Original Article

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A retrospective study of the tolerability of nintedanib for severe
idiopathic pulmonary fibrosis in the real world
Masayuki Nakamura1, Masaki Okamoto1, Kiminori Fujimoto2, Tomohiro Ebata2, Masaki Tominaga1,
Takashi Nouno 1 , Yoshiaki Zaizen 1 , Shinjiro Kaieda 1 , Tohru Tsuda 3 , Tomotaka Kawayama 1 ,Tomoaki Hoshino1
1

Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, 2Department of Radiology and Center for Diagnostic

Imaging, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; 3Kirigaoka Tsuda Hospital, Kokura-kita-ku, Kitakyushu,
Fukuoka 802-0052, Japan
Contributions: (I) Conception and design: M Nakamura, M Okamoto, T Kawayama, T Hoshino; (II) Administrative support: T Kawayama, T
Hoshino; (III) Provision of study materials or patients: M Nakamura, M Okamoto, M Tominaga; (IV) Collection and assembly of data: M Nakamura,
M Okamoto, T Nouno, Y Zaizen, S Kaieda; (V) Data analysis and interpretation: M Nakamura, M Okamoto, K Fujimot, T Ebata; (VI) Manuscript
writing: All authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Masaki Okamoto. Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University
School of Medicine, Asahi-machi 67, Kurume, Fukuoka 830-0011, Japan. Email: okamoto_masaki@med.kurume-u.ac.jp.

Background: Nintedanib is a tyrosine kinase inhibitor that has been shown to suppress progression of
idiopathic pulmonary fibrosis (IPF). The efficacy and tolerability of nintedanib for IPF has been previously
proven in the INPULSIS® and INPULSIS-On® trials. The aim of our study was to clarify the tolerabilityof nintedanib in the real world for severe IPF patients who were unable to enter the INPULSIS® and
INPULSIS-On® trials.
Methods: We retrospectively investigated medical records of 8 patients with severe IPF and 14 patientswith non-severe IPF who had been treated with nintedanib. The criteria to define severe IPF were forced
vital capacity (FVC) of <50% predicted and/or diffusing capacity of the lung for carbon monoxide/alveolar
volume (DLCO/VA) of <30% predicted or unmeasurable. Severity of adverse event was evaluated using
the Common terminology criteria for each adverse event version 4.0. We compared changes in FVC andserum KL-6 level, incidence and severity of adverse events, and incidence of permanent or temporary
discontinuation of nintedanib in between severe and non-severe IPF groups.
Results: The median treatment period was 578.5 days. The most frequent adverse event was diarrhea (73%).
Only 2 patients required permanent discontinuation of nintedanib due to adverse events. There was nodifference in incidence or severity of adverse events or incidence of permanent or temporary discontinuationof nintedanib in between severe and non-severe IPF groups. Among subjects, decline in FVC during
6 months post-nintedanib treatment were significantly lower than prior to treatment, but change in serumKL-6 level showed no significant difference between these 2 timepoints.
Conclusions: Our study showed that nintedanib was tolerable for IPF patients who would not have been
eligible for entry into previous clinical trials due to low pulmonary function. Although therapeutic strategy
for severe IPF should be planned carefully, initiation of nintedanib treatment should not be dismissed solely
for reasons of low pulmonary function.
Keywords: Idiopathic pulmonary fibrosis (IPF); nintedanib; anti-fibrotic drug; severity; tolerability
Submitted Jan 20, 2019. Accepted for publication Apr 26, 2019.
doi: 10.21037/atm.2019.05.33
View this article at: http://dx.doi.org/10.21037/atm.2019.05.33© Annals of Translational Medicine. All rights reserved.

Ann Transl Med 2019 | http://dx.doi.org/10.21037/atm.2019.05.33

Nakamura et al. Nintedanib for severe IPF

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Introduction
Idiopathic pulmonary fibrosis (IPF), a pathologicallyusual interstitial pneumonia (UIP), is the most common
form of idiopathic interstitial pneumonia (IIP) (1-3).
Estimates of the IPF prevalence per 100,000 people werereported as ranging from 2 to 43 cases globally, with
10 cases in Japan (1,4). Patients with IPF have a grave
prognosis with a median survival of 2–5 years (1-3), themajor cause of death being acute exacerbation (AE) and/or gradual respiratory failure (4). It has been hypothesizedthat the main pathogenesis of IPF progression is aberrant
wound healing and fibrosis to initial epithelial injury (5).
Nintedanib is a triple kinase inhibitor targeting the plateletderived growth factor (PDGF), vascular endothelial
growth factor (VEGF) and fibroblast growth factor (FGF)
receptors, which are molecules that contribute to over
repairing. The INPULSIS ®-1 and -2 trials, conducted
as above two replicate phase 3 trials, demonstrated thatnintedanib significantly reduced the decline of forced
vital capacity (FVC) during 52 weeks in IPF patients(nintedanib groups; −2.8% and −3.1% predicted, placebogroups; −6.0% and −6.2% predicted in INPULSIS ®-1and -2 trials, respectively) (6). The most frequent adverse
event of nintedanib was diarrhea with rates of 62.4%
in INPULSIS ® trials (6,7). However, the proportion ofpatients who discontinued taking nintedanib caused due
to diarrhea was less than 5%. Although elevation of serum
aminotransferase levels to more than three times the upper
limit of the normal range was seen in 5.0% of the patientsin the INPULSIS® trials, these elevations were reversible(6,7). Brunnemer et al. suggested that diarrhea was the mostcommon nintedanib-induced adverse event (33%) but was
generally manageable by temporary discontinuation anddose reduction in the real world (8). These results suggested
that nintedanib has a high efficacy and a manageable
tolerability in IPF patients.
The results of the INPULSIS ® trials suggested that
there was no significant difference in the decline of FVC
during 52 weeks between patients with baseline FVC
values of more than 70% and 50–70% predicted (6).
However, the eligibility criteria for patient inclusion in the
INPULSIS® trials included FVC of >50% predicted anddiffusing capacity of the lung for carbon monoxide (DLCO)
of 30–79% predicted. The INPULSIS® trials did not clarify
the efficacy of nintedanib for severe IPF patients with low
pulmonary function. Wuyts et al. analyzed the efficacy of
nintedanib for patients with severe IPF who had an FVCof ≤ 50% predicted and entered an open label extension of© Annals of Translational Medicine. All rights reserved.

the INPULSIS® trials (INPULSIS®-ON trial). That study
suggested that there was no significant difference of FVC
decline in the INPULSIS®-ON trial between patients who
had a baseline FVC values of ≤ 50% predicted and thosewith values of >50% predicted (decline in FVC; −62.3 and−87.9 mL, number; 24 and 558, respectively) (9). However,
the available data to clarify the tolerability of nintedanib
for severe IPF patients is limited in clinical practice. In thisretrospective study, we analyzed whether nintedanib wastolerable for severe IPF patients who would not have been
eligible for entry into the INPULSIS® and INPULSISOn® trials due to low pulmonary function.
Methods
Study subjects
The characteristics of the study subjects are shown in
Table 1. We retrospectively reviewed medical records andhigh-resolution computed tomography (HRCT) images
covering the period between July 2015 and August 2016 forall subjects. We included 22 patients (20 males, median age
71.5 years) treated with nintedanib at either our hospital oran affiliated one. All included patients were diagnosed ashaving IPF in accordance with the recent official guidelines(1-3). Other diseases such as connective tissue diseases
were excluded. Patients complicated by malignant disease
who had not undergone radical therapy were also excluded,
as such patients show poor survival and deterioration of
their general condition, making it difficult to evaluate thetherapeutic effect of nintedanib for IPF.
The criteria we used to define “severe IPF” group were
FVC <50% predicted, D LCO/alveolar volume (D LCO/VA)<30% predicted, or unmeasurable DLCO/VA due to having
low FVC. These criteria overlapped with some of the
exclusion criteria for the INPULSIS® trials (6). Patientswith IPF who met none of the criteria for severe IPF wereclassified into a “non-severe IPF” group. The disease
severity staging was performed in accordance with the
GAP score as reported previously i.e., classifying patients
into three stages based on clinical (e.g., gender, age) andphysiologic (e.g., FVC, D LCO) variables (10). The GAP
stage was able to predict 1-, 2-, and 3-year mortalities for
IPF (10).
We received specific approval for all procedures fromthe Institutional Review Board (IRB) of our hospital inaccordance with the ethical standards of the Helsinki
Declaration of 2013. The IRB approval No. and date of
approval for our study were 16186 and 30 November
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Table 1 Patient characteristics and clinical course
Variable

All case

Severe IPF group

Non-severe IPF group

Number

22

8

14

Age

71.5 (66.0–78.0)

73.0 (65.0–78.0)

71.5 (68.3–75.5)

0.87

Gender: male/female

20 (91%)/2 (9%)

8 (100%)/012 (86%)/2 (14%)

0.50

19 (86%)/3 (14%)

7 (88%)/1 (12%)

12 (86%)/2 (14%)

1.0

1.66 (1.44–1.81)

1.72 (1.43–1.81)

1.65 (1.50–1.82)

0.84

A+B+C

15 (68%)5 (63%)

10 (71%)1.0

B+C

5 (23%)

2 (25%)

3 (22%)B

2 (9%)

1 (12%)

1 (7%)

6 (27%)

2 (25%)

4 (29%)

Smoker/non-smoker
2

Body surface area (m )P value

HRCT pattern based on INPULSIS criteria

Diagnosing histologically
GAP stage

5 (23%)/13 (59%)/4 (18%) 1 (12%)/3 (38%)/4 (50%)

Serum KL-6 level (IU/mL)

1,043.0 (680.5–1,383.8)%FVC%DLCO/VA

1.0

4 (29%)/10 (71%)/0

0.017*

1,023.0 (563.3–1,300.3)

1,043.0 (680.5–1,557.8)

0.61

63.0 (43.1–79.0)

41.7 (40.3–47.5)

68.6 (58.8–86.4)

0.0013*64.0 (44.7–88.2)

70.6 (35.0–112.9)

61.1 (44.7–88.2)

0.67%FVC <50%

3 (14%)

3 (38%)

00.0364*%FVC <50% and unmeasurable of %DLCO/VA

4 (18%)

4 (50%)

00.0096*%DLCO/VA <30%

1 (4%)

1 (12%)

00.36

578.5 (285.5–683.5)

354.5 (143.8–589.0)

596.5 (474.8–705.5)

0.088

Pulmonary function

Observation period (days)*, P<0.05, statistically significant. HRCT, high-resolution computed tomography; IPF, idiopathic pulmonary fibrosis; FVC, forced vital
capacity; DLCO/VA, diffusing capacity of the lung for carbon monoxide/alveolar volume.

2016, respectively.
Interpretation of high-resolution computed tomography
images
HRCT examinations without contrast medium were
performed at the start of treatment with nintedanib using
a variety of scanners. The protocol consisted of endinspiration in the supine position, and 0.5- to 1.5-mm
collimation sections reconstructed with a high-spatialfrequency algorithm at 1-cm or 2-cm intervals. Images wereinterpreted at a window setting appropriate for viewing thelung parenchyma [window level, −600 to −700 Hounsfield
units (HU); window width, 1,200 to 1,500 HU].
We classified IPF patients by HRCT in accordancewith the radiological criteria used for the INPULSIS ®
trials (6). Briefly, if the HRCT findings for a subject
corresponded to A, B and C as described below, A and C,© Annals of Translational Medicine. All rights reserved.

or B and C, we considered them to be consistent with a
UIP pattern. These INPULSIS criteria based on HRCT
were as follows: (A) definite honeycomb lung destruction
with basal and peripheral predominance; (B) presence ofreticular abnormality and traction bronchiectasis consistent
with fibrosis showing basal and peripheral predominance;(C) atypical features are absent, specifically: nodules andconsolidation. Ground-glass attenuation (GGA), if present,
is less extensive than a reticular opacity pattern. Two boardcertificated diagnostic radiologists, who specialized indiffuse lung diseases and had 31 and 10 years of experiencein chest CT interpretation, independently evaluatedthe HRCT findings and categorized each case into the
INPULSIS criteria A, B, or C. The radiologists wereblinded to the clinical information. Representative HRCT
images are shown in Figure 1. Disagreements about the
HRCT findings between the two radiologists were resolved
by consensus after assessing the inter-observer agreement.

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Nakamura et al. Nintedanib for severe IPF

Figure 1 HRCT findings. We diagnosed “consistent with UIP pattern” in accordance with the radiological criteria used in the INPULSIS®
trials, if HRCT findings for patients were A, B and C, A and C, or B and C as follows: (A) definite honeycomb lung destruction with basal
and peripheral predominance; (B) presence of reticular abnormality and traction bronchiectasis consistent with fibrosis with basal andperipheral predominance; (C) atypical features absent, specifically nodules and consolidation. Ground-glass attenuation, if present, is lessextensive than a reticular opacity pattern. The finding of HRCT scans in a 78-year-old man with severe IPF showing features A, B and C(left palel). The finding of HRCT scans in a 77-year-old man with non-severe IPF showing features B and C (right panel). HRCT, highresolution computed tomography; UIP, usual interstitial pneumonia; IPF, idiopathic pulmonary fibrosis.

Evaluation of treatment tolerability and efficacy
We evaluated the severity of adverse events using theCommon terminology criteria for adverse events version
4.0 (CTCAE ver. 4.0) described as supplementary materials.
We analyzed differences in the incidence and CTCAE ver.
4.0 grade of nintedanib-related adverse event and in theincidence of permanent or temporary discontinuation of
nintedanib due to adverse event.
For evaluating the treatment efficacy, we analyzed
changes in FVC and serum KL-6 levels, which is reported
as a diagnostic and prognostic biomarker of IPF (11-13),
over 6 months.

with regard to their assessment of individual cases as towhether the HRCT findings met the INPULSIS criteria
A, B, or C (kappa =0.56, P<0.01). After consensus readingof the HRCT images, 15 cases (68%) were classified ashaving criteria A, B and C, 5 (23%) as having B and C, and
2 (9%) as having B alone. Twenty cases who met criteria A,
B, and C or B and C were considered to be consistent with
UIP pattern. The remaining 2 cases who met only criteria
B were inconsistent with UIP pattern and diagnosed as IPF
based on histological features of lung tissue obtained bysurgical lung biopsy (SLB).
Patient characteristics and clinical course

Statistical analysis
Data were expressed as the median [25th to 75th percentilesof the interquartile range (IQR)]. Differences between two
groups were analyzed appropriately by the Wilcoxon-ranksum test or Fisher’s exact test. P values <0.05 was taken
to represent statistical significance. All statistical analyses
were performed using the JMP 13.0 program (SAS InstituteJapan, Tokyo, Japan).
Results
Inter-observer agreement of HRCT image interpretation
There was significant agreement between the 2 observers© Annals of Translational Medicine. All rights reserved.

Table 1 shows patient characteristics and clinical course
and Table 2 summarized the individual characteristics ofthe patients with severe IPF. One patient with IPF andstage 4 non-small cell lung cancer was excluded fromthis study. Six patients were able to be diagnosed as UIP,
histologically. Among them, 3 patients underwent SLB for
differential diagnosis of chronic hypersensitivity pneumonia
or smoking-related interstitial pneumonia and 3 patients
underwent lobectomy for lung cancer. Median FVC for all
subjects was 63.0% (43.1–79.0%) predicted and median
DLCO/VA was 64.0% (44.7–88.2%) predicted at the baseline.
Eight (36%) of the patients were classified as having
severe IPF and 14 (64%) as having non-severe IPF. Of the
8 subjects in the severe IPF group, 3 patients (14%) had

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Table 2 Summary of individual patient characteristics with severe IPF
Age (years), gender

HRCT pattern*

KL-6 (IU/mL)%FVC%DLCO/VA

GAP stage

Case 1

68, male

B

768

48.9

125.6

2

Case 264, male

A+B+C

1,109

40.9

Unmeasurable

3

Case 378, male

A+B+C

362

25.9

Unmeasurable

3

Case 466, male

A+B+C

1,347

42.1

66.4

2

Case 583, male

B+C

937

41.2

Unmeasurable

3

Case 678, male

A+B+C

495

43.4

Unmeasurable

3

Case 755, male

B+C

2,467

40.1

74.8

1

Case 878, male

A+B+C

1,160

78.8

24.5

2

No.

*, diagnosed by INPULSIS criteria. HRCT, high-resolution computed tomography; IPF, idiopathic pulmonary fibrosis; FVC, forced vital
capacity; DLCO/VA, diffusing capacity of the lung for carbon monoxide/alveolar volume.

FVC of <50% predicted with DLCO/VA of ≥30% predicted,
4 patients (18%) had FVC of <50% predicted withunmeasurable DLCO/VA, and 1 patient (4%) had DLCO/VA of<30% predicted with FVC of ≥50% predicted. The baseline
FVC was lower in the severe IPF group than in the nonsevere IPF group (P=0.0013). The disease severity staging
based on the GAP score was higher in the severe IPF groupthan in the non-severe IPF group (P=0.017). Four (18%) of
the 22 patients received drug therapies in combination withnintedanib at the start of therapy. Those therapies included
corticosteroid alone in 2 subjects and corticosteroid withcyclosporine A in 2. The overall median treatment period
was 578.5 (285.5–683.5) (range: 47.0–787.0) days, and thisperiod did not differ between the severe and non-severe IPF
groups.
Evaluation of tolerability
Table 3 gives details of the adverse events. A total of 33
drug-related adverse events were observed in 20 (91%) of
the 22 patients with IPF. The highest severity of adverse
events evaluated by CTCAE ver. 4.0 was grade 1 in 11
patients (50%), grade 2 in 6 (27%), and grade 3 in 3 (13%).
None of the patient had grade 4 or 5 adverse event. Specificadverse events included diarrhea in 16 patients (73%),
elevation of the serum aspartate or alanine aminotransferase
level in 12 (55%), nausea in 2 (9%), vomiting in 2 (9%), andthrombocytopenia in 1 (4%). Only 2 (9%) of the 22 patients,
including 1 each with severe and non-severe IPF, required
permanent discontinuation of nintedanib due to adverse
events. Temporary discontinuation of nintedanib wasnecessary in 10 (45%) of the 22 patients, including 2 with

© Annals of Translational Medicine. All rights reserved.

severe and 8 with non-severe IPF. The adverse events that
led to permanent discontinuation of nintedanib included
vomiting in 1 patients and nausea with thrombocytopenia in
1. All IPF patients were started on 300 mg/day nintedanib.
Fifteen (68%) of the 22 patients, including 4 with severe
and 11 with non-severe IPF, required a reduction in thenintedanib dose to 200 mg/day due to adverse events. There
was no difference in the incidence of total adverse events,
diarrhea or elevation of the serum aminotransferase level as
specific adverse event, or in the incidence of permanent or
temporary discontinuation of nintedanib in between severe
and non-severe IPF groups. No clinical data, including IPF
severity, was associated with the proportion of patients who
had an adverse event with CTCAE grade ≥2 (Table 4) or theincidence of permanent or temporary discontinuation of
nintedanib (data not shown). These results suggest that thebaseline severity of IPF was not associated with nintedanib
tolerability.
Evaluation of efficacy of nintedanib
Changes in FVC and serum KL-6 level during 6 months
prior to and after treatment are shown in Figure 2.
Changes in FVC both prior to and after treatment
were unmeasurable in 2 of severe IPF patients due todeterioration of IPF or death. In addition, change in
FVC after treatment was unmeasurable in 1 severe IPF
patients. Changes in FVC prior to and after treatment were
measurable for all non-severe IPF patients, and changes
in serum KL-6 levels were measurable in all subjects. For
the total group of subjects, declines in FVC after treatment
were significantly lower than those prior to treatment

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Nakamura et al. Nintedanib for severe IPF

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Table 3 Adverse events of treatment with nintedanib
Variable

All cases

Severe cases

Non-severe cases

Number228

14

20 (91%)7 (88%)

13 (93%)

No adverse event

2 (9%)

1 (13%)

1 (7%)1

11 (50%)3 (37%)

8 (57%)

2

6 (27%)

3 (37%)

3 (21%)

3

3 (13%)

1 (13%)

2 (14%)

4

0

0

0

Discontinuation of treatment

12 (55%)

3 (37%)

9 (64%)

Permanent discontinuation

2 (9%)

1 (13%)

1 (7%)

Temporary discontinuation

10 (45%)2 (25%)

8 (57%)

16 (73%)5 (63%)

11 (79%)12/4/0/0

4/1/0/0

8/3/0/0

12 (55%)4 (50%)

8 (57%)

10/1/1/0

3/1/0/0

7/0/1/0

2 (9%)

1 (13%)

1 (7%)

0/1/1/0

0/1/0/0

0/0/1/0

2 (9%)

1 (13%)

1 (7%)

1/0/1/0

0/0/1/0

1/0/0/0

1 (4%)0

1 (7%)

0/0/1/0

0/0/0/0

0/0/1/0

Incidence of more than 1 adverse event

P value

Highest severity of adverse event evaluated by CTCAE
ver. 4.0-grade
0.84

0.38

Adverse event
Diarrhea
Grade (1/2/3/4 or 5)
Elevation of aminotransferase
Grade (1/2/3/4 or 5)
NauseaGrade (1/2/3/4 or 5)
Vomiting
Grade (1/2/3/4 or 5)
Thrombocytopenia
Grade (1/2/3/4 or 5)

0.62

1.0

CTCAE ver. 4.0, Common terminology criteria for adverse events version 4.0.

(median FVC change: −2.4% and −4.5% predicted; subject
number: 20 and 19, respectively; P=0.028). In contrast,
there was no difference in the change in serum KL-6 level
between the 6 months prior to and after the nintedanib
treatment (median values; −19.5 and −46.0 IU/mL, number;
both of 22, P=0.34).
Discussion
In the present study, the major adverse events of nintedanib
were the diarrhea and elevation of serum aminotransferase
level. These adverse events were mild to moderate inseverity and did not lead to permanent discontinuation of
nintedanib. Among the 22 IPF patients, nausea, vomiting© Annals of Translational Medicine. All rights reserved.

or thrombocytopenia led to permanent discontinuation of
nintedanib in only 2 patients, of whom 1 had severe IPF.
These results indicate that nintedanib treatment for IPF
patients was well tolerated, as reported in the INPULSIS®
trials and the previous real world study (6,8).
We classified the 22 patients with IPF into severe andnon-severe cases on the basis of baseline FVC and DLCO.
Some previous reports have suggested that low FVC and/or DLCO at the baseline are associated with poor survival
in IPF patients (4,14-18). In the present study, 8 patientswith severe IPF have a higher disease severity staging
based on the GAP index than those with non-severe
IPF. We discovered that there was no difference in theincidence or severity of adverse events or in the proportion

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Table 4 Correlation between clinical data and disease stability
VariableSeverity grade (CTCAE ver. 4.0)

P value

Grade 0 or 1

≥ Grade 2

13

9

Age

72.0 (69.5–77.5)

66.0 (65.0–80.0)

0.50

Gender: male/female

12 (92%)/1 (8%)

8 (89%)/1 (11%)

1.0

11 (85%)/2 (15%)

8 (89%)/1 (11%)

1.0

1.69 (1.49–1.79)

1.64 (1.42–1.91)

0.71

2 (15%)/10 (77%)/1 (8%)

3 (33%)/3 (33%)/3 (33%)

0.14

4 (31%)/9 (69%)

4 (45%)/5 (55%)

0.67

9 (69%)

6 (67%)

1.0

1,060.0 (606.5–1,389.5)

1,026.0 (758.0–1,548.0)

0.50%FVC predicted

66.6 (49.8–82.4)

52.4 (41.7–72.3)

0.33%DLCO/VA predicted

67.6 (44.5–99.3)

61.5 (42.6–83.1)

0.57

NumberSmoker/non-smoker
2

Body surface area (m )GAP stage (1/2/3)
IPF severity (severe/non-severe)
INPULSIS-A + B + C pattern on HRCT
Serum KL-6 level (IU/mL)
Pulmonary function at baseline

HRCT, high-resolution computed tomography; FVC, forced vital capacity; DLCO/VA, diffusing capacity of the lung for carbon monoxide/
alveolar volume; AE, acute exacerbation; CTCAE ver. 4.0, Common terminology criteria for adverse events version 4.0.

Change in clinical data during 6 months

A

B

0

0
–10
–20

–4
–4.5

–2.4

P=0.028*

–30
–40
–50

-8
Prior to treatment
After treatment

–19.5

–46.0

P=0.34

Figure 2 Changes in FVC predicted during 6 months prior toand after treatment. (A) Median changes in FVC predicted during
6 months prior to and after treatment were −4.5% and −2.4%; (B)median changes in serum KL-6 level during 6 months prior to andafter treatment were −19.5 and −46.0 IU/mL. *P value<0.05. FVC,
forced vital capacity; NS, not significant.

of permanent or temporary nintedanib discontinuation
between the groups with severe and non-severe IPF.
Wuyts et al. suggested that incidence of diarrhea led totreatment discontinuation were similar between patientswith baseline FVC ≤50% and >50% predicted, respectively© Annals of Translational Medicine. All rights reserved.

(4.9% and 5.4%), as reported in the INPULSIS-On ®
trials (9). Recently, the INSTAGE® trial was conducted
to evaluate the efficacy and safety of combination therapy
with nintedanib and sildenafil as compared with nintedanibalone for patients with severe IPF with D LCO of <35%predicted. In this trial, the proportions of patients who
had a reduction in dose, or interruption or permanent
discontinuation of nintedanib due to adverse events, weresimilar to those in the INPULSIS® trials (19). However,randomized controlled trials are unable to accurately
replicate the clinical practice, because the subjects selected
may be younger or have fewer comorbidities. In the present
study, we suggested that nintedanib was tolerable for severe
IPF patients who would not have been eligible for entry
into the INPULSIS ® and INPULSIS-On ® trials due tolow pulmonary function. It is believed that patients in poor
general condition have a higher risk of drug-related adverse
events. Indeed, it has been reported that poor performancestatus is a risk factor for epidermal growth factor receptor
tyrosine kinase inhibitor-related ILD (20). Clinicians arelikely concerned that initiation of nintedanib treatment
for advanced IPF may increase the risk of adverse events.
On the other hand, anti-fibrotic drug therapy is started formore than a few cases with severe IPF in Japan, because
severe patients can receive public medical expenses (21).

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Nakamura et al. Nintedanib for severe IPF

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A Careful consideration is required to decide whether toperform anti-fibrotic drug treatment or palliative therapy
only for severe IPF patients. Our study results suggest that
initiation of nintedanib treatment should not be dismissed
solely for reasons of low pulmonary function.
In the present study, no clinical parameters at thebaseline were associated with nintedanib treatment
tolerability. Although Ikeda et al. had suggested that a low
body surface area was associated with hepatotoxicity ofnintedanib with CTCAE ver.4.0 grade ≥2, this association
was not confirmed in the present study (22). However,the discrepancy may be caused by the difference in theincidence of elevated aminotransferase with CTCAE ver.4.0
grade ≥2 between our study and theirs (9% vs. 23.5%,
respectively).
In the present study, the significant reduction of decline
in FVC prior to and after treatment for the subjects overall
may be associated with the suppressive effect of nintedanib
on FVC decline that was reported in the INPULSIS® trials.
Our study was unable to clarify the efficacy of nintedanib
for severe IPF patients, because change in FVC prior to andafter treatment was unable to be measured in all patientswith severe IPF. However, the previous study suggested thatnintedanib was effective for the severe IPF patients who
had FVC of ≤50% predicted and entered the INPULSIS®ON trial (9). This result suggests that nintedanib treatment
may be effective for severe IPF patients even in clinicalpractice. A prospective study is needed to clarify the efficacy
of nintedanib for severe IPF in the real world.
The present study had some limitations. First, it was
the retrospective single-center study involving a small
number of patients with severe IPF. However, we consider
that our findings regarding the tolerability of nintedanib
nevertheless have clinical importance. Second, we evaluatedonly the short-term efficacy of nintedanib treatment. We
intend to analyze the efficacy and tolerability of nintedanib
for a longer period in a further study with larger sample
size. Third, change of FVC could not be measured in all
subjects. This may have affected our results.
Conclusions
We suggested that nintedanib was tolerable for severe
IPF patients who would not have been eligible for entry
into the previous clinical trials due to low pulmonary
function. Although the therapeutic strategy for severe IPF
should be planned carefully, the initiation of nintedanib
treatment should not be dismissed solely for reasons of© Annals of Translational Medicine. All rights reserved.

low pulmonary function.
Acknowledgements
We would like to thank past and present doctors andtechnicians in our laboratory.
Footnote
Conflicts of Interest: The authors have no conflicts of interest
to declare.
Ethical Statement: The study was approved by theInstitutional Review Board (IRB) of our hospital (No.
16186).
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Cite this article as: Nakamura M, Okamoto M, Fujimoto
K, Ebata T, Tominaga M, Nouno T, Zaizen Y, Kaieda S,
Tsuda T, Kawayama T, Hoshino T. A retrospective study ofthe tolerability of nintedanib for severe idiopathic pulmonary
fibrosis in the real world. Ann Transl Med 2019. doi: 10.21037/
atm.2019.05.33© Annals of Translational Medicine. All rights reserved.

Ann Transl Med 2019 | http://dx.doi.org/10.21037/atm.2019.05.33

Supplementary

Patients and methods
Evaluation of tolerability
We evaluated the severity of adverse events using Common
terminology criteria for adverse events, version 4.0 (CTCAE
ver. 4.0). The severity of an elevation in aspartate or alaninetransaminase (AST or ALT, respectively) was defined asfollows: grade 1 was >3.0× the upper limit of the normal
range (IU/L), grade 2 was >3.0–5.0× the upper limit of
the normal range, grade 3 was >5.0–20.0× the upper limitof the normal range, and grade 4 was >20.0× the upper
limit of the normal range. Diarrhea severity was defined asfollows: grade 1 was an increase of <4 stools per day overbaseline or a mild increase in ostomy output compared withbaseline; grade 2 was increase of 4–6 stools per day overbaseline or a moderate increase in ostomy output comparedwith baseline; grade 3 was an increase of ≥7 stools per day
over baseline, incontinence, hospitalization, severe increasein ostomy output compared with baseline, or omitting

self-care activities of daily living; and grade 4 was lifethreatening consequences or urgent intervention indicated.
Nausea severity was defined as follows: grade 1 was lossof appetite without alteration in eating habits; grade 2
was oral intake decreased without significant weight loss,
dehydration, or malnutrition; and grade 3 was inadequate
oral caloric or fluid intake, tube feeding, total parenteralnutrition (TPN), or hospitalization. Vomiting severity wasdefined as follows: grade 1 was 1–2 episodes (separated by
5 min) in 24 h; grade 2 was 3–5 episodes (separated by
5 min) in 24 h; grade 3 was ≥6 episodes (separated by 5 min)in 24 h, tube feeding, TPN, or hospitalization; and grade 4
was life-threatening consequences or urgent intervention
indicated. Thrombocytopenia severity was defined asfollows: grade 1 was platelet count decreased below thelower limit of normal to 7.5×104 platelets/µL, grade 2 was<7.5–5.0×104 platelets/µL, and grade 3 was <5.0 to <2.5×104
platelets/µL.