BACKGROUND: Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is 
implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim 
of this study was to investigate the efficacy and safety of simtuzumab, a 
monoclonal antibody against LOXL2, in patients with IPF.
METHODS: In this randomised, double-blind, phase 2 trial, we recruited patients 
aged 45-85 years with definite IPF diagnosed prior to 3 years of screening from 
183 hospitals and respiratory clinics in 14 countries. Eligible patients, 
stratified by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) 
concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) 
to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The 
primary endpoints were progression-free survival, defined as time to all-cause 
death or a categorical decrease from baseline in FVC % predicted, in the 
intention-to-treat population, in patients with sLOXL2 concentrations in the 
50th percentile or higher, and in patients with sLOXL2 concentrations in the 
75th percentile or higher. Treatment duration was event-driven, and interim 
analyses were planned and conducted after approximately 120 and 200 
progression-free survival events, respectively, occurred. We compared treatment 
groups with the stratified log-rank test. This study is registered with 
ClinicalTrials.gov, number NCT01769196.
FINDINGS: Patients with IPF were recruited between Jan 31, 2013, and June 1, 
2015. The intention-to-treat population included 544 randomly assigned patients 
(272 patients in both groups), and the safety population included 543 randomly 
assigned patients who received at least one dose of study medication. The study 
was terminated when the second interim analysis met the prespecified futility 
stopping criteria in the intention-to-treat population. We noted no difference 
in progression-free survival between simtuzumab and placebo in the 
intention-to-treat population (median progression free survival times of 12·6 
months and 15·4 months for simtuzumab and placebo, respectively; stratified HR 
1·13, 95% CI 0·88-1·45; p=0·329) and in patients with baseline sLOXL2 in the 
50th percentile or higher (median progression-free survival 11·7 months and 14·3 
months for simtuzumab and placebo, respectively; stratified HR 1·03, 95% CI 
0·74-1·43; p=0·851), or in the 75th percentile or higher (median 
progression-free survival 11·6 months and 16·9 months for simtuzumab and 
placebo, respectively; stratified HR 1·20, 95% CI 0·72-2·00; p=0·475). The 
incidence of adverse events and serious adverse events was similar between 
treatment groups. The most common adverse events in both the simtuzumab and 
placebo groups were dyspnoea, cough, upper respiratory tract infection, and 
worsening of IPF; and the most common grade 3 or 4 adverse events were worsening 
of IPF, dyspnoea, and pneumonia.
INTERPRETATION: Simtuzumab did not improve progression-free survival in a 
well-defined population of patients with IPF. Our data do not support the use of 
simtuzumab for patients with IPF.
FUNDING: Gilead Sciences Inc.