Nintedanib Reduces Decline in Lung Function in Idiopathic Pulmonary Fibrosis

27 Nov, 20

Introduction

Idiopathic pulmonary fibrosis (IPF) is characterized by worsening dyspnea and a progressive loss of lung function. Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A randomized, double-blind phase 2 trial demonstrated reduced decline in FVC, fewer acute exacerbations and preservation of health-related quality of life (QoL) in IPF patients following treatment with 150 mg of nintedanib twice daily.

Aim

The two replicate phase 3 trials (INPULSIS-1 and INPULSIS-2) assessed the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with IPF.

Patient Profile

Age >40 years with a diagnosis of IPF within the previous 5 years
FVC 50% or more of the predicted value
Diffusion capacity of the lung for carbon monoxide (DLCO) 30 to 79% of the predicted value
High-resolution computed tomography (HRCT) of the chest performed within the previous 12 months

Method

Study Design

Randomized, double-blind, placebo-controlled, parallel-group 52-week phase 3 studies

Treatment Strategy

The study population was randomized in a 3:2 ratio to receive 150 mg of nintedanib twice daily or placebo for 52 weeks
The patients were followed up 4 weeks later after completion of the 52-week treatment period
Spirometry was conducted at baseline; at 2, 4, 6, 12, 24, 36, and 52 weeks; and at the follow-up visit.

End Points

Primary End Point

Annual rate of decline in FVC

Secondary End Points

Time to the first acute exacerbation
Change from baseline in the total score on the St. George's Respiratory Questionnaire
Adverse events (AEs)

Results

A total of 1066 patients were recruited. In the INPULSIS-1 study, 309 and 204 received nintedanib and placebo respectively. In the INPULSIS-2 study, 329 and 219 received nintedanib and placebo respectively
The adjusted annual rate of change in FVC between the groups is shown in Table 1.

Table 1. Comparison of adjusted annual rate of change in FVC

	Nintedanib group	Placebo group	Difference	P value
	Adjusted annual rate of change of FVC
INPULSIS-1	-114.7 ml	-239.9 ml	125.3 ml	<0.001
INPULSIS-2	-113.6 ml	-207.3 ml	93.7 ml	<0.001

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; p=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (HR, 0.38; p=0.005)
In INPULSIS-1, there was no significant between-group difference in the adjusted mean change in the total SGRQ score from baseline to week 52 (4.34 points vs 4.39 points; difference, −0.05; p=0.97)
In INPULSIS-2, there was a significantly smaller increase in the total SGRQ score at week 52 in the nintedanib group than in the placebo group (2.80 points vs. 5.48 points; difference, −2.69; p=0.02)
The most frequent adverse event in the nintedanib groups was diarrhea
The proportion of patients with serious AEs was similar in the groups.

Conclusions

Nintedanib reduced the decline in forced vital capacity (FVC), which is consistent with a slowing of disease progression in patients with idiopathic pulmonary fibrosis (IPF).
The most frequent adverse event reported by the nintedanib groups was diarrhea, which led to discontinuation of the study drug in less than 5% of patients.

N Engl J Med. 2014 May 29;370(22):2071-82.