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Efficacy and Safety of Sirolimus for Treating Lymphangioleiomyomatosis (LAM)

Primary Purpose

Lymphangioleiomyomatosis

Status
Unknown status
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Sirolimus
Placebo sirolimus
Sponsored by
Office of Rare Diseases (ORD)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphangioleiomyomatosis focused on measuring Lymphangiomyomatosis, Lung Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • University of California Los Angeles
  • National Jewish Medical and Research Center
  • University of Florida, Gainesville
  • National Heart, Lung, and Blood Institute
  • Harvard's Brigham and Women's Hospital
  • University of Cincinnati Medical Center
  • Cleveland Clinic Foundation
  • Oregon Health & Science University
  • Medical University of South Carolina
  • University of Texas Health Center at Tyler
  • Toronto General Hospital
  • National Kinki-Chou Hospital
  • Niigata University Medical and Dental Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

1

2

Arm Description

Participants will receive sirolimus daily for 1 year followed with serial pulmonary functional tests and 6-minute walk tests over a 2-year period.

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.

Outcomes

Primary Outcome Measures

FEV1 response
Severity graded adverse events

Secondary Outcome Measures

FVC response
Diffusing capacity for carbon monoxide
Lung volume
Distance walked in 6 minutes
Volumetric estimate of lung cyst size and mass of tissue in the chest
Biomarkers
Chylous effusions
Pneumothoraces
Hemorrhagic renal episodes
Mortality

Full Information

First Posted
December 20, 2006
Last Updated
August 27, 2009
Sponsor
Office of Rare Diseases (ORD)
Collaborators
FDA Office of Orphan Products Development
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1. Study Identification

Unique Protocol Identification Number
NCT00414648
Brief Title
Efficacy and Safety of Sirolimus for Treating Lymphangioleiomyomatosis (LAM)
Official Title
Lymphangioleiomyomatosis Efficacy and Safety Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2009
Overall Recruitment Status
Unknown status
Study Start Date
December 2006 (undefined)
Primary Completion Date
September 2010 (Anticipated)
Study Completion Date
September 2011 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
Office of Rare Diseases (ORD)
Collaborators
FDA Office of Orphan Products Development

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphangioleiomyomatosis
Keywords
Lymphangiomyomatosis, Lung Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Participants will receive sirolimus daily for 1 year followed with serial pulmonary functional tests and 6-minute walk tests over a 2-year period.
Arm Title
2
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamycin
Intervention Description
A sirolimus dose of 2 mg will be given in the form of 2 tablets (1 mg/tablet) per day for 1 year.
Intervention Type
Drug
Intervention Name(s)
Placebo sirolimus
Other Intervention Name(s)
Other names: placebo
Intervention Description
A placebo dose of 2 mg will be given in the form of 2 tablets (1 mg/tablet) per day for 1 year.
Primary Outcome Measure Information:
Title
FEV1 response
Time Frame
measured at Month 12
Title
Severity graded adverse events
Time Frame
measured at Month 12
Secondary Outcome Measure Information:
Title
FVC response
Time Frame
measured at Month 24
Title
Diffusing capacity for carbon monoxide
Time Frame
measured at Month 24
Title
Lung volume
Time Frame
measured at Month 24
Title
Distance walked in 6 minutes
Time Frame
measured at Month 24
Title
Volumetric estimate of lung cyst size and mass of tissue in the chest
Time Frame
measured at Month 24
Title
Biomarkers
Time Frame
measured at Month 24
Title
Chylous effusions
Time Frame
measured at Month 24
Title
Pneumothoraces
Time Frame
measured at Month 24
Title
Hemorrhagic renal episodes
Time Frame
measured at Month 24
Title
Mortality
Time Frame
measured at Month 12

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Frank McCormack, MD
Organizational Affiliation
University of Cincinnati Medical Center Division of Pulmonary and Critical Care Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Bruce Trapnell, MD
Organizational Affiliation
Cincinnati Children's Hospital Medical Center Division of Pulmonary Biology
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90024
Country
United States
Facility Name
National Jewish Medical and Research Center
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
Facility Name
University of Florida, Gainesville
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32611
Country
United States
Facility Name
National Heart, Lung, and Blood Institute
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Harvard's Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Cincinnati Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
University of Texas Health Center at Tyler
City
Tyler
State/Province
Texas
ZIP/Postal Code
75708
Country
United States
Facility Name
Toronto General Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2N2
Country
Canada
Facility Name
National Kinki-Chou Hospital
City
Sakai
State/Province
Osaka
ZIP/Postal Code
591-8555
Country
Japan
Facility Name
Niigata University Medical and Dental Hospital
City
Niigata
ZIP/Postal Code
951-8520
Country
Japan

12. IPD Sharing Statement

Citations:
PubMed Identifier
12411287
Citation
Karbowniczek M, Astrinidis A, Balsara BR, Testa JR, Lium JH, Colby TV, McCormack FX, Henske EP. Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. Am J Respir Crit Care Med. 2003 Apr 1;167(7):976-82. doi: 10.1164/rccm.200208-969OC. Epub 2002 Oct 31.
Results Reference
background
PubMed Identifier
15327383
Citation
Bissler JJ, Kingswood JC. Renal angiomyolipomata. Kidney Int. 2004 Sep;66(3):924-34. doi: 10.1111/j.1523-1755.2004.00838.x.
Results Reference
background
PubMed Identifier
11257622
Citation
Matsui K, Beasley MB, Nelson WK, Barnes PM, Bechtle J, Falk R, Ferrans VJ, Moss J, Travis WD. Prognostic significance of pulmonary lymphangioleiomyomatosis histologic score. Am J Surg Pathol. 2001 Apr;25(4):479-84. doi: 10.1097/00000478-200104000-00007.
Results Reference
background
PubMed Identifier
11520734
Citation
Franz DN, Brody A, Meyer C, Leonard J, Chuck G, Dabora S, Sethuraman G, Colby TV, Kwiatkowski DJ, McCormack FX. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med. 2001 Aug 15;164(4):661-8. doi: 10.1164/ajrccm.164.4.2011025.
Results Reference
background
PubMed Identifier
12045200
Citation
Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM, Panettieri RA Jr, Krymskaya VP. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem. 2002 Aug 23;277(34):30958-67. doi: 10.1074/jbc.M202678200. Epub 2002 Jun 3.
Results Reference
background
PubMed Identifier
18184959
Citation
Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):140-51. doi: 10.1056/NEJMoa063564.
Results Reference
background
PubMed Identifier
21410393
Citation
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 HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28;364(17):1595-606. doi: 10.1056/NEJMoa1100391. Epub 2011 Mar 16.
Results Reference
derived
PubMed Identifier
21180274
Citation
Xu KF, Wang L, Tian XL, Gui YS, Peng M, Cai BQ, Zhu YJ. The St. George's Respiratory Questionnaire in lymphangioleiomyomatosis. Chin Med Sci J. 2010 Sep;25(3):140-5. doi: 10.1016/s1001-9294(10)60038-7.
Results Reference
derived

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Efficacy and Safety of Sirolimus for Treating Lymphangioleiomyomatosis (LAM)

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