Lymphangioleiomyomatosis
Conditions
Keywords
Lymphangioleiomyomatosis,, High Resolution CT scan,, chest x-ray,, 6 minute walk test,, pulse oximetry,, renal MRI,, Pikometer
Brief summary
This was an exploratory study to determine whether escalating doses of RAD001 (everolimus) were safe and effective in patients with Lymphangioleiomyomatosis
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.
Interventions
DRUGEverolimus
Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations | 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) |
| Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Extended Pulmonary Function Testing | 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 |
| Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO) | Baseline, 26 weeks | Carbon Monoxide Diffusing Capacity (DLCO) one of the extended pulmonary function testing which was also measured using a body plethysmograph. |
| Change From Baseline in Forced Vital Capacity (FVC) | 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. |
| Change From Baseline in Oxygen Saturation | Baseline, 26 weeks | Oxygen saturation means the amount of oxygen in blood stream. Oxygen saturation was measured by using a Pulse Oximeter. |
| Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity | 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. |
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | 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. |
Countries
France, Italy, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Everolimus : Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Core Study (26 Week) | Adverse Event | 3 |
| Core Study (26 Week) | Withdrawal by Subject | 1 |
| Extension (36 Week) | Adverse Event | 3 |
Baseline characteristics
| Characteristic | Everolimus |
|---|---|
| Age, Continuous | 44 years STANDARD_DEVIATION 13.4 |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 8 / 24 |
Outcome results
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)
Time frame: Baseline, 26 weeks
Population: Pharmacodynamic analysis included patients who received study drug without any major protocol violation. Same patients in different dose groups were included in this analysis with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus 2.5 mg/Day | Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations | -464.3 pg/mL | Standard Deviation 745.23 |
| Everolimus 5 mg/Day | Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations | -1113.2 pg/mL | Standard Deviation 1468.9 |
| Everolimus 10 mg/Day | Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations | -1771.7 pg/mL | Standard Deviation 2091.6 |
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.
Time frame: pre-dose and at 2 hour post dose at week 26
Population: Pharmacokinetics analysis set. Patients with measurable data at particular time points were included in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus 2.5 mg/Day | Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State | Trough (C0, ss) | 3.1 ng/mL | Standard Deviation 1.33 |
| Everolimus 2.5 mg/Day | Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State | Peak (C2, ss) | 12.1 ng/mL | Standard Deviation 3.56 |
| Everolimus 5 mg/Day | Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State | Trough (C0, ss) | 5.8 ng/mL | Standard Deviation 3.02 |
| Everolimus 5 mg/Day | Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State | Peak (C2, ss) | 22.6 ng/mL | Standard Deviation 7.22 |
| Everolimus 10 mg/Day | Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State | Trough (C0, ss) | 11.0 ng/mL | Standard Deviation 3.45 |
| Everolimus 10 mg/Day | Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State | Peak (C2, ss) | 45.7 ng/mL | Standard Deviation 12.52 |
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.
Time frame: Baseline, 26 weeks
Population: Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus 2.5 mg/Day | Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity | 46.9 meters (m) | Standard Deviation 115.3 |
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.
Time frame: Baseline, 26 weeks
Population: Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus 2.5 mg/Day | Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO) | -0.782 ml/min/mmHg | Standard Deviation 1.5351 |
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
Time frame: Baseline, 26 weeks
Population: Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus 2.5 mg/Day | Change From Baseline in Extended Pulmonary Function Testing | TGV | 0.267 Liters (L) | Standard Deviation 1.0368 |
| Everolimus 2.5 mg/Day | Change From Baseline in Extended Pulmonary Function Testing | RV | 0.169 Liters (L) | Standard Deviation 0.9055 |
| Everolimus 2.5 mg/Day | Change From Baseline in Extended Pulmonary Function Testing | TLC | 0.199 Liters (L) | Standard Deviation 0.8645 |
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.
Time frame: Baseline, 26 weeks
Population: Pharmacodynamic analysis set for everolimus reporting arm. Patients with both baseline and 26 weeks assessment were included in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Everolimus 2.5 mg/Day | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | 114 mL |
Comparison: Proof of Concept was proposed as follows:~* 90% level of proof that difference in FEV1 change from baseline everolimus vs. Historical Placebo Control arm from MILES study \> 0 mL~* 50% level of proof that difference in FEV1 change from baseline everolimus vs. Historical Placebo Control arm from MILES study \>= 100 mL~Historical data from 43 patients treated with placebo from the MILES study were down weighted to an effective sample size of 18 for comparison.95% CI: [93, 279]Bayesian analysis
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.
Time frame: Baseline, 26 weeks
Population: Pharmacodynamic analysis set for everolimus reporting arm. Patients with both baseline and 26 weeks assessment were included in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Everolimus 2.5 mg/Day | Change From Baseline in Forced Vital Capacity (FVC) | 10 mL |
Comparison: Proof of Concept was proposed as follows:~* 90% level of proof that difference in FVC change from baseline everolimus vs. Historical Placebo Control arm from MILES study \> 0 mL~* 50% level of proof that difference in FVC change from baseline everolimus vs. Historical Placebo Control arm from MILES study \>= 100 mL~Historical data from 43 patients treated with placebo from the MILES study were down weighted to an effective sample size of 18 for comparison.95% CI: [-45, 196]Bayesian analysis
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.
Time frame: Baseline, 26 weeks
Population: Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus 2.5 mg/Day | Change From Baseline in Oxygen Saturation | 0.8 percentage of oxygen | Standard Deviation 2.13 |