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Efficacy and Safety of Sirolimus for Treating Lymphangioleiomyomatosis (LAM)

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ClinicalTrials.gov Identifier: NCT00414648
Recruitment Status : Unknown
Verified August 2009 by Office of Rare Diseases (ORD).
Recruitment status was:  Active, not recruiting
First Posted : December 21, 2006
Last Update Posted : August 28, 2009
Sponsor:
Collaborator:
FDA Office of Orphan Products Development
Information provided by:
Office of Rare Diseases (ORD)

Study Description
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Brief Summary:
Lymphangioleiomyomatosis (LAM) is a rare lung disease that is caused by genetic mutations. It results in the uncontrolled growth and proliferation of an unusual type of smooth muscle cell. 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 immunosuppressive medication, in stabilizing or improving lung function in people with LAM.

Condition or disease Intervention/treatment Phase
Lymphangioleiomyomatosis Drug: Sirolimus Drug: Placebo sirolimus Phase 3

Detailed Description:

LAM is an uncommon, progressive, cystic lung disease that predominantly affects young women. It is believed to be caused by defects within cellular pathways that regulate nutrient uptake, cell size, cell migration, and cell proliferation. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes. Individuals with LAM often experience pneumothorax and chylothorax, as well progressive loss of lung function. LAM is frequently fatal and existing therapies for the disease have not proven effective. Lung transplantation can be considered as a last option, but alternative treatments are needed. Sirolimus is an immunosuppressive drug that is often used in people who have had kidney transplants. It directly affects the genetic 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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Lymphangioleiomyomatosis Efficacy and Safety Trial
Study Start Date : December 2006
Estimated Primary Completion Date : September 2010
Estimated Study Completion Date : September 2011

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: 1
Participants will receive sirolimus daily for 1 year followed with serial pulmonary functional tests and 6-minute walk tests over a 2-year period.
 Drug: Sirolimus
A sirolimus dose of 2 mg will be given in the form of 2 tablets (1 mg/tablet) per day for 1 year.
Other Name: Rapamycin
Placebo Comparator: 2
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.
 Drug: Placebo sirolimus
A placebo dose of 2 mg will be given in the form of 2 tablets (1 mg/tablet) per day for 1 year.
Other Name: Other names: placebo


Outcome Measures
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Primary Outcome Measures :
  1. FEV1 response [ Time Frame: measured at Month 12 ]
  2. Severity graded adverse events [ Time Frame: measured at Month 12 ]

Secondary Outcome Measures :
  1. FVC response [ Time Frame: measured at Month 24 ]
  2. Diffusing capacity for carbon monoxide [ Time Frame: measured at Month 24 ]
  3. Lung volume [ Time Frame: measured at Month 24 ]
  4. Distance walked in 6 minutes [ Time Frame: measured at Month 24 ]
  5. Volumetric estimate of lung cyst size and mass of tissue in the chest [ Time Frame: measured at Month 24 ]
  6. Biomarkers [ Time Frame: measured at Month 24 ]
  7. Chylous effusions [ Time Frame: measured at Month 24 ]
  8. Pneumothoraces [ Time Frame: measured at Month 24 ]
  9. Hemorrhagic renal episodes [ Time Frame: measured at Month 24 ]
  10. Mortality [ Time Frame: measured at Month 12 ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18 or older
  • Diagnosis of LAM as determined by a biopsy and chest CT scan; or chest CT scan in the setting of tuberous sclerosis, angiomyomata or chylous pleural effusion; or chest CT scan and 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
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00414648


Locations
United States, California
University of California Los Angeles
Los Angeles, California, United States, 90024
United States, Colorado
National Jewish Medical and Research Center
Denver, Colorado, United States, 80206
United States, Florida
University of Florida, Gainesville
Gainesville, Florida, United States, 32611
United States, Maryland
National Heart, Lung, and Blood Institute
Bethesda, Maryland, United States, 20892
United States, Massachusetts
Harvard's Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
United States, Ohio
University of Cincinnati Medical Center
Cincinnati, Ohio, United States, 45267
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
University of Texas Health Center at Tyler
Tyler, Texas, United States, 75708
Canada, Ontario
Toronto General Hospital
Toronto, Ontario, Canada, M5G 2N2
Japan
National Kinki-Chou Hospital
Sakai, Osaka, Japan, 591-8555
Niigata University Medical and Dental Hospital
Niigata, Japan, 951-8520
Sponsors and Collaborators
Office of Rare Diseases (ORD)
FDA Office of Orphan Products Development
Investigators
Principal Investigator: Frank McCormack, MD University of Cincinnati Medical Center Division of Pulmonary and Critical Care Medicine
Principal Investigator: Bruce Trapnell, MD Cincinnati Children's Hospital Medical Center Division of Pulmonary Biology
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:
Click here for the Rare Lung Disease Consortium Web site  This link exits the ClinicalTrials.gov site

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Frank McCormack, MD, University of Cincinnati Medical Center
ClinicalTrials.gov Identifier: NCT00414648     History of Changes
Obsolete Identifiers: NCT00408343, NCT00720746
Other Study ID Numbers: RDCRN 5702
RLD 5702
1U54RR019498-01 ( U.S. NIH Grant/Contract )
First Posted: December 21, 2006    Key Record Dates
Last Update Posted: August 28, 2009
Last Verified: August 2009

Keywords provided by Office of Rare Diseases (ORD):
Lymphangiomyomatosis
Lung Disease

Additional relevant MeSH terms:
Lymphangioleiomyomatosis
Lymphangiomyoma
Lymphatic Vessel Tumors
Neoplasms by Histologic Type
Neoplasms
Perivascular Epithelioid Cell Neoplasms
Neoplasms, Connective and Soft Tissue
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
 Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs