Efficacy and Safety of Sirolimus in LAM

NCT00414648 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: RDCRN 5702U54RR019498-01FD-003362-01
• Study Type: interventional
• Target: 89
• Locations: 3 countries
• Sites: 13

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.

Conditions

Lymphangioleiomyomatosis

Keywords

Lymphangiomyomatosis; mTOR

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Percent of Participants With Serious Adverse Events

  Baseline to Month 12

• Changes in FVC Slope in ml/Month

  Baseline to Month 12

• Rate of Change in Diffusing Capacity for Carbon Monoxide (DLCO) in ml/Min/mmHg

  Baseline to Month 12

• Rate of Change in Total Lung Volume in ml Per Month

  Baseline to Month 12

• Rate of Change in Six Minute Walk Distance in Meters/Month

  Baseline to Month 12

Study Arms (2)

Active Agent (Sirolimus)

EXPERIMENTAL

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

Placebo Arm

PLACEBO COMPARATOR

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

Interventions

Sirolimus DRUG

A sirolimus dose of 2 tablets (1 mg/tablet) per day for 1 year.

Also known as: Rapamycin

Active Agent (Sirolimus)

Placebo DRUG

A placebo dose of 2 tablets per day for 1 year.

Also known as: Other names: placebo

Placebo Arm

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Cincinnati: lead
• Office of Rare Diseases (ORD): collaborator
• FDA Office of Orphan Products Development: collaborator
• National Center for Research Resources (NCRR): collaborator

Study Sites (13)

University of California Los Angeles

Los Angeles, California, 90024, United States

Location

National Jewish Medical and Research Center

Denver, Colorado, 80206, United States

Location

University of Florida, Gainesville

Gainesville, Florida, 32611, United States

Location

National Heart, Lung, and Blood Institute

Bethesda, Maryland, 20892, United States

Location

Harvard's Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Cincinnati Medical Center

Cincinnati, Ohio, 45267, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Texas Health Center at Tyler

Tyler, Texas, 75708, United States

Location

Toronto General Hospital

Toronto, Ontario, M5G 2N2, Canada

Location

National Kinki-Chou Hospital

Sakai, Osaka, 591-8555, Japan

Location

Niigata University Medical and Dental Hospital

Niigata, Japan

Location

Related Publications (12)

• 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.

  PMID: 34461049 BACKGROUND

• 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.

  PMID: 29940164 BACKGROUND

• 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.

  PMID: 16210669 BACKGROUND

• 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.

  PMID: 29140122 BACKGROUND

• 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.

  PMID: 27628078 BACKGROUND

• 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.

  PMID: 21410393 RESULT

• 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.

  PMID: 26799509 RESULT

• 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.

  PMID: 30846465 RESULT

• 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.

  PMID: 24159565 RESULT

• 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.

  PMID: 25979023 RESULT

• Harun N, Gupta N, McCormack FX, Macaluso M. Dynamic use of historical controls in clinical trials for rare disease research: A re-evaluation of the MILES trial. Clin Trials. 2023 Jun;20(3):223-234. doi: 10.1177/17407745231158906. Epub 2023 Mar 17.

  PMID: 36927115 DERIVED

• 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.

  PMID: 21180274 DERIVED

Related Links

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

MeSH Terms

Conditions

Lymphangioleiomyomatosis

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Lymphangiomyoma; Neoplasm, Lymphatic Tissue; Neoplasms by Histologic Type; Neoplasms; Perivascular Epithelioid Cell Neoplasms; Neoplasms, Connective and Soft Tissue; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

The observation period of the trial was truncated for some subjects, driven by funding limitations, need for timely reporting and drug expiration factors. Please see supplement to McCormack FX, et al. Efficacy and safety of sirolimus in LAM. N Engl J Med. 2011, 28;364:1595-606. PMID: 21410393 for more detail.

Results Point of Contact

• Title: Francis X. McCormack, MD
• Organization: Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati

mccormfx@ucmail.uc.edu

513-558-4831

Study Officials

• Francis X McCormack, MD

  University of Cincinnati Medical Center Division of Pulmonary and Critical Care Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 20, 2006
• First Posted: December 21, 2006
• Study Start: December 1, 2006
• Primary Completion: September 1, 2010
• Study Completion: February 1, 2011
• Last Updated: November 2, 2023
• Results First Posted: November 2, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1); JP (2); US (10)