# Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED) - DCC

> **NIH NIH U01** · UNIVERSITY OF SOUTH FLORIDA · 2021 · $291,401

## Abstract

Project summary/abstract
Lymphangioleiomyomatosis (LAM) is low-grade metastasizing neoplasm of women, driven by activating
mutations in the mTOR pathway that result in cystic destruction of the lung. The benign appearing, mutation
bearing smooth muscle-like LAM cells that infiltrate the lung arise from an unknown source and execute a
program of matrix remodeling that leads to cyst formation, recurrent pneumothorax, chylous pleural effusion
and progressive respiratory failure. There has been tremendous progress in LAM in the past decade, including
a rich molecular understanding of disease pathogenesis, development of a diagnostic and prognostic
biomarker, and the discovery of a treatment. The randomized controlled Rare Lung Disease Consortium
(RLDC) Multicenter International LAM Efficacy of Sirolimus (MILES) Trial (Sponsor-FXM, IND 71,340)
demonstrated that mTOR inhibition with sirolimus is an effective suppressive therapy for LAM, stabilizing lung
function, functional performance, and quality of life in women with abnormal lung function. Side effects due to
sirolimus were common in MILES, although SAEs were balanced in the sirolimus and placebo groups. The
beneficial effects of sirolimus waned when the drug was held in the second year of the trial. Although the
primary eligibility criterion was forced expiratory volume in 1 second (FEV1) ≤ 70%, enrolled MILES patients
had more advanced respiratory impairment, with about half of lung function remaining (on average), limiting the
generalizability of the findings to mild disease. Fear of toxicities and lifelong therapy lead most clinicians and
patients to wait until lung function becomes abnormal before initiating sirolimus therapy to stabilize the
damaged lung. This approach is suboptimal and inadequate. The Multicenter Interventional LAM Early Disease
Trial (MILED) is phase III, randomized, placebo-controlled trial to determine if early, long term (2 yr), low dose
(1 mg/day) sirolimus treatment of patients with well-preserved lung function will safely prevent disease
progression. Sixty patients with normal FEV1 (FEV1>70%) will be enrolled and randomized to 1 mg/day
sirolimus or placebo, and followed for 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).
Secondary endpoints will include between group differences in adverse events, 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 using the infrastructure created for the RLDC, using the Rare Lung Disease
Clinic Network, which is currently following over 1300 U.S. LAM patients and conducting the TRAIL trial. The
LAM Foundation will be an integral partner and will assist with study recruitment and patient participation. Data
will be managed by the University of South Florida Data Management and Coordinating...

## Key facts

- **NIH application ID:** 10249943
- **Project number:** 5U01HL131529-05
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** JEFFREY P KRISCHER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $291,401
- **Award type:** 5
- **Project period:** 2016-09-20 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249943

## Citation

> US National Institutes of Health, RePORTER application 10249943, Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED) - DCC (5U01HL131529-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10249943. Licensed CC0.

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