Keywords idiopathic pulmonary fibrosis - pirfenidone - interstitial lung disease - pulmonary function - anti-fibrotic
Schlüsselwörter idiopathische Lungenfibrose - Pirfenidon - interstitielle Lungenerkrankung - Lungenfunktion - antifibrotisch
1. Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease, characterized by scarring of the lung and worsening lung function [1 ]. As the most common form of idiopathic interstitial lung disease IPF primarily occurs in individuals aged 50 years and older [1 ]. If left untreated, IPF is associated with high morbidity and mortality with a mean life expectancy of 3 years after diagnosis [2 ]. Based on the definition of IPF unified in a consensus statement from 2000 [3 ], a review of epidemiological studies from around the world showed a huge variability in the prevalence and incidence of IPF due to different methodologies [4 ]. In Europe and North America the annual incidence ranges from 2.8 to 19 per 100,000 inhabitants [5 ] and the prevalence of 8.2 per 100,000 inhabitants marks IPF as an orphan disease [6 ]. Risk factors associated with development of IPF include genetic predisposition, environmental and occupational exposures, tobacco smoking, a family history of idiopathic lung disease, and comorbidities such as gastroesophageal reflux disease (GERD) and viral infections [7 ].
Diagnostic procedures have been updated several times since 2000, whereby high-resolution computed tomography (HRCT) remains crucial in the diagnostic work-up. IPF diagnosis is based on exclusion and is supported by the presence of a usual interstitial pneumonia (UIP) pattern in HRCT in patients without surgical lung biopsy or by certain pattern combinations in HRCT and biopsy. The multidisciplinary discussion of all findings represents the golden standard in the diagnostic process [7 ]
[8 ].
At the time of diagnosis, the course of disease is unpredictable and may vary widely between individual IPF patients. Thus, the treatment course has to be tailored to each patient’s individual requirements, taking the patient’s medical history and co-morbidities into consideration. Advances in understanding the pathology of IPF have shifted the focus of pharmacotherapy over the last two decades from anti-inflammatory approaches to anti-fibrotic treatment options [9 ]. Pirfenidone is an oral antifibrotic therapy that inhibits fibroblast proliferation and production of fibrosis-related proteins and cytokines [10 ]. Based on data from four randomized controlled trials demonstrating a clinically meaningful treatment effect and a favorable benefit-risk profile [11 ]
[12 ]
[13 ], pirfenidone was approved for the treatment of mild-to-moderate IPF in adults in the European Union in 2011. Following the additional randomized controlled trial ASCEND confirming the beneficial effect on disease progression [14 ], pirfenidone received marketing authorization in the United States in 2014. Treatment with pirfenidone for 1 year reduced the proportion of patients with a ≥10% decline in percentage predicted forced vital capacity (FVC) or death by 44% and improved progression-free survival by 38% compared with placebo. A strong recommendation (based on systematic review of randomized controlled trials, post hoc analyses, and real-world evidence) was granted for pirfenidone in national guidelines [15 ] and a conditional recommendation (based on moderate confidence in estimates of effect) in international guidelines [16 ]. Long-term safety studies corroborated the safety profile of pirfenidone [17 ]
[18 ]. In order to obtain additional prospective data on the effectiveness of pirfenidone outside the tightly controlled conditions of a clinical trial, the non-interventional study AERplus was conducted to investigate the clinical course of mild-to-moderate IPF in pirfenidone-treated patients in a real-world setting.
2 Methods
2.1 Patients
Adult patients with a definite diagnosis of IPF and mild-to-moderate lung function
impairment who were naïve to pirfenidone or had been treated with pirfenidone less than 30
days prior to enrolment, were eligible for inclusion. Exclusion criteria were:
hypersensitivity against any ingredient of pirfenidone; concomitant use of fluvoxamine;
severe hepatic impairment or end-stage liver failure; severe renal impairment (creatinine
clearance <30 ml/min) or end-stage renal failure requiring dialysis, or enrolment in
interventional clinical trials. All patients were required to provide their written informed
consent prior to enrolment.
2.2 Study design
AERplus was a prospective, open-label, single-arm, non-interventional multicenter
post-marketing surveillance study, conducted at 18 sites (hospitals and outpatient centers)
in Germany from June 2014 to December 2016 (NCT02622477). The study design and all relevant
documents (e.g., protocol, informed consent, and questionnaires) were reviewed by the ethics
committee of the Otto-von-Guericke-Universität Magdeburg (Ref. no. 161/13) and are
consistent with the ethical standards included in the Declaration of Helsinki of 1964 and
its later amendments. The planned duration of documentation for each patient was 12 months,
consisting of an initial visit for enrolment, three follow-up visits at 3, 6, and 9 months,
and an end-of-study visit at 12 months. Patients were treated with pirfenidone (week 1: 3×1
capsule of 267 mg per day; week 2: 3×2 capsules/day; from week 3: 3×3 capsules/day) up to 12
months. The decision to prescribe pirfenidone was made by the treating physician
independently from the decision to enroll the patient and in accordance with the locally
applicable Summary of Product Characteristics (SmPC).
2.3 Study assessments
Patient data were obtained during scheduled visits and entered into an electronic case
report form (eCRF) by the investigator or study nurse. The composite endpoint disease
progression was defined by the following four qualifying events: relative decrease of ≥10%
in vital capacity (VC) or ≥15% in diffusing capacity of the lung for carbon monoxide
(DLCO ) and/or ≥50m in 6-minute walking distance (6-MWD) vs. baseline
assessment, or if the investigator stated “lack of response/progression” as reason for
therapy discontinuation. Assessments of pulmonary function were performed at each visit and
included FVC, Forced expiratory volume in 1 second (FEV1 ), total lung capacity (TLC), VC,
DLCO , and Gender, Age and Physiology (GAP) Index [19 ]. Exercise capacity was assessed by 6-MWD. Exacerbations (assessed according to the
discretion of the investigator) were recorded at each follow-up visit. Data on quality of
life in chronic cough (Leicester Cough Questionnaire, LCQ [20 ]) and dyspnea severity (University of California San Diego Shortness of Breath
Questionnaire, SOBQ [21 ]) were obtained by patient questionnaires (completed before each scheduled visit).
Safety data collected throughout the study included the incidence of adverse drug reactions
(ADR) and serious adverse reactions (SAR). ADRs were adverse events judged by the
investigator as possibly or probably related to pirfenidone.
2.4 Statistical analyses
There were no predefined statistical hypotheses. A descriptive and exclusively
explorative evaluation to obtain a statement on the clinical progression of mild-to-moderate
IPF under therapy with pirfenidone was performed using SAS version 9.3 (SAS Institute Inc.,
Cary, NC, USA). The analysis population consisted of all patients who were enrolled and
received ≥1 dose of pirfenidone. For the effectiveness evaluation, changes in the following
parameters were analyzed: disease progression, pulmonary function, exercise capacity, and
LCQ and SOBQ scores. Due to the exploratory nature of the study, a formal sample size
calculation was not performed. All patient data were anonymized.
3 Results
3.1 Baseline characteristics, patient disposition, and pirfenidone exposure
In total, 59 patients from 18 sites were enrolled in the study. Three patients did not
have any documented data, two did not receive any pirfenidone, and three patients were
excluded from the analysis set due to protocol violations (modified or unknown dosing on
initial drug administration, n=2; informed consent form missing, n=1). Thus, the analysis
population comprised 51 patients. Baseline demographics for the analysis population are
summarized in [Table 1 ]. A heterogenous variety of comorbidities including emphysema was documented in 15
patients (29.4%). After the initial 3-week dose adjustment phase all 51 patients received
the full maintenance dose of 9 capsules pirfenidone/day. At each post-baseline visit, more
than 50% of the patients who were still in the study, reported to have taken the full
maintenance dose. Dose adjustments were reported in 26 patients. One or more of the
following reasons for dose adjustments were documented: ADRs (n=15), patient wish (n=4),
other reason (not further specified, N=8), and no information (N=8). During the study, 5
patients (9.8%) took IPF-related concomitant medication such as N-acetylcysteine (N=2) and
glucocorticoids (N=3). The 12-month study period was completed by 17 patients (33.3%), while
34 patients (66.7%) dropped out prematurely. The reasons for drop out are presented in [Table 2 ].
Table 1 Patient demographics and baseline characteristics.
Parameter
N=51
† No other risk factors were obtained than those listed here.
‡ Multiple answers possible; § N=43; ¶ N=36;
# N=30; BAL, bronchoalveolar lavage; IPF, idiopathic pulmonary fibrosis;
SD, standard deviation.
Gender, n (%)
41 (80.4)
10 (19.6)
Age, mean ± SD (years)
70.6 ± 8.8
Time since IPF diagnosis, mean ± SD (weeks)
44.2 ± 74.7
Risk factors†
Smoking status
Smokers
Former smokers
Non-smokers
Exposure to asbestos
Yes
No
No information/unknown
Not assessed
Exposure to stone dust
Yes
No
No information/unknown
Not assessed
2 (3.9)
23 (45.1)
26 (51.0)
5 (9.8)
29 (56.9)
12 (23.5)
5 (9.8)
5 (9.8)
27 (52.9)
15 (29.4)
4 (7.8)
Methods used for initial IPF diagnosis‡ , n (%)
Total
Imaging techniques
Histopathology
BAL
Auscultation
Additional examinations
51 (100.0)
41 (80.4)
22 (43.1)
24 (47.1)
21 (41.2)
10 (19.6)
IPF medication prior to study start‡ , n (%)
13 (25.5)
4 (7.8)
5 (9.8)
6 (11.8)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
Lung function, mean ± SD (% predicted)
Forced vital capacity (%)§
Vital capacity (%)§
Forced expiratory volume in 1 second (%)§
Total lung capacity (%)§
Diffusing capacity of the lung for carbon monoxide (%)¶
70.2 ± 17.9
68.4 ± 16.5
78.6 ± 18.0
71.3 ± 14.3
45.2 ± 14.8
6-minute walking distance# , mean ± SD (m)
378.0 ± 107.9
GAP index§ , mean ± SD
4.5 ± 1.55
Table 2 Reasons for drop-out (N=34).
Reason, N (%)
N=34
† The investigator stated “lack of response/progression” as reason for
therapy discontinuation; ‡ For these 2 patients, only the discontinuation
was reported.
Lost to follow-up
10 (29.4)
Adverse drug reaction
8 (23.5)
Patient’s wish
8 (23.5)
“Lack of response/progression”†
2 (5.9)
Death
1 (2.9)
Other
3 (8.8)
Death – not reason for therapy discontinuation‡
2 (5.9)
3.2 Effectiveness
Data for the calculation of disease progression was available for 34 patients. Disease
progression at any visit was reported for 23 (67.6%) of these 34 patients. In detail, ≥10%
relative decrease of VC and ≥15% relative decrease of DLCO , respectively, were
observed in 13 patients each (38.2%), ≥50 m decrease of 6-MWD in 9 patients (26.5%), and in
2 patients (5.9%) the investigator stated “lack of response/progression” as the reason for
therapy discontinuation. The proportion of patients with disease progression relative to
baseline over the course of the study is shown in [Fig. 1 ]. The proportion of these patients was 44.1% at month 3, 50.0% at month 6, 57.1% at
month 9, and 50.0% at month 12.
Fig. 1 Disease progression. Disease progression was defined as relative VC decrease of at
least 10% compared to baseline, or relative decrease of DLCO of at least 15%
compared to baseline, or decrease of the 6-minute walk distance (6-MWD) of at least 50 m
compared to baseline, or if the investigator stated „lack of response/progression” as
reason for therapy discontinuation. 6-MWD, 6-Minute walking distance; DLCO ,
diffusing capacity of the lung for carbon monoxide; VC, vital capacity.
Overall, pulmonary function parameters remained stable over the course of the study
([Fig. 2 ]). A mean GAP score of stage II was maintained over the course of the study ([Table 3 ]). On treatment, 6‑MWD values fluctuated between visits (mean changes relative to the
previous visit: –15.3 ± 47.8 at month 3; 20.4 ± 20.4 ± 67.2 at month 6; –15.2 ± 34.2 at
month 9; 8.2 ± 61.8 at month 12), but remained more or less steady from baseline (378.0 ±
107.9) to month 12 (432.9 ± 117.5) ([Fig. 3 ]). Similarly, no substantial changes were observed in total LCQ scores ([Fig. 4 ]) and mean total SOBQ scores ([Table 3 ]).
Fig. 2 Pulmonary function. BL, baseline; DLCO , diffusing capacity of the lung
for carbon monoxide; FEV1 , forced expiratory volume in 1 second; FVC, forced vital
capacity; SD, standard deviation; VC, vital capacity.
Fig. 3 6-Minute Walking Distance. SD, standard deviation.
Fig. 4 Leicester Cough Questionnaire. Values denote total LCQ score ± standard deviation.
The total score ranges from 3–21. Higher scores represent higher quality of life. LCQ,
Leicester Cough Questionnaire.
Table 3 GAP and SOBQ score.
Baseline
Month 3
Month 6
Month 9
Month 12
† N=34; The GAP index score was calculated based on the following
variables: gender, age, FVC, and DLCO . Higher GAP index scores correspond
to a greater need for transplantation or treatment and a higher risk of mortality
within the next 3 years. The total point score is used to classify patients as stage
I (0–3 points), stage II (4–5 points), or stage III (6–8 points). Total SOBQ score
values range between 0 and 120. Higher scores corresponded to more severe
breathlessness. SOBQ, University of California San Diego Shortness of Breath
Questionnaire.
GAP index
N
43
37
28
22
17
GAP stage (mean GAP index score ± SD)
Stage II
(4.5 ± 1.55)
Stage II
(4.6 ± 1.48)
Stage II
(4.8 ± 1.60)
Stage II
(4.9 ± 1.75)
Stage II
(4.6 ± 2.03)
Change vs. previous visit, Mean ± SD
–
0.1 ± 0.74†
0.2 ± 0.88
0.3 ± 0.72
–0.1 ± 0.83
SOBQ score
N
41
25
18
17
11
Mean ± SD
52.6 ± 29.3
55.8 ± 28.8
54.3 ± 28.3
58.0 ± 25.7
48.6 ± 29.5
Exacerbations as assessed at the discretion of the investigator were documented for 6 of
43 patients (14.0%) with available observations during the course of study: for 3 patients
at month 3, for 2 patients at month 6, and for 1 patient at month 9. All of these patients
experienced one exacerbation each.
3.3 Safety
In total, 29 patients (56.9%) experienced at least one ADR ([Table 4 ]). The most common non-serious ADRs were nausea (9.8%), decreased appetite (9.8%),
dizziness (9.8%), and pruritus (7.8%). Six patients discontinued pirfenidone due to
non-serious ADRs. Twelve patients (23.5%) experienced serious adverse reactions. SARs with a
case frequency of ≥2 were pneumonia, pulmonary fibrosis, dyspnea, and syncope. SARs led to
discontinuation of pirfenidone in 5 patients. In 4 patients, events of IPF exacerbation,
pneumonia and subsequently renal failure, and dyspnea had fatal outcomes. No other fatal
outcomes were reported in this study.
Table 4 Adverse drug reactions.
Parameter
N=51
† Multiple answers possible. ‡ Since idiopathic pulmonary
fibrosis was a criterion for enrollment, this category of adverse events refers to
worsening of disease. § The events of fatal IPF exacerbation, pneumonia,
and dyspnea in 3 of these patients can be plausibly explained by the underlying
condition of IPF, rather than being attributed to pirfenidone according to the
discretion of the investigator. The fourth patient died due to community-acquired
pneumonia requiring ventilation, ventilation insufficiency and kidney failure
(assessed by the physician as unlikely related to pirfenidone). ADR, adverse drug
reaction; SAR, serious adverse reaction.
Any non-serious ADR
29 (56.9)
Most common non-serious ADRs (incidence ≥5%)†
5 (9.8)
5 (9.8)
5 (9.8)
3 (5.9)
3 (5.9)
4 (7.8)
3 (5.9)
Any serious adverse reaction†
12 (23.5)
Pneumonia
Dyspnea
Pulmonary fibrosis‡
Syncope
Acute cholecystitis
Anemia
Colon cancer
Deep vein thrombosis
Disease progression
Dysphagia
ECG ST segment depression
Fall
Hypoventilation
Leukopenia
Lumbal vertebral fraction
Nausea
Performance status decreased
Pneumonia aspiration
Renal failure
Respiratory tract infection
Sepsis
Squamous cell carcinoma
Tongue neoplasm
3 (5.9)
2 (3.9)
2 (3.9)
2 (3.9)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
SAR with fatal outcome§
4 (7.8)
4 Discussion
To the best of our knowledge this was the first prospective multicenter study to assess
the effectiveness of pirfenidone on mild-to-moderate IPF in a real-world setting in Germany.
Previous studies analyzed patient records from single centers retrospectively [22 ] or included patients who had participated in interventional clinical trials [23 ], which was an exclusion criterion in the present study. Our study results indicated a
deceleration of decline in exercise capacity, lung parameters, shortness of breath, and cough
severity-related quality of life. On the other hand, disease progression in 67.6% of patients
with available data was also observed. Pirfenidone is not curative but able to slow disease
progression, thus halting the deterioration of dyspnea and delaying the development of
respiratory failure [24 ]. This is also reflected in the more or less stable GAP Index between 4–5 points, which
pertains to Stage II of the three GAP stages with a 1-year mortality of 16.2% [19 ]. A decline in FVC of 10% or more over a 6-month period is associated with an increased
risk of mortality [25 ]
[26 ]. Therefore, the stable mean FVC values observed throughout our study might hint at
deceleration of lung function decline. Yet, in light of the high drop-out rate, caution has to
be observed with the interpretation of these results. Furthermore, it must be assumed that
patients with more pronounced therapy responses were more likely to continue the study, while
those with poor response tended to drop out.
The rate of disease progression was considerably lower in the German single-center studies
(30% [23 ] and 38% [22 ]), which may be attributable to a less stringent definition, using only two qualifying
events. The authors defined progression as a reduction of FVC ≥10% predicted and/or
DLCO ≥15% predicted [22 ] or reduction of VC >5% predicted and/or DLCO >10% [23 ]. The present study applied a more stringent definition of the composite endpoint
progression using four qualifying events (relative decrease of ≥10% in VC or ≥15% in
DLCO and/or ≥50m in 6-MWD vs. baseline assessment, or if the investigator stated
“lack of response/progression” as reason for therapy discontinuation). The importance of
taking measures other than FVC into account in the evaluation of disease progression in an
individual patient has been emphasized in a consensus meeting [27 ]. Concomitant emphysema, a known confounder in interpreting measurements of FVC and
DLCO
[28 ], was reported in one patient only and should therefore not affect the overall
results.
While the demographic and baseline characteristics, including gender distribution, age and
most parameters of pulmonary function, of our study population were similar to the previous
phase III clinical trials [12 ]
[14 ], the German retrospective study [22 ], and the INSIGHTS IPF registry [29 ], fewer patients were former smokers. The percentage of non-smokers comprised only one
third in the previous studies and more than 50% in the present study.
The incidence of adverse events was similar to that observed by Bonella and coworkers
[23 ] and an Italian long-term safety study [30 ], and thus lower compared to the CAPACITY [12 ] and PASSPORT [18 ] studies as well as the German and Japanese retrospective studies [22 ]
[31 ]. Compared to the pan-European 2-year PASSPORT study, a smaller proportion of patients
discontinued treatment due to ADRs [18 ], which may be a consequence of the shorter follow-up period. The rate of treatment
discontinuations due to adverse events was similar to the German retrospective study [22 ], but higher than the rate observed in clinical trials [12 ]
[14 ] and other real-world studies [23 ]
[31 ]
[32 ], reinforcing the need for accompanying patient support programs. These could educate
patients about potential symptoms they may expect, offer advice in preventing, mitigating and
managing ADRs, and provide a helpline for questions and individual support. The decision to
withdraw pirfenidone after occurrence of events such as skin reactions or gastrointestinal
ADRs was consistent with the respective recommendations for risk minimization for these ADRs
in the current pirfenidone SmPC [33 ]. Overall, the profile of adverse events reported as related to the study drug is
within the range of what can be expected in this population of severely ill patients and is
consistent with the current label [33 ].
This study is limited by its non-interventional single-arm design which allows the
identification of associations, but excludes the conclusion of causal relationships. Yet, this
study design has advantages in terms of patient heterogeneity and compliance assessment as it
collects data in a real-world setting. Other limitations were the limited number of patients
and missing values due to drop-outs. Our results should be interpreted with caution due to the
declining numbers of patients over the course of the study. This is not uncommon in real-life
and reflects the poor treatment persistence generally observed in IPF patients [34 ]
[35 ]. The strength of this study is represented by objective measurements of pulmonary
function and the use of validated scores to assess severity of dyspnea [21 ], quality of life in chronic cough [20 ], and staging of IPF [19 ]. Hence, the study provides a comprehensive view of the treatment effect with
pirfenidone in Germany.
In conclusion, the results of this non-interventional study are in line with the
established benefit-risk profile of pirfenidone. Therefore, pirfenidone can be considered a
valuable treatment option to slow disease progression in patients with mild-to-moderate
IPF.
