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

November 16, 2020 updated by: Novartis Pharmaceuticals

An Exploratory, Open-label, Non-randomized, Within-patient Multiple Dose-escalation Safety, Tolerability, PK and Efficacy Trial of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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

Enrollment (Actual)

24

Phase

  • Phase 2

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

  • France
      • Lyon, France
        • Novartis Investigative Site
  • Italy
      • Milan, Italy
        • Novartis Investigative Site
  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Center for LAM Research and Clinical Care
    • Ohio
      • Cincinnati, Ohio, United States, 45267
        • University of Cincinnati, Department of Internal Medicine, Pulmonary, Critical Care & Sleep Medicine,

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

Female

Description

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

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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Everolimus

All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks.

The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks.
Drug: Everolimus
Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.
Other Names:
  • RAD001

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations
Time Frame: Baseline, 26 weeks
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)
Baseline, 26 weeks
Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State
Time Frame: pre-dose and at 2 hour post dose at week 26
Venous blood samples (2 mL) for pharmacokinetic evaluation were collected pre dose and 2 hours post dose at preselected visits.
pre-dose and at 2 hour post dose at week 26

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in Forced Vital Capacity (FVC)
Time Frame: Baseline, 26 weeks
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.
Baseline, 26 weeks
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)
Time Frame: Baseline, 26 weeks

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.
Baseline, 26 weeks
Change From Baseline in Extended Pulmonary Function Testing
Time Frame: Baseline, 26 weeks
Extended pulmonary function testing such as Total Lung Capacity (TLC), Thoracic Gas Volume (TGV), Residual Volume (RV) were measured using a body plethysmograph
Baseline, 26 weeks
Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO)
Time Frame: Baseline, 26 weeks
Carbon Monoxide Diffusing Capacity (DLCO) one of the extended pulmonary function testing which was also measured using a body plethysmograph.
Baseline, 26 weeks
Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity
Time Frame: Baseline, 26 weeks
A standardized 6-minute walk test (6MWT) was performed in accordance with the guidelines of the American Thoracic Society 2002. The test was done about the same time of day to avoid diurnal variation in an environment that had an adequate temperature to avoid additional burden to the patient due to heat or cold air. The distance walked in six minutes (6MWD) was recorded.
Baseline, 26 weeks
Change From Baseline in Oxygen Saturation
Time Frame: Baseline, 26 weeks
Oxygen saturation means the amount of oxygen in blood stream. Oxygen saturation was measured by using a Pulse Oximeter.
Baseline, 26 weeks

Collaborators and Investigators

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

Sponsor

Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis, 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

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

January 1, 2010

Primary Completion (Actual)

June 1, 2012

Study Completion (Actual)

June 1, 2012

Study Registration Dates

First Submitted

January 28, 2010

First Submitted That Met QC Criteria

January 28, 2010

First Posted (Estimate)

January 29, 2010

Study Record Updates

Last Update Posted (Actual)

November 19, 2020

Last Update Submitted That Met QC Criteria

November 16, 2020

Last Verified

October 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CRAD001X2201
  • 2010-019825-32 (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.

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