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Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial) (MILES)

Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial)

Safety(No difference in the frequency of AE for grade3-5 between sirolimus and placebo).

effective

Sirolimus inhibits the progression of LAM and stabilize the disease activity.

http://www.bmrctr.jp/lam/

Frank McCormack, M.D.

University of Cincinnati Medical Center

MSB 6053, 231 Albert Sabin Way, Cincinnati, OH 45267-0564

Koh Nakata, M.D., Ph.D.

Bioscience Medical Research Center (BMRC), Niigata University Medical & Dental Hospital

1-757 Asahimachi-Dohri, Niigata 951-8520, Japan

+81-25-227-0847

radical@med.niigata-u.ac.jp

COMPLETED

May. 08, 2008

Interventional

Randomized, double-blind, placebo-controlled

double blind

Yes

3

1 Age 18 or over
2 Signed and dated informed consent
3 Diagnosis of LAM as determined by biopsy; or chest CT scan findings compatible with LAM in the setting of tuberous sclerosis, angiomyolipoma or chylous pleural effusion
4 Abnormal lung function i.e., postbronchodilator FEV1 less than or equal to 70% of predicted

1 History of myocardial infarction or stroke related to atherosclerosis
2 Pregnancy or breast feeding
3 Inadequate contraception
4 Significant hematologic or hepatic abnormality
5 Intercurrent infection at initiation of sirolimus
6 Recent surgery (involving entry into a body cavity) within 2 months of initiation of sirolimus
7 Use of an investigational drug within the last 30 days
8 Uncontrolled hyperlipidemia
9 Previous lung transplantation
10 Inability to attend scheduled clinic visits
11 Inability to give informed consent
12 Inability to perform pulmonary function testing
13 Creatinine > 2.5 mg/dl
14 Chylous ascites sufficient to affect diaphragmatic function
15 Pleural effusion sufficient to affect pulmonary function
16 Acute pneumothorax within the past 2 months
17 Malignancy other than uncomplicated skin cancer in the past 2 years
18 Previous or current use of estrogen therapy

Female

Lymphangioleiomyomatosis (LAM)

Intervention type:DRUG Name of intervention:Sirolimus Dose form / Japanese Medical Device Nomenclature:TABLET Route of administration / Site of application:ORAL Dose per administration:2 2 mg Dosing frequency / Frequency of use:QD 1 Planned duration of intervention:12 months Intended dose regimen:12 months on, 12 months off detailes of teratment arms:Phase III international study initiated to evaluate the rate of change slope in forced expiratory volume in 1 second (FEV1) as a primary endpoint at sirolimus 2mg for one year, and 11 study sites from US, Canada and Japan joined. Subjects were randomly assigned to either sirolimus or placebo group via EDC system by the Data and Technology Coordinating Center (DTCC) based in Florida, US and a principal investigator at each study site sent data and information on adverse events to DTCC and were analyzed at DTCC. From Japan, Niigata University Medical and Dental Hospital and National Hospital Organization (NHO) Kinki-Chuo Chest Medical Center participated in the study. 111pts were recruited by August 2009, and the study was completed in by August 2010 and the final analysis was performed. Niigata University Medical and Dental Hospital and National Hospital Organization (NHO) Kinki-Chuo Chest Medical Center started the study in May 2008 and 28pts were recruited by August 2009. 299 Two hundred ninety nine adverse events were observed at both hospitals. Of these, 3pts were hospitalized. Those patients were recovered by the tentative discontinuation of study drug and the treatment. The study was completed in by September 2010 and 89 pts completed one year treatment and the final analysis results were reported in December 2010. FEV1 slope, which is a was the primary endpoint, was 1+2ml per month increase in sirolimus group (46pts) and 12+20ml per month decrease in placebo group(43pts), and there was significant difference between sirolimus and placebo groups (P<0.001). Comparative intervention name:Placebo Dose form / Japanese Medical Device Nomenclature:TABLET Route of administration / Site of application:ORAL Dose per administration: Dosing frequency / Frequency of use:QD Planned duration of intervention:12 months Intended dose regimen:12 months on, 12 months off

FEV1 response

FVC response, six minute walk, diffusing capacity, lung volumes, dyspnea (shortness of breath) scores by questionnaire, mortality, 3 dimensional CT, adverse events