Articles

Nintedanib in patients with progressive fibrosing interstitial

lung diseases—subgroup analyses by interstitial lung disease
diagnosis in the INBUILD trial: a randomised, double-blind,
placebo-controlled, parallel-group trial
Athol U Wells, Kevin R Flaherty, Kevin K Brown, Yoshikazu Inoue, Anand Devaraj, Luca Richeldi, Teng Moua, Bruno Crestani, Wim A Wuyts,
Susanne Stowasser, Manuel Quaresma, Rainer-Georg Goeldner, Rozsa Schlenker-Herceg, Martin Kolb on behalf of the INBUILD trial investigators*

Summary
Background The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with Lancet Respir Med 2020
progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to Published Online
establish the effects of nintedanib in subgroups based on ILD diagnosis. March 5, 2020
https://doi.org/10.1016/
S2213-2600(20)30036-9
Methods The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in
See Online/Comment
15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of https://doi.org/10.1016/
fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, S2213-2600(20)30062-X
and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants *Full list of investigators
fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered included in appendix p 2
appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo- National Institute for Health
random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, Research Respiratory
Biomedical Research Unit,
investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after Royal Brompton and Harefield
database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who NHS Foundation Trust,
received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented London, UK (Prof A U Wells MD);
by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, Division of Pulmonary and
Critical Care Medicine,
unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with University of Michigan,
ClinicalTrials.gov, number NCT02999178. Ann Arbor, MI, USA
(Prof K R Flaherty MD);
Findings Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least Department of Medicine,
National Jewish Health,
one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune Denver, CO, USA
ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, (Prof K K Brown MD); Clinical
and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was Research Center, National
Hospital Organization Kinki-
consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis
Chuo Chest Medical Center,
73·1 [95% CI −8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia Sakai City, Osaka, Japan
141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [−31·4 to 168·1]; and other ILDs (Prof Y Inoue MD); Department
197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups of Radiology, Royal Brompton
and Harefield NHS Foundation
were consistent with those reported in the overall population.
Trust, London, UK
(Prof A Devaraj MD); National
Interpretation The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in Heart and Lung Institute,
specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as Imperial College, London, UK
(Prof A Devaraj); Fondazione
measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of
Policlinico A. Gemelli IRCCS,
the underlying ILD diagnosis. Università Cattolica del Sacro
Cuore, Rome, Italy
Funding Boehringer Ingelheim. (Prof L Richeldi MD); Division of
Pulmonary and Critical Care
Medicine, Mayo Clinic
Copyright © 2020 Elsevier Ltd. All rights reserved. Rochester, Rochester, MN, USA
(T Moua MD); Université de
Introduction others, chronic hypersensitivity pneumonitis (HP),4 Paris, Inserm U1152, APHP,
Hôpital Bichat, Centre de
Interstitial lung diseases (ILDs) other than idiopathic idiopathic non-specific interstitial pneumonia (iNSIP),5 reference constitutif pour les
pulmonary fibrosis (IPF) might be associated with a unclassifiable idiopathic interstitial pneumonia (IIP),6 maladies pulmonaires rares,
progressive fibrosing phenotype, characterised by sarcoidosis,7 and autoimmune ILDs such as those Paris, France
increasing fibrosis on high resolution CT (HRCT), associated with rheumatoid arthritis (RA-ILD)8 and (Prof B Crestani MD); Unit for
Interstitial Lung Diseases,
decline in lung function, worsening symptoms and systemic sclerosis (SSc-ILD).9 Similar to observations in Department of Pulmonary
quality of life, and early mortality.1–3 ILDs associated with patients with IPF, short-term decline in forced vital Medicine, University Hospitals
a progressive fibrosing phenotype include, among capacity (FVC) has been associated with early mortality Leuven, Leuven, Belgium

www.thelancet.com/respiratory Published online March 5, 2020 https://doi.org/10.1016/S2213-2600(20)30036-9 1

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(Prof W A Wuyts MD);

Boehringer Ingelheim
International, Ingelheim am
Rhein, Germany
(S Stowasser MD,
M Quaresma Lic ); Boehringer
Ingelheim Pharma, Biberach,
Germany (R-G Goeldner PhD);
Boehringer Ingelheim
Pharmaceuticals, Ridgefield,
CT, USA
(R Schlenker-Herceg MD); and
McMaster University and
St Joseph’s Healthcare,
Hamilton, Ontario, Canada
(Prof M Kolb MD)
Correspondence to:
Prof Athol U Wells, Royal
Brompton Hospital, Sydney
Street, London SW3 6HP, UK
See Online for appendix
Research in context
Evidence before this study
Interstitial lung diseases (ILDs) other than idiopathic
pulmonary fibrosis (IPF) might be associated with a
progressive fibrosing phenotype. In the INBUILD trial,
nintedanib slowed the rate of decline in forced vital capacity
(FVC) versus placebo in patients with fibrosing ILDs other than
IPF who met criteria for progression of ILD in the 24 months
before screening. We searched PubMed for all English-
language papers published between Jan 1, 1990, and
Nov 1, 2019, using the search terms “hypersensitivity
pneumonitis”, “idiopathic non-specific interstitial
pneumonia”, “unclassifiable idiopathic interstitial
pneumonia”, “sarcoidosis” or “exposure-related interstitial
lung disease”, “autoimmune disease”, “rheumatoid arthritis”,
“systemic sclerosis” or “mixed connective tissue disease” with
“nintedanib”. We found no studies other than the INBUILD
trial that have investigated the effects of nintedanib in
patients with ILD diagnoses other than IPF.
Added value of this study
Although the INBUILD trial was not designed or powered to
provide evidence for a benefit of nintedanib in specific ILD
subgroups, these new analyses suggest that the effect of
nintedanib on reducing the rate of decline in FVC was
consistent across prespecified subgroups based on ILD
diagnosis, both in patients with a usual interstitial pneumonia-
like fibrotic pattern on high-resolution computed tomography
(HRCT) and in patients with other fibrotic patterns on HRCT.
The safety profile of nintedanib in the subgroups was
consistent with observations in the overall population.
Implications of all the available evidence
An accurate initial ILD diagnosis is crucial to inform prognosis
and ensure that patients receive optimal management, but
once progressive fibrosis occurs despite management,
diagnostic precision is less important in establishing who will
benefit from treatment with nintedanib.

in patients with progressive fibrosing ILDs.10–12 Based on
their clinical and pathophysiological similarities, it has
been postulated that progressive fibrosing ILDs be
lumped together for the purpose of investigating
potential therapies.1 A similar basket approach has been
used in trials of other diseases with unmet medical
needs.13,14
Nintedanib is a tyrosine-kinase inhibitor that has
been shown in non-clinical studies to inhibit processes
fundamental to the progression of lung fibrosis.15,16
Clinical trials have shown that nintedanib reduces the
rate of progression of ILD in patients with IPF17 and
SSc-ILD.18 The INBUILD trial was a prospective,
randomised, placebo-controlled trial of nintedanib in
which patients with fibrosing ILDs other than IPF were
grouped together on the basis of the progressive
behaviour of their ILD.19 The results showed that
nintedanib slowed ILD progression as measured by the
rate of decline in FVC (mL/year) compared with
placebo,20 with adverse events that were similar to those
observed in patients with IPF and SSc-ILD.17,18,20
Although the INBUILD trial was not designed or
powered to provide evidence for a benefit of nintedanib
in specific ILD subgroups, exploratory subgroup
analyses based on grouped ILD diagnoses were
prespecified. In this study we aimed to establish the
effect of nintedanib on FVC decline and its safety profile
in subgroups based on ILD diagnosis.
Methods
Study design and participants
The INBUILD trial was a randomised, double-blind,
placebo-controlled, parallel group trial done at 153 sites
in 15 countries.20 The trial was carried out in compliance
with the protocol,20 the principles of the Declaration of
Helsinki and the Harmonised Tripartite Guideline for
Good Clinical Practice from the International Conference
on Harmonisation, and was approved by local authorities.
All participants provided written informed consent.
Eligibility criteria for the INBUILD trial have been
published.20 Briefly, participants were aged 18 years and
above and had a fibrosing ILD other than IPF, diagnosed
by the investigator according to their usual clinical
practice. As the efficacy and safety of nintedanib in IPF
had already been shown,17 patients with a diagnosis of
IPF were actively excluded. Participants had features of
fibrosing lung disease (reticular abnormality with
traction bronchiectasis, with or without honeycombing)20
of greater than 10% extent on HRCT, confirmed by
central review, FVC of at least 45% predicted, and
diffusing capacity of the lung for carbon monoxide
(DLco) of at least 30% and less than 80% predicted.
Participants fulfilled protocol-defined criteria for ILD
progression in the 24 months before screening, despite
management considered appropriate in clinical practice
for the individual ILD.20 For every participant, the
investigator documented an ILD diagnosis on the case
report form based on the following nine options: iNSIP,
unclassifiable IIP, HP, RA-ILD, mixed connective tissue
disease-ILD (MCTD-ILD), SSc-ILD, exposure-related
ILD, sarcoidosis, and other fibrosing ILD. In the case of
other fibrosing ILD, physicians were asked to provide a
diagnosis in a text box.
The protocol did not allow for use of azathioprine,
cyclosporin, mycophenolate mofetil, tacrolimus,
rituximab, cyclophosphamide, or oral corticosteroids
more than 20 mg/day at randomisation, but initiation of
these medications was allowed after 6 months of study
treatment in cases of clinically significant deterior­ation
of ILD or connective tissue disease, at the discretion of

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the investigator. The proportion of patients who took a
restricted medication at baseline or at any time during
the 52-week treatment period was lower in the nintedanib
group than in the placebo group (12% vs 24%).
Randomisation and masking
Participants were randomly assigned 1:1 to receive oral
nintedanib 150 mg twice daily or matching placebo;
332 patients were randomised to nintedanib and 331 were
randomised to placebo. Randomisation was stratified by
HRCT pattern (usual interstitial pneumonia [UIP]-like
fibrotic pattern or other fibrotic patterns) based on central
review. A UIP-like pattern was an HRCT pattern in which
the predominant pattern was definite or probable UIP.20
A vendor employed by the sponsor allocated participants
via an interactive web-based response system, using a
pseudo-random number generator, in block sizes of four.
Nintedanib (Boehringer Ingelheim, Biberach, Germany)
and placebo were provided by the sponsor as soft
gelatine capsules with identical appearance. Participants,
investigators, and other personnel involved in the trial
conduct and analysis were masked to treatment
assignment until after data­ base lock. The success of
masking was not evaluated.
Procedures
Participants were to receive randomised masked
treatment for at least 52 weeks. Treatment interruptions
(for ≤4 weeks for adverse events considered related to
trial medication or ≤8 weeks for other adverse events)
and dose reductions to 100 mg twice daily were allowed
to manage adverse events. Specific recommendations
were provided for the manage­ment of diarrhoea and liver
enzyme elevations.20 After resolution of the adverse
event, nintedanib could be re­ introduced or the dose
increased to 150 mg twice daily. Participants who
discontinued treatment were asked to attend all visits as
originally planned.
Outcomes
Here we report analyses of the annual rate of decline in
FVC in the nine subgroups based on the ILD diagnoses
reported in the case report form and in the following
five groups created to allow for more meaningful
statistical analyses: HP, autoimmune ILDs (RA-ILD,
SSc-ILD, MCTD-ILD, plus participants with an
autoimmune disease noted in the other fibrosing ILDs
category of the case report form), iNSIP, unclassifiable
IIP, and other ILDs (sarcoidosis, exposure-related ILDs
and selected participants in other fibrosing ILDs). In
addition, we explored the influence of these groups on
the treatment effect by doing analyses in which each
of these five groups was excluded one by one. Finally,
we evaluated the annual rate of decline in FVC in
two groups, with one group comprising participants
with diagnoses likely to be considered as a differential
diagnosis when evaluating a patient for IPF (HP,
www.thelancet.com/respiratory Published online March 5, 2020 https://doi.org/10.1016/S2213-2600(20)30036-9 3
Articles
unclassifiable IIP, iNSIP, interstitial pneumonia with
autoimmune features [IPAF] as documented in the
other fibrosing ILD category in the case report form)
and the other group comprising all other diagnoses. All
the subgroup analyses were done in the overall
population, in participants with a UIP-like fibrotic
pattern on HRCT, and in participants with other fibrotic
patterns on HRCT.
Safety was assessed based on adverse events reported
by the investigators (irrespective of causality) over
52 weeks (or until 28 days after last trial drug intake for
participants who discontinued the trial drug before
week 52). Adverse events were coded by means of
preferred terms in the Medical Dictionary for Regulatory
Activities, version 22.0.
Statistical analysis
In the overall population, the annual rate of decline in
FVC (mL/year) in subgroups was analysed by means of a
random coefficient regression model (with random
slopes and intercepts) including baseline FVC (mL),
HRCT pattern (UIP-like fibrotic pattern or other fibrotic
patterns), and baseline by time, treatment by subgroup,
and treatment by subgroup by time interactions. The
same model was used for analyses in participants with a
UIP-like fibrotic pattern and in participants with other
fibrotic patterns on HRCT except that HRCT pattern was
not included as a term. Nominal p values for treatment
by subgroup by time interaction were obtained from tests
of heterogeneity across all expression levels of the
subgrouping, with no adjustment for multiple testing.
All the analyses done in the overall population and in
participants with a UIP-like fibrotic pattern on HRCT,
except for the analysis in which the five groups were
excluded one by one among participants with a UIP-like
fibrotic pattern on HRCT, were prespecified. Analyses
were done by means of SAS version 9.4. Adverse events
are presented descriptively.
The INBUILD trial is registered with ClinicalTrials.gov,
number NCT02999178.
Role of the funding source
The funder participated in the study design, data
collection, data analysis, data interpretation, and the
writing of the report. The corresponding author had full
access to all data in the study and had final responsibility
for the decision to submit for publication.
Results
Participants were recruited between Feb 23, 2017, and
April 27, 2018. A total of 663 of 1010 participants
assessed for eligibility received at least one dose of
nintedanib (n=332) or placebo (n=331), of whom
412 (62·1%) had a UIP-like fibrotic pattern on HRCT.
The distribution of participants across the nine ILD
subgroups in the overall population is shown in
the appendix p 4. The largest subgroups were HP
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(173 participants [26%]), iNSIP (125 participants [19%]),
unclassifiable IIP (114 participants [17%]), and RA-ILD,
(89 participants [13%]). The other five subgroups each
contained less than 10% of the participants. Baseline
characteristics of the nine subgroups are shown in
appendix p 12. With the exception of SSc-ILD and MCTD-
ILD (larger number of female participants, younger) and
sarcoidosis (larger number of male participants, older),
approximately half of the participants were male and
around 60 years of age. FVC % predicted was similar
across the subgroups.
The distribution of participants across the five groups
in the overall population is shown in figure 1 and their
baseline characteristics in table 1. The distribution of ILD
diagnoses in participants with a UIP-like fibrotic pattern
on HRCT and participants with other fibrotic patterns on
HRCT are shown in the appendix (p 5, 6). The effect of
nintedanib versus placebo on reducing the annual rate of
FVC decline was consistent across the five groups in the
overall population (p=0·41 for treatment by subgroup by
time interaction; figure 2). Similarly, there appeared to be
no meaningful differences in the effect of nintedanib
versus placebo across the five groups in those with a
UIP-like fibrotic pattern on HRCT (p=0·17; appendix p 7)
Hypersensitivity pneumonitis
Autoimmune interstitial lung
12·2%
diseases
26·1% Idiopathic non-specific
interstitial pneumonia
Unclassifiable IIP
17·2% Other interstitial lung diseases
or in participants with other fibrotic patterns on HRCT
(p=0·80; appendix p 7). Post-hoc analyses of the annual
rate of decline in FVC in which the five groups were
excluded one by one suggested that no diagnostic group
drove the treatment effect in the overall population
(figure 3), in participants with a UIP-like fibrotic pattern
(appendix p 8), or in participants with other fibrotic
patterns (appendix p 8). The effect of nintedanib versus
placebo on reducing the annual rate of FVC decline
(mL/year) was also consistent across the nine subgroups
in the overall population (appendix p 9), in participants
with a UIP-like fibrotic pattern on HRCT (appendix p 10)
and in participants with other fibrotic patterns on HRCT
(appendix p 10).
In the analysis based on two groups, the effect of
nintedanib versus placebo on FVC decline was consistent
between participants with a diagnosis within the group
likely to be considered as a differential diagnosis of IPF
versus all other participants in the overall population
(figure 4). Similar results were observed in participants
with a UIP-like fibrotic pattern on HRCT (appendix p 11)
and in participants with other fibrotic patterns on HRCT
(appendix p 11).
Overall, the safety profile of nintedanib in the subgroups
was consistent with its safety profile in the overall
population: diarrhoea, nausea, vomiting, weight decrease,
and liver enzyme increases were more frequently reported
in participants treated with nintedanib than placebo.
Owing to the low number of adverse events in some of
the nine subgroups, adverse events are displayed only in
the five groups of the overall population (table 2).

25·6%
18·9%
Figure 1: Interstitial lung disease diagnoses in five groups (overall population)
Autoimmune interstitial lung diseases (ILDs)=those associated with
rheumatoid arthritis, systemic sclerosis, mixed connective tissue disease, plus
autoimmune ILDs in the other fibrosing ILDs category. Other ILDs=sarcoidosis,
exposure-related ILDs and other terms in the other fibrosing ILDs category.
Discussion
Participants were selected for participation in the
INBUILD trial based on the progressive longitudinal
behaviour of their fibrosing ILD, irrespective of their
underlying diagnosis (with the exclusion of IPF) or
fibrotic pattern on HRCT. We have previously reported
that the effect of nintedanib versus placebo on the annual
rate of decline in FVC (mL/year) in this trial was

Hypersensitivity Autoimmune Idiopathic non-specific Unclassifiable Other ILDs* (n=81)

pneumonitis (n=173) interstitial lung interstitial pneumonia idiopathic interstitial
diseases (n=170) (n=125) pneumonia (n=114)
Male 89 (51%) 80 (47%) 63 (50%) 62 (54%) 62 (77%)
Age, years 65·5 (8·3) 64·3 (10·6) 65·4 (9·4) 68·4 (9·4) 66·2 (11·2)
Former or current smoker 91 (53%) 85 (50%) 43 (34%) 62 (54%) 57 (70%)
Usual interstitial pneumonia-like 90 (52%) 127 (75%) 71 (57%) 77 (68%) 47 (58%)
fibrotic pattern on HRCT
Forced vital capacity, mL 2244 (739) 2330 (699) 2351 (761) 2286 (730) 2548 (727)
Forced vital capacity, % predicted 65·2 (14·2) 70·9 (14·9) 71·3 (17·3) 69·8 (15·4) 68·4 (16·6)
Diffusing capacity of the lung for 45·3 (14·4) 48·0 (15·1) 47·4 (12·5) 45·2 (11·9) 43·2 (12·2)
carbon monoxide, % predicted†
Data are n (%) or mean (SD). *Included sarcoidosis, exposure-related ILDs and selected other terms in other fibrosing interstitial lung diseases such as pleuroparenchymal
fibroelastosis, and cryptogenic organising pneumonia. †Corrected for haemoglobin.

Table 1: Baseline characteristics

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n analysed Difference Treatment by

(95% CI) subgroup by
time interaction

Nintedanib Placebo

Hypersensitivity pneumonitis 84 89 73·1 (–8·6 to 154·8) p=0·41

Autoimmune interstitial lung diseases 82 88 104·0 (21·1 to 186·9)
iNSIP 64 61 141·6 (46·0 to 237·2)
Unclassifiable IIP 64 50 68·3 (–31·4 to 168·1)
Other interstitial lung diseases 38 43 197·1 (77·6 to 316·7)
All patients 332 331 107·0 (65·4 to 148·5)

–200 –100 0 100 200 300 400 500

Favours placebo Favours nintedanib

Figure 2: Annual rate of decline in forced vital capacity (mL/year) in five groups by interstitial lung disease diagnosis (overall population)
iNSIP=idiopathic non-specific interstitial pneumonia. IIP=idiopathic interstitial pneumonia. Other interstitial lung diseases (ILDs)=sarcoidosis, exposure-related ILDs
and other terms in the other fibrosing ILDs category.

n analysed Estimate p value

(95% CI)

Nintedanib Placebo

iNSIP, unclassifiable IIP, autoimmune ILDs, 248 242 119·4 (67·7 to 171·2) <0·001
other fibrosing ILDs (excludes HP)
HP, unclassifiable IIP, autoimmune ILDs, 267 270 98·7 (53·8 to 143·6) <0·001
other fibrosing ILDs (excludes iNSIP)
HP, iNSIP, autoimmune ILDs, other fibrosing 267 281 116·4 (72·4 to 160·4) <0·001
ILDs (excludes unclassifiable IIP)
HP, iNSIP, unclassifiable IIP, other fibrosing 250 243 108·0 (59·1 to 157·0) <0·001
ILDs (excludes autoimmune ILDs)
HP, iNSIP, unclassifiable IIP, autoimmune 293 288 94·5 (50·7 to 138·2) <0·001
ILDs (excludes other ILDs)
All patients 332 331 107·0 (65·4 to 148·5) <0·001

–20 0 20 40 60 80 100 120 140 160 180

Favours placebo Favours nintedanib

Figure 3: Annual rate of decline in forced vital capacity (mL/year) with one of the five groups by interstitial lung disease diagnosis excluded at a time (overall
population)
iNSIP=idiopathic non-specific interstitial pneumonia. IIP=idiopathic interstitial pneumonia. ILD=interstitial lung disease. HP=hypersensitivity pneumonitis.

n analysed Difference Treatment by

(95% CI) subgroup by
time interaction

Nintedanib Placebo

Patients with HP, unclassifiable IIP, 214 204 87·4 (35·3 to 139·4) p=0·21
iNSIP, and IPAF*
Other patients† 118 127 142·9 (74·0 to 211·8)
All patients 332 331 107·0 (65·4 to 148·5)

–100 0 100 200 300

Favours placebo Favours nintedanib

Figure 4: Annual rate of decline in forced vital capacity (mL/year) in patients with a diagnosis likely to be considered as a differential diagnosis of IPF
(hypersensitivity pneumonitis, unclassifiable idiopathic interstitial pneumonia, idiopathic non-specific interstitial pneumonia, or interstitial pneumonia
with autoimmune features) versus all other patients (overall population)
HP=hypersensitivity pneumonitis. IIP=idiopathic interstitial pneumonia. iNSIP=idiopathic non-specific interstitial pneumonia. IPAF=interstitial pneumonia with
autoimmune features.*IPAF was based on selected terms in other fibrosing interstitial lung diseases. †ILD associated with rheumatoid arthritis and systemic sclerosis,
mixed connective tissue disease-ILD, sarcoidosis, exposure-related ILDs, and selected other terms in other fibrosing ILDs.

consistent between patients with a UIP-like fibrotic reduction 49%), with a relative reduction of 57% in the
pattern on HRCT (relative reduction 61%) and patients overall population.20 The additional analyses shown here
with other fibrotic patterns on HRCT (relative show a consistent effect of nintedanib in reducing the rate

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Hypersensitivity Autoimmune Idiopathic non-specific Unclassifiable idiopathic Other ILDs*

pneumonitis interstitial lung diseases interstitial pneumonia interstitial pneumonia
Nintedanib Placebo Nintedanib Placebo Nintedanib Placebo Nintedanib Placebo Nintedanib Placebo
(n=84) (n=89) (n=82) (n=88) (n=64) (n=61) (n=64) (n=50) (n=38) (n=43)
Any adverse event 83 (99%) 85 (96%) 79 (96%) 79 (90%) 54 (84%) 48 (79%) 64 (100%) 46 (92%) 37 (97%) 38 (88%)
Most frequent adverse events†
Diarrhoea 59 (70%) 24 (27%) 52 (63%) 24 (27%) 41 (64%) 11 (18%) 45 (70%) 9 (18%) 25 (66%) 11 (26%)
Nausea 24 (29%) 13 (15%) 22 (27%) 10 (11%) 16 (25%) 1 (2%) 25 (39%) 3 (6%) 9 (24%) 4 (9%)
Bronchitis 10 (12%) 11 (12%) 13 (16%) 13 (15%) 4 (6%) 8 (13%) 7 (11%) 7 (14%) 7 (18%) 8 (19%)
Nasopharyngitis 11 (13%) 11 (12%) 10 (12%) 13 (15%) 9 (14%) 9 (15%) 12 (19%) 6 (12%) 2 (5%) 1 (2%)
Dyspnoea 11 (13%) 16 (18%) 6 (7%) 10 (11%) 3 (5%) 2 (3%) 10 (16%) 6 (12%) 6 (16%) 10 (23%)
Vomiting 21 (25%) 7 (8%) 14 (17%) 6 (7%) 11 (17%) 2 (3%) 12 (19%) 0 3 (8%) 2 (5%)
Cough 11 (13%) 17 (19%) 2 (2%) 6 (7%) 4 (6%) 4 (7%) 10 (16%) 8 (16%) 6 (16%) 9 (21%)
Decreased appetite 8 (10%) 9 (10%) 15 (18%) 1 (1%) 8 (13%) 3 (5%) 11 (17%) 1 (2%) 6 (16%) 3 (7%)
Headache 9 (11%) 12 (13%) 7 (9%) 4 (5%) 5 (8%) 4 (7%) 10 (16%) 3 (6%) 4 (11%) 0
Alanine 11 (13%) 4 (4%) 14 (17%) 3 (3%) 8 (13%) 2 (3%) 8 (13%) 1 (2%) 2 (5%) 2 (5%)
aminotransferase
increased
Progression of ILD‡ 3 (4%) 10 (11%) 3 (4%) 7 (8%) 5 (8%) 9 (15%) 5 (8%) 8 (16%) 0 5 (12%)
Weight decreased 9 (11%) 4 (4%) 10 (12%) 1 (1%) 7 (11%) 1 (2%) 12 (19%) 5 (10%) 3 (8%) 0
Aspartate 11 (13%) 3 (3%) 11 (13%) 4 (5%) 8 (13%) 1 (2%) 7 (11%) 2 (4%) 1 (3%) 2 (5%)
aminotransferase
increased
Abdominal pain 14 (17%) 2 (2%) 7 (9%) 2 (2%) 2 (3%) 1 (2%) 9 (14%) 0 2 (5%) 3 (7%)
Severe adverse event§ 19 (23%) 22 (25%) 13 (16%) 16 (18%) 9 (14%) 10 (16%) 15 (23%) 13 (26%) 4 (11%) 12 (28%)
Serious adverse 29 (35%) 34 (38%) 28 (34%) 28 (32%) 14 (22%) 17 (28%) 25 (39%) 17 (34%) 11 (29%) 14 (33%)
event¶
Fatal adverse event 4 (5%) 4 (4%) 3 (4%) 4 (5%) 2 (3%) 5 (8%) 0 1 (2%) 2 (5%) 3 (7%)
Adverse event 16 (19%) 6 (7%) 14 (17%) 9 (10%) 13 (20%) 5 (8%) 14 (22%) 7 (14%) 8 (21%) 7 (16%)
leading to permanent
treatment
discontinuation
Data are n (%) of patients with ≥1 such adverse event reported over 52 weeks (or until 28 days after last trial drug intake in patients who discontinued trial drug before
week 52). *Included sarcoidosis, exposure-related interstitial lung diseases and selected other terms in other fibrosing ILDs. †Adverse events, coded using preferred terms in
the Medical Dictionary for Regulatory Activities, reported in >10% of patients in either treatment group in the overall population. ‡Based on the preferred term interstitial lung
disease in the Medical Dictionary for Regulatory Activities. §Adverse event that was incapacitating or that caused an inability to work or to perform usual activities. ¶Adverse
event that resulted in death, was life-threatening, resulted in admission to hospital or prolongation of hospitalisation, resulted in persistent or clinically significant disability
or incapacity, was a congenital anomaly or birth defect, or was deemed to be serious for any other reason.

Table 2: Adverse events in five groups by ILD diagnosis (overall population)

of FVC decline across subgroups based on ILD diagnosis,
both in patients with a UIP-like fibrotic pattern and
in patients with other fibrotic patterns on HRCT.
Furthermore, we have shown that no individual ILD
diagnostic group drove the overall effect on the rate of FVC
decline. Although all these analyses were exploratory in
quantifying the benefits of nintedanib in individual
diseases, there was no statistical evidence of a differential
treatment effect of nintedanib across ILD subgroups. More
precise quantification of the treatment effect in individual
diseases would require larger stand-alone studies.
In the INBUILD trial, diagnoses were based on the
usual clinical practice of the investigators and not reviewed
centrally. The lack of central review might be regarded as a
strength in terms of the applicability of the findings of this
trial to real-world clinical practice. In the differential
diagnosis of ILDs, considerable challenges exist in
separating idiopathic from non-idiopathic disease,21 as
well as in differentiating the IIPs,22 with some patients
not fulfilling criteria for any specific ILD even after
multidisciplinary review.23 Thus, the consistent results
observed in this trial between groups of participants with
the diagnoses that are most difficult to differentiate from
IPF (ie, chronic HP, iNSIP, or unclassifiable IIP) and
those with diagnoses that are easier to distinguish from
IPF (eg, autoimmune disease) are of clinical relevance.
Our findings should not be misinterpreted as implying
that it is not important that patients receive an accurate
ILD diagnosis. An accurate ILD diagnosis remains crucial
to the management of individual patients; for example,
the removal of the suspected inciting antigen in patients
with hyper­sensitivity pneumonitis, and the diagnosis and
treatment of non-ILD manifestations of auto­ immune
diseases. However, our findings suggest that in patients
with a fibrosing ILD that has progressed despite
management considered appropriate in clinical practice,

6 www.thelancet.com/respiratory Published online March 5, 2020 https://doi.org/10.1016/S2213-2600(20)30036-9


the underlying diagnosis is not as important when
establishing who might benefit from treatment with
nintedanib. This has implications for the discussions held
with patients with progressive fibrosing ILD in whom
the specific ILD diagnosis is uncertain regarding the
risk:benefit of undergoing procedures such as surgical
lung biopsy in order to obtain a more confident diagnosis.
Overall, our findings suggest that the optimal approach to
the diagnosis and management of fibrosing ILD is not a
question of splitting versus lumping, but rather of
splitting by diagnosis followed by lumping when a
progressive fibrosing phenotype develops. We believe that
the keys to the optimal management of fibrosing ILD are
early diagnosis, early initiation of appropriate pharma­
cological or non-pharmacological therapies, and close
monitoring to enable identification of a progressive
phenotype, to ensure that patients receive treatment to
stabilise or slow disease progression.
Although patients with IPF were excluded from our
trial, the findings also have implications for the treatment
of patients with a provisional or low confidence diagnosis
of IPF. Although some clinicians are ready to introduce
antifibrotic therapy in this setting, a large survey of
clinicians suggests that this view is not uniformly held.24
It is possible that reluctance to use antifibrotic therapy
when a diagnosis of IPF is tentative reflects uncertainty
with regard to the benefits of such treatment in patients
with differential diagnoses of IPF. Thus, the finding that
the benefits of nintedanib are consistent across disorders
that mimic the clinical course of IPF might serve to
reassure clinicians that the use of nintedanib is justified
not only in patients in whom a diagnosis of IPF has been
confirmed, but also in patients, not included in the
current study, in whom a diagnosis of IPF has been made
with low confidence.
A limitation of our data lies in the low number of
patients with rarer fibrosing ILDs such as MCTD-ILD,
sarcoid­osis, and pleuroparenchymal fibroelastosis. Given
the challenges in recruiting participants with very rare
diseases, this limitation is unlikely to be overcome in
future clinical trials. Thus, we consider the INBUILD
trial, done in patients with a broad range of progressive
fibrosing ILDs, as the only feasible means of exploring
treatment effects in this patient population, and its
results as justification for the use of nintedanib in these
patients. Importantly, the adverse event profile of
nintedanib was similar across the ILD diagnostic
subgroups and consistent with the profile established in
patients with IPF.25
In conclusion, although the INBUILD trial was not
powered to provide evidence for a benefit of nintedanib
in specific diagnostic subgroups, these analyses suggest
that nintedanib reduces the rate of ILD progression, as
measured by FVC decline, in patients who have a chronic
fibrosing ILD and progressive phenotype, despite
management considered appropriate in clinical practice,
irrespective of the underlying ILD diagnosis.
www.thelancet.com/respiratory Published online March 5, 2020 https://doi.org/10.1016/S2213-2600(20)30036-9 7
Articles
Contributors
AUW, KRF, KKB, YI, AD, LR, SS, and RS-H were involved in the design
of the study. R-GG was involved in data analysis. All authors were
involved in the interpretation of the data and in the writing and critical
review of the manuscript.
Declaration of interests
AUW reports personal fees from Blade Therapeutics, Boehringer
Ingelheim, and InterMune–Roche. KRF reports grants and personal fees
from Boehringer Ingelheim and Roche–Genentech; and personal fees
from Bellerophon Therapeutics, Blade Therapeutics, Celgene, FibroGen,
Respivant, Sanofi Genzyme, and Veracyte. KKB reports grants from
National Heart, Lung, and Blood Institute; personal fees from Biogen,
Blade Therapeutics, Galapagos, Galecto Biotech, Huitai Biomedicine,
Lifemax, Lilly, MedImmune, monARC Bionetworks, Pliant Therapeutics,
ProMetic, Third Pole Therapeutics, Theravance, Three Lakes Partners,
and Veracyte; personal fees and non-financial support from Boehringer
Ingelheim; and other support from Genoa and the Open Source
Imaging Consortium. YI reports grants from the Japan Agency for
Medical Research and Development, and Japanese Ministry of Health,
Labour, and Welfare; and other support from Asahi Kasei, Boehringer
Ingelheim, Savara Pharmaceuticals, and Shionogi. AD reports personal
fees from Boehringer Ingelheim, Galapagos, Galecto Biotech,
GlaxoSmithKline, and Roche. LR reports personal fees from Asahi
Kasei, Biogen, Bristol-Myers Squibb, Celgene, CSL Behring, FibroGen,
ImmuneWorks, Nitto, Pliant Therapeutics, Promedior, Respivant, and
Toray; and grants and personal fees from Boehringer Ingelheim and
Roche. TM has nothing to declare. BC reports grants, personal fees, and
non-financial support from Boehringer Ingelheim and Roche; personal
fees and non-financial support from AstraZeneca, Bristol-Myers Squibb,
and Sanofi; and personal fees from Genzyme. WAW reports grants and
other support paid to his institution from Boehringer Ingelheim; and
grants paid to his institution from Roche. SS, MQ, R-GG, and RS-H are
employees of Boehringer Ingelheim. MK reports grants and personal
fees from Boehringer Ingelheim, Gilead, GlaxoSmithKline, ProMetic,
and Roche and personal fees from AstraZeneca, Covance, Galapagos NV,
Indalo, and Third Pole Therapeutics.
Data sharing
Information on data sharing is provided in the appendix.
Acknowledgments
The INBUILD trial was funded by Boehringer Ingelheim. The authors
thank the patients and investigators who participated in this trial.
Writing assistance, supported financially by Boehringer Ingelheim, was
provided by Elizabeth Ng and Wendy Morris of FleishmanHillard
Fishburn, London, UK, during the development of this manuscript.
The authors were fully responsible for all content and editorial decisions,
were involved at all stages of development and provided their approval
on the final version. Boehringer Ingelheim was given the opportunity to
review the manuscript for medical and scientific accuracy as well as
intellectual property considerations.
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