Lymphangioleiomyomatosis
Conditions
Keywords
Lymphangiomyomatosis, mTOR
Brief summary
Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that is caused by genetic mutations. It results in the uncontrolled growth of an unusual type of smooth muscle cell in the lung. These cells invade lung tissue, including the airways, blood vessels, and lymph vessels, and restrict the flow of air, blood, and lymph, respectively. Respiratory failure, lung collapse (pneumothorax), and pleural effusions (chylothorax) are hallmarks of the disease. This study will evaluate the safety and effectiveness of sirolimus, an inhibitor of the mTOR pathway, in stabilizing or improving lung function in people with LAM.
Detailed description
LAM is an uncommon, progressive, cystic lung disease that predominantly affects young women. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes, which regulate cellular pathways that control nutrient sensing, cell size, cell migration, and cell proliferation. Individuals with LAM often experience pneumothorax and chylothorax, as well progressive loss of lung function. Sirolimus is drug that was approved for the prevention of kidney transplant rejection. It directly affects the cellular pathway that causes LAM. This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with LAM. Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and month 24; and a volumetric computed tomography scan will occur at baseline, month 12, and month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.
Interventions
DRUGSirolimus
A sirolimus dose of 2 tablets (1 mg/tablet) per day for 1 year.
DRUGPlacebo
A placebo dose of 2 tablets per day for 1 year.
Sponsors
Office of Rare Diseases (ORD)
FDA Office of Orphan Products Development
National Center for Research Resources (NCRR)
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Unlabeled sirolimus tablets were provided by Pfizer. Identical appearing placebo tablets were obtained from a commercial source. Sirolimus levels were reported only to the medical monitor. To maintain the blind, when dose adjustments were made in the sirolimus group, a sham adjustment was also made in the placebo group
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 or older * Signed and dated informed consent * Diagnosis of LAM based on compatible chest CT scan and a) biopsy or cytology consistent with LAM, or b) presence of tuberous sclerosis, angiomyolipoma or chylous pleural effusion; or c) a VEGF-D level of at least 800 pg/ml * Forced expiratory volume in one second (FEV1) of 70% or less of predicted value after administration of a bronchodilator
Exclusion criteria
* Known allergy to sirolimus * History of heart attack, angina, or stroke due to clogging, narrowing, and hardening of the arteries and blood vessels * Significant hematologic or hepatic abnormality (transaminase levels greater than three times the upper limit of normal, HCT less than 30%, platelets less than 80,000/cubic mm, adjusted absolute neutrophil count less than 1,000/cubic mm, total white blood cell count less than 3,000/cubic mm) * Intercurrent infection at the time treatment with sirolimus begins * Any surgery involving entry into a body cavity or requiring three or more sutures within 8 weeks of initiation of study drug * Use of an investigational drug within the 30 days prior to random assignment * Uncontrolled hyperlipidemia * Previous lung transplant or currently on lung transplant list * Unable to attend scheduled study visits * Unable to perform pulmonary function tests * Creatinine levels greater than 2.5 mg/dl * Chylous ascites severe enough to affect diaphragmatic function * Pleural effusion severe enough to affect pulmonary function, as determined by the study physician * History of acute pneumothorax within the 2 months prior to study entry * History of malignancy within the 2 years prior to study entry (except for squamous or basal cell skin cancer) * Use of estrogen containing medication within the thirty days prior to randomization * Unable or unwilling to use adequate contraception * Pregnant, breastfeeding, or plans to become pregnant within the next 2 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Forced Expiratory Volume in One-second (FEV1) Slope in Milliliters Per Month | Baseline to Month 12 | FEV1 values reported are in liters or milliliters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. Normative ranges are determined in populations stratified by gender, height, age and race/ethnicity. Higher FEV1 values indicate better lung function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in FVC Slope in ml/Month | Baseline to Month 12 | FVC values are reported in liters or milliliters. Normative ranges are determined in populations that are stratified by gender, height, age and race/ethnicity. There are no minimum or maximum values as it is a physiologic measure of lung function and varies from individual to individual. Higher FVC scores indicate better lung function. |
| Rate of Change in Diffusing Capacity for Carbon Monoxide (DLCO) in ml/Min/mmHg | Baseline to Month 12 | Diffusing capacity for carbon monoxide is abbreviated DLCO. DLCO is measured in liters and milliliters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. A lower DLCO means that there is lower lung function. |
| Percent of Participants With Serious Adverse Events | Baseline to Month 12 | — |
| Rate of Change in Six Minute Walk Distance in Meters/Month | Baseline to Month 12 | Number of meters walked in six minutes. There is no minimum or maximum number of feet walked as this varies from individual to individual. A higher number of feet walked indicates better exercise tolerance |
| Rate of Change in Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels in pg/ml Per Month | Baseline to Month 12 | Serum VEGF-D is a protein produced by LAM cells that serves as a biomarker of mTOR activation and sirolimus response. Mean serum levels of VEGF-D in normal subjects are around 350 pg/ml. Higher levels of serum VEGF-D are correlated with greater degrees of mTOR activation, and a fall in VEGF-D levels suggest suppression of the mTOR axis. |
| Rate of Change in Total Lung Volume in ml Per Month | Baseline to Month 12 | There are two methods for measurement of total lung volume, nitrogen or helium wash out (total lung capacity or TLC), or plethysmography (Total gas volume or TGV). TLC or TGV is measured in milliliters or liters. Normative ranges for TLC or TGV are stratified by age, height, and sex in population based studies of normal subjects.. There are no definite minimum and maximum values of lung volume as it is a physiological measure of lung function and varies from individual to individual. A low TGV or TLC is suggestive of a restrictive lung disease, and a high TGV or TLC is consistent with obstructive lung disease with hyperinflation. |
Countries
Canada, Japan, United States
Participant flow
Recruitment details
Recruitment began in December, 2006 and ended in August 2009. Recruitment occurred at the hospital based study sites.
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus Treatment Arm Participants will receive sirolimus daily for 1 year followed with serial pulmonary functional tests and 6-minute walk tests over a 2-year period. Note: study truncated to 1 year with daily sirolimus in 2010. Second year of follow up eliminated after August 31, 2010. | 46 |
| Placebo Treatment Arm Participants will receive placebo sirolimus daily for 1 year followed with serial pulmonary functional tests and 6-minute walk tests over a 2-year period. Note: study truncated to 1 year with daily placebo sirolimus in 2010. Second year of follow up eliminated after August 31, 2010. | 43 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 5 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Sirolimus Treatment Arm | Placebo Treatment Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 46 Participants | 43 Participants | 89 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 12 Participants | 27 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 29 Participants | 30 Participants | 59 Participants |
| Sex: Female, Male Female | 46 Participants | 43 Participants | 89 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 1 / 43 |
| other Total, other adverse events | 46 / 46 | 43 / 43 |
| serious Total, serious adverse events | 23 / 46 | 18 / 43 |
Outcome results
Primary
Changes in Forced Expiratory Volume in One-second (FEV1) Slope in Milliliters Per Month
FEV1 values reported are in liters or milliliters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. Normative ranges are determined in populations stratified by gender, height, age and race/ethnicity. Higher FEV1 values indicate better lung function.
Time frame: Baseline to Month 12
Population: Intention to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Changes in Forced Expiratory Volume in One-second (FEV1) Slope in Milliliters Per Month | 1 milliliters per month | Standard Deviation 2 |
| Placebo | Changes in Forced Expiratory Volume in One-second (FEV1) Slope in Milliliters Per Month | -12 milliliters per month | Standard Deviation 2 |
Comparison: FEV1 slopep-value: <0.001Regression, Linear
Secondary
Changes in FVC Slope in ml/Month
FVC values are reported in liters or milliliters. Normative ranges are determined in populations that are stratified by gender, height, age and race/ethnicity. There are no minimum or maximum values as it is a physiologic measure of lung function and varies from individual to individual. Higher FVC scores indicate better lung function.
Time frame: Baseline to Month 12
Population: Intention To Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Changes in FVC Slope in ml/Month | 8 milliliters/month | Standard Deviation 3 |
| Placebo | Changes in FVC Slope in ml/Month | -11 milliliters/month | Standard Deviation 3 |
p-value: 0.001Regression, Linear
Secondary
Percent of Participants With Serious Adverse Events
Time frame: Baseline to Month 12
Population: Intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Percent of Participants With Serious Adverse Events | 50 percentage of participants with SAE |
| Placebo | Percent of Participants With Serious Adverse Events | 41.86 percentage of participants with SAE |
p-value: 0.441Chi-squared
Secondary
Rate of Change in Diffusing Capacity for Carbon Monoxide (DLCO) in ml/Min/mmHg
Diffusing capacity for carbon monoxide is abbreviated DLCO. DLCO is measured in liters and milliliters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. A lower DLCO means that there is lower lung function.
Time frame: Baseline to Month 12
Population: Intention to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Rate of Change in Diffusing Capacity for Carbon Monoxide (DLCO) in ml/Min/mmHg | -0.01 ml/min/mmHg | Standard Deviation 0.02 |
| Placebo | Rate of Change in Diffusing Capacity for Carbon Monoxide (DLCO) in ml/Min/mmHg | -0.06 ml/min/mmHg | Standard Deviation 0.03 |
p-value: 0.17Regression, Linear
Secondary
Rate of Change in Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels in pg/ml Per Month
Serum VEGF-D is a protein produced by LAM cells that serves as a biomarker of mTOR activation and sirolimus response. Mean serum levels of VEGF-D in normal subjects are around 350 pg/ml. Higher levels of serum VEGF-D are correlated with greater degrees of mTOR activation, and a fall in VEGF-D levels suggest suppression of the mTOR axis.
Time frame: Baseline to Month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Rate of Change in Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels in pg/ml Per Month | -88.01 pg/ml per month | Standard Deviation 16.61 |
| Placebo | Rate of Change in Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels in pg/ml Per Month | -2.42 pg/ml per month | Standard Deviation 17.23 |
p-value: 0.001Regression, Linear
Secondary
Rate of Change in Six Minute Walk Distance in Meters/Month
Number of meters walked in six minutes. There is no minimum or maximum number of feet walked as this varies from individual to individual. A higher number of feet walked indicates better exercise tolerance
Time frame: Baseline to Month 12
Population: Intention to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Rate of Change in Six Minute Walk Distance in Meters/Month | 1.65 meters/month | Standard Deviation 0.81 |
| Placebo | Rate of Change in Six Minute Walk Distance in Meters/Month | 1.47 meters/month | Standard Deviation 0.87 |
p-value: 0.88Regression, Linear
Secondary
Rate of Change in Total Lung Volume in ml Per Month
There are two methods for measurement of total lung volume, nitrogen or helium wash out (total lung capacity or TLC), or plethysmography (Total gas volume or TGV). TLC or TGV is measured in milliliters or liters. Normative ranges for TLC or TGV are stratified by age, height, and sex in population based studies of normal subjects.. There are no definite minimum and maximum values of lung volume as it is a physiological measure of lung function and varies from individual to individual. A low TGV or TLC is suggestive of a restrictive lung disease, and a high TGV or TLC is consistent with obstructive lung disease with hyperinflation.
Time frame: Baseline to Month 12
Population: Intention to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Rate of Change in Total Lung Volume in ml Per Month | 8 milliliters/month | Standard Deviation 7 |
| Placebo | Rate of Change in Total Lung Volume in ml Per Month | -2 milliliters/month | Standard Deviation 7 |
p-value: 0.34Regression, Linear