripheral vascular disease or stroke. * Previous organ transplantation * Inability to give informed consent * Inability to perform pulmonary function or 6 minute walk tests and imaging assessments Other protocol-defined inclusion/exclusion criteria may apply

Locations (4)

Center for LAM Research and Clinical Care

Boston, Massachusetts, United States

University of Cincinnati, Department of Internal Medicine, Pulmonary, Critical Care & Sleep Medicine,

Cincinnati, Ohio, United States

Novartis Investigative Site

Lyon, France

Novartis Investigative Site

Milan, Italy

Outcomes

Primary Outcomes

Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations

Blood samples (1 mL) for determination of VEGF-D were collected from a forearm vein (direct venipuncture or from an indwelling cannula) and 2 aliquots of serum were collected. VEGF-D levels were determined from only 1 of the 2 serum aliquots, with the second acting as a back-up. A serum VEGF-D \>800 pg/mL level supports a diagnosis of Lymphangioleiomyomatosis (LAM)

Time frame: Baseline, 26 weeks

Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State

Venous blood samples (2 mL) for pharmacokinetic evaluation were collected pre dose and 2 hours post dose at preselected visits.

Time frame: pre-dose and at 2 hour post dose at week 26

Secondary Outcomes

Change From Baseline in Forced Vital Capacity (FVC)

All spirometry evaluation followed recommendations of the Standardization of Lung Function Testing. All spirometry maneuvers were performed in sitting position whilst wearing nose clips. At least three acceptable maneuvers were performed for each time point, and results met within-test and between-test criteria for acceptability. The highest value was obtained of FVC from any of the three maneuvers that met acceptability criteria. Change from baseline in FVC was compared between everolimus and historical placebo data from multicenter trial of sirolimus in LAM. (MILES NCT00414648) due to absence of placebo group in this current study on a rare lung disease. These two studies had different study designs, so the change from baseline to 6 months (26 weeks) in MILES study was estimated from the publicly reported rate of change per month to provide a meaningful comparison. This historical control be can be viewed on the Novartis Clinical Trial Results website.

Time frame: Baseline, 26 weeks

Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)

All spirometry evaluation followed the recommendations of the Standardization of Lung Function Testing. All spirometry maneuvers were performed in the sitting position whilst wearing nose clips. At least three acceptable maneuvers were performed for each time point, and the results met within-test and between-test criteria for acceptability. The highest value was obtained of FEV1 from any of the three maneuvers that met acceptability criteria. Change from baseline in FEV1 was compared between everolimus and historical placebo data from the MILES study (NCT00414648) due to the absence of a placebo group in this current study on a rare lung disease. These two studies had different study designs, so the change from baseline to 6 months (26 weeks) in MILES study was estimated from the publicly reported rate of change per month in order to provide a meaningful comparison. This historical control can be viewed on the Novartis Clinical Trial Results website.

Data from ClinicalTrials.gov

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