Efficacy and Safety of Sirolimus in LAM (MILES)

Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus Trial

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.

Study Overview

• Status: Completed
• Conditions: Lymphangioleiomyomatosis
• Intervention / Treatment: Drug: Sirolimus; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
• Japan
  • Niigata, Japan
    • Niigata University Medical And Dental Hospital
  • Osaka
    • Sakai, Osaka, Japan, 591-8555
      • National Kinki-Chou Hospital
• United States
  • California
    • Los Angeles, California, United States, 90024
      • University of California Los Angeles
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Medical and Research Center
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida, Gainesville
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Heart, Lung, and Blood Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Harvard's Brigham and Women's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Tyler, Texas, United States, 75708
      • University of Texas Health Center at Tyler

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Agent (Sirolimus); Participants receive sirolimus daily for 1 year and are followed with serial pulmonary function tests, 6-minute walk tests, and symptom and QOL questionnaires over a 2-year period.	Drug: Sirolimus; A sirolimus dose of 2 tablets (1 mg/tablet) per day for 1 year.; Other Names: Rapamycin
Placebo Comparator: Placebo Arm; Participants receive placebo daily for 1 year and followed with serial pulmonary function tests, 6-minute walk tests, and symptom and QOL questionnaires over a 2-year period.	Drug: Placebo; A placebo dose of 2 tablets per day for 1 year.; Other Names: Other names: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Participants With Serious Adverse Events		Baseline to Month 12
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.	Baseline to Month 12
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.	Baseline to Month 12
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.	Baseline to Month 12
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	Baseline to Month 12
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.	Baseline to Month 12

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Collaborators: National Center for Research Resources (NCRR); Office of Rare Diseases (ORD); FDA Office of Orphan Products Development
• Investigators: Principal Investigator: Francis X McCormack, MD, University of Cincinnati Medical Center Division of Pulmonary and Critical Care Medicine

Publications and helpful links

General Publications

• Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, Finlay GA, Olson EJ, Ruoss SJ, Maurer JR, Raffin TA, Peavy HH, McCarthy K, Taveira-Dasilva A, McCormack FX, Avila NA, Decastro RM, Jacobs SS, Stylianou M, Fanburg BL; NHLBI LAM Registry Group. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med. 2006 Jan 1;173(1):105-11. doi: 10.1164/rccm.200409-1298OC. Epub 2005 Oct 6.
• 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.
• 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.
• McCarthy C, Gupta N, Johnson SR, Yu JJ, McCormack FX. Lymphangioleiomyomatosis: pathogenesis, clinical features, diagnosis, and management. Lancet Respir Med. 2021 Nov;9(11):1313-1327. doi: 10.1016/S2213-2600(21)00228-9. Epub 2021 Aug 27.
• Gupta N, Lee HS, Ryu JH, Taveira-DaSilva AM, Beck GJ, Lee JC, McCarthy K, Finlay GA, Brown KK, Ruoss SJ, Avila NA, Moss J, McCormack FX; NHLBI LAM Registry Group. The NHLBI LAM Registry: Prognostic Physiologic and Radiologic Biomarkers Emerge From a 15-Year Prospective Longitudinal Analysis. Chest. 2019 Feb;155(2):288-296. doi: 10.1016/j.chest.2018.06.016. Epub 2018 Jun 22.
• Gupta N, Finlay GA, Kotloff RM, Strange C, Wilson KC, Young LR, Taveira-DaSilva AM, Johnson SR, Cottin V, Sahn SA, Ryu JH, Seyama K, Inoue Y, Downey GP, Han MK, Colby TV, Wikenheiser-Brokamp KA, Meyer CA, Smith K, Moss J, McCormack FX; ATS Assembly on Clinical Problems. Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2017 Nov 15;196(10):1337-1348. doi: 10.1164/rccm.201709-1965ST.
• McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, Steagall WK, Johnson SR, Sahn SA, Ryu JH, Strange C, Seyama K, Sullivan EJ, Kotloff RM, Downey GP, Chapman JT, Han MK, D'Armiento JM, Inoue Y, Henske EP, Bissler JJ, Colby TV, Kinder BW, Wikenheiser-Brokamp KA, Brown KK, Cordier JF, Meyer C, Cottin V, Brozek JL, Smith K, Wilson KC, Moss J; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med. 2016 Sep 15;194(6):748-61. doi: 10.1164/rccm.201607-1384ST.
• Argula RG, Kokosi M, Lo P, Kim HJ, Ravenel JG, Meyer C, Goldin J, Lee HS, Strange C, McCormack FX; MILES Study Investigators. A Novel Quantitative Computed Tomographic Analysis Suggests How Sirolimus Stabilizes Progressive Air Trapping in Lymphangioleiomyomatosis. Ann Am Thorac Soc. 2016 Mar;13(3):342-9. doi: 10.1513/AnnalsATS.201509-631OC.
• Gupta N, Lee HS, Young LR, Strange C, Moss J, Singer LG, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Downey GP, Taveira-DaSilva AM, Krischer JP, Setchell K, Trapnell BC, Inoue Y, McCormack FX; NIH Rare Lung Disease Consortium. Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis. Eur Respir J. 2019 Apr 4;53(4):1802066. doi: 10.1183/13993003.02066-2018. Print 2019 Apr.
• Young L, Lee HS, 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, Downey GP, Swigris JJ, Taveira-DaSilva AM, Krischer JP, Trapnell BC, McCormack FX; MILES Trial Group. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med. 2013 Aug;1(6):445-52. doi: 10.1016/S2213-2600(13)70090-0.
• Lo P, Brown MS, Kim H, Kim H, Argula R, Strange C, Goldin JG. Cyst-based measurements for assessing lymphangioleiomyomatosis in computed tomography. Med Phys. 2015 May;42(5):2287-95. doi: 10.1118/1.4916655.

Helpful Links

• Click here for the Health Informatics Institute of the University of South Florida

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: December 20, 2006
• First Submitted That Met QC Criteria: December 20, 2006
• First Posted (Estimated): December 21, 2006

Study Record Updates

• Last Update Posted (Actual): November 2, 2023
• Last Update Submitted That Met QC Criteria: October 11, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: mTOR; Lymphangiomyomatosis
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphangiomyoma; Lymphatic Vessel Tumors; Perivascular Epithelioid Cell Neoplasms; Lymphangioleiomyomatosis; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: RDCRN 5702; U54RR019498-01 (U.S. NIH Grant/Contract); FD-003362-01 (Other Grant/Funding Number: FDA Office of Orphan Product Development)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes