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

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

Study Overview

• Status: Recruiting
• Conditions: Lymphangioleiomyomatosis; LAM
• Intervention / Treatment: Drug: Sirolimus

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Susan McMahan Sellers, BSN, RN; Phone Number: 513-558-4376; Email: susan.mcmahan@uc.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Withdrawn
      • UCLA
    • Palo Alto, California, United States, 94305
      • Completed
      • Stanford University
  • Colorado
    • Denver, Colorado, United States, 80206-2761
      • Completed
      • National Jewish Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University
      • Contact: Srihari Veeraraghavan, MD; Phone Number: 404-778-5736; Email: veeraraghavan@emory.edu
      • Contact: Tracy Halaby, RN; Phone Number: 404-714-7458; Email: tracy.halaby@emory.edu
      • Principal Investigator: Srihari Veeraraghavan, MD
  • Illinois
    • Chicago, Illinois, United States, 60153
      • Recruiting
      • Loyola University
      • Contact: Daniel Dilling, M.D.; Phone Number: 708-216-4946; Email: ddillin@lumc.edu
      • Contact: Jose Corral, M.S.N.; Phone Number: 708-216-5744; Email: jcorral@luc.edu
      • Principal Investigator: Dan Dilling, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 20892
      • Completed
      • Brigham and Woman's Hospital
  • New York
    • New York, New York, United States, 10032
      • Withdrawn
      • Columbia University
  • Ohio
    • Cincinnati, Ohio, United States, 45174
      • Recruiting
      • University of Cincinnati
      • Contact: Susan McMahan, BSN; Phone Number: 513-558-4376; Email: susan.mcmahan@uc.edu
      • Contact: Frank McCormack, M.D.; Phone Number: 513-558-4831; Email: frank.mccormack@uc.edu
      • Principal Investigator: Frank McCormack, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Completed
      • University of Pennsylvania
  • Washington
    • Seattle, Washington, United States, 98104
      • Recruiting
      • Swedish Health
      • Contact: George Pappas, MD; Phone Number: 206-469-0264; Email: george.pappas@swedish.org
      • Contact: Julie Wallick; Phone Number: 206-215-3986; Email: Julie.wallick@swedish.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Overencapsulated matrix	Drug: Sirolimus; mTOR inhibitor or placebo; Other Names: Rapamycin
Active Comparator: Treatment; Over-encapsulated 1 mg sirolimus tablet	Drug: Sirolimus; mTOR inhibitor or placebo; Other Names: Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume in 1 Second (FEV1 slope)	Rate of lung function decline	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diffusing Capacity for Carbon Monoxide (DLCO)	Rate of decline in diffusing capacity	2 years
Total Lung Capacity (TLC)	Rate of change in total lung capacity	2 years

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); The LAM Foundation; National Center for Advancing Translational Sciences (NCATS)
• Investigators: Study Chair: Francis X. McCormack, M.D., University of Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: May 10, 2017
• First Submitted That Met QC Criteria: May 10, 2017
• First Posted (Actual): May 12, 2017

Study Record Updates

• Last Update Posted (Actual): October 30, 2023
• Last Update Submitted That Met QC Criteria: October 25, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• 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: RLDC5713; U01HL131755-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be publicly available once the study in published. Deidentified data will be shared with a data use agreement between the requesting entity and the University of Cincinnati.
• IPD Sharing Time Frame: Estimated Spring 2026
• IPD Sharing Access Criteria: After study completion and publication, deidentified data may be requested by an email to the PI, Frank McCormack, with a data use agreement between the University of Cincinnati and the requesting entity.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No