Long‐term treatment with nintedanib in Asian patients with idiopathic pulmonary fibrosis: Results from INPULSIS®‐ON

ABSTRACT Background and objective The efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) were investigated in the placebo‐controlled INPULSIS® trials. All patients who completed an INPULSIS® trial could receive open‐label nintedanib in the extension trial INPULSIS®‐ON. Methods We assessed the long‐term efficacy and safety of nintedanib in patients of Asian race who were treated in INPULSIS®‐ON. Analyses were descriptive. Results A total of 215 Asian patients were treated in INPULSIS®‐ON, of whom 121 continued nintedanib in INPULSIS®‐ON and 94 initiated nintedanib in INPULSIS®‐ON having received placebo in an INPULSIS® trial. At baseline of INPULSIS®‐ON, the mean (SD) age of Asian patients was 66.3 (7.5) years, 80.5% were males and mean (SD) forced vital capacity (FVC) was 78.9 (19.3) % predicted. Median total exposure to nintedanib in both INPULSIS® and INPULSIS®‐ON was 42.2 months; maximum exposure was 64.1 months. In INPULSIS®, the annual rate (SE) of decline in FVC over 52 weeks in Asian patients was −124 (20) mL/year in the nintedanib group and −218 (24) mL/year in the placebo group. In INPULSIS®‐ON, the annual rate (SE) of decline in FVC over 192 weeks in Asian patients was −127 (11) mL/year. Diarrhoea was reported in Asian patients at event rates of 58.8 and 82.5 events per 100 patient exposure–years in patients who continued and initiated nintedanib in INPULSIS®‐ON, respectively. Conclusion The effect of nintedanib on slowing disease progression in Asian patients with IPF is sustained over the long term. Long‐term treatment with nintedanib has an acceptable safety and tolerability profile.


INTRODUCTION
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterized by worsening lung function, dyspnoea and impaired quality of life. 1,2 The reported incidence of IPF varies depending on the methodology used to identify cases. 3 In a study in Japan based on a retrospective review of medical records, the annual incidence of IPF was estimated as 2.2 cases per 100 000. 4 IPF has a very poor prognosis, with a median survival in patients not receiving antifibrotic therapy of approximately 3 years. 4,5 Nintedanib, an inhibitor of multiple tyrosine kinases, 6 is an approved treatment for IPF. The efficacy and safety of 52 weeks' treatment with nintedanib 150 mg twice daily (bd) in patients with IPF were demonstrated in the Phase III INPULSIS ® trials. 7 In both trials, nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) versus placebo. Based on pooled data from both trials, the annual rate of decline in FVC was −113.6 mL/year in patients treated with nintedanib and −223.5 mL/year in patients treated with placebo (between-group difference: 109.9 mL/year (95% CI: 75.9, 144.0)). Furthermore, nintedanib was associated with a numerical reduction in the risk of an investigatorreported acute exacerbation (hazard ratio (HR): 0.64 (95% CI: 0.39, 1.05); P = 0.08). 7 The adverse event profile of nintedanib was characterized mainly by gastrointestinal events, particularly diarrhoea. 7 Recently, the long-term efficacy and safety of nintedanib were confirmed in the open-label extension of the INPULSIS ® trials, INPULSIS ® -ON, which showed that the effects of nintedanib on slowing disease progression persisted beyond 4 years, and that the safety and tolerability profile of nintedanib over long-term use was consistent with that observed in shorter studies. 8 A total of 215 (29%) patients who participated in INPULSIS ® -ON were Asian in race. Here, we report the results of a subgroup analysis of the efficacy and safety of nintedanib in Asian patients in INPULSIS ® -ON.

Trial design
The INPULSIS ® and INPULSIS ® -ON trials were conducted according to the principles laid down in the Declaration of Helsinki and the International Conference of Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice and were approved by local authorities. An independent ethics committee or institutional review board at each participating centre approved the trial protocols. Patients provided informed consent before entering an INPULSIS ® trial and reconfirmed informed consent before entering INPULSIS ® -ON. The trials were registered with clinicaltrials.gov (NCT01335464, NCT01335477 and NCT01619085).
In the INPULSIS ® trials, patients were randomized 3:2 to receive nintedanib 150 mg bd or placebo for 52 weeks (Fig. S1 in Supplementary Information). Dose reductions to 100 mg bd and treatment interruptions were allowed to manage adverse events. Recommendations for the management of diarrhoea and hepatic enzyme elevations were provided to the investigators. 7 Patients who completed the 52-week treatment period and follow-up visit 4 weeks later in an INPULSIS ® trial were eligible to enter INPULSIS ® -ON. Patients who were receiving nintedanib 150 mg bd or its placebo at the end of an INPULSIS ® trial received nintedanib 150 mg bd in INPULSIS ® -ON. Patients who were receiving nintedanib 100 mg bd or its placebo at the end of an INPULSIS ® trial could begin INPULSIS ® -ON either on the nintedanib 100 or 150 mg bd dose. After unblinding of the INPULSIS ® trials, patients were allowed to increase their dose from 100 to 150 mg bd during INPULSIS ® -ON. The first patient was enrolled into INPULSIS ® -ON in July 2012. The database was locked for final analysis in September 2017.

End points
The following exploratory efficacy end points were analysed in all patients and in Asian patients in INPULSIS ® -ON: annual rate of decline in FVC over 192 weeks, absolute change in FVC from baseline to week 192, time to first acute exacerbation (as defined by Richeldi et al. 7 ) and mortality. A time point of 192 weeks was chosen for assessing changes in FVC as this was the time point reached by the last patient who was still receiving nintedanib when the trial ended. Data on adverse events (including acute exacerbations and deaths) were collected until 28 days after treatment discontinuation. Asian race was based on the race selected by patients at enrolment into the INPULSIS ® trials.
Patients were asked to select their race from the following options: White, Asian, Black/African American, American Indian/Alaska Native and Hawaiian/Pacific Islander.

Statistical analysis
Efficacy and safety analyses were descriptive and conducted in patients who received ≥1 dose of nintedanib in INPULSIS ® -ON. A random coefficient regression model was used to analyse the annual rate of decline in FVC, with age, height and sex as fixed effects, and patient-specific intercept and time as random effects. The model used all FVC values from baseline to week 192 to calculate the slope of FVC decline. For patients who discontinued nintedanib, an end-of-trial visit was conducted plus a follow-up visit 28 days after treatment discontinuation; after this, no more data were collected for patients who had discontinued. Kaplan-Meier estimates are presented for time to first acute exacerbation. The incidence of acute exacerbations was calculated as the number of patients with ≥1 acute exacerbation/total years at risk × 100. Total years at risk was considered as the time from the start of treatment to the start of the first event (for patients with an event) or the end of the time at risk (for patients without an event) + 1 day.
Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1. Safety topics of interest included major adverse cardiovascular events (MACE), myocardial infarction and bleeding. Incidence rates of adverse events were calculated per 100 patient exposure-years (PEY).

Adverse events
Adverse events in Asian patients in INPULSIS ® and INPULSIS ® -ON are shown in Tables 2 and 3. As in the overall trial populations, diarrhoea was the most  Data are n (%) of patients. † An event that was incapacitating or that caused an inability to work or to perform usual activities. ‡ An event that resulted in death, was immediately life-threatening, resulted in persistent or clinically significant disability or incapacity, required or prolonged hospitalization, was related to a congenital anomaly or birth defect or was deemed serious for any other reason.
§ Adverse events leading to permanent drug discontinuation in >1.5% of patients in any group shown by the preferred term in MedDRA. ¶ (Table S3 in Supplementary Information). The event rate of myocardial infarction was 1.4 and 0.5 events per 100 PEY in these groups, respectively. The event rate of bleeding was 9.6 and 3.3 events per 100 PEY in these groups, respectively. The incidence rate of elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥3× upper limit of normal (ULN) was 4.0 per 100 patient-years both in Asian patients who continued and initiated nintedanib in INPULSIS ® -ON (Table S4 in

Acute exacerbations and deaths
Among Asian patients in INPULSIS ® -ON, the incidence rate of acute exacerbations was 7.3 per 100 patientyears in patients who continued nintedanib and 8.6 per  100 patient-years in patients who initiated nintedanib (Fig. 3, Table S5 in Supplementary Information). A total of 36 (29.8%) patients who continued nintedanib and 27 (28.7%) patients who initiated nintedanib died over 5 years' follow-up in INPULSIS ® -ON.

DISCUSSION
Our analyses of data from the INPULSIS ® -ON trial suggest that the safety and efficacy of nintedanib in Asian patients with IPF are maintained over the long term. These data from Asian patients are consistent with those observed in the overall trial population in INPULSIS ® -ON. 8 The annual rate (SE) of decline in FVC over 192 weeks in INPULSIS ® -ON was −135 (6) mL/year in the overall population and −127 (11) mL/year in Asian patients. It has been suggested that the course and prognosis of IPF may differ between Asian and White patients. 4,[9][10][11] However, subgroup analyses of data from the INPULSIS ® trials showed that the annual rate of FVC decline in placebo-treated patients, and the effect of nintedanib on FVC decline, was consistent between Asian and White patients 12,13 and between Japanese patients and the overall population. 14 In the INPULSIS ® trials, the proportion of patients who had an acute exacerbation was similar in the Asian subgroup as in the overall trial population, with Asian race not identified as a variable that increased the risk of acute exacerbations in a formal risk factor analysis. 15 In INPULSIS ® -ON, 39 (18.1%) Asian patients had an acute exacerbation compared with 100 (13.6%) patients in the overall trial population. It is unclear whether the small differences observed in the rates of acute exacerbations between Asian and White patients reflect differences between races or simply different methodologies used to recognize acute exacerbations in different countries. Caution must be exercised in the interpretation of these data, given the small number of events observed and the challenges in classifying events as acute exacerbations of IPF.  , initiated nintedanib.
The safety and tolerability profile of nintedanib observed in Asian patients participating in the INPULSIS ® and INPULSIS ® -ON trials were consistent with that observed in the overall trial populations, 7,8 with diarrhoea being the most commonly reported adverse event. A similar safety and tolerability profile was recently reported in a real-world study of Korean patients treated with nintedanib. 16 In Asian patients in INPULSIS ® -ON, treatment discontinuations due to diarrhoea were uncommon (3% of patients). Data from the overall trial population in INPULSIS ® -ON indicate that discontinuations due to diarrhoea occurred most frequently in the first year of the trial. 17 Event rates of MACE, myocardial infarction and bleeding in Asian patients in INPULSIS ® -ON were low and consistent with those observed in the overall trial population. 8 A shortcoming of the present analysis was that patients chose their race from a small list of options provided to them, which resulted in a group of 'Asian' patients with various genetic and cultural backgrounds.
As with all open-label studies, interpretation of the data from INPULSIS ® -ON data is limited by the lack of a comparator group. Patients in the INPULSIS ® trials whose disease progressed more slowly, or who had fewer/less severe adverse events, would have been more likely to complete the INPULSIS ® trial and thus enter INPULSIS ® -ON. In addition, patients with a more benign course of disease might have been more likely to remain on treatment in INPULSIS ® -ON, so potentially reducing the FVC decline and mortality observed in INPULSIS ® -ON. However, as all available FVC measurements collected between baseline and week 192 were used to calculate the rate of decline in FVC, patients with rapid decline in FVC and early discontinuation contributed equally to the calculation as those with slower decline who were still on treatment at week 192.
In summary, results from a subgroup analysis of data from INPULSIS ® -ON, the open-label extension of the INPULSIS ® trials, suggest that the effect of nintedanib on slowing disease progression in Asian patients with IPF is sustained over the long term. Long-term treatment with nintedanib, up to 64 months, had an acceptable safety and tolerability profile, consistent with that observed in shorter studies.

Supplementary Information
Additional supplementary information can be accessed via the html version of this article at the publisher's website.