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

Lymphangioleiomyomatosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01059318
• Other study ID #: CRAD001X2201
• Secondary ID: 2010-019825-32
• Status: Completed
• Phase: Phase 2
• Start date: January 2010
• Est. completion date: June 2012

Study information

• Verified date: October 2020
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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".

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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 ß2-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 ß2-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

Related Conditions & MeSH terms

• Lymphangioleiomyomatosis

Intervention

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

Locations

Country	Name	City	State
France	Novartis Investigative Site	Lyon
Italy	Novartis Investigative Site	Milan
United States	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

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  France,  Italy, 

References & Publications (1)

McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	Baseline, 26 weeks
Primary	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.	pre-dose and at 2 hour post dose at week 26
Secondary	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.	Baseline, 26 weeks
Secondary	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.	Baseline, 26 weeks
Secondary	Change From Baseline in Extended Pulmonary Function Testing	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
Secondary	Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO)	Carbon Monoxide Diffusing Capacity (DLCO) one of the extended pulmonary function testing which was also measured using a body plethysmograph.	Baseline, 26 weeks
Secondary	Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity	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
Secondary	Change From Baseline in Oxygen Saturation	Oxygen saturation means the amount of oxygen in blood stream. Oxygen saturation was measured by using a Pulse Oximeter.	Baseline, 26 weeks