title: Efficacy and safety of sirolimus in lymphangioleiomyomatosis.
abstract: BACKGROUND
  Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM.
  
  
  METHODS
  We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)).
  
  
  RESULTS
  During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups.
  
  
  CONCLUSIONS
  In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).
authors.affiliation: University of Cincinnati, Cincinnati, OH, USA. frank.mccormack@uc.edu
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Inoue
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.forename: Lianne G
authors.initials: LG
authors.lastname: Singer
authors.forename: Charlie
authors.initials: C
authors.lastname: Strange
authors.forename: Koh
authors.initials: K
authors.lastname: Nakata
authors.forename: Alan F
authors.initials: AF
authors.lastname: Barker
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chapman
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.forename: James M
authors.initials: JM
authors.lastname: Stocks
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lynch
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Goldberg
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.forename: Brent W
authors.initials: BW
authors.lastname: Kinder
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Sullivan
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Colby
authors.forename: Roy T
authors.initials: RT
authors.lastname: McKay
authors.forename: Marsha M
authors.initials: MM
authors.lastname: Cohen
authors.forename: Leslie
authors.initials: L
authors.lastname: Korbee
authors.forename: Angelo M
authors.initials: AM
authors.lastname: Taveira-DaSilva
authors.forename: Hye-Seung
authors.initials: HS
authors.lastname: Lee
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D057194:Intention to Treat Analysis; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy* / Q000503:physiopathology; D055118:Medication Adherence; D008875:Middle Aged; D019370:Observation; D011788:Quality of Life; D020123:Sirolimus / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014797:Vital Capacity / Q000187:drug effects
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus