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Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial (MILED)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03150914
Recruitment Status : Recruiting
First Posted : May 12, 2017
Last Update Posted : January 27, 2022
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Advancing Translational Sciences (NCATS)
The LAM Foundation
Information provided by (Responsible Party):
Francis McCormack, University of Cincinnati

Brief Summary:
This is a study to determine if early, long-term low dose sirolimus is effective for preventing progression to more advanced stages.

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

Detailed Description:
The primary objective of the MILED trial is to determine if early, long term (2 yr), low dose (fixed at 1 mg/day) treatment of patients with well-preserved lung function will prevent disease progression to more advanced stages. Sixty patients with FEV1>70% predicted will be enrolled and randomized to receive 1 mg/day sirolimus or placebo, and followed for a period of 2 years with pulmonary function testing every 4 months. The primary endpoint will be the between-group (placebo vs. sirolimus) difference in the rate of change in FEV1 (in liters) over two years. Secondary endpoints will include severity grade adverse events, time to 200cc or 10% FEV1 decline, forced vital capacity, lung volumes, diffusing capacity, serum VEGF-D, and early airflow obstruction assessed using hyper-polarized gas MRI. The study will be conducted through the Rare Lung Disease Clinic Network, a confederacy of clinics organized by the LAM Foundation that is currently following over 1300 U.S. LAM patients and conducting the Department of Defense sponsored Trial of an Aromatase Inhibitor in LAM (TRAIL) trial. The LAM Foundation will assist with study recruitment and dissemination of results, and the University of South Florida will function as the Data Coordinating Center. Successful completion of this study will define the safety and efficacy of low dose sirolimus in patients with normal lung function, and determine if sirolimus can be used to prevent disease progression to symptomatic stages.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Intention to treat, randomized, placebo controlled, double blind
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Tablets are over-encapsulated. Both participant and care givers are blinded to treatment assignment. Dose adjustments for out of range sirolimus levels are made by a medical monitor at the Data Center. Sham dose adjustments are made in the placebo group
Primary Purpose: Treatment
Official Title: Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial
Actual Study Start Date : January 1, 2018
Estimated Primary Completion Date : June 30, 2024
Estimated Study Completion Date : June 30, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Sirolimus

Arm Intervention/treatment
Placebo Comparator: Placebo
Overencapsulated matrix
Drug: Sirolimus
mTOR inhibitor or placebo
Other Name: Rapamycin

Active Comparator: Treatment
Over-encapsulated 1 mg sirolimus tablet
Drug: Sirolimus
mTOR inhibitor or placebo
Other Name: Rapamycin

Primary Outcome Measures :
  1. Forced Expiratory Volume in 1 Second (FEV1 slope) [ Time Frame: 2 years ]
    Rate of lung function decline

Secondary Outcome Measures :
  1. Diffusing Capacity for Carbon Monoxide (DLCO) [ Time Frame: 2 years ]
    Rate of decline in diffusing capacity

  2. Total Lung Capacity (TLC) [ Time Frame: 2 years ]
    Rate of change in total lung capacity

Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Female, age 18 or over
  2. Signed and dated informed consent
  3. Diagnosis of LAM as determined by compatible lung CT and one of the following

    1. biopsy (lung, abdominal mass, lymph node or kidney) or cytology from thoracic or abdominal sources revealing LAM, or
    2. tuberous sclerosis, angiomyolipomata (diagnosed by CT, MRI by the site radiologist or biopsy) or chylous pleural effusion (verified by tap), or
    3. VEGF-D level ≥ 800 pg/ml.
  4. Post-bronchodilator forced expiratory volume in one second of > 70%
  5. Presence of markers of non-trivial burden of LAM or likely progression based on one of the following:

    1. pretrial FEV 1 rate of decline of >60cc/yr, comparing enrollment FEV1 to any prior measurement in the past 3 years, or
    2. baseline supplemental oxygen requirement with exercise, or
    3. pre-menopausal and one of the following (if post-menopausal, must have a VEGF-D level ≥ 600 pg/ml and one of the following) baseline diffusing capacity for carbon monoxide ≤80% predicted,

a) baseline residual volume ≥120% predicted, b) baseline desaturation by 4% or more on six minute walk testing on room air c) more than 20 cysts on the carinal cut of the CT

Exclusion Criteria:

  1. Existing or imminent (within 12-18 months) clinical indication for treatment with mTOR inhibitors, based on judgment of site investigator
  2. DLCO <60% predicted
  3. Resting room air saturation <90%
  4. Exercise induced desaturation nadir on room air < 85%
  5. History of myocardial infarction, angina or stroke related to atherosclerosis
  6. Pregnant, breast feeding, or plan to become pregnant in the next 2.5 years
  7. Inadequate contraception
  8. Significant hematologic, renal, metabolic or hepatic abnormality (i.e. transaminase levels > three times the UL of normal range, HCT < 30%, platelets < 80,000/mm3, adjusted absolute neutrophil count < 1,000/ mm3, total WBC < 3,000/ mm3), creatinine >2.5 mg/dl, uncontrolled hyperlipidemia
  9. Acute or chronic infection, such as (nontuberculous mucobacteria or active hepatitis B or C infections)
  10. Recent surgery (involving entry into a body cavity or requiring 3 or more sutures) within three weeks of initiation of study drug
  11. Use of sirolimus, everolimus or investigational treatment for LAM within the 30 days prior to randomization
  12. Previous lung transplantation or active on transplant list
  13. Inability to attend scheduled clinic visits, or perform pulmonary function testing
  14. Pleural effusion or chylous ascites sufficient to affect pulmonary function based on the opinion of the Site Investigator
  15. Acute pneumothorax within the past month
  16. History of malignancy in the past two years, other than squamous or basal cell skin cancer.
  17. Use of estrogen containing medications within the 30 days prior to randomization.
  18. Known allergy to sirolimus

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): NCT03150914

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Contact: Susan McMahan Sellers, BSN, RN 513-558-4376 susan.mcmahan@uc.edu

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United States, California
UCLA Withdrawn
Los Angeles, California, United States, 90095
Stanford University Completed
Palo Alto, California, United States, 94305
United States, Colorado
National Jewish Hospital Completed
Denver, Colorado, United States, 80206-2761
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Srihari Veeraraghavan, MD    404-778-5736    veeraraghavan@emory.edu   
Contact: Tracy Halaby, RN    404-714-7458    tracy.halaby@emory.edu   
Principal Investigator: Srihari Veeraraghavan, MD         
United States, Illinois
Loyola University Recruiting
Chicago, Illinois, United States, 60153
Contact: Daniel Dilling, M.D.    708-216-4946    ddillin@lumc.edu   
Contact: Jose Corral, M.S.N.    708-216-5744    jcorral@luc.edu   
Principal Investigator: Dan Dilling, MD         
United States, Massachusetts
Brigham and Woman's Hospital Completed
Boston, Massachusetts, United States, 20892
United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: Jeanine D'Armiento, MD    212-305-3745    jmd12@columbia.edu   
Contact: Laura Fonseca    212-305-3745    lf2560@cumc.columbia.edu   
Principal Investigator: Jeanine D'Armiento, MD         
United States, Ohio
University of Cincinnati Recruiting
Cincinnati, Ohio, United States, 45174
Contact: Susan McMahan, BSN    513-558-4376    susan.mcmahan@uc.edu   
Contact: Frank McCormack, M.D.    513-558-4831    frank.mccormack@uc.edu   
Principal Investigator: Frank McCormack, MD         
United States, Pennsylvania
University of Pennsylvania Completed
Philadelphia, Pennsylvania, United States, 19104
United States, Washington
Swedish Health Recruiting
Seattle, Washington, United States, 98104
Contact: George Pappas, MD    206-469-0264    george.pappas@swedish.org   
Contact: Julie Wallick    206-215-3986    Julie.wallick@swedish.org   
Sponsors and Collaborators
University of Cincinnati
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Advancing Translational Sciences (NCATS)
The LAM Foundation
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Study Chair: Francis X. McCormack, M.D. Univerisity of Cincinnati
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Responsible Party: Francis McCormack, Professor, University of Cincinnati
ClinicalTrials.gov Identifier: NCT03150914    
Other Study ID Numbers: RLDC5713
U01HL131755-01 ( U.S. NIH Grant/Contract )
First Posted: May 12, 2017    Key Record Dates
Last Update Posted: January 27, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be publicly available once the study in published
Supporting Materials: Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: estimated December 2024

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphatic Vessel Tumors
Neoplasms by Histologic Type
Perivascular Epithelioid Cell Neoplasms
Neoplasms, Connective and Soft Tissue
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs