INPULSIS-ON*, the open-label extension of the phase III INPULSIS trials, demonstrated the safety of nintedanib over a long-term period of treatment in patients with idiopathic pulmonary fibrosis (IPF).

Participants were 734 adults (mean age 67.2 years, 80 percent male, 59 percent Caucasian, mean FVC** predicted 76.2 percent) with IPF who had completed one of the two 52-week INPULSIS studies and post-study follow-up after 4 weeks. After a 4- to 12-week drug-free interval, patients who had received either nintedanib 150 mg twice/day or placebo at the end of INPULSIS received nintedanib 150 mg twice/day in INPULSIS-ON, while patients who had received 100 mg twice/day or placebo at the end of INPULSIS received either 100 or 150 mg twice/day nintedanib in INPULSIS-ON.

Forty-one percent of patients were initiating nintedanib in INPULSIS-ON (treated with placebo during INPULSIS). Inclusive of both INPULSIS and INPULSIS-ON, patients received nintedanib for a median 44.7 months.

The most common adverse event (AE) that occurred in INPULSIS-ON was diarrhoea, with event rates of 60.1 and 71.2 events per 100 patient exposure-years in patients who continued (received nintedanib in INPULSIS) and initiated nintedanib, respectively, with diarrhoea leading to permanent treatment discontinuation in 5 and 10 percent of patients who continued and initiated nintedanib, respectively. [Lancet Respir Med 2018;doi:10.1016/S2213-2600(18)30339-4]

Bleeding event rate was 8.4 and 6.7 per 100 patient-exposure years in patients who continued and initiated nintedanib in INPULSIS-ON, respectively, major adverse cardiovascular event rate was 3.6 and 2.4 per 100 patient-exposure years, and myocardial infarction rate was 1.3 and 0.7 per 100 patient-exposure years.

The most common AE that led to permanent discontinuation of treatment was IPF progression (12 and 14 percent in patients who continued and initiated nintedanib in INPULSIS-ON, respectively).

The annual rate of decline in FVC over 192 weeks was -145.0 and -119.7 mL per year in patients who continued and initiated nintedanib, respectively, in INPULSIS-ON, while mean change in FVC percentage predicted was -7.5 percent vs -6.3 percent in these respective groups.

Acute exacerbation rates were similar between patients who continued and initiated nintedanib (5.8 vs 5.2 per 100 patient-years).

“These results from INPULSIS-ON … show that nintedanib had a manageable safety and tolerability profile over the long term. No new safety signals were identified over a treatment duration of up to 68 months,” said the researchers.

However, Professor Athol Wells from the Royal Brompton Hospital in London, UK, who was not involved in the study, recommended caution in interpreting the efficacy data which was restricted to patients who completed 4 years of nintedanib treatment.

As 69 and 72 percent of patients who continued and initiated nintedanib, respectively, discontinued the trial regimen, 4-year efficacy only applied to about 30 percent of patients, he said in an accompanying commentary, highlighting the importance of carrying out a study assessing long-term efficacy in an intention-to-treat population. [Lancet Respir Med 2018;doi:10.1016/S2213-2600(18)30385-0]

The researchers also acknowledged that the patient population in INPULSIS-ON was more likely to comprise those with better tolerability of nintedanib and those with less disease progression, potentially leading to bias.