Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

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Efﬁcacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis
Article in New England Journal of Medicine · May 2014

DOI: 10.1056/NEJMoa1402584
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New England Journal of Medicine P14-07514
2014, 370 : 22 2071-2082
_______________________________________________________________________________________________________________
Please follow your local copyright law
new england
The
journal of medicine
established in 1812 may 29, 2014 vol. 370 no. 22
Efficacy and Safety of Nintedanib in Idiopathic

Pulmonary Fibrosis
Luca Richeldi, M.D., Ph.D., Roland M. du Bois, M.D., Ganesh Raghu, M.D., Arata Azuma, M.D., Ph.D.,
Kevin K. Brown, M.D., Ulrich Costabel, M.D., Vincent Cottin, M.D., Ph.D., Kevin R. Flaherty, M.D.,
David M. Hansell, M.D., Yoshikazu Inoue, M.D., Ph.D., Dong Soon Kim, M.D., Martin Kolb, M.D., Ph.D.,
Andrew G. Nicholson, D.M., Paul W. Noble, M.D., Moisés Selman, M.D., Hiroyuki Taniguchi, M.D., Ph.D.,
Michèle Brun, M.Sc., Florence Le Maulf, M.Sc., Mannaïg Girard, M.Sc., Susanne Stowasser, M.D.,
Rozsa Schlenker-Herceg, M.D., Bernd Disse, M.D., Ph.D., and Harold R. Collard, M.D.,
for the INPULSIS Trial Investigators*
A BS T R AC T
Background
Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets The authors’ affiliations are listed in the
multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of Appendix. Address reprint requests to
Dr. Richeldi at the National Institute for
nintedanib twice daily reduced lung-function decline and acute exacerbations in Health Research, Southampton Respira-
patients with idiopathic pulmonary fibrosis. tory Biomedical Research Unit, Mailpoint
813, LE75 E Level, South Academic Block,
Methods University Hospital Southampton NHS
We conducted two replicate 52-week, randomized, double-blind, phase 3 trials Foundation Trust, Tremona Rd., Southamp-
(INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of ton SO16 6YD, United Kingdom, or at
l.richeldi@soton.ac.uk.
nintedanib twice daily as compared with placebo in patients with idiopathic pul-
monary fibrosis. The primary end point was the annual rate of decline in forced * A complete list of investigators in the
vital capacity (FVC). Key secondary end points were the time to the first acute INPULSIS trials is provided in the Supple-
mentary Appendix, available at NEJM.org.
exacerbation and the change from baseline in the total score on the St. George’s
Respiratory Questionnaire, both assessed over a 52-week period. This article was published on May 18, 2014,
at NEJM.org.
Results
A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib N Engl J Med 2014;370:2071-82.
or placebo. The adjusted annual rate of change in FVC was −114.7 ml with nintedanib DOI: 10.1056/NEJMoa1402584
Copyright © 2014 Massachusetts Medical Society.
versus −239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI],
77.7 to 172.8; P<0.001) in INPULSIS-1 and −113.6 ml with nintedanib versus −207.3 ml
with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2.
In INPULSIS-1, there was no significant difference between the nintedanib and placebo
groups in the time to the first acute exacerbation (hazard ratio with nintedanib,
1.15; 95% CI, 0.54 to 2.42; P = 0.67); in INPULSIS-2, there was a significant benefit
with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P = 0.005).
The most frequent adverse event in the nintedanib groups was diarrhea, with rates
of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in
INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.
Conclusions
In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in
FVC, which is consistent with a slowing of disease progression; nintedanib was fre-
quently associated with diarrhea, which led to discontinuation of the study medica-
tion in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and
INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.)
n engl j med 370;22 nejm.org may 29, 2014 2071
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The n e w e ng l a n d j o u r na l of m e dic i n e
I
diopathic pulmonary fibrosis is a fatal adverse events reported by site investigators as
lung disease characterized by worsening dys- acute exacerbations, in order to determine wheth-
pnea and progressive loss of lung function.1 er the events met the criteria for an acute exacer-
A decline in forced vital capacity (FVC) is consis- bation of idiopathic pulmonary fibrosis as de-
tent with disease progression and is predictive of fined in the protocol, available with the full text
reduced survival time.1-6 of this article at NEJM.org. The members of these
Idiopathic pulmonary fibrosis is believed to committees are listed in Section B in the Supple-
arise from an aberrant proliferation of fibrous mentary Appendix, also available at NEJM.org.
tissue and tissue remodeling due to the abnor- Both trials were conducted in accordance with
mal function and signaling of alveolar epithelial the principles of the Declaration of Helsinki and
cells and interstitial fibroblasts.7 The activation the Harmonized Tripartite Guideline for Good
of cell-signaling pathways through tyrosine ki- Clinical Practice from the International Confer-
nases such as vascular endothelial growth fac- ence on Harmonization and were approved by
tor (VEGF), fibroblast growth factor (FGF), and local authorities. The clinical protocol was ap-
platelet-derived growth factor (PDGF) has been proved by an independent ethics committee or
implicated in the pathogenesis of the disease.8-10 institutional review board at each participating
Nintedanib (formerly known as BIBF 1120) is center. All patients provided written informed
an intracellular inhibitor that targets multiple consent before study entry.
tyrosine kinases, including the VEGF, FGF, and All the authors were involved in the design of
PDGF receptors.11 The results of an earlier trial the study and had access to the data, which were
(To Improve Pulmonary Fibrosis with BIBF 1120 analyzed by the study sponsor, Boehringer Ingel-
[TOMORROW]), a randomized, double-blind, heim. All the authors vouch for the accuracy and
placebo-controlled, phase 2 dose-finding study completeness of the data analyses and the fidel-
involving 432 patients with idiopathic pulmonary ity of each study to the protocol. The protocol
fibrosis, suggested that 12 months of treatment and statistical analysis plans are available at
with 150 mg of nintedanib twice daily was asso- NEJM.org. The manuscript was drafted by the
ciated with a reduced decline in FVC, fewer acute first, second, and last authors and revised by all
exacerbations, and the preservation of health- the authors. Medical writing assistance, paid for
related quality of life.12 We conducted two repli- by Boehringer Ingelheim, was provided by the
cate phase 3 trials (INPULSIS-1 and INPULSIS-2) Fleishman-Hillard Group.
to evaluate the efficacy and safety of treatment
with 150 mg of nintedanib twice daily in patients Patients
with idiopathic pulmonary fibrosis. Patients were eligible to participate in the two
trials if they were 40 years of age or older and
Me thods had received a diagnosis of idiopathic pulmonary
fibrosis within the previous 5 years. Additional
Study Design and Oversight eligibility criteria were an FVC that was 50% or
The INPULSIS studies were randomized, double- more of the predicted value, a diffusion capacity
blind, placebo-controlled, parallel-group trials of the lung for carbon monoxide (DLCO) that was
performed at 205 sites in 24 countries in the 30 to 79% of the predicted value, and high-reso-
Americas, Europe, Asia, and Australia. An inde- lution computed tomography (HRCT) of the chest
pendent data monitoring committee regularly performed within the previous 12 months. HRCT
reviewed the data, particularly serious adverse images (for all patients) and lung-biopsy speci-
events, adverse events leading to discontinuation mens (if available) were reviewed centrally by a
of the study drug, and the results of laboratory single radiologist and a single pathologist to verify
analyses, and made recommendations concern- eligibility according to the protocol. Eligibility cri-
ing the continuation of the trials. An adjudica- teria with regard to findings on HRCT and surgi-
tion committee that was independent of the in- cal lung biopsy are shown in Table S1 and Table S2,
vestigators and whose members were unaware of respectively, in the Supplementary Appendix.
the group assignments reviewed medical docu- Concomitant therapy with up to 15 mg of
mentation to adjudicate the primary cause of prednisone per day, or the equivalent, was per-
all deaths. The committee also adjudicated all mitted if the dose had been stable for 8 or more
2072 n engl j med 370;22 nejm.org may 29, 2014
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2014, 370 : 22 2071-2082
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Nintedanib in Idiopathic Pulmonary Fibrosis
weeks before screening; patients receiving other End Points

therapies for idiopathic pulmonary fibrosis, The primary end point for both INPULSIS trials
including high-dose prednisone, azathioprine, was the annual rate of decline in FVC (measured
N-acetylcysteine, and any investigational treat- in milliliters per year). Key secondary end points
ments for idiopathic pulmonary fibrosis, were were the time to the first acute exacerbation (as
excluded. After 6 months of study treatment, reported by a site investigator) and the change
patients whose condition had deteriorated could from baseline in the total score on the St.
receive azathioprine, cyclophosphamide, cyclo- George’s Respiratory Questionnaire (SGRQ), both
sporine, N-acetylcysteine, or more than 15 mg of assessed over the 52-week treatment period. The
prednisone per day, or the equivalent, at the dis- SGRQ is a self-administered questionnaire that
cretion of the investigator. In cases of acute exac- is used to assess health-related quality of life. It
erbation reported by an investigator at any time comprises three domains (symptoms, activity,
during the trial, any treatments could be initiated and impact). The total score and the score for
or doses increased as deemed appropriate by the each domain range from 0 to 100, with higher
investigator. Other key exclusion criteria are listed scores indicating worse health-related quality of
in Section C in the Supplementary Appendix. life.14,15 A minimally important difference in the
score has not been established for patients with
Study Protocol idiopathic pulmonary fibrosis; in patients with
After a screening period, eligible patients were chronic obstructive pulmonary disease, this dif-
randomly assigned in a 3:2 ratio to receive 150 mg ference is 4 points.16 Patients completed the SGRQ
of nintedanib twice daily or placebo for 52 weeks. at baseline and at 6, 12, 24, and 52 weeks. Acute
An interactive telephone and Web-based response exacerbations were defined as events meeting all
system was used to perform randomization. of the following criteria: unexplained worsening
Patients, investigators, and the study sponsor or development of dyspnea within the previous
were unaware of the study-group assignments 30 days; new diffuse pulmonary infiltrates visu-
throughout the study. Completion of the 52-week alized on chest radiography, HRCT, or both, or
treatment period was followed by a follow-up visit the development of parenchymal abnormalities
4 weeks later. Spirometric tests were conducted with no pneumothorax or pleural effusion (new
at baseline; at 2, 4, 6, 12, 24, 36, and 52 weeks; ground-glass opacities) since the preceding visit;
and at the follow-up visit. Spirometric testing and exclusion of any known causes of acute wors-
was conducted in accordance with criteria pub- ening, including infection, left heart failure, pul-
lished by the American Thoracic Society and the monary embolism, and any identifiable cause of
European Respiratory Society.13 All spirometric acute lung injury, in accordance with routine clin-
measurements were performed on machines pro- ical practice and microbiologic studies. All acute
vided by the sponsor, and the results were cen- exacerbations reported by the site investigators
trally reviewed, with training and ongoing feed- were categorized by the adjudication committee,
back provided for the site investigators. whose members were unaware of the study-group
Dose interruption or reduction of the dose assignments, as confirmed or suspected or were
from 150 mg twice daily to 100 mg twice daily not considered to be an acute exacerbation accord-
was allowed for the management of adverse ing to prespecified criteria.17
events. After an adverse event had resolved, the Other prespecified secondary end points in-
dose could be reinstituted at 150 mg twice daily. cluded the absolute change from baseline in FVC
The site investigators were provided with recom- (in milliliters and as a percentage of the pre-
mendations for the management of diarrhea and dicted value) over the 52-week treatment period,
elevated levels of liver enzymes. To minimize the the proportion of patients with an FVC response
amount of missing data, patients who discontin- (defined as the proportion of patients in whom
ued the study drug prematurely were asked to the percentage of predicted FVC did not decline
attend all scheduled visits and to undergo all by more than 5 percentage points or by more
examinations as originally planned. For patients than 10 percentage points at week 52), the risk
who discontinued the drug prematurely but did of an acute exacerbation, the change from base-
not agree to attend all visits, data on vital status line in SGRQ domain scores over the 52-week
were collected at week 52. treatment period, death from any cause, death
Page 3 of 50
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from a respiratory cause, and death that oc- ary for Regulatory Activities, version 16.1. Safety
curred between randomization and 28 days after analyses were descriptive. For information on
the last dose of the study drug. All mortality end the statistical analysis of other end points, see
points were measured as the time to death. Section D in the Supplementary Appendix.
Safety was assessed by means of clinical and For each trial, the sample size was calculated
laboratory evaluation at study visits and the re- to provide 90% power to detect a between-group
cording of adverse events. difference of 100 ml in the annual rate of FVC
decline. On the basis of data from the phase 2
Statistical Analysis trial, the standard deviation for the change in
Efficacy and safety analyses were conducted for pa- FVC from baseline was assumed to be 300 ml in
tients who were randomly assigned to a study group both groups. Assuming that it would not be pos-
and received at least one dose of the study medi- sible to evaluate data for 2% of patients, the
cation. The primary end point was analyzed with sample size was calculated as 194 patients in the
the use of a random coefficient regression model placebo group and 291 patients in the ninteda-
(with random slopes and intercepts) that includ- nib group for a two-group t-test at a one-sided
ed sex, age, and height as covariates. The treat- significance level of 2.5%. Since the primary
ment effect was determined by using estimated analysis was based on a random coefficient re-
slopes for each study group (on the basis of the gression model that included adjustment for sev-
time-by-treatment interaction term from the eral variables and took into account information
mixed model). All available FVC values from base- across time, we expected that the power would
line to week 52 were used in the primary model, be greater than the 90% calculated for the t-test.
including FVC measurements at the follow-up
visit for patients who discontinued the study R e sult s
medication prematurely and did not complete the
study visits through week 52. The statistical Patients
model used for the primary analysis allowed for Between May 2011 and September 2012, a total
missing data, assuming that they were missing of 1066 patients underwent randomization:
at random; missing data were not imputed for 515 patients in INPULSIS-1 and 551 patients in
the primary analysis, but data collected after dis- INPULSIS-2 (Fig. S1 in the Supplementary Ap-
continuation of the study drug were used in the pendix). In INPULSIS-1, a total of 513 patients
primary analysis. Significance tests were two- received at least one dose of the study medica-
sided, with an alpha value of 0.05. tion (309 received nintedanib and 204 received
The superiority of nintedanib over placebo placebo). A total of 78 patients (25.2%) in the
with respect to the primary and key secondary nintedanib group and 36 patients (17.6%) in the
end points was tested with the use of a hierar- placebo group discontinued the study medica-
chical procedure to account for multiple com- tion prematurely. Of these patients, 31 (39.7%)
parisons (see Section D in the Supplementary in the nintedanib group and 11 (30.6%) in the
Appendix). Sensitivity analyses were performed placebo group completed visits up to week 52.
to assess the robustness of the results for the The most frequent reason for premature discon-
primary and key secondary end points. Multiple tinuation of the study medication was at least
imputation sensitivity analyses were performed one adverse event (65 patients [21.0%] in the
to assess the effect of missing data and provide nintedanib group and 24 [11.8%] in the placebo
estimates of the treatment effect under different group). In INPULSIS-2, a total of 548 patients
assumptions about missing data (Fig. S2 in the received at least one dose of the study medica-
Supplementary Appendix). For the time to the tion (329 received nintedanib and 219 received
first acute exacerbation, a sensitivity analysis placebo). A total of 78 patients (23.7%) in the nin-
based on the occurrence of confirmed or sus- tedanib group and 44 patients (20.1%) in the pla-
pected acute exacerbations (as determined by the cebo group discontinued the study medication
adjudication committee) in pooled data from the prematurely. Of these patients, 26 (33.3%) in
two trials was prespecified. the nintedanib group and 10 (22.7%) in the pla-
The frequency and severity of adverse events cebo group completed visits up to week 52. The
were documented according to the Medical Diction- most frequent reason for premature discontinu-
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2014, 370 : 22 2071-2082
_______________________________________________________________________________________________________________
ation of the study medication was at least one In each trial, the baseline characteristics of
adverse event (62 patients [18.8%] in the nin- patients in the nintedanib and placebo groups
tedanib group and 35 [16.0%] in the placebo were similar (Table 1, and Table S3 in the Sup-
group). The proportion of patients with missing plementary Appendix). The mean duration of
FVC data at week 52 was approximately 15%; exposure to the study drug in the nintedanib
the proportion of patients with missing data did and placebo groups was similar (approximately
not differ significantly between the nintedanib 45 weeks in each trial), but a higher proportion
and placebo groups (Fig. S2 in the Supplementary of patients in the nintedanib group than in the
Appendix). placebo group had dose reductions or interrup-
Table 1. Baseline Characteristics of Patients in INPULSIS-1 and INPULSIS-2.*
Characteristic INPULSIS-1 INPULSIS-2

Nintedanib Placebo Nintedanib Placebo
(N = 309) (N = 204) (N = 329) (N = 219)
Male sex — no. (%) 251 (81.2) 163 (79.9) 256 (77.8) 171 (78.1)
Age — yr 66.9±8.4 66.9±8.2 66.4±7.9 67.1±7.5
Weight — kg 82.0±16.8 81.2±16.3 76.6±15.9 76.3±16.5
Body-mass index† 28.6±4.5 28.1±4.6 27.6±4.6 27.2±4.5
Smoking status — no. (%)
Never smoked 71 (23.0) 51 (25.0) 103 (31.3) 71 (32.4)
Former smoker 217 (70.2) 144 (70.6) 218 (66.3) 139 (63.5)
Current smoker 21 (6.8) 9 (4.4) 8 (2.4) 9 (4.1)
Time since diagnosis of idiopathic pulmonary fibrosis 1.7±1.4 1.6±1.4 1.6±1.3 1.6±1.3
— yr
Specimen from surgical lung biopsy available 60 (19.4) 33 (16.2) 84 (25.5) 52 (23.7)
— no. (%)
Systemic corticosteroid therapy — no. (%)‡ 68 (22.0) 43 (21.1) 68 (20.7) 46 (21.0)
FVC
Mean — ml 2757±735 2845±820 2673±776 2619±787
Median — ml 2700 2721 2615 2591
Percentage of predicted value 79.5±17.0 80.5±17.3 80.0±18.1 78.1±19.0
FEV1:FVC (%) 81.5±5.4 80.8±6.1 81.8±6.3 82.4±5.7
DLco
mmol/min/kPa 4.0±1.2 4.0±1.1 3.8±1.2 3.7±1.3
Percentage of predicted value§ 47.8±12.3 47.5±11.7 47.0±14.5 46.4±14.8
Spo2 — % 95.9±2.0 95.9±1.9 95.8±2.6 95.7±2.1
Total SGRQ score¶ 39.6±17.6 39.8±18.5 39.5±20.5 39.4±18.7
* Plus–minus values are means ±SD. FEV1 denotes forced expiratory volume in 1 second, FVC forced vital capacity, and
Spo2 oxygen saturation of peripheral blood.
† The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡ Prednisone at a dose of no more than 15 mg per day or the equivalent was permitted if the dose had been stable for at
least 8 weeks before screening.
§ The percentage of the predicted value for the diffusion capacity of the lung for carbon monoxide (DLco) was calculated
with the use of the equation described by the European Community for Steel and Coal in Cotes et al.18 In INPULSIS-2,
data were available for 218 patients in the placebo group.
¶ In INPULSIS-1, the total score on the St. George’s Respiratory Questionnaire (SGRQ) was available for 298 patients
in the nintedanib group and 202 patients in the placebo group; in INPULSIS-2, the total SGRQ score was available for
326 patients in the nintedanib group and 217 patients in the placebo group. The total score ranges from 0 to 100, with
higher scores indicating worse health-related quality of life.
Page 5 of 50
2076
2014, 370 : 22
A INPULSIS-1 B INPULSIS-1
0 50
−50 0
Nintedanib, 150 mg twice daily
−50
−100
−100
−150 −114.7 Placebo
2071-2082
New England Journal of Medicine
−150
in FVC (ml/yr)
−200 Difference, 125.3 Adjusted mean difference,
Mean Observed Change

from Baseline in FVC (ml)
(95% CI, 77.7–172.8) −200 109.9 (95% CI, 71.3–148.6)
P<0.001 P<0.001
−250
Adjusted Annual Rate of Change

−250
−239.9 0 2 4 6 12 24 36 52
−300 Week
Nintedanib, Placebo
150 mg (N=204) No. of Patients
The
Twice Daily Nintedanib 303 301 298 292 284 274 250
(N=309) Placebo 202 198 200 194 192 187 165
C INPULSIS-2 D INPULSIS-2
0 50
−50 0
n engl j med 370;22

Nintedanib, 150 mg twice daily
−50
−100
−100
−150 −113.6 Placebo
nejm.org
Difference, 93.7
n e w e ng l a n d j o u r na l
−150
(95% CI, 44.8–142.7)
of
in FVC (ml/yr)
−200 Adjusted mean difference,
P<0.001
Mean Observed Change

from Baseline in FVC (ml)
−200 109.8 (95% CI, 70.9–148.6)
P<0.001
−250 −207.3
Adjusted Annual Rate of Change

−250
may 29, 2014

0 2 4 6 12 24 36 52
−300 Week
m e dic i n e
Nintedanib, Placebo
150 mg (N=219) No. of Patients
Twice Daily Nintedanib 323 315 315 312 303 295 269
(N=329) Placebo 215 210 207 209 203 196 180
Figure 1. Annual Rate of Decline and Change from Baseline over Time in Forced Vital Capacity (FVC) in INPULSIS-1 and INPULSIS-2, According to Study Group.
Between-group differences (the FVC value in the nintedanib group vs. the value in the placebo group) are shown for the adjusted rate of decline in FVC (Panels A and C) and the
mean observed change from baseline at week 52 (Panels B and D). I bars indicate standard errors for the adjusted annual rate of decline in FVC and the observed change from
baseline.
Page 6 of 50
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2014, 370 : 22 2071-2082
_______________________________________________________________________________________________________________
tions (Table S4 in the Supplementary Appendix).
* Between-group differences are expressed as odds ratios for FVC response. FVC decline denotes an absolute decline in the percentage of the predicted value. For the FVC response at week 52,
there was a total of 309 participants in the nintedanib group in INPULSIS-1 and a total of 329 participants in the nintedanib group and 219 participants in the placebo group in INPULSIS-2.
P Value
<0.001
<0.001
The dose intensity — the amount of drug admin-
0.001
0.18
istered divided by the amount that would have
been administered had the regimen of 150 mg
Nintedanib vs. Placebo

twice daily been followed throughout the study
or until permanent discontinuation of the study
(70.9 to 148.6)
(1.26 to 2.55)
(0.89 to 1.86)
(1.9 to 4.3)
Difference,
(95% CI)
medication — was more than 90% in 75.9% of
109.8
1.79
1.29
3.1
patients in the nintedanib groups.
INPULSIS-2
Lung Function
In both trials, the adjusted annual rate of change
in FVC was significantly lower in the nintedanib
86 (39.3)
140 (63.9)
(N = 217)
Placebo
group than in the placebo group. In INPULSIS-1,
−205.0
−6.2
the rate was −114.7 ml per year in the nintedanib
group as compared with −239.9 ml per year in
the placebo group, representing a difference of
125.3 ml per year (95% confidence interval [CI],
Nintedanib
175 (53.2)
229 (69.6)
(N = 327)
77.7 to 172.8; P<0.001) (Fig. 1A). In INPULSIS-2,
−95.3
−3.1
the rate was −113.6 ml per year in the nintedanib
group as compared with −207.3 ml per year in
the placebo group, representing a difference of
P Value
93.7 ml per year (95% CI, 44.8 to 142.7; P<0.001)

<0.001
<0.001
0.001
<0.001
(Fig. 1C). In both trials, the results of prespeci-
fied sensitivity analyses were consistent with
Nintedanib vs. Placebo
the results of the primary analysis (Fig. S2 in the

Supplementary Appendix). In particular, in the
(71.3 to 148.6)
(1.28 to 2.66)
(1.32 to 2.79)
(2.1 to 4.3)
Difference,
(95% CI)
multiple imputation analyses, which were based

109.9
1.85
1.91
3.2
on the conservative assumption that missing data

were informative rather than random, the esti-
INPULSIS-1
mates of treatment effect and the corresponding

confidence intervals were consistent with the re-
sults of the primary analysis in each study. This
78 (38.2)
116 (56.9)
(N = 204)
finding shows that the primary results are robust

Placebo
−205.0
−6.0
and were not influenced by alternative assump-

tions about missing data. In addition, the mean
observed changes in FVC over time (unadjusted,
Table 2. Secondary Lung-Function End Points at Week 52.
nonimputed results) were consistent with the re-

Nintedanib
163 (52.8)
218 (70.6)
(N = 307)
sults of the primary analysis in both trials (Fig.

−95.1
−2.8
1B and 1D).
In each trial, a significantly greater propor-
tion of patients in the nintedanib group than in
FVC decline ≤10 percentage points
Adjusted absolute mean change from
FVC decline ≤5 percentage points
the placebo group had a response in FVC when

FVC response at wk 52 — no. (%)*
patients with a response were defined as those

baseline in FVC — % of
who did not have an absolute decline in the per-

baseline in FVC — ml
centage of predicted FVC that was more than

predicted value
5 percentage points at week 52 (Table 2). When

patients with a response in FVC were defined as
those who did not have an absolute decline in the
percentage of predicted FVC that was more than
End Point
10 percentage points at week 52, a significantly

greater proportion of patients in the nintedanib
group than in the placebo group had a response
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_______________________________________________________________________________________________________________
A INPULSIS-1
15
Cumulative Incidence of First Investigator-

14
13
Reported Acute Exacerbation (%)

12
11
10
9
8
Hazard ratio, 1.15 (95% CI, 0.54–2.42)
7
P=0.67
6
5
4 Nintedanib, 150 mg twice daily
3
2
1 Placebo
0
0 30 60 90 120 150 180 210 240 270 300 330 360 373
Days
No. of Patients
Nintedanib 309 306 304 292 290 288 283 282 280 275 271 267 258 233
Placebo 204 202 200 197 197 197 193 191 191 188 186 181 178 170
B INPULSIS-2
15
Cumulative Incidence of First Investigator-
14
13
Reported Acute Exacerbation (%)
12
11
10
9 Placebo
8 Hazard ratio, 0.38 (95% CI, 0.19–0.77)
7 P=0.005
6
5
4
3
2 Nintedanib, 150 mg twice daily
1
0
0 30 60 90 120 150 180 210 240 270 300 330 360 373
Days
No. of Patients
Nintedanib 329 326 323 317 315 307 306 302 300 295 291 286 279 259
Placebo 219 217 215 211 210 206 200 198 195 193 190 186 181 171
Figure 2. Time to First Investigator-Reported Acute Exacerbation in INPULSIS-1 and INPULSIS-2.
in INPULSIS-1; in INPULSIS-2, the difference tion of patients in the nintedanib group than in
between the groups was not significant. the placebo group had an FVC response with
A prespecified pooled analysis of the primary both definitions of a response (a decline in the
end point showed a significant treatment effect, percentage of predicted FVC that was not more
(between-group difference in the annual rate of than 5 percentage points and a decline that was
FVC change, −109.9 ml [95% CI, 75.9 to −144.0]) not more than 10 percentage points at week 52)
(Fig. S3A in the Supplementary Appendix). (Table S5 in the Supplementary Appendix).
Pooled data on the absolute change from base-
line in FVC are shown in Table S5 and Figure Acute Exacerbations
S3B in the Supplementary Appendix. A pre- In INPULSIS-1, there was no significant differ-
specified pooled analysis of data from the two ence between the nintedanib and placebo groups
trials showed that a significantly greater propor- in the time to the first acute exacerbation (haz-
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_______________________________________________________________________________________________________________
ard ratio in the nintedanib group, 1.15; 95% CI, and S7B in the Supplementary Appendix) and in
0.54 to 2.42; P = 0.67) (Fig. 2A), and the propor- the pooled analysis (Table S7C in the Supple-
tion of patients with at least one investigator- mentary Appendix).
reported acute exacerbation was similar in the
nintedanib and placebo groups (6.1% and 5.4%, Deaths
respectively). In INPULSIS-2, there was a signifi- In the prespecified pooled analysis, there was no
cant increase in the time to the first acute exac- significant between-group difference in death
erbation in the nintedanib group as compared from any cause, death from a respiratory cause,
with the placebo group (hazard ratio, 0.38; 95% or death that occurred between randomization
CI, 0.19 to 0.77; P = 0.005) (Fig. 2B), and the pro- and 28 days after the last dose of the study drug
portion of patients with at least one investigator- (Table S8 in the Supplementary Appendix). The
reported acute exacerbation was lower in the proportion of patients who died from any cause
nintedanib group than in the placebo group over the 52-week treatment period was 5.5% in
(3.6% vs. 9.6%). In the prespecified pooled analy- the nintedanib group and 7.8% in the placebo
sis, there was no significant difference between group (hazard ratio in the nintedanib group,
the nintedanib and placebo groups in time to first 0.70; 95% CI, 0.43 to 1.12; P = 0.14) (Fig. S8 in the
investigator-reported acute exacerbation (hazard Supplementary Appendix).
ratio, 0.64; 95% CI, 0.39 to 1.05; P = 0.08); the
proportion of patients with at least one investiga- Adverse Events
tor-reported acute exacerbation was 4.9% in the The most frequent adverse event in the ninteda-
nintedanib group and 7.6% in the placebo group nib groups in both trials was diarrhea (Table 3).
(Fig. S4 and S5 in the Supplementary Appendix). Among the patients in the nintedanib groups
A prespecified sensitivity analysis of pooled data who had diarrhea, most reported events that
on the time to the first adjudicated acute exacer- were of mild or moderate intensity (93.7% in
bation (confirmed or suspected) showed that INPULSIS-1 and 95.2% in INPULSIS-2). Diarrhea
nintedanib had a significant benefit as com- led to premature discontinuation of the study
pared with placebo (Table S6 and Fig. S6 in the drug in 14 patients receiving nintedanib (4.5%)
Supplementary Appendix). and none of the patients receiving placebo in
INPULSIS-1 and in 14 patients receiving ninteda-
SGRQ Score nib (4.3%) and 1 receiving placebo (0.5%) in
In INPULSIS-1, there was no significant between- INPULSIS-2.
group difference in the adjusted mean change in In both trials, the proportion of patients with
the total SGRQ score from baseline to week 52 serious adverse events was similar in the ninteda-
(4.34 points in the nintedanib group and 4.39 nib and placebo groups (Table 3). In INPULSIS-1,
points in the placebo group; difference, −0.05; serious adverse events were reported in 31.1% of
95% CI, −2.50 to 2.40; P = 0.97); in INPULSIS-2, patients in the nintedanib group and in 27.0%
there was a significantly smaller increase in the of patients in the placebo group; in INPULSIS-2,
total SGRQ score at week 52 (consistent with less the percentages were 29.8% and 32.9%, respec-
deterioration in health-related quality of life) in tively.
the nintedanib group than in the placebo group In both trials, a higher proportion of patients in
(2.80 points vs. 5.48 points; difference, −2.69; the nintedanib groups than in the placebo groups
95% CI, −4.95 to −0.43; P = 0.02) (Fig. S7A and S7B had elevated levels of liver enzymes (Table S9 in
in the Supplementary Appendix). the Supplementary Appendix). In INPULSIS-1, a
In the prespecified pooled analysis of the to- total of 15 patients in the nintedanib group
tal SGRQ score, there was no significant differ- (4.9%) and 1 patient in the placebo group (0.5%)
ence in the adjusted mean change from baseline had levels of aspartate aminotransferase, alanine
to week 52 between the nintedanib and placebo aminotransferase, or both that were three or
groups (difference, −1.43 points; 95% CI, −3.09 more times the upper limit of the normal range.
to 0.23; P = 0.09) (Fig. S7C in the Supplementary In INPULSIS-2, a total of 17 patients in the nin-
Appendix). Changes from baseline in SGRQ do- tedanib group (5.2%) and 2 patients in the pla-
main scores were consistent with the changes in cebo group (0.9%) had such elevations.
the total SGRQ score in each trial (Tables S7A Among the infrequent events (those occurring
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_______________________________________________________________________________________________________________
Table 3. Adverse Events.
Event INPULSIS-1 INPULSIS-2

(N = 309) (N = 204) (N = 329) (N = 219)
number of patients (percent)

Any adverse event 298 (96.4) 181 (88.7) 311 (94.5) 198 (90.4)
Any adverse event, excluding progression 296 (95.8) 179 (87.7) 311 (94.5) 197 (90.0)
of idiopathic pulmonary fibrosis*
Most frequent adverse events†
Diarrhea 190 (61.5) 38 (18.6) 208 (63.2) 40 (18.3)
Nausea 70 (22.7) 12 (5.9) 86 (26.1) 16 (7.3)
Nasopharyngitis 39 (12.6) 34 (16.7) 48 (14.6) 34 (15.5)
Cough 47 (15.2) 26 (12.7) 38 (11.6) 31 (14.2)
Progression of idiopathic pulmonary fibrosis* 31 (10.0) 21 (10.3) 33 (10.0) 40 (18.3)
Bronchitis 36 (11.7) 28 (13.7) 31 (9.4) 17 (7.8)
Upper respiratory tract infection 28 (9.1) 18 (8.8) 30 (9.1) 24 (11.0)
Dyspnea 22 (7.1) 23 (11.3) 27 (8.2) 25 (11.4)
Decreased appetite 26 (8.4) 14 (6.9) 42 (12.8) 10 (4.6)
Vomiting 40 (12.9) 4 (2.0) 34 (10.3) 7 (3.2)
Weight loss 25 (8.1) 13 (6.4) 37 (11.2) 2 (0.9)
Severe adverse events‡ 81 (26.2) 37 (18.1) 93 (28.3) 62 (28.3)
Serious adverse events‡ 96 (31.1) 55 (27.0) 98 (29.8) 72 (32.9)
Fatal adverse events 12 (3.9) 10 (4.9) 25 (7.6) 21 (9.6)
Adverse events leading to treatment 65 (21.0) 22 (10.8) 58 (17.6) 33 (15.1)
discontinuation§
Gastrointestinal disorders 26 (8.4) 3 (1.5) 21 (6.4) 2 (0.9)
Respiratory, thoracic, and mediastinal 12 (3.9) 10 (4.9) 8 (2.4) 18 (8.2)
disorders
Investigation results¶ 10 (3.2) 1 (0.5) 8 (2.4) 1 (0.5)
Cardiac disorders 5 (1.6) 4 (2.0) 2 (0.6) 3 (1.4)
General disorders and conditions involving 8 (2.6) 3 (1.5) 2 (0.6) 1 (0.5)
site of study-drug administration∥
* Progression of idiopathic pulmonary fibrosis was defined in accordance with the definition of idiopathic pulmonary fi-
brosis in the Medical Dictionary for Regulatory Activities, version 16.1, which includes disease worsening and exacerba-
tions of idiopathic pulmonary fibrosis.
† The most frequent adverse events were defined as those with an incidence of more than 10% in any study group.
‡ A severe adverse event was related to intensity and was defined as an event that was incapacitating or that caused an in-
ability to work or to perform usual activities. A serious adverse event was defined as any adverse event that resulted in death,
was immediately life-threatening, resulted in persistent or clinically significant disability or incapacity, required or pro-
longed hospitalization, was related to a congenital anomaly or birth defect, or was deemed serious for any other reason.
§ Adverse events leading to study-drug discontinuation were reported when they occurred in 2% or more of patients in
any study group and are listed according to system organ class. The analysis included adverse events with an onset
after administration of the first dose of study medication and up to 28 days after administration of the last dose.
¶ Investigation results refer to the results of clinical laboratory tests, radiologic tests, physical examination, and physio-
logic tests.
∥ These events include disorders or conditions that involve several body systems or sites, including chest pain, fatigue,
asthenia, and general deterioration of physical health.
in less than 2% of a study group) that were of (0.5%) in INPULSIS-1, and in 5 patients in the
potential clinical importance, myocardial infarc- nintedanib group (1.5%) and 1 patient in the
tion was reported in 5 patients in the nintedanib placebo group (0.5%) in INPULSIS-2. In total, two
group (1.6%) and 1 patient in the placebo group events in the nintedanib groups and one event in
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_______________________________________________________________________________________________________________
the placebo groups were fatal. Occurrences of results show that although adverse events asso-
adverse events related to cardiac disorders, in- ciated with nintedanib treatment were not infre-
cluding ischemic heart disease, are summarized quent, the dosing regimen used in the INPULSIS
in Table S10 in the Supplementary Appendix. trials was successful in minimizing treatment
discontinuations. Although serious adverse events
Discussion reflecting ischemic heart disease were balanced
between the nintedanib and placebo groups, a
In both the INPULSIS trials, nintedanib signifi- higher percentage of patients in the nintedanib
cantly reduced the rate of decline in FVC over the groups had myocardial infarctions. The clinical
52-week treatment period. The robustness of this significance of this finding is unknown, and
finding was supported by the results of all pre- further observation in larger cohorts is needed.
specified sensitivity analyses, including those In conclusion, data from the INPULSIS trials
assessing alternative ways of handling missing show that in patients with idiopathic pulmonary
data. The treatment effect for the annual rate of fibrosis, nintedanib reduced the decline in FVC,
decline in FVC was consistent with the treatment which is consistent with a slowing of disease
effect for the absolute change from baseline in progression. There were significant differences
FVC. The curves for changes from baseline in in favor of nintedanib for the time to the first
FVC over time in the nintedanib and placebo acute exacerbation and the change from baseline
groups separated early in the two studies and in the total SGRQ score in INPULSIS-2 but not
continued to diverge over time. in INPULSIS-1. Adverse events were common in
A smaller proportion of patients in the ninteda- the nintedanib groups in both trials; nonethe-
nib groups than in the placebo groups had an less, most patients continued to receive ninted-
absolute decline in the percentage of predicted anib for the duration of the treatment period.
FVC of more than 5 percentage points, an obser- Supported by Boehringer Ingelheim and by grants from the
National Institute for Health Research (NIHR) Southampton
vation that supports the clinical relevance of the Respiratory Biomedical Research Unit at the University Hospital
results. No consistent effect of nintedanib on Southampton NHS Foundation Trust (to Dr. Richeldi) and from
the time to the first acute exacerbation or on the the NIHR Respiratory Disease Biomedical Research Unit at the
Royal Brompton and Harefield NHS Foundation Trust and
change in the total SGRQ score was observed in Imperial College London (to Drs. Hansell and Nicholson).
the two trials. This difference in the key second- Dr. Richeldi reports receiving fees for serving on advisory
ary end point results between INPULSIS-1 and boards from InterMune, MedImmune, Roche, and Takeda, con-
sulting fees from Biogen Idec, Sanofi-Aventis, and ImmuneWorks,
INPULSIS-2 was not explained by the differences lecture fees from Shionogi, and grant support from InterMune.
in baseline characteristics between the trials. Dr. du Bois reports receiving consulting fees from InterMune.
Acute exacerbations of idiopathic pulmonary Dr. Raghu reports receiving consulting fees from Boehringer
Ingelheim, Biogen Idec, Gilead, FibroGen, and Promedior. Dr.
fibrosis are events of major clinical significance Azuma reports receiving fees for serving on advisory boards
that are associated with high morbidity and from Shionogi and Takeda and for serving on steering commit-
mortality.17,19 The INPULSIS trials showed that tees from InterMune. Dr. Brown reports receiving fees for serv-
ing on an advisory board from MedImmune, fees for serving on
the effect of nintedanib was inconsistent with steering committees for Actelion, Centocor, Gilead, and Sanofi-
respect to the risk of investigator-reported acute Genzyme, consulting fees from Actelion, Altitude Pharma,
exacerbations. Exacerbations are relatively rare Amgen, Biogen-Stromedix, Celgene, Centocor, FibroGen, Genen-
tech, GeNO, Genoa Pharma, Gilead, Mesoblast, Moerae Matrix,
events in patients with idiopathic pulmonary fi- Novartis, Pfizer, Promedior, Sanofi-Genzyme, Veracyte, and
brosis who are in clinical trials and are difficult Galecto, and grant support from Actelion, Amgen, Genentech,
to assess and categorize, which may explain Gilead, and Sanofi-Genzyme. Dr. Costabel reports receiving fees
for serving on advisory boards and steering committees from
some of the heterogeneity in our findings.20 InterMune, consulting fees from Gilead, Centocor, Roche, and
In both trials, the most frequent adverse Bayer, lecture fees from InterMune and Bayer, and grant support
events in the nintedanib groups were gastrointes- through his institution from InterMune, Gilead, Centocor, and
Sanofi-Aventis. Dr. Cottin reports receiving fees for serving on
tinal in nature, with the majority of patients who advisory boards and for consulting from Bayer, Gilead, Glaxo-
received nintedanib reporting diarrhea. However, SmithKline, InterMune, and Roche, fees for serving on an advi-
the proportion of patients in the nintedanib sory board and contributing to educational material from
Boehringer Ingelheim, lecture fees from Actelion, Boehringer
groups with diarrhea that led to premature dis- Ingelheim, and InterMune, and travel support from Actelion,
continuation of the study medication was less than GlaxoSmithKline, and InterMune. Dr. Flaherty reports receiv-
5% (4.5% in INPULSIS-1 and 4.3% in INPULSIS-2). ing consulting fees from FibroGen, Genentech, Gilead, Ikaria,
ImmuneWorks, MedImmune, Novartis, Takeda, Vertex, Veracyte,
In both trials, the mean dose intensity in the Roche, and InterMune, lecture fees from GlaxoSmithKline,
nintedanib groups was greater than 90%. These Forest, Excel, and the France Foundation, and grant support from
Page 11 of 50
2014, 370 : 22 2071-2082
_______________________________________________________________________________________________________________
ImmuneWorks, InterMune, and Bristol-Myers Squibb. Dr. Kolb Ingelheim. Dr. Collard reports receiving consulting fees through
reports receiving consulting fees from InterMune and grant sup- his institution from Bayer, FibroGen, Gilead, InterMune, Meso-
port from InterMune and GlaxoSmithKline. Dr. Nicholson reports blast, Moerae Matrix, Pfizer, Promedior, and Takeda and grant
receiving lecture fees from InterMune. Dr. Noble reports receiving support through his institution from Genentech. No other poten-
consulting fees from InterMune, Moerae Matrix, Bristol-Myers tial conflict of interest relevant to this article was reported.
Squibb, Roche-Genentech, and Takeda. Dr. Taniguchi reports re- Disclosure forms provided by the authors are available with
ceiving fees for serving on advisory boards from Shionogi, Olympus, the full text of this article at NEJM.org.
AstraZeneca and Chugai and lecture fees from AstraZeneca, Asahi We thank the patients who participated in the trials, the fol-
Kasei Pharma, Abbott, Bayer, Eli Lilly, Eisai, GlaxoSmithKline, lowing employees of Boehringer Ingelheim for their contribu-
Kyorin, Novartis, Meiji Seika Pharma, Ono Pharmaceutical, Philips tions, Madelyne Pohu for data management support, Omar
Respironics, Pfizer, Taiho Pharmaceutical, Terumo, Teijin Pharma, Sefiani and Stephane Bouget for programming support, and
and Fukuda Denshi. Drs. Brun, Le Maulf, Girard, Stowasser, Julie Fleming and Wendy Morris of Fleishman-Hillard Group for
Schlenker-Herceg, and Disse report being employees of Boehringer writing assistance.
APPENDIX
The authors’ affiliations are as follows: National Institute for Health Research Southampton Respiratory Biomedical Research Unit and
Clinical and Experimental Sciences, University of Southampton, Southampton (L.R.), and Imperial College London (R.M.B.) and Royal
Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London (D.M.H., A.G.N.)
— all in the United Kingdom; University of Washington, Seattle (G.R.); Nippon Medical School, Tokyo (A.A.), National Hospital Orga-
nization Kinki-Chuo Chest Medical Center, Osaka (Y.I.), and Tosei General Hospital, Aichi (H.T.) — all in Japan; National Jewish
Health, Denver (K.K.B.); Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen (U.C.), and Boehringer Ingelheim
Pharma GmbH, Ingelheim am Rhein (S.S., B.D.) — both in Germany; Louis Pradel Hospital, University of Lyon, Lyon (V.C.), and
Boehringer Ingelheim, Reims (M.B., F.L.M., M.G.) — both in France; University of Michigan Health System, Ann Arbor (K.R.F.); Asan
Medical Center, University of Ulsan, Seoul, South Korea (D.S.K.); McMaster University, Hamilton, ON, Canada (M.K.); Cedars–Sinai
Medical Center, Los Angeles (P.W.N.); Instituto Nacional de Enfermedades Respiratorias, Mexico City (M.S.); Boehringer Ingelheim
Pharmaceuticals, Ridgefield, CT (R.S.-H.); and University of California San Francisco, San Francisco (H.R.C.).
References
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183:788-824. 8. Chaudhary NI, Roth GJ, Hilberg F, tion of the St. George’s Respiratory Ques-
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et al. Fibrotic idiopathic interstitial pneu- et al. Efficacy of a tyrosine kinase inhibitor and outcome. Eur Respir J 2011;37:356-63.
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SUPPLEMENTARY APPENDIX
Supplement to: Richeldi L, du Bois RM, Raghu G, et al. Efficacy and Safety of Nintedanib in
Idiopathic Pulmonary Fibrosis. N Engl J Med 2014.
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CONTENTS
Section A: List of investigators
Section B: Study committees
Section C: Key exclusion criteria
Section D: Statistical analysis
Table S1: Eligibility criteria based on chest HRCT if a surgical lung biopsy was not available
Table S2: Eligibility criteria based on surgical lung biopsy
Table S3: Baseline characteristics (race)
Table S4: Exposure to study drug in INPULSIS™-1 and INPULSIS™-2
Table S5: Secondary lung function endpoints in INPULSIS™-1 and INPULSIS™-2 at week 52
(pooled data)
Table S6: Adjudicated acute exacerbations within 52 weeks in INPULSIS™-1 and
INPULSIS™-2 and pooled data
Table S7A: Adjusted mean change from baseline in SGRQ domain scores over 52 weeks in
INPULSIS™-1
Table S7B: Adjusted mean change from baseline in SGRQ domain scores over 52 weeks in
INPULSIS™-2
Table S7C: Adjusted mean change from baseline in SGRQ domain scores over 52 weeks in
INPULSIS™-1 and INPULSIS™-2 (pooled data)
Table S8: Overall, respiratory and on-treatment time to death in INPULSIS™-1 and
INPULSIS™-2 (pooled data)
Table S9: Liver enzyme elevations in INPULSIS™-1 and INPULSIS™-2
Table S10: Summary of cardiac disorder adverse events in INPULSIS™-1 and INPULSIS™-2
Figure S1: Patient flow
Figure S2: Sensitivity analyses of the primary endpoint
2|P a g e
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Figure S3: Annual rate of decline and change from baseline in FVC in INPULSIS™-1 and
Figure S4: Time to first acute exacerbation based on investigator-reported acute
exacerbations in INPULSIS™-1 and INPULSIS™-2 (pooled data)
Figure S5: Incidence of investigator-reported acute exacerbations within 52 weeks in
INPULSIS™-1 and INPULSIS™-2 and pooled data
Figure S6: Time to first acute exacerbation based on confirmed and suspected acute
exacerbations (per adjudication) in INPULSIS™-1 and INPULSIS™-2 (pooled data)
Figure S7: Change from baseline in SGRQ total score over 52 weeks
Figure S8: Time to death in INPULSIS™-1 and INPULSIS™-2 (pooled data)
3|P a g e
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Section A: List of investigators
Australia: T. Corte, Royal Prince Alfred Hospital, Camperdown, New South Wales; H. Davies,
Repatriation General Hospital, Daw Park, South Australia; I. Glaspole, Alfred Hospital,
Melbourne, Victoria; J. Mulder, Frankston Hospital, Frankston, Victoria; E. Veitch, Concord
Repatriation General Hospital, Concord, New South Wales. Belgium: P. De Vuyst, Erasme
University Hospital, Brussels; G. Liistro, Cliniques Universitaires Saint-Luc, Brussels; Y.
Sibille, Cliniques Universitaires UCL de Mont-Godinne, Yvoir; W. Vincken, Universitair
Ziekenhuis Brussel, Brussels; W. Wuyts, Universitair Ziekenhuis Leuven Gasthuisberg
Campus, Leuven. Canada: C. Fell, Peter Lougheed Centre, Calgary, Alberta; P. Hernandez,
Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia; M. Kolb, St. Joseph’s
Healthcare, Hamilton, Ontario. Chile: A. Undurraga, Instituto Nacional de Torax, Santiago.
China: C. Bai, Zhongshan Hospital Fudan University, Shanghai; P. Chen, The General
Hospital of Shenyang Military Command, Shenyang; Z. Gao, Peking University People’s
Hospital, Beijing; J. Kang, The First Hospital of Chinese Medical University, Shenyang; H. Li,
Shanghai Pulmonary Hospital, Shanghai; Z. Li, Xijing Hospital, 4th Military Medical University,
Xi’an; H. Wan, Shanghai Ruijin Hospital, Shanghai; H. Wang, Beijing Friendship Hospital,
Beijing; F. Wen, West China Hospital Sichuan University, Chengdu; Q. Xiao, Xiangya
Hospital, Central South University, Changsha; Z. Xu, Peking Union Medical College Hospital,
Beijing; W. Zhang, The First Affiliated Hospital of Nanchang University, Nanchang; X. Zheng,
General Hospital of Ningxia Medical University, Yinchuan; H. Zhu, Shanghai Huadong
Hospital, Shanghai. Czech Republic: N. Pauk, University Hospital Na Bulovce, Praha; P.
Reiterer, Masaryk Hospital, Usti nad Labem; M. Vasakova, Thomayer’s Hospital, Clinic of
Pneumology, Praha. Finland: U. Hodgson, HYKS Keuhkosairauksien tutkimusyksikkö,
Helsinki. France: A. Bourdin, Hôpital A. Villeneuve, Pneumologie, Montpellier; J. Cadranel,
Hôpital Tenon, Pneumologie, Paris; P. Camus, Hôpital du Bocage, Pneumologie, Dijon; P.
Chanez, Hôpital Nord, Pneumologie, Marseille; V. Cottin, Hôpital Louis Pradel, Pneumologie,
Lyon; B. Crestani, Hôpital Bichat, Pneumologie, Paris; D. Israel-Biet, Hôpital Européen
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Georges-Pompidou, Pneumologie, Paris; S. Jouneau, Hôpital Pontchaillou, Pneumologie,
Rennes; F. Lebargy, Hôpital Maison Blanche, Pneumologie, Reims; C. H. Marquette, Hôpital
Pasteur, Pneumologie, Nice; G. Prévot, Hôpital Larrey, Pneumologie, Toulouse; D. Valeyre,
Hôpital Avicenne, Pneumologie, Bobigny; B. Wallaert, Hôpital Calmette, Pneumologie, Lille.
Germany: R. Bonnet, Zentralklinik Bad Berka GmbH, Bad Berka; U. Costabel, Ruhrlandklinik,
Essen; S. Gläser, Ernst-Moritz-Arndt-Universtität, Greifswald; C. Grohé, Evangelische
Lungenklinik Berlin; A. Guenther, Universitätsklinikum Gießen, Gießen; P. Hammerl,
Fachklinik für Lungenerkrankugen, Immenhausen; G. Höffken, Uniklinik Carl Gustav Carus,
Dresden; C. Karagiannidis, Kliniken der Stadt Koeln, Koeln; J. Kirschner, CIMS
Studienzentrum Bamberg UG, Bamberg; A. Kirsten, LungenClinic, Grosshansdorf; S. Korn,
Johannes-Gutenberg-Universtitätsklinik, Mainz; M. Kreuter, Universitätsklinikum Heidelberg,
Heidelberg; J. Müller-Quernheim, Klinik der Albert-Ludwig-Universität, Freiburg; C. Neurohr,
Klinikum Großhadern der L.M.-Universtität, München; M. Pfeifer, Krankenhaus, Donaustauf;
N. Schönfeld, HELIOS-Kliniken Emil von Behring, Berlin; R. Wiewrodt, Universitätsklinikum
Münster, Medizinischen Poliklinik D, Münster. Greece: K. Antoniou, University Hospital of
Heraklion, University Pulmonology Cl, Heraklion, Crete; Z. Daniil, University Hospital of
Larissa, Pulmonology Clinic, Larissa; F. Diamantea, General Hospital of Athens
“Sismanoglio”, 3rd Pneumonology Department, Athens; N. Koulouris, Athens Hospital of Chest
Diseases “Sotiria”, Athens; G. Mathioudakis, General Hospital of Nikaia, Pulmonology Clinic,
Nikaia. India: A. G. Ghosal, National Allergy Asthma Bronchitis Institute, Kolkata; S. Kadappa
Shivappa, Chest and Maternity Centre, Bangalore; M. M. Kawedia, Jehangir Hospital, Pune;
P. Khatavkar, King Edward Memorial Hospital, Mumbai; A. Kumar, Asthma Bhawan, Jaipur;
P. Mehta, Mehta Hospital and Cardiopulmonary Care Centre, Ahmedabad; V. Singh, SMS
Medical College and Hospital, Jaipur; K. Srikanth, PSG Hospitals, Coimbatore; H. Thakker,
Qualysure Clinical Research Solution, Ahmedabad; Z. Udwadia, P.D. Hinduja National
Hospital and Medical Research Center, Mumbai. Ireland: J. Egan, Mater Misericordiae
University Hospital, Department of Respiratory Medicine, Dublin. Israel: G. Fink, Kaplan
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Medical Center, Pulmonary Institute, Rehovot; M. R. Kramer, Rabin Medical Center, Petah
Tiqwa; M. Yigla, Rambam Medical Center, Haifa. Italy: C. Agostini, Università degli Studi,
Dipartimento di Medicina Clinica e Sperimentale, Padova; F. De Benedetto, P.O. Clinicizzato
SS. Annunziata, U.O. di Pneumologia, Chieti; S. Harari, Ospedale S. Giuseppe
Fatebenefratelli, Pneumologia, Milano; F. Luppi, Università Modena e Reggio Emilia, Malattie
dell’Apparato Respiratorio, Modena; P. L. Paggiaro and L. M. Tavanti, Azienda Ospedaliera
Universitaria Pisana, Ospedale Cisanello, Fisiop. Respiratoria, Pisa; A. Pesci, Nuovo
Ospedale “S. Gerardo”, U.O. Pneumologia, Monza; V. Poletti, Ospedale Morgagni-Pierantoni,
Dipartimento Toracico U.O. Pneumologia, Forli; P. Rottoli, Presidio Ospedale Le Scotte,
Clinica Pneumologica, Siena; C. Saltini, Policlinico Università Tor Vergata, Malattie
Respiratorie, Roma; A. Sanduzzi Zamparelli, Università Federico II – II Clinica Pneumologica,
Napoli; C. Vancheri, A.O.U. Policlinico Dipartimento di Medicina Interna e Special. Sez. Mal.
Resp., Catania. Japan: M. Bando, Jichi Medical University Hospital, Pulmonary Medicine,
Tochigi; Y. Hasegawa, Nagoya University Hospital, Respiratory Medicine, Aichi; K.
Hashimoto, Tottori University Hospital, Respiratory Medicine, Tottori; S. Homma, Toho
University Omori Medical Center, Respiratory Medicine, Tokyo; N. Inase, Tokyo Medical and
Dental University, Pulmonary Medicine, Tokyo; Y. Inoue and T. Arai, National Hospital
Organization Kinki-Chuo Chest Medical Center, Department of Internal Medicine, Osaka; S.
Izumi, National Center for Global Health and Medicine, Respiratory Medicine, Tokyo; T.
Kawamura, Himeji Medical Center, Respiratory Tract Medicine, Hyogo; K. Kishi, Toranomon
Hospital, Department of Respiratory Medicine, Respiratory Center, Tokyo; Y. Kondo, Tosei
General Hospital, Department of Allergy and Respiratory Medicine, Aichi; K. Kuwano, The
Jikei University Hospital, Division of Respiratory Disease, Department of Internal Medicine,
Tokyo; Y. Miura, Nippon Medical School Hospital, Respiratory Medicine, Tokyo; Y. Nishioka,
Tokuschima University Hospital, Respiratory Medicine and Rheumatology, Tokushima; O.
Nishiyama, Kinki University Hospital, Respiratory Medicine and Allergy, Osaka; T. Ogura,
Kanagawa Cardiovascular and Respiratory Center, Respiratory Medicine, Kanagawa; S.
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Ohkouchi, Tohoku University Hospital, Department of Respiratory Medicine, Miyagi; T. Saito,
Ibarakihigashi National Hospital, Ibaraki Department of Respiratory Medicine, Naka; Y.
Setoguchi, Tokyo Medical University Hospital, Department of Respiratory Medicine,
Respiratory Center, Tokyo; J. Shindoh, Ogaki Municipal Hospital, Respiratory Med, Gifu; Y.
Taguchi, Tenri Hospital, Department of Respiratory Medicine, Nara; M. Tanakadate,
Toranomon Hospital Kajigaya, Pulmonary and Critical Care Medicine, Kanagawa; K. Tomii,
Kobe City Medical Center General Hospital, Respiratory Medicine, Hyogo; Y. Sugita, Saitama
Cardiovascular and Respiratory Center, Respiratory Medicine, Saitama; T. Yamaguchi, JR
Tokyo General Hospital, Respiratory Medicine, Tokyo; K. Yoshimori, Fukujuji Hospital,
Respiratory Medicine, Tokyo. Korea: S. H. Jeong, Gachon University Gil Hospital, Incheon;
D. S. Kim, Asan Medical Center, Seoul; Y. W. Kim, Seoul National University Hospital, Seoul;
C. S. Park, Soon Chun Hyang University Hospital Bucheon, Bucheon; J. S. Song, The
Catholic University of Korea, Yeouido St. Mary’s Hospital, Seoul; S. T. Uh, Soon Chun Hyang
University Hospital Seoul, Seoul. Mexico: M. Selman, Instituto Nacional de Enfermedades
Respiratorias, Ciudad de Mexico. Netherlands: P. Bresser, Onze Lieve Vrouwe Gasthius,
Amsterdam; J. C. Grutters, St. Antonius Ziekenhuis, Nieuwegein, Utrecht; M. S. Wijsenbeek,
Erasmus Medisch Centrum, Rotterdam. Portugal: A. Arrobas, Centro Hospitalar e
Universitário de Coimbra, EPE, Centro Hospitalar Coimbra, Pneumology Department,
Coimbra; J. Cardoso, Centro Hospitalar Lisboa Central, EPE, Hospital de Santa Marta,
Pneumology Department, Lisboa; R. Costa, Hospital Fernando Fonseca, EPE, Pneumology
Department, Amadora; A. Morais, Centro Hospitalar São João, EPE, Pneumology
Department, Porto; S. Neves, Centro Hospitalar de Vila Nova Gaia/Espinho, Pneumology
Department, Vila Nova de Gaia; M. Serrado, Centro Hospitalar Lisboa Norte, EPE, Hospital
Pulido Valente, Pneumology II Department, Lisboa. Russia: M. Ilkovick, Scientific Research
Institute of Pulmonology, Saint Petersburg; A. Vizel, GOU VPO Kazan State Medical
University of Roszdrav, Kazan. Spain: I. Alfageme Michavila, Hospital de Valme, Sevilla; J.
Ancochea, Hospital Universitario de la Princesa, Madrid; D. Castillo Villegas, Hospital de la
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Santa Cruz y San Pablo, Barcelona; M. Molina-Molina, Ciutat Sanitaria Universitaria Bellvitge,
Barcelona; F. Morell, Hospital Vall d’Hebron, Barcelona; A. Xaubet, Hospital Clinic i Provincial
de Barcelona, Neumología, Barcelona. Turkey: S. Aktogu Ozkan, Dr. Suat Seren Gogus
Hastaliklari ve Gogus Cerrahisi Egit ve Arastirma Hastanesi, Konak/zmir; O. Kayacan,
Ankara Universitesi Tip Fakültesi Gögüs Hastaliklari, Ankara; G. Ongen, Istanbul Universitesi
Cerrahpasa Tip Fakultesi Gogus Hastaliklari, Istanbul; N. Mogulkoc, Ege Universitesi Tip
Fakultesi Gögüs Hastaliklari ABD, zmir; E. Tuncay, Yedikule Gogus Hastaliklari ve Gogus
Cer Egitim ve Arastirma Hastanesi, Istanbul. United Kingdom: P. Beirne, St James’s
University Hospital, Respiratory Medicine, Leeds; H. Bettinson, Churchill Hospital, Oxford
Centre for Respiratory Medicine, Oxford; P. Burge, Birmingham Heartlands Hospital,
Department of Respiratory Medicine, Birmingham; O. Dempsey, Aberdeen Royal Infirmary,
Respiratory Department, Aberdeen; T. Maher, Royal Brompton Hospital, Interstitial Lung
Disease Unit, London; A. Millar, Southmead Hospital, North Bristol Lung Centre, Bristol; L.
Spencer, University Hospital Aintree, Aintree Chest Centre, Liverpool; D. Thickett, Queen
Elizabeth Hospital, Lung Investigation Unit, Birmingham. United States: J. Alvarez, Loess Hill
Research Center, Council Bluffs, Iowa; C. Andrews, Diagnostics Research Group, San
Antonio, Texas; O. Bajwa, Allegheny General Hospital, Allegheny-Singer Research Institute,
Pittsburgh, Pennsylvania; A. Baker, Lynchburg Pulmonary Associates, Lynchburg,
Tennessee; R. Baughman, University of Cincinnati Medical Center, Cincinnati, Ohio; J.
Belperio, David Geffen School of Medicine at UCLA, Los Angeles, California; J. Bradley,
Consultants in Pulmonary Medicine, Olathe, Kansas; H. Collard, University of California at
San Francisco, San Francisco, California; F. Cordova, Temple Lung Center Ambulatory Care
Center, Philadelphia, Pennsylvania; C. Daniels, Mayo Clinic College of Medicine, Rochester,
New York; J. de Andrade, University of Alabama, Division of Pulmonary, Birmingham,
Alabama; K. Dushay, Rhode Island Hospital, Providence, Rhode Island; R. Enelow,
Dartmouth Hitchock Medical Center, Lebanon, Pennsylvania; N. Ettinger, Cardiopulmonary
Associates, Chesterfield, Missouri; K. Gibson, University of Pittsburgh School of Medicine,
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Pittsburgh, Pennsylvania; M. Gotfried, Pulmonary Associates Clinical Trials, Phoenix,
Arizona; A. Hajari Case, Georgia Clinical Research, Austell, Georgia; D. Hotchkin, Oregon
Clinic, PC, Portland, Oregon; J. T. Huggins, Medical University of South Carolina, Charleston,
South Carolina; M. Kaye, Minnesota Lung Center, Ltd., Minneapolis, Minnesota; C. Kershaw,
University of Texas Southwestern Medical Center, Dallas, Texas; S. Kureishy, Metroplex
Pulmonary and Sleep Centre, McKinney, Texas; L. Lancaster, Vanderbilt University Medical
Center, Nashville, Tennessee; D. Lederer, New York Presbyterian Hospital, New York, New
York; Y. Mageto, Vermont Lung Center, Colchester, Vermont; J. Masson, Pulmonary and
Critical Care Associates, Albany, New York; K. Meyer, University of Wisconsin Hospital and
Clinics, Madison, Wisconsin; P. Mohabir, Stanford Medical Center Pulmonary and Critical
Care Clinic, Stanford, California; L. Morrison, Duke University Medical Center, Durham, North
Carolina; S. Nathan, Inova Fairfax Hospital, Falls Church, Virginia; I. Noth, University of
Chicago, Chicago, Illinois; D. Oelberg, Western Connecticut Medical Group P.C., Danbury,
Connecticut; F. Rahaghi, Cleveland Clinic Florida, Weston, Florida; D. Riley, University of
Medicine and Dentistry of NJ, New Brunswick, New Jersey; A. Rizzo, Lung Health and Sleep
Enhancement Center, LLC, Newark, New Jersey; M. Rossman, Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania; J. Ruzi, Arizona Pulmonary Specialists, Scottsdale,
Arizona; P. Sachs, Pulmonary Associates of Stamford, Stamford, Connecticut; T.
Schaumberg, Oregon Clinic, PC, Portland, Oregon; M. Scholand, Lung Health Research
Center, Salt Lake City, Utah; C. Schroeder, Sansum Clinic, Santa Barbara, California; F.
Seifer, FDC Seifer PLC Pulmonary, Shelbyville, Illinois; J. Shea, DCOL Center for Clinical
Research, Longview, Texas; D. Sinkowitz, UCLA David Geffen School of Medicine, Torrance,
California; J. Tabak, Miami Research Associates, South Miami, Florida; J. Taylor, MultiCare
Pulmonary Specialists, Tacoma, Washington; J. Thompson, Baptist Pulmonary and Critical
Care Associates, Lexington, Kentucky; C. Thurm, Jamaica Hospital Medical Center,
Department of Medicine, Jamaica, New York; J. Tita, ID Clinical Research, Ltd., Toledo, Ohio;
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M. Wencel, Via Christi Clinic, PA, Wichita, Kansas; J. Westerman, Jasper Summit Research,
LLC, Jasper, Alabama.
Section B: Study committees
Data Monitoring Committee (DMC): Joe Lasky (New Orleans, USA), Maurits Demedts
(Leuven, Belgium), Minne Casteels (Leuven, Belgium), Robert Loddenkemper (Berlin,
Germany), Jörg Michaelis (Mainz, Germany). The co-chairs of this committee were Joe Lasky
and Maurits Demedts.
Adjudication Committee: Jesse Roman (Louisville, USA), Gregory Tino (Philadelphia, USA)
and Maurizio Luisetti (Pavia, Italy).
Section C: Key exclusion criteria
Patients with abnormal laboratory parameters (liver transaminases or bilirubin above 1.5-fold
upper limit of normal), cardiac disease (i.e. myocardial infarction within 6 months or unstable
angina within 1 month of randomization), or who, in the opinion of the investigator, were likely
to receive a lung transplant during the study were not permitted to enter the trial. Patients who
were taking full-dose anticoagulant therapy or high-dose antiplatelet therapy at screening, or
had received treatment with NAC or prednisone >15 mg/day or equivalent within 2 weeks of
screening, or pirfenidone, azathioprine, cyclophosphamide, cyclosporine A or any
investigational drug within 8 weeks of screening, were excluded.
Section D: Statistical analysis
In the pooled analysis, the annual rate of decline in FVC was analyzed using random
coefficient regression with fixed effects for trial, treatment, sex, age, height and random effect
of patient-specific intercept and time.
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For the individual studies, absolute change from baseline in FVC over 52 weeks was
analyzed using mixed model for repeated measures (MMRM), with treatment and visit as fixed
effects, baseline value, sex, age and height as covariates, and treatment-by-visit and
baseline-by-visit as interaction terms. The patient effect was assumed to be random. The
treatment effect was obtained using the model estimates of the change from baseline in FVC
at 52 weeks for each treatment group (using the treatment by visit interaction term from the
mixed model). In the pooled analysis, the absolute change from baseline in FVC over 52
weeks was analyzed using the same model, but with trial as an additional fixed effect.
In the individual trials, the proportion of FVC responders at week 52 was analyzed
using logistic regression with treatment term and age, sex, height and baseline FVC %
predicted as covariates. Odds ratios and 95% confidence intervals were provided.
Responders were defined as patients who did not have an absolute decline in FVC %
predicted greater than 5% or greater than 10% at week 52. Patients with no FVC value at
week 52 were considered to be non-responders. For the pooled analysis, the proportion of
FVC responders at week 52 was analyzed using the same model, but with trial as an
additional covariate.
In the individual trials, changes from baseline in SGRQ total and domain scores over
52 weeks were analyzed using a MMRM including treatment and visit as fixed effects,
baseline score as a covariate, and treatment-by-visit and baseline-by-visit as interaction
terms. The patient effect was assumed to be random. In the pooled analysis, changes from
baseline in SGRQ total and domain scores over 52 weeks were analyzed using MMRM, with
fixed effects for trial, treatment, visit, treatment-by-visit, baseline SGRQ total score, baseline
SGRQ total score-by-visit and random effect for patient.
For the analysis of the time to first acute exacerbation endpoints, the time to event
information was used to produce Kaplan-Meier plots for each treatment group and was
primarily analyzed using the log rank test, with hazard ratios and confidence intervals (CIs)
obtained using the Cox’s proportional hazards model adjusted for sex, height and age.
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For the survival analyses, a log rank test was used to compare treatment groups and a
Cox model adjusted for sex, age and height was used to determine hazard ratios. Since the
number of deaths was expected to be low, the protocol specified that survival analyses would
additionally be performed on the pooled data from the two trials. In order to improve the
precision of the treatment effect estimates for the efficacy endpoints and to increase the size
of the safety database, a pooled analysis of the two trials was pre-specified as an additional
supportive analysis; the statistical methods were the same as for the individual trials, but with
the addition of trial as a fixed effect or covariate in the models. For the pooled analyses, the
Cox proportional hazards model was also adjusted for trial.
A hierarchical procedure was used to demonstrate the superiority of nintedanib over
placebo for the primary and key secondary endpoints. The consecutive steps of the hierarchy
were only considered if the previous step was significant at the 1-sided 2.5% level and the
results were in favor of nintedanib. Two alternative hierarchies of endpoints, with a different
order of the key secondary endpoints for US and EU/rest of world submission, were tested.
Given the positive outcome on the primary endpoint in both trials, it was possible to continue
the pre-specified confirmatory testing procedure for the key secondary endpoints in both trials.
In INPULSIS™-2, the result for time to first acute exacerbation and for change from baseline
in SGRQ total score at week 52 were both statistically significant, hence a formal confirmatory
testing could proceed for both key secondary endpoints, whatever the hierarchy (US or
EU/rest of world). In INPULSIS™-1, neither the result for time to first acute exacerbation nor
for change from baseline in SGRQ total score at week 52 was statistically significant, hence
the statistical testing was only made on a nominal basis for the second key secondary
endpoint, whatever the hierarchy (US or EU/rest of world).
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Table S1: Eligibility criteria based on chest HRCT if a surgical lung biopsy was not available
To qualify to enter the INPULSIS™ trials if a surgical lung biopsy was not available, the criteria A and B and C; or criteria A and C; or criteria B and
C had to be met.
A Definite honeycomb lung destruction with basal and peripheral predominance

B Presence of reticular abnormality and traction bronchiectasis
consistent with fibrosis with basal and peripheral predominance
C Atypical features are absent, specifically nodules and consolidation. Ground
glass opacity, if present, is less extensive than reticular opacity pattern
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Table S2: Eligibility criteria based on surgical lung biopsy
The following histopathological criteria were applied for the review of surgical lung biopsy specimens. In cases where there was disagreement
between the expert radiologist (David M. Hansell) and expert pathologist (Andrew G. Nicholson), cases were discussed by the two experts and a
consensus was reached between the two experts as to whether the patient should be included.
Definite UIP Following conditions fully met:
x Presence of a predominance of subpleural/paraseptal established interstitial fibrosis associated with mild to moderate non-
specific chronic inflammation
x Presence of fibroblastic foci adjacent to areas of established fibrosis
x Atypical features are absent or minimal, specifically: alveolar macrophage accumulation, organizing pneumonia,
bronchocentricity, germinal centers, inorganic dusts (e.g. asbestos bodies), granulomas (more than one), eosinophil
accumulation, inflammation outside areas of fibrosis, hyaline membranes
Probable UIP Following conditions met to an extent that favors UIP:
x Presence of a predominance of subpleural/paraseptal established interstitial fibrosis associated with mild to moderate non-
specific chronic inflammation
x Presence of fibroblastic foci adjacent to areas of established fibrosis
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Following conditions only are met, with a requirement for clinico-radiologic correlation to confirm or refute diagnosis of IPF:
x Honeycomb change only
Possible UIP x Appearances of a lung disease that favor a diagnosis other than UIP
Definitely not x Convincing histologic appearances of a diffuse lung disease other than UIP
UIP
UIP, usual interstitial pneumonia
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Table S3: Baseline characteristics (race)

INPULSIS™-1 INPULSIS™-2
150 mg twice (n=204) 150 mg twice (n=219)
daily (n=309) daily (n=329)
Race, n (%)
White 198 (64.1) 135 (66.2) 162 (49.2) 113 (51.6)
Asian 66 (21.4) 41 (20.1) 128 (38.9) 87 (39.7)
Black 0 0 2 (0.6) 0
Missing* 45 (14.6) 28 (13.7) 37 (11.2) 19 (8.7)
*In France, it was not permitted to collect data on race.
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Table S4: Exposure to study drug in INPULSIS™-1 and INPULSIS™-2
Nintedanib Nintedanib
Placebo Placebo
150 mg twice 150 mg twice
(n=204) (n=219)
Duration of exposure to study drug, weeks, mean (SD) 44.8 (14.6) 47.4 (12.4) 44.8 (14.8) 47.0 (12.2)
Dose intensity, %, mean (SD) 93.5 (12.0) 98.9 (4.6) 93.9 (10.6) 99.0 (4.4)
Duration on 150 mg twice daily, weeks, mean (SD) 38.8 (17.8) 46.3 (13.2) 38.5 (18.0) 46.3 (12.8)
Patients with dose reduction to 100 mg twice daily, n (%) 82 (26.5) 10 (4.9) 96 (29.2) 6 (2.7)
Duration on 100 mg twice daily, weeks, mean (SD) 18.7 (14.5) 15.9 (16.8) 19.5 (14.6) 10.6 (18.0)
Patients with treatment interruption, n (%) 79 (25.6) 24 (11.8) 72 (21.9) 18 (8.2)
Duration off-treatment, weeks, mean (SD) 3.9 (3.2) 3.1 (1.9) 3.2 (2.0) 4.4 (2.4)
Dose intensity equals amount of drug administered over the study/amount of drug that would have been received had the 150 mg twice daily dose been
administered throughout the study or until discontinuation in patients who discontinued prematurely. Duration off-treatment equals the sum of all treatment
interruptions during on-treatment period.
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Table S5: Secondary lung function endpoints in INPULSIS™-1 and INPULSIS™-2 at week 52 (pooled data)
Nintedanib 150 mg Placebo Difference vs. P-value

twice daily (n=634) (n=421) placebo (95% CI)
-94.5 -205.0 110.6 (83.2, 137.9) <0.001
baseline in FVC (mL)
-2.9 -6.1 3.2 (2.4, 4.0) <0.001
baseline in FVC (% predicted)
Nintedanib 150 mg Placebo Odds ratio P-value
twice daily (n=638) (n=423) (95% CI)
Proportion of FVC responders defined as
patients with no absolute decline in FVC % 338 (53.0) 164 (38.8) 1.8 (1.4, 2.4) <0.001
predicted of >5% at week 52, n (%)
Proportion of FVC responders defined as
patients with no absolute decline in FVC % 447 (70.1) 256 (60.5) 1.6 (1.2, 2.1) <0.001
predicted of >10% at week 52, n (%)
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Table S6: Adjudicated acute exacerbations within 52 weeks in INPULSIS™-1 and INPULSIS™-2 and pooled data
INPULSIS™-1 INPULSIS™-2 Pooled data
Nintedanib Placebo Nintedanib Placebo Nintedanib Placebo
150 mg twice (n=204) 150 mg twice (n=219) 150 mg twice (n=423)
daily (n=309) daily (n=329) daily (n=638)
Number (%) of patients with at least one

19 (6.1) 11 (5.4) 12 (3.6) 21 (9.6) 31 (4.9) 32 (7.6)
acute exacerbation (investigator-reported)
Number (%) of adjudicated acute
exacerbation events
Confirmed 2 (0.6) 1 (0.5) 2 (0.6) 3 (1.4) 4 (0.6) 4 (0.9)
Suspected 5 (1.6) 7 (3.4) 3 (0.9) 13 (5.9) 8 (1.3) 20 (4.7)
No acute exacerbation 12 (3.9) 5 (2.5) 7 (2.1) 7 (3.2) 19 (3.0) 12 (2.8)
Insufficient data for adjudication 1 (0.3) 0 (0.0) 0 (0.0) 1 (0.5) 1 (0.2) 1 (0.2)
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Table S7A: Adjusted mean change from baseline in SGRQ domain scores over 52 weeks in INPULSIS™-1
INPULSIS™-1
Nintedanib Placebo Difference vs. placebo P-value
150 mg twice daily (95% CI)
SGRQ symptoms domain*
Adjusted mean (SE) change from baseline 1.56 (1.104) 3.89 (1.351) -2.32 (-5.74, 1.10) 0.18
SGRQ activity domain†
SGRQ impact domain‡
Adjusted mean (SE) change from baseline 4.87 (0.923) 4.01 (1.113) 0.86 (-1.97, 3.70) 0.55
† ‡
*n=300 for nintedanib 150 mg twice daily and n=202 for placebo; n=295 for nintedanib 150 mg twice daily and n=200 for placebo; n=291 for nintedanib 150 mg
twice daily and n=202 for placebo. The scores for every SGRQ domain range from 0 to 100, with higher scores indicating worse health-related quality of life.
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Table S7B: Adjusted mean change from baseline in SGRQ domain scores over 52 weeks in INPULSIS™-2
INPULSIS™-2
SGRQ activity domain†
Adjusted mean (SE) change from baseline 3.89 (0.863) 7.20 (1.052) -3.31 (-5.97, -0.64) 0.02
SGRQ impact domain‡
*n=323 for nintedanib 150 mg twice daily and n=214 for placebo; †n=322 for nintedanib 150 mg twice daily and n=214 for placebo; ‡n=320 for nintedanib 150 mg
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Table S7C: Adjusted mean change from baseline in SGRQ domain scores over 52 weeks in INPULSIS™-1 and INPULSIS™-2 (pooled
data)
†
SGRQ activity domain
‡
SGRQ impact domain
*n=623 for nintedanib 150 mg twice daily and n=416 for placebo; †n=617 for nintedanib 150 mg twice daily and n=414 for placebo; ‡n=611 for nintedanib 150 mg
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Table S8: Overall, respiratory and on-treatment time to death in INPULSIS™-1 and INPULSIS™-2 (pooled data)
Nintedanib 150 mg Placebo Hazard ratio P-value

twice daily (n=638) (n=423) (95% CI)
All-cause mortality
Deaths, n (%) 35 (5.5) 33 (7.8) 0.70 (0.43, 1.12) 0.14
Deaths due to respiratory cause*
Deaths due to respiratory cause, n (%) 24 (3.8) 21 (5.0) 0.74 (0.41, 1.34) 0.34
†
On-treatment deaths
On-treatment deaths, n (%) 24 (3.8) 26 (6.1) 0.68 (0.39, 1.19) 0.16
*Adjudicated by Adjudication Committee; †On-treatment death includes deaths that occurred between randomization and 28 days after last trial drug intake.
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Table S9: Liver enzyme elevations in INPULSIS™-1 and INPULSIS™-2
Nintedanib Nintedanib
Placebo Placebo
150 mg twice 150 mg twice
(n=204) (n=219)
Patients with maximum elevations in ALT and/or AST, n (%)
3x ULN 15 (4.9) 1 (0.5) 17 (5.2) 2 (0.9)
5x ULN 6 (1.9) 0 (0.0) 8 (2.4) 1 (0.5)
8x ULN 2 (0.6) 0 (0.0) 3 (0.9) 1 (0.5)
Patients with elevations in maximum total bilirubin, n (%)
1.5x ULN 5 (1.6) 1 (0.5) 10 (3.0) 2 (0.9)
2x ULN 1 (0.3) 0 (0.0) 2 (0.6) 2 (0.9)
In INPULSIS™-1, 3 patients (1.0%), 2 patients (0.6%) and 1 patient (0.3%) in the nintedanib group experienced elevations in ALT, AST and bilirubin, respectively,
that led to premature discontinuation of trial medication. In INPULSIS™-2, 2 patients (0.6%) in the nintedanib group and 1 patient (0.5%) in the placebo group
experienced increased blood bilirubin that led to premature discontinuation of trial medication. In the nintedanib group, 1 patient (0.3%) experienced increased
ALT and 1 patient (0.3%) experienced increased AST that led to premature discontinuation of trial medication. Hy’s law criteria were met in no patients in the
nintedanib groups and in one patient in the placebo group in INPULSIS™-2.
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Table S10: Summary of cardiac disorder adverse events in INPULSIS™-1 and INPULSIS™-2
N (%) INPULSIS™-1 INPULSIS™-2
150 mg twice (n=204) 150 mg twice (n=219)
Any adverse event cardiac disorder* 30 (9.7) 19 (9.3) 34 (10.3) 26 (11.9)
Serious adverse event cardiac disorder* 14 (4.5) 11 (5.4) 18 (5.5) 12 (5.5)
Fatal adverse event cardiac disorder* 1 (0.3) 2 (1.0) 2 (0.6) 4 (1.8)
Ischemic heart disease† 13 (4.2) 10 (4.9) 14 (4.3) 7 (3.2)

†
Serious ischemic heart disease 8 (2.6) 7 (3.4) 7 (2.1) 3 (1.4)
*System organ class ‘cardiac disorder’, †Standard MedDRA query ‘ischemic heart disease’ (includes myocardial infarction).
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Figure S1: Patient flow
Figure S1A: Patient flow in INPULSIS™-1
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Figure S1B: Patient flow in INPULSIS™-2
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Figure S2: Sensitivity analyses of the primary endpoint
Figure S2A: Forest plot showing the sensitivity analyses results of the primary endpoint in
INPULSIS™-1
Figure S2B: Forest plot showing the sensitivity analyses results of the primary endpoint in
INPULSIS™-2
Pre-specified sensitivity analyses carried out to assess the robustness to data handling included
analyses using only on-treatment data, including data after lung transplant (there were no patients
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with FVC data post-lung transplant), and using three scenarios of multiple imputation for missing
data at week 52.
In each trial, no differences between the treatment groups in terms of the proportion of patients
with missing data at week 52 were observed. The amount of missing data at week 52 was
acceptable. In INPULSIS™-1, 77 patients (15.0% [15.2% nintedanib; 14.7% placebo]) had a
missing FVC value at week 52. Of these, 14/47 patients in the nintedanib group and 13/30 patients
in the placebo group had died before week 52. Of all the patients with missing data at week 52,
27/47 patients in the nintedanib arm and 20/30 patients in the placebo arm had FVC data up to
week 24 or week 36. In INPULSIS™-2, 85 patients (15.5% [14.6% nintedanib; 16.9% placebo])
had a missing FVC value at week 52. Of these, 22/48 patients in the nintedanib group and 19/37
patients in the placebo group had died before week 52. Of all the patients with missing data at
week 52, 24/48 patients in the nintedanib arm and 25/37 patients in the placebo arm had FVC data
up to week 24 or week 36.
In multiple imputation sensitivity analysis 1, missing FVC values at week 52 in patients who were
alive at week 52 were imputed assuming a similar rate of FVC decline as in patients from the
corresponding treatment group who prematurely discontinued trial drug but had a week 52 FVC
value. Missing FVC values at week 52 in patients who died before week 52 were imputed
assuming a similar rate of FVC decline as in placebo patients with a week 52 FVC value who
prematurely discontinued trial drug with the most severe declines.
alive at week 52 were imputed assuming a similar rate of FVC decline as in patients from the
placebo group who prematurely discontinued trial drug but had a week 52 FVC value. Missing
FVC values at week 52 in patients who died before week 52 were imputed assuming a similar rate
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of FVC decline as in placebo patients with a week 52 FVC value who prematurely discontinued
trial drug with the most severe declines.
alive at week 52 were imputed assuming a similar rate of FVC decline as in all patients in the
placebo group who were included in the primary analysis. Missing FVC values at week 52 in
patients who died before week 52 were imputed assuming a similar rate of FVC decline as in all
placebo patients included in the primary analysis with the most severe declines.
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Figure S3: Annual rate of decline and change from baseline in FVC in INPULSIS™-1 and
Figure S3A: Adjusted annual rate (SE) of decline in FVC (mL/year) in INPULSIS™-1 and
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Figure S3B: Change from baseline (SEM) in FVC (mL) over time in INPULSIS™-1 and
*Adjusted mean difference vs. placebo at week 52 based on MMRM.
SE, standard error; SEM, standard error of the mean
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Figure S4: Time to first acute exacerbation based on investigator-reported acute
exacerbations in INPULSIS™-1 and INPULSIS™-2 (pooled data)
Circles denote censored data; patients who did not experience an event before or at day 373 were censored
at day 373 or last contact date (whichever occurred first).
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Figure S5: Incidence of investigator-reported acute exacerbations within 52 weeks in
INPULSIS™-1 and INPULSIS™-2 and pooled data
RR, risk ratio
The risk of having at least 1 acute exacerbation was defined as the number of patients with at
least 1 acute exacerbation divided by their total time at risk x100. Risk ratio was calculated as the
ratio of risk of acute exacerbation rates in both treatment groups. The log of the risk ratio was
assumed to follow a normal distribution with variance equal to the sum of the reciprocals of the
number of patients with at least one exacerbation in each treatment group.
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Figure S6: Time to first acute exacerbation based on confirmed and suspected acute
exacerbations (per adjudication) in INPULSIS™-1 and INPULSIS™-2 (pooled data)
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Figure S7: Change from baseline in SGRQ total score over 52 weeks
Figure S7A: Adjusted mean (SE) change from baseline in SGRQ total score at week 52 in
INPULSIS™-1
Figure S7B: Adjusted mean (SE) change from baseline in SGRQ total score at week 52 in
INPULSIS™-2
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Figure S7C: Adjusted mean (SE) change from baseline in SGRQ total score at week 52 in
The SGRQ total score ranges from 0 to 100, with higher scores indicating worse health-related quality of life.
SE, standard error
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Figure S8: Time to death in INPULSIS™-1 and INPULSIS™-2 (pooled data)
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Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

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Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

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Efﬁcacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

Article in New England Journal of Medicine · May 2014

234 authors, including:

Vincent Cottin Yoshikazu Inoue

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Dong Soon Kim Paul W Noble

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Efficacy and Safety of Nintedanib in Idiopathic

n engl j med 370;22 nejm.org may 29, 2014 2071

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Nintedanib in Idiopathic Pulmonary Fibrosis

weeks before screening; patients receiving other End Points

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Nintedanib in Idiopathic Pulmonary Fibrosis

Table 1. Baseline Characteristics of Patients in INPULSIS-1 and INPULSIS-2.*

Characteristic INPULSIS-1 INPULSIS-2

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Mean Observed Change

Adjusted Annual Rate of Change

n engl j med 370;22

Mean Observed Change

Adjusted Annual Rate of Change

may 29, 2014

Nintedanib in Idiopathic Pulmonary Fibrosis

tions (Table S4 in the Supplementary Appendix).

Nintedanib vs. Placebo

93.7 ml per year (95% CI, 44.8 to 142.7; P<0.001)

the results of the primary analysis (Fig. S2 in the

multiple imputation analyses, which were based

on the conservative assumption that missing data

mates of treatment effect and the corresponding

finding shows that the primary results are robust

and were not influenced by alternative assump-

nonimputed results) were consistent with the re-

sults of the primary analysis in both trials (Fig.

Adjusted absolute mean change from

FVC decline ≤5 percentage points

the placebo group had a response in FVC when

patients with a response were defined as those

who did not have an absolute decline in the per-

centage of predicted FVC that was more than

5 percentage points at week 52 (Table 2). When

10 percentage points at week 52, a significantly

n engl j med 370;22 nejm.org may 29, 2014 2077

Cumulative Incidence of First Investigator-

Reported Acute Exacerbation (%)

Figure 2. Time to First Investigator-Reported Acute Exacerbation in INPULSIS-1 and INPULSIS-2.

2078 n engl j med 370;22 nejm.org may 29, 2014

Nintedanib in Idiopathic Pulmonary Fibrosis

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Table 3. Adverse Events.

Event INPULSIS-1 INPULSIS-2

number of patients (percent)

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Nintedanib in Idiopathic Pulmonary Fibrosis

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Nintedanib in Idiopathic Pulmonary Fibrosis

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