Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial

NCT ID: NCT03150914

Last Updated: 2024-12-24

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-01
• Study Completion Date: 2025-06-30

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.

Conditions

LAM; Lymphangioleiomyomatosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Placebo

Overencapsulated matrix

Group Type: PLACEBO_COMPARATOR

Sirolimus

Intervention Type: DRUG

mTOR inhibitor or placebo

Treatment

Over-encapsulated 1 mg sirolimus tablet

Group Type: ACTIVE_COMPARATOR

Sirolimus

Intervention Type: DRUG

mTOR inhibitor or placebo

Interventions

Sirolimus

mTOR inhibitor or placebo

Intervention Type: DRUG

Other Intervention Names

Rapamycin

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

National Center for Advancing Translational Sciences (NCATS)

NIH

Sponsor Role: collaborator

The LAM Foundation

OTHER

Sponsor Role: collaborator

University of Cincinnati

OTHER

Sponsor Role: lead

Responsible Party

Francis McCormack

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Francis X. McCormack, M.D.

Role: STUDY_CHAIR

University of Cincinnati

Locations

Stanford University

Palo Alto, California, United States

National Jewish Hospital

Denver, Colorado, United States

Emory University

Atlanta, Georgia, United States

Loyola University

Chicago, Illinois, United States

Brigham and Woman's Hospital

Boston, Massachusetts, United States

University of Cincinnati

Cincinnati, Ohio, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Swedish Health

Seattle, Washington, United States

Countries

United States

Other Identifiers

U01HL131755-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

RLDC5713

Identifier Type: -

Identifier Source: org_study_id