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

• ClinicalTrials.gov Identifier: NCT03150914
• Recruitment Status: Recruiting
• First Posted: May 12, 2017
• Last Update Posted: January 27, 2022
• Sponsor: University of Cincinnati
• Collaborators: 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

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

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

Locations

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

Investigators

• Study Chair: Francis X. McCormack, M.D.; Univerisity of Cincinnati

More Information

• 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
• 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lymphangioleiomyomatosis; Lymphangiomyoma; Lymphatic Vessel Tumors; Neoplasms by Histologic Type; Neoplasms; Perivascular Epithelioid Cell Neoplasms; Neoplasms, Connective and Soft Tissue; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Sirolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs