Articles

Inhaled treprostinil and forced vital capacity in patients with

interstitial lung disease and associated pulmonary
hypertension: a post-hoc analysis of the INCREASE study
Steven D Nathan, Aaron Waxman, Sudarshan Rajagopal, Amy Case, Shilpa Johri, Hilary DuBrock, David J De La Zerda, Sandeep Sahay,
Christopher King, Lana Melendres-Groves, Peter Smith, Eric Shen, Lisa D Edwards, Andrew Nelsen, Victor F Tapson

Summary
Background INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in Lancet Respir Med 2021
patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise Published Online
capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements June 29, 2021
https://doi.org/10.1016/
in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the
S2213-2600(21)00165-X
effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest.
See Online/Comment
https://doi.org/10.1016/
Methods In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups S2213-2600(21)00264-2
defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and Advanced Lung Disease and
older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within Transplant Program, Inova
6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat Fairfax Hospital, Falls Church,
VA, USA (Prof S D Nathan MD,
population, defined as individuals who were randomly assigned and received at least one dose of study drug. The C King MD); Pulmonary and
INCREASE study is registered with ClinicalTrials.gov, NCT02630316. Critical Care Medicine,
Department of Internal
Medicine, Brigham and
Findings Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil
Women’s Hospital, Boston, MA,
was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI USA (A Waxman MD); Division
–30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; –25·2 to 114·0; p=0·21) at week 16, with associated percentage of Cardiology, Department of
of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup Medicine, Duke University
Medical Center, Durham, NC,
analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI
USA (S Rajagopal MD);
–32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with Piedmont Healthcare, Austell,
idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; –20·4 to 189·5; p=0·11) at week 8 and GA, USA (A Case MD);
168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, Pulmonary Associates of
Richmond, Richmond, VA, USA
dyspnoea, dizziness, nausea, fatigue, and diarrhoea.
(S Johri MD); Department of
Internal Medicine, Division of
Interpretation In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with Pulmonary and Critical Care,
improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic Mayo Clinic, Rochester, MN,
USA (H DuBrock MD); Division
interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising
of Pulmonary & Critical Care
therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo- Medicine, University of Miami
controlled study. Health System, Miami, FL, USA
(D J De La Zerda MD); Division of
Pulmonary, Critical Care and
Funding United Therapeutics Corporation. Sleep Medicine, Houston
Methodist Hospital, Houston,
Copyright © 2021 Elsevier Ltd. All rights reserved. TX, USA (S Sahay MD);
Pulmonary & Critical Care
Division, University of New
Introduction fibrosis, and unclassifiable ILD—indicate that both Mexico, 1 University of New
Interstitial lung diseases (ILDs) encompass a broad agents have antifibrotic effects beyond idiopathic Mexico, DoIM MSC10-5550,
range of conditions that are categorised by varying pulmonary fibrosis.5,6,7 These results suggest that once Albuquerque, NM, USA
amounts of inflammation and fibrosis. Idiopathic lung fibrosis supervenes, there are pathways common to (L Melendres-Groves MD);
United Therapeutics
interstitial pneumonias are a category of ILD, of which various forms of ILD that might be targets for therapy. Corporation, Research Triangle
idiopathic pulmonary fibrosis is the most common Treprostinil is a stable analogue of prostacyclin, which Park, NC, USA (P Smith PharmD,
form.1 Clinical trials of idiopathic pulmonary fibrosis promotes vasodilation of pulmonary and systemic E Shen PharmD,
treatments have resulted in approval in many countries arterial vascular beds and inhibits platelet aggregation.8 L D Edwards PhD,
A Nelsen PharmD); Division of
of two so-called antifibrotic agents, pirfenidone and The inhaled formulation of treprostinil is approved in Pulmonary and Critical Care
nintedanib.2,3,4 Both drugs have been shown to slow loss the USA for the treatment of WHO group 1 pulmonary Medicine, Cedars-Sinai Medical
of lung function, as measured by forced vital capacity hypertension.8,9 In addition to its effects on the Center, Los Angeles, CA, USA
(FVC). Results of clinical trials for both drugs in other pulmonary vasculature, there are data to suggest that (Prof V F Tapson MD)

forms of fibrotic lung disease—including scleroderma- treprostinil has antifibrotic properties. Specifically,
associated ILD, ILDs characterised by progressive treprostinil has been shown to affect extracellular matrix

www.thelancet.com/respiratory Published online June 29, 2021 https://doi.org/10.1016/S2213-2600(21)00165-X 1

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Correspondence to:
Prof Steven D Nathan, Advanced
Lung Disease and Lung
Transplant Program,
Falls Church, VA 22042, USA
steven.nathan@inova.org
Research in context
Evidence before this study
Clinical trials in patients with chronic fibrosing interstitial lung
diseases (ILDs) have led to the development of two antifibrotic
agents, nintedanib and pirfenidone. These therapies have been
shown to reduce the rate of decline in lung function and are
now recommended in clinical practice guidelines for patients
with idiopathic pulmonary fibrosis. The INCREASE study was a
randomised clinical trial of patients with ILD and pulmonary
hypertension that evaluated the safety and efficacy of inhaled
treprostinil. The study met its primary endpoint of change in the
peak 6-min walk distance at week 16. Pulmonary function
testing was obtained as a safety parameter in this study.
Somewhat unexpectedly, this study also showed that inhaled
treprostinil was associated with improvements in forced vital
capacity (FVC) over a 16-week period. We searched PubMed on
June 9, 2021, using the search terms “treprostinil” and “lung
function” for all articles published from database inception up to
June 9, 2021, with no language restrictions. One retrospective
study of 22 patients with interstitial lung disease and associated
pulmonary hypertension treated with inhaled treprostinil
assessed lung function. No significant changes were observed in
percentage predicted FVC but this study was limited by its
observational, uncontrolled design. The effects of inhaled
treprostinil on lung function in this disease population have
otherwise not been studied.
Added value of this study
In this post-hoc analysis of the INCREASE trial, inhaled
treprostinil was associated with significant improvements in
the percentage of predicted FVC at week 8 and week 16.
Improvement in FVC was greatest among patients with
idiopathic interstitial pneumonia, particularly those with
idiopathic pulmonary fibrosis. These results suggest that
inhaled treprostinil might have independent antifibrotic
properties beyond traditional vasodilatory effects. Whether this
will be substantiated in a study of patients with interstitial lung
disease, with or without pulmonary hypertension, remains to
be determined.
Implications of all the available evidence
The present study serves as proof of concept that inhaled
treprostinil can have a beneficial effect on the loss of lung
function in patients with ILDs and associated pulmonary
hypertension. These findings were most pronounced in
patients with idiopathic pulmonary fibrosis. Further studies are
needed to investigate the clinical benefits of inhaled treprostinil
in this patient population, with or without associated
pulmonary hypertension, and to explore potential mechanisms
of action.

remodelling and fibrosis in vitro by reducing recruit­
ment of fibrocytes to sites of vascular remodelling, as
well as suppressing profibrotic fibroblast activity and
the synthesis and deposition of collagen and fibronectin
in mice.10,11
The INCREASE study was a 16-week randomised
controlled trial that was designed to evaluate the safety
and efficacy of inhaled treprostinil in patients with ILD
and pulmonary hypertension documented by right heart
catheterisation. Patients received inhaled treprostinil, up
to 12 breaths (72 μg) four times daily, or placebo.12 The
dose of drug or placebo was adjusted, with dose escalation
(an additional breath, four times daily) occurring as often
as every 3 days, with a target dose of nine breaths
four times daily and a maximum dose of 12 breaths
four times daily. Investigators adjusted the dose for each
individual patient to achieve the maximum tolerated
dose. The study met its primary endpoint of change in
the peak 6-min walk distance, a measure of exercise
capacity, at week 16. Secondary endpoints, including
change in N-terminal pro-brain natriuretic peptide
(NT-proBNP) concentration at week 16 and time to
clinical worsening, were also met. Pulmonary function
testing was done as a safety assessment at baseline,
week 8, and week 16, and was previously reported.12
The aim of this post-hoc analysis was to further
characterise the effects of inhaled treprostinil on FVC
among the overall study population and in various
subgroups of interest, including specific disease sub­
groups and patients stratified by median baseline clinical
characteristics.
Methods
Study design and participants
INCREASE was a multicentre, randomised, double-blind,
placebo-controlled, parallel-group trial. The steering
committee in collaboration with the sponsor (United
Therapeutics Corporation) designed the study and
oversaw its conduct. Detailed study procedures and
results have been described previously.12 The study
population included patients aged 18 years and older
with a diagnosis of ILD based on evidence of diffuse
parenchymal lung disease on chest CT done within
6 months before random assignment (not centrally
adjudicated). Confirmation of WHO group 3 pulmonary
hypertension was required, based on right heart
catheterisation within 1 year before random assignment
(including pulmonary vascular resistance >3 Wood units,
pulmonary capillary wedge pressure ≤15 mm Hg, and
mean pulmonary arterial pressure ≥25 mm Hg). Patients
with connective tissue disease-associated ILD were
additionally required to have a baseline FVC <70%.
Patients were randomly assigned (1:1) to inhaled
treprostinil (Tyvaso; United Therapeutics Corporation,
Research Triangle Park, NC, USA) or placebo in a double-
blind manner. No new antifibrotics or anti-inflammatory

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Idiopathic interstitial Idiopathic pulmonary Combined pulmonary Connective tissue p value*

pneumonia including fibrosis only (n=92) fibrosis and emphysema disease-associated ILD
idiopathic pulmonary (n=82) (n=72)
fibrosis (n=146)
Sex ·· ·· ·· ·· <0·0001
Female 60 (41%) 31 (34%) 23 (28%) 55 (76%) ··
Male 86 (59%) 61 (66%) 59 (72%) 17 (24%) ··
Age, years 67·8 (11·2) 70·8 (9·1) 71·7 (9·8) 57·2 (11·5) ··
Age group, years ·· ·· ·· ·· <0·0001
<65 41 (28%) 15 (16%) 12 (15%) 53 (74%) ··
65 to <80 93 (64%) 67 (73%) 54 (66%) 19 (26%) ··
≥80 12 (8%) 10 (11%) 16 (20%) 0 ··

Race ·· ·· ·· ·· <0·0001
White 113 (77%) 76 (83%) 69 (84%) 34 (47%) ··
Black 24 (16%) 10 (11%) 12 (15%) 32 (44%) ··
American Indian or Alaska 2 (1%) 2 (2%) 0 1 (1%) ··
Native
Asian 6 (4%) 4 (4%) 1 (1%) 4 (6%) ··
Multiple 0 0 0 1 (1%) ··
Unknown 1 (1%) 0 0 0 ··
Ethnicity† ·· ·· ·· ·· 0·35
Hispanic or Latino 14 (10%) 10 (11%) 4 (5%) 8 (11%) ··
Not Hispanic or Latino 132 (90%) 82 (89%) 77 (95%) 64 (89%) ··
Time since diagnosis, years 0·6 (1·58) 0·5 (1·52) 0·4 (0·63) 0·6 (1·15) 0·59
Use of supplemental oxygen 102 (70%) 68 (74%) 64 (78%) 44 (61%) 0·073
Use of background therapy ·· ·· ·· ·· <0·0001
None 91 (62%) 43 (47%) 69 (84%) 69 (96%) ··
Pirfenidone only 34 (23%) 30 (33%) 6 (7%) 2 (3%) ·
Nintedanib only 21 (14%) 19 (21%) 7 (9%) 1 (1%) ·
Pulmonary function tests
Total lung capacity % 60·7 (16·1) 60·2 (16·0) 77·8 (14·7) 52·9 (13·5) <0·0001
predicted, %
Total lung capacity, L 3·6 (1·2) 3·7 (1·1) 4·8 (1·2) 2·9 (1·2) <0·0001
FVC% predicted, % 59·5 (17·2) 60·8 (17·7) 82·5 (18·8) 49·5 (13·4) <0·0001
FVC, mL 2175·7 (764·6) 2192·1 (724·6) 2992·6 (799·8) 1630·6 (552·4) <0·0001
FEV1% predicted, % 64·3 (19·0) 67·4 (18·8) 77·0 (21·1) 51·0 (15·1) <0·0001
FEV1, mL 1757·0 (585·8) 1793·1 (551·4) 2051·1 (598·6) 1320·1 (456·2) <0·0001
DLCO% predicted, % 30·0 (12·1) 29·1 (11·5) 27·6 (11·3) 28·3 (11·7) 0·35
DLCO, mL/min/mm Hg 8·2 (4·6) 8·0 (4·7) 6·9 (3·0) 7·0 (4·0) 0·058
Data are n (%) or mean (SD). DLCO=diffusing capacity for carbon monoxide. FVC=forced vital capacity. ILD=interstitial lung disease. *p value compares idiopathic interstitial
pneumonia including idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema, and connective tissue disease populations only. †One patient in the
placebo group had a missing response for ethnicity.

Table 1: Baseline characteristics by disease cause

therapies could be started during the study. The protocol
was approved by the institutional review board at each
participating site; all participants provided written
informed consent.
Procedures and outcomes
This post-hoc analysis assessed the results of pulmonary
function testing, which was prespecified as a safety
endpoint and done at baseline, week 8, and week 16 (or at
early termination) after sufficient recovery from the 6-min
walk tests. Pulmonary function tests were done locally at
each study site. We evaluated pulmonary function testing
for the overall study population and by subgroup based on
disease cause (idiopathic interstitial pneumonia [including
idiopathic pulmonary fibrosis], idiopathic pulmonary
fibrosis alone, combined pulmonary fibrosis and
emphysema, and connective tissue disease-associated
ILD) and subgroups stratified by median baseline
characteristics (percentage of predicted FVC, percentage
of predicted diffusing capacity for carbon monoxide
[DLCO], pulmonary vascular resistance, mean pulmonary
arterial pressure, NT-proBNP concentration, and 6-min

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LSM difference: LSM difference: LSM difference:

A 28·5 (SE 30·1) 44·4 (SE 35·4) 108·2 (SE 46·9)
50 95% CI: 95% CI: –25·2 to 114·0 A 95% CI: 15·3 to 201·1)
–30·8 to 87·7 p=0·21 100 Treatment group p=0·023
40
LSM change from baseline in FVC (mL)

p=0·35 80 Inhaled treprostinil

LSM change from baseline in FVC (mL)

30
60 Placebo
20 N=58 N=52
N=129 40
10 N=141 20
0 0
–20
–10
–40
–20 –60 N=70
–30 N=140 –80
–40 N=124 –100 LSM difference:
Treatment group –120 46·5 (SE 39·9)
–50 –140 95% CI: –32·5 to 125·5 N=62
Inhaled treprostinil
–60 Placebo –160 p=0·25
–70 –180
–200
B B LSM difference:
4 LSM difference: 4 2·9 (SE 1·1)
LSM change from baseline in FVC% predicted (%)

LSM difference:

LSM change from baseline in FVC% predicted (%)

LSM difference: 1·8 (SE 0·8) 95% CI: 0·7 to 5·0
3 1·8 (SE 0·7) 2·0 (SE 0·9)
95% CI: 0·2 to 3·4 3 p=0·0096
95% CI: 0·4 to 3·2 95% CI: 0·1 to 3·8
2 p=0·028
p=0·014 2 p=0·037
N=52
1 N=58
N=141 N=129 1
0 0
–1 N=124 –1
N=140
N=70 N=62
–2 –2
–3 –3
–4 –4
0 8 16 0 8 16
Treatment week
Treatment week
Figure 1: Change in FVC at week 8 and week 16 for the overall population
(A) LSM change in FVC (mL) by week for the overall intention-to-treat Figure 2: Change in FVC at week 8 and week 16 for patients with idiopathic
population. (B) LSM change in percentage of predicted FVC by week for the interstitial pneumonia
overall intention-to-treat population. Bars above and below the dots represent (A) LSM change in FVC (mL) by week for the subgroup of patients with
the SE. Mixed model repeated measures methodology was used to compare idiopathic interstitial pneumonia who received treprostinil or placebo.
differences between the inhaled treprostinil and placebo group. FVC=forced vital (B) LSM change in percentage of predicted FVC by week for the subgroup of
capacity. LSM=least squares mean. patients with idiopathic interstitial pneumonia. Bars above and below the dots
represent the SE. Mixed model repeated measures methodology was used to
walk distance). An additional safety endpoint was the compare differences between the inhaled treprostinil and placebo group.
FVC=forced vital capacity. LSM=least squares mean.
incidence of acute exacerbations of disease, determined by
individual site principal investigators. Other prespecified
safety endpoints (not included in the present analysis) interaction as fixed effects, and baseline FVC as a covariate.
were adverse events, oxygenation measured by pulse An unstructured variance or covariance structure shared
oximetry and supplemental oxygen requirement, clinical across treatment groups was used to model the within-
laboratory parameters, vital signs, electrocardiograms, subject errors. Treatment differences, associated 95% CIs,
and cardiopulmonary hospitalisations.12 and p values were calculated. Change in percentage of
predicted FVC was analysed similarly using the MMRM
Statistical analysis model, with the percentage of predicted FVC as the
The analyses reported here were post-hoc and exploratory. dependent variable, with treatment, week, and treatment-
All assessments are summarised by descriptive statistics, by-week interaction as fixed effects, and baseline percentage
as appropriate. Comparisons for categorical assessments of predicted FVC as a covariate. An unstructured variance
were done by Mantel-Haenszel tests and comparisons for or covariance structure shared across treatment groups was
continuous assessments were done by Mann-Whitney used to model the within-subject errors. Changes during
tests. All analyses were done on the intention-to-treat the 16-week study were evaluated for the entire cohort and
population, defined as individuals who were randomly for disease-specific subgroups. Only observed data were
assigned and received at least one dose of study drug. The included in the analysis; no data were imputed. When
change in FVC was analysed using mixed model repeated stratifying by baseline characteristics, median values were
measures (MMRM) methodology. The MMRM model used as a cutoff (eg, below vs above median). The time to
included the change from baseline in FVC as the dependent first acute exacerbation was analysed via Kaplan-Meier
variable, with treatment, week, and treatment-by-week curves and log-rank test. p<0·05 was considered to indicate

4 www.thelancet.com/respiratory Published online June 29, 2021 https://doi.org/10.1016/S2213-2600(21)00165-X

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a statistically significant difference and no adjustments LSM difference:

LSM difference:
were made for multiplicity because this was an unplanned, A 84·5 (SE 52·7) 168·5 (SE 64·5)
post-hoc analysis. Analyses were done with SAS version 95% CI: –20·4 to 189·5 95% CI: 40·1 to 297·0
110
p=0·11 p=0·011
9.4. The INCREASE study is registered with ClinicalTrials. 90

LSM change from baseline in FVC (mL)

70
gov, NCT02630316. 50 N=31 N=28
30
Role of the funding source 10
–10
In collaboration with the authors, the funder of the study
–30 N=46
participated in study design, data collection, data analysis, –50
data interpretation, and writing of the report. –70
–90
–110 Treatment group
Results –130 Inhaled treprostinil
N=41

Between Feb 3, 2017, and Aug 30, 2019, 326 patients were –150 Placebo
enrolled in the INCREASE trial. Reasons for screen –170

failures, baseline characteristics by treatment assign­ B

ment, and study discontinuations have been described 5 LSM difference:
LSM change from baseline in FVC% predicted (%)

previously.12 146 (45%) of 326 patients had idiopathic LSM difference:

2·5 (SE 1·2) 3·5 (SE 1·4)
4
interstitial pneumonia, of whom 92 (28%) had idiopathic 95% CI: 0·1 to 4·9 95% CI: 0·7 to 6·3)
3 p=0·015
pulmonary fibrosis, 37 (11%) had non-specific interstitial p=0·038
pneumonia, and 13 (4%) had unclassified idiopathic 2 N=28
interstitial pneumonia. 82 (25%) of 326 patients had N=31
1
combined pulmonary fibrosis and emphysema, and
72 (22%) patients had connective tissue disease- 0

associated ILD. 19 (6%) of 326 patients had chronic –1

hypersensitivity pneumonitis, six (2%) had occupational
lung disease, and one (<1%) had other idiopathic
interstitial pneumonia. Demographic details of the
four largest groups—idiopathic interstitial pneumonia
(including idiopathic pulmonary fibrosis), idiopathic
pulmonary fibrosis alone, combined pulmonary fibrosis
and emphysema, and connective tissue disease-
associated ILD—are shown in table 1. Notable differences
included variable baseline pulmonary function tests
between disease subtypes and younger age of patients
with connective tissue disease-associated ILD. Anti­
fibrotic therapy was most prevalent in patients with
idiopathic pulmonary fibrosis, with 19 (21%) of
92 patients on nintedanib and 30 (33%) patients on
pirfenidone. Baseline pulmonary function tests, haemo­
dynamics, 6-min walk distance, NT-proBNP concen­
tration, and St George’s Respiratory Questionnaire data
by disease group and treatment assignment are shown in
the appendix (p 2).
In the inhaled treprostinil group, a median of ten breaths
(IQR 8·5–12) and 12 breaths (9–12), corresponding to
66 μg and 72 μg per session, was achieved at week 8 and
week 16, respectively, with 67 (51%) of 132 patients at
week 8 and 67 (58%) of 116 patients at week 16 achieving
10–12 breaths (60–72 μg). 40 (25%) of 163 patients in the
inhaled treprostinil group and 38 (23%) of 163 patients in
the placebo group discontinued study drug prematurely
but were encouraged to remain in the study and complete
study assessments up to week 16. 33 patients assigned
to inhaled treprostinil and 35 assigned to placebo
discontinued study participation.12
Inhaled treprostinil was associated with a non-
significant increase in placebo-corrected (the treatment
N=46
–2 N=41
–3
0 8 16
Treatment week
Figure 3: Change in FVC at week 8 and week 16 for patients with idiopathic
pulmonary fibrosis
(A) LSM change in FVC (mL) by week for the subgroup of patients with
idiopathic pulmonary fibrosis who received treprostinil or placebo.
(B) LSM change in percentage of predicted FVC by week for the subgroup of
patients with idiopathic pulmonary fibrosis. Bars above and below the dots
represent the SE. Mixed model repeated measures methodology was used to
compare differences between the inhaled treprostinil and placebo groups.
FVC=forced vital capacity. LSM=least squares mean.
difference between inhaled treprostinil and placebo) least
squares mean FVC of 28·5 mL (SE 30·1; 95% CI
–30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4;
–25·2 to 114·0; p=0·21) at week 16 (figure 1A). The
percentage of predicted FVC differences at week 8
(least squares mean 1·8%; SE 0·7; 95% CI 0·4 to 3·2; See Online for appendix
p=0·014) and week 16 (1·8%; 0·8; 0·2 to 3·4; p=0·028)
were statistically significant, indicating potential benefit of
inhaled treprostinil compared with placebo (figure 1B).
A subgroup analysis of patients with idiopathic interstitial
pneumonia showed significant FVC differences at week 16
(108·2 mL; SE 46·9; 95% CI 15·3 to 201·1; p=0·023)
although not at week 8 (46·5 mL; 39·9; –32·5 to 125·5;
p=0·25; figure 2A), and significant differences in
percentage of predicted FVC at week 8 (2·0%; SE 0·9;
95% CI 0·1 to 3·8; p=0·037) and week 16 (2·9%; 1·1;
0·7 to 5·0; p=0·0096) favouring inhaled treprostinil
(figure 2B). Further analysis of patients with idiopathic
pulmonary fibrosis showed non-significant FVC
differences of 84·5 mL (SE 52·7; 95% CI –20·4 to 189·5;

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concentration, and median baseline 6-min walk distance

Inhaled Placebo (n) Placebo-corrected p value
treprostinil (n) difference in week-16 (table 2). We identified no responder or non-responder
FVC, mL subgroup based on analyses of percentage of predicted
FVC% predicted FVC (<60% or ≥60%), percentage of predicted DLCO
<60 62 50 27·5 0·61 (<27% or ≥27%), or mean pulmonary arterial pressure
(53·3; –77·4 to 132·4) (<35 mm Hg or ≥35 mm Hg). However, a subgroup
≥60 67 74 59·2 0·22 analysis of 114 patients with pulmonary vascular
(47·8; –34·9 to 153·4) resistance of 5·275 Wood units or greater showed a
DLCO% predicted significant difference favouring inhaled treprostinil
<27 52 61 35·4 0·49 versus placebo, with a mean placebo-corrected difference
(51·6; –66·2 to 137·1) in FVC of 112·5 mL at 16 weeks (SE 52·6; 95% CI
≥27 70 60 33·3 0·49 9·0 to 215·9; p=0·033; table 2). Similarly, a subgroup
(48·5; –62·3 to 128·9)
analysis of 110 patients with NT-proBNP concentration of
Pulmonary vascular resistance, Wood units
503·85 pg/mL or greater showed a significant difference
<5·275 64 75 –1·6 0·97
(47·9; –95·9 to 92·8)
favouring inhaled treprostinil compared with placebo,
≥5·275 65 49 112·5 0·033
with a placebo-corrected difference in FVC of 94·4 mL at
(52·6; 9·0 to 215·9) 16 weeks (SE 47·4; 95% CI 0·7 to 188·2; p=0·048; table 2).
Mean pulmonary arterial pressure, mm Hg 14 patients in the inhaled treprostinil group were on
<35 63 63 63·4 0·21 pirfenidone versus 18 patients in the placebo group.
(50·2; –35·4 to 162·1) There was no significant placebo-corrected difference
≥35 66 61 25·6 0·61 favouring inhaled treprostinil at 16 weeks (91·5 mL;
(50·2; –73·2 to 124·4) SE 110·2; 95% CI –134·2 to 317·1; p=0·41) in the
NT-proBNP, pg/mL pirfenidone-treated subgroup. Seven patients in the
<503·85 62 75 19·9 0·71 inhaled treprostinil group were on nintedanib versus
(53·7; –86·3 to 126·1)
15 patients in the placebo group. The placebo-corrected
≥503·85 63 47 94·4 0·048
(47·4; 0·7 to 188·2)
difference for inhaled treprostinil was 113·0 mL at
6-min walk distance, m
16 weeks (SE 77·1; 95% CI –46·9 to 272·8; p=0·16) in
the nintedanib-treated subgroup. When patients on
<259 63 56 64·5 0·21
(51·7; –37·3 to 166·4) pirfenidone or nintedanib were evaluated as a group,
≥259 66 68 27·6 0·57 those receiving inhaled treprostinil had no statistically
(48·7; –68·4 to 123·5) significant difference in placebo-corrected FVC (81·5 mL;
Data are mean (SE; 95% CI) unless otherwise indicated. DLCO=diffusing capacity SE 71·0; 95% CI –60·9 to 223·8; p=0·26) or percentage of
for carbon monoxide. FVC=forced vital capacity. NT-proBNP=N-terminal predicted FVC (1·2%; 1·5; –1·8 to 4·2; p=0·43) at week 16.
pro-brain natriuretic peptide. The most frequent adverse events, which have been
Table 2: Placebo-corrected difference in week-16 FVC stratified by reported previously, included cough, headache, dyspnoea,
median baseline clinical characteristics dizziness, nausea, fatigue, and diarrhoea.12 We found no
difference in the frequency of these adverse events
according to disease subtype (table 3). We also observed
p=0·11) at week 8 and significant differences of 168·5 mL no difference in exacerbations between disease subtypes
(64·5; 40·1 to 297·0; p=0·011) at week 16 (figure 3A), and (appendix p 3).
differences in percentage of predicted FVC at week 8 and Regarding safety, no significant treatment-related
week 16 of 2·5% (SE 1·2; 95% CI 0·1 to 4·9; p=0·038) changes associated with inhaled treprostinil in pulse
and 3·5% (1·4; 0·7 to 6·3; p=0·015), respectively, oximetry or supplemental oxygen use were reported
compared with placebo (figure 3B). Of note, 49 (53%) of during the study. However, there were significantly
92 patients with idiopathic pulmonary fibrosis were on fewer lung disease exacerbations in the treprostinil
antifibrotic therapy at baseline. FVC changes for patients group than the placebo group. Specifically, 43 (26%) of
with connective tissue disease-associated ILD and 163 patients in the treatment group had an exacerbation
combined pulmonary fibrosis and emphysema are shown of underlying lung disease compared with 63 (39%) of
in the appendix (pp 4–5). Histograms showing FVC 163 patients in the placebo group (p=0·02 by Fisher’s
categorical changes in 5% increments for the overall study exact test).12 Time to investigator-reported exacerbations
population and the four disease categories are provided in in the two groups is shown in the appendix (p 8), with
the appendix (pp 6–8). inhaled treprostinil associated with a significant
We stratified change in FVC over 16 weeks by baseline treatment effect (log-rank p=0·040).
lung function (median percentage of predicted FVC and
median percentage of predicted DLCO), haemo­dynamics Discussion
(median pulmonary vascular resistance and mean The INCREASE study was designed to evaluate the
pulmonary arterial pressure), median baseline NT-proBNP effects of inhaled treprostinil in patients with various

6 www.thelancet.com/respiratory Published online June 29, 2021 https://doi.org/10.1016/S2213-2600(21)00165-X

 Articles

ILDs and associated pulmonary hypertension. The study

Idiopathic interstitial Idiopathic Combined Connective tissue
met its primary endpoint: compared with placebo, pneumonia including pulmonary pulmonary fibrosis disease-associated
treprostinil improved exercise capacity, assessed by idiopathic pulmonary fibrosis only and emphysema ILD (n=72)
6-min walk distance, from baseline at 16 weeks.12 The fibrosis (n=146) (n=92) (n=82)
study also met several secondary endpoints, including Number of subjects 115 (79%) 71 (77%) 63 (77%) 49 (68%)
time to clinical worsening and change in concentration with adverse event of
interest
of NT-proBNP, a marker of cardiac dysfunction that
Cough 55 (38%) 30 (33%) 32 (39%) 31 (43%)
likely reflects right ventricular strain in patients with
Dyspnoea 44 (30%) 24 (26%) 28 (34%) 17 (24%)
pulmonary hypertension due to interstitial lung disease.
Headache 35 (24%) 19 (21%) 22 (27%) 15 (21%)
Lung function, specifically spirometry, was measured at
baseline and at week 8 and week 16 as a safety measure to Dizziness 29 (20%) 17 (18%) 15 (18%) 5 (7%)

ensure that there were no deleterious effects of inhaled Nausea 28 (19%) 18 (20%) 11 (13%) 9 (13%)
treprostinil. We felt that investigation of any deleterious Fatigue 20 (14%) 12 (13%) 13 (16%) 11 (15%)
effects was important because of the patients’ pre- Diarrhoea 23 (16%) 13 (14%) 9 (11%) 6 (8%)
existing lung disease. A noteworthy finding previously Productive cough 4 (3%) 3 (3%) 2 (2%) 5 (7%)
reported in the primary publication12 was that, rather Dyspnoea on exertion 4 (3%) 2 (2%) 2 (2%) 1 (1%)
than causing any decrement, inhaled treprostinil Upper-airway cough 3 (2%) 1 (1%) 1 (1%) 2 (3%)
syndrome
was unexpectedly associated with a placebo-corrected
Sinus headache 2 (1%) 1 (1%) 1 (1%) 0
improvement in FVC. Further subgroup analyses
revealed the FVC difference between the inhaled Muscle fatigue 1 (1%) 1 (1%) 1 (1%) 0

treprostinil group and placebo group to be larger in the
idiopathic interstitial pneumonia subgroup, and even
more so in the idiopathic pulmonary fibrosis
subpopulation.
FVC is widely accepted as the standard efficacy
endpoint for clinical trials in idiopathic pulmonary
fibrosis and other fibrotic lung disorders.13 Indeed,
clinical trials evaluating change in FVC over 52 weeks
have resulted in the approval of both pirfenidone and
nintedanib for the treatment of idiopathic pulmonary
fibrosis.3,4 Nintedanib has since been approved for other
fibrotic disorders, including scleroderma-associated ILD
and a broader group of ILDs characterised by a
progressive fibrotic phenotype.5,6 The disease groups
included in a previous cohort study6 of nintedanib were
very similar to those of the INCREASE study.12 Our
findings lend support to the study of different forms of
fibrotic disease as a group, although the idiopathic
pulmonary fibrosis subgroup did show the strongest
efficacy signal.
No drug has been shown to have an effect on fibrosis
when administered via inhalation. However, there is
inherent attractiveness to this mode of delivery because
of greater deposition of drug at the site of disease,
resulting in fewer systemic side-effects and preservation,
or possibly improvement, of ventilation–perfusion
matching. Fibrotic lung diseases, and idiopathic
pulmonary fibrosis in particular, are characterised by
areas of vascular ablation and perivascular fibrosis,
which raises the issue of adequate systemic drug delivery
to high-value target cells, including fibroblasts and
myofibroblasts.14 The finding of a placebo-corrected
improvement in FVC indicates that inhaled treprostinil
might have distinct antifibrotic properties. Indeed,
animal studies and biological pathways support this
concept.10,11 Amelioration of loss of lung function has
been described previously with sildenadil, another
Data are n (%). ILD=interstitial lung disease.
Table 3: Adverse events by disease cause
medication approved in the USA and Europe for the
treatment of pulmonary arterial hypertension, in patients
with idiopathic pulmonary fibrosis on background
nintedanib.15 This observation lends cre­ dence to the
possibility that the pulmonary vasculature itself might be
involved in the perpetuation of the fibrotic process or
that pulmonary hypertension and fibrosis have shared
pathways. However, this synergy was not replicated when
sildenafil was combined with pirfenidone.16
Two of our subgroup analyses showed a significant
difference in FVC change between the inhaled treprostinil
group and the placebo group. These analyses were in
patients with higher pulmonary vascular resistance and
higher NT-proBNP concentration. Therefore, pulmonary
vessels themselves might contribute to the restrictive
physiology, perhaps through vascular compliance, which
is ameliorated by inhaled treprostinil. An alternative,
speculative concept is that the presence of more severe
pulmonary hypertension might hasten the progression of
fibrosis. A further hypothesis is that these FVC findings
are related to improved right ventricular function or
cardiac output in those receiving inhaled treprostinil, as
evidenced by the greater treatment effect in those with
higher baseline pulmonary vascular resistance and
NT-proBNP concentration, but less striking differences
when stratifying by baseline mean pulmonary arterial
pressure. Decreased right ventricular size and function
and improved cardiac output in those with more severe
pulmonary hypertension could lead to improvement in
respiratory muscle function and thus FVC.
It is interesting to compare the findings in our
idiopathic pulmonary fibrosis population with those of
the pivotal phase 3 studies of pirfenidone and

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 Articles
nintedanib.2–4,17,18 First, INCREASE was only a 16-week
study compared with 52-week and 72-week studies for
these other agents. Whether our results will dissipate, be
sustained, or improve up to 52 weeks is open to
speculation given how unpredictable disease behaviour
can be over time. The magnitude of the difference was
very similar with inhaled treprostinil at 16 weeks
(168·5 mL) compared with the combined pirfenidone
(148 mL per year) and nintedanib (110·9 ml per year)
datasets at 52 weeks.17,18 However, in addition to the
different follow-up periods, there were varying imputation
methods and nuanced differences that limit meaningful
comparisons between studies.18,19 The difference in the
FVC change in INCREASE was partly driven by a
numerical FVC increase in the treatment group, which
contrasts with the pirfenidone and nintedanib studies,
where the difference lay in the rate of decrement in both
groups (although there were some patients with
numerical increases in FVC).18,19 This fact raises the
question of whether inhaled treprostinil can ameliorate
fibrosis; this is conceivable perhaps for areas of fresh
collagen deposition or through so-called switching off of
myofibroblasts that might contribute to restrictive
physiology through their contractile properties.20–22 An
alternative explanation is that treprostinil improved vessel
capacitance and stiffness, affecting the measured FVC.
Although we observed a significant difference in the
change in percentage of predicted FVC over the 16-week
study period for the cohort as a whole, the difference was
not significant when evaluated FVC by change in mL.
This apparent discrepancy could be due to the narrower
CIs when FVC is expressed as a percentage of the
predicted value. Many patients with idiopathic pulmonary
fibrosis were already on antifibrotic therapy; however, the
number of patients on nintedanib or pirfenidone in
combination with inhaled treprostinil was too small to
draw efficacy conclusions. The smaller numerical
difference when combining the two antifibrotics
(81·5 mL) versus each individually (113·0 mL for patients
on nintedanib and 91·5 mL for patients on pirfenidone)
is a function of MMRM statistical methodology.
Nonetheless, the numerical differences show the potential
role of combination therapy for idiopathic pulmonary
fibrosis and targeting the disease concomitantly via the
systemic and inhaled routes.
FVC was measured as a safety endpoint in the context
of the INCREASE study. Other pulmonary function tests,
including DLCO, were also measured as safety endpoints
but did not show a difference between groups. A
longer-term study of inhaled treprostinil in patients with
ILD and pulmonary hypertension is ongoing and will
provide information on gas exchange (NCT02633293).
Other safety endpoints, including pulse oximetry
and change in supplemental oxygen needs, did not
show any deleterious effects, mitigating concerns about
potential worsening of ventilation–perfusion matching.
Additionally, the incidence of investigator-reported acute
8 www.thelancet.com/respiratory Published online June 29, 2021 https://doi.org/10.1016/S2213-2600(21)00165-X
exacerbations was significantly less in the treprostinil
group, allaying any concerns that this inhaled medication
might induce acute exacerbations. Therefore, it is possible
that inhaled treprostinil might actually ameliorate acute
exacerbations of the underlying ILD.
Our analysis has its limitations. First, this was a post-
hoc analysis of a parameter that was initially intended as a
safety endpoint, and the study was not powered to detect
differences in FVC among the different subgroups in the
analysis. The study was of relatively short duration, with
21% of patients discontinuing prematurely before
week 16.12 The number of patients was relatively small for
the subgroup analyses. There was no efficacy signal from
the connective tissue disease-associated ILD group or the
combined pulmonary fibrosis and emphysema group,
which raises questions about global antifibrotic properties
and whether our findings are relevant for only certain
subgroups of fibrotic disorders. Also, the relatively rapid
rate of FVC decrement in the placebo group over a short
period of time was unexpected. Aside from patients with
more severe disease being at higher risk of progression,
an interesting hypothesis is that perhaps the pulmonary
vasculature is mechanistically linked to the progression of
fibrosis.23 Finally, the finding of fewer acute exacerbations
in the inhaled treprostinil group should be regarded with
caution, since these acute exacerbations were investigator-
determined and not centrally adjudicated. The unusually
high rate of acute exacerbations in both study groups is
noteworthy. It is possible that patients with more advanced
disease who have any worsening are more likely to be
increasingly symptomatic, with the default labelling of an
acute exacerbation, without necessarily fulfilling all the
criteria. We cannot rule out the possibility that any inhaled
therapy, be it placebo or treatment, might increase the
propensity for acute exacerbations.
In conclusion, inhaled treprostinil appears to have a
salutary effect on loss of lung function in patients with
ILD and associated pulmonary hypertension. This
finding, although intriguing and hypothesis generating,
warrants further validation in a prospective, randomised,
placebo-controlled study. A clinical trial of inhaled
treprostinil is underway in patients with idiopathic
pulmonary fibrosis, with or without associated pul­
monary hypertension (NCT04708782). This study will
use a primary endpoint of change in FVC over 52 weeks
and will support the findings of our post-hoc analysis.
Contributors
SDN, AW, PS, ES, LDE, AN, and VFT made substantial contributions to
the conception and design of the work. SDN, AW, SR, AC, SJ, HD,
DJDLZ, SS, CK, LM-G, and VFT contributed to the acquisition of the
study data. Data were analysed by SDN, AW, PS, ES, LDE, AN, and VFT.
LDE was responsible for the statistical analysis. SDN, AW, and VFT
participated on the INCREASE steering committee during the study.
SDN, AW, SR, AC, SJ, HD, DJDLZ, SS, CK, LM-G, PS, ES, AN, and VFT
contributed to data interpretation, and to drafting and revision of the
manuscript. SDN, ES, and LDE have accessed and verified the data.
All authors agree to be accountable for all aspects of the work, ensuring
that questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved. All authors have read and

approved the manuscript. The corresponding author and all co-authors
had full access to all the data in the study and had final responsibility for
the decision to submit for publication.
Declaration of interests
SDN has received research funding and consulting fees from United
Therapeutics, and consulting fees from Boehringer Ingelheim,
Roche-Genentech, and Galapagos; he is on the speaker’s bureau for
Boehringer Ingelheim and Roche-Genentech. AW reports grants from
United Therapeutics, during the conduct of the study. SR reports
grants from United Therapeutics, during the conduct of the study;
grants and personal fees from United Therapeutics and Janssen
Pharmaceuticals; and personal fees from Altavant Sciences, Liquidia
Technologies, Insmed, and Bayer Pharmaceuticals, outside the
submitted work. AC reports grants from United Therapeutics, during
the conduct of the study. SJ reports grants from United Therapeutics,
during the conduct of the study; grants and personal fees from Bayer
Pharmaceuticals and Janssen Research & Development; and grants
from Bellerophon Therapeutics, outside the submitted work.
HD reports grants from United Therapeutics, during the conduct of
the study; and grants and personal fees from Actelion Pharmaceuticals,
outside the submitted work. DJDLZ reports grants from United
Therapeutics, during the conduct of the study. SS reports grants from
United Therapeutics, during the conduct of the study; personal fees
and non-financial support from Bayer Pharmaceuticals, United
Therapeutics, and Actelion Pharmaceuticals; personal fees from
Liquidia, Altavant Sciences, GSK, and Boehringer Ingelheim;
and grants from ACCP CHEST ILD, outside the submitted work.
CK reports grants from United Therapeutics, during the conduct of the
study; and personal fees from United Therapeutics, Actelion,
Boehringer Ingelheim, and Genentech, outside the submitted work.
LM-G reports grants and personal fees from United Therapeutics,
during the conduct of the study; and personal fees from United
Therapeutics, Janssen Pharmaceuticals, and Bayer Pharmaceuticals,
outside the submitted work. PS, ES, LDE, and AN report personal fees
from United Therapeutics, during the conduct of the study;
and personal fees from United Therapeutics, outside the submitted
work. VFT reports grants from United Therapeutics, during the
conduct of the study; and personal fees from United Therapeutics,
outside the submitted work.
Data sharing
Qualified researchers who provide methodologically sound, genuine
research proposals can submit data requests to United Therapeutics
Corporation to obtain specific de-identified clinical trial data.
Acknowledgments
We thank all patients who volunteered for the study, and the clinical and
research teams at the INCREASE centres.
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