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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. Identifier: NCT03150914
Recruitment Status : Recruiting
First Posted : May 12, 2017
Last Update Posted : April 29, 2020
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Advancing Translational Science (NCATS)
The LAM Foundation
Information provided by (Responsible Party):
Francis McCormack, University of Cincinnati

Tracking Information
First Submitted Date  ICMJE May 10, 2017
First Posted Date  ICMJE May 12, 2017
Last Update Posted Date April 29, 2020
Actual Study Start Date  ICMJE January 1, 2018
Estimated Primary Completion Date June 30, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 10, 2017)
Forced Expiratory Volume in 1 Second (FEV1 slope) [ Time Frame: 2 years ]
Rate of lung function decline
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2017)
  • Diffusing Capacity for Carbon Monoxide (DLCO) [ Time Frame: 2 years ]
    Rate of decline in diffusing capacity
  • Total Lung Capacity (TLC) [ Time Frame: 2 years ]
    Rate of change in total lung capacity
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial
Official Title  ICMJE Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial
Brief Summary This is a study to determine if early, long-term low dose sirolimus is effective for preventing progression to more advanced stages.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE
  • LAM
  • Lymphangioleiomyomatosis
Intervention  ICMJE Drug: Sirolimus
mTOR inhibitor or placebo
Other Name: Rapamycin
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Overencapsulated matrix
    Intervention: Drug: Sirolimus
  • Active Comparator: Treatment
    Over-encapsulated 1 mg sirolimus tablet
    Intervention: Drug: Sirolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 10, 2017)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2023
Estimated Primary Completion Date June 30, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

    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:

    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. premenopausal status or VEGF-D ≥ 600 pg/ml and any one of the following: A) baseline diffusing capacity for carbon monoxide ≤80% predicted, B) baseline residual volume ≥120% predicted, C) baseline desaturation by 4% or more on six minute walk testing on room air D) 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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Susan McMahan, BSN, RN 513-558-4376
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03150914
Other Study ID Numbers  ICMJE RLDC5713
U01HL131755-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be publicly available once the study in published
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: estimated December 2022
Responsible Party Francis McCormack, University of Cincinnati
Study Sponsor  ICMJE University of Cincinnati
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • National Center for Advancing Translational Science (NCATS)
  • The LAM Foundation
Investigators  ICMJE
Study Chair: Francis X. McCormack, M.D. Univerisity of Cincinnati
PRS Account University of Cincinnati
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP