A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.
BACKGROUND
In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients.


METHODS
In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis.


RESULTS
In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation.


CONCLUSIONS
Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).
From the University of California, San Francisco, San Francisco (T.E.K.), InterMune, Brisbane (W.Z.B., E.A.F., E.G., D.K.), and Cedars-Sinai Medical Center, Los Angeles (P.W.N.) - all in California; Neumocare, Clínica San Borja, Lima, Peru (S.C.-B.); Alfred Hospital, Melbourne, VIC (I.G.), and Prince Charles Hospital, Brisbane, QLD (P.M.H.) - both in Australia; University of Miami Miller School of Medicine, Miami (M.K.G.); Vanderbilt University Medical Center, Nashville (L.L.); Columbia University Medical Center, New York (D.J.L.); Inova Fairfax Hospital, Falls Church, VA (S.D.N.); Paulista School of Medicine, Federal University of São Paulo, São Paulo (C.A.P.); Medical University of South Carolina, Charleston (S.A.S.); Atlantic Health System-Overlook Medical Center, Summit, NJ (R.S.); and National Jewish Health, Denver (J.J.S.).
Talmadge E
TE
King
Williamson Z
WZ
Bradford
Socorro
S
Castro-Bernardini
Elizabeth A
EA
Fagan
Ian
I
Glaspole
Marilyn K
MK
Glassberg
Eduard
E
Gorina
Peter M
PM
Hopkins
David
D
Kardatzke
Lisa
L
Lancaster
David J
DJ
Lederer
Steven D
SD
Nathan
Carlos A
CA
Pereira
Steven A
SA
Sahn
Robert
R
Sussman
Jeffrey J
JJ
Swigris
Paul W
PW
Noble
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000933:Antifibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014797:Vital Capacity / Q000187:drug effects
D000933:Antifibrinolytic Agents; D004791:Enzyme Inhibitors; D011728:Pyridones; C093844:pirfenidone