Clinical trial NCT00414648: Efficacy and Safety of Sirolimus in LAM
Official title: Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lymphangioleiomyomatosis
Keywords: Lymphangiomyomatosis
mTOR
Lead sponsor: University of Cincinnati
Sponsor class: OTHER
Collaborators: name: Office of Rare Diseases (ORD)
name: FDA Office of Orphan Products Development
name: National Center for Research Resources (NCRR)
First posted: 2006-12-21
Enrollment: 89
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in Forced Expiratory Volume in One-second (FEV1) Slope in Milliliters Per Month
timeFrame: Baseline to Month 12
Secondary outcomes:
measure: Percent of Participants With Serious Adverse Events
timeFrame: Baseline to Month 12
measure: Changes in FVC Slope in ml/Month
timeFrame: Baseline to Month 12
measure: Rate of Change in Diffusing Capacity for Carbon Monoxide (DLCO) in ml/Min/mmHg
timeFrame: Baseline to Month 12
measure: Rate of Change in Total Lung Volume in ml Per Month
timeFrame: Baseline to Month 12
measure: Rate of Change in Six Minute Walk Distance in Meters/Month
timeFrame: Baseline to Month 12
measure: Rate of Change in Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels in pg/ml Per Month
timeFrame: Baseline to Month 12
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Denver
country: United States
facility: National Jewish Medical and Research Center
state: Colorado
city: Gainesville
country: United States
facility: University of Florida, Gainesville
state: Florida
city: Bethesda
country: United States
facility: National Heart, Lung, and Blood Institute
state: Maryland
city: Boston
country: United States
facility: Harvard's Brigham and Women's Hospital
state: Massachusetts
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Tyler
country: United States
facility: University of Texas Health Center at Tyler
state: Texas
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Sakai
country: Japan
facility: National Kinki-Chou Hospital
state: Osaka
city: Niigata
country: Japan
facility: Niigata University Medical and Dental Hospital
Study officials:
affiliation: University of Cincinnati Medical Center Division of Pulmonary and Critical Care Medicine
name: Francis X McCormack, MD
role: PRINCIPAL_INVESTIGATOR
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