Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial

Jürgen Behr; Steven D Nathan; Wim A Wuyts; Nesrin MOĞULKOÇ BISHOP; Demosthenes E Bouros; Katerina Antoniou; Julien Guiot; Mordechai R Kramer; Klaus-Uwe Kirchgaessler; Monica Bengus; Frank Gilberg; Andras Perjesi; Sergio Harari; Athol U Wells

Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial

Makaleler > Tam Makale · 2020

Yazarlar: Jürgen Behr, Steven D Nathan, Wim A Wuyts, Nesrin MOĞULKOÇ BISHOP, Demosthenes E Bouros, Katerina Antoniou, Julien Guiot, Mordechai R Kramer, Klaus-Uwe Kirchgaessler, Monica Bengus, Frank Gilberg, Andras Perjesi, Sergio Harari, Athol U Wells

The Lancet Respiratory Medicine, SCI Expanded İndekslerine Giren Dergi, Uluslararası, 2020, cilt 9, ss 85-95

Özet

SummaryBackground The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis (IPF) at risk of pooroutcomes from pulmonary hypertension, whether already present or likely to develop, is uncertain. We aimed toassess the efficacy and safety of sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeksin patients with advanced IPF and at risk of group 3 pulmonary hypertension.Methods We did a multicentre, international, double-blind, randomised, placebo-controlled, phase 2b study at56 university clinics, research hospitals, and tertiary sites in Canada, Europe (Belgium, Czech Republic, Germany,Greece, Hungary, Italy, the Netherlands, Spain, and Turkey), Israel, and Africa (Egypt and South Africa).Eligible patients (aged 40–80 years) had advanced IPF (carbon monoxide diffusing capacity ?40% predicted atscreening), and were at risk of group 3 pulmonary hypertension (mean pulmonary artery pressure of ?20 mm Hgwith pulmonary artery wedge pressure of ?15 mm Hg on previous right-heart catheterisation, or intermediate or highprobability of group 3 pulmonary hypertension on echocardiography as defined by the 2015 European Society ofCardiology and European Respiratory Society guidelines). Patients were randomly assigned 1:1 to oral sildenafiltablets (20 mg three times daily) or placebo, both in addition to oral pirfenidone capsules (801 mg three times daily),using a validated interactive voice-based or web-based response system with permuted block randomisation, stratifiedby previous right-heart catheterisation (yes or no) and forced expiratory volume in 1 s to forced vital capacity ratio(<0·8 or ?0·8). The composite primary endpoint was disease progression, defined as either a relevant decline in6-min walk distance, respiratory-related admission to hospital, or all-cause mortality, after 52 weeks and was assessedin the intention-to-treat population; safety was assessed in all patients who received at least one dose of the studydrug. This trial is registered with ClinicalTrials.gov, NCT02951429, and is no longer recruiting. The 11-month safetyfollow-up is ongoing.Findings Between Jan 13, 2017, and Aug 30, 2018, 247 patients were screened for eligibility, 177 of whom wererandomly assigned to a treatment group (n=88 sildenafil; n=89 placebo) and were assessed for the primary outcome.There was no difference in the proportion of patients with disease progression over 52 weeks between the sildenafil(64 [73%] of 88 patients) and placebo groups (62 [70%] of 89 patients; between-group difference 3·06% [95% CI–11·30 to 17·97]; p=0·65). Serious treatment-emergent adverse events were reported in 54 (61%) patients in thesildenafil group and 55 (62%) patients in the placebo group. Treatment-emergent adverse events leading to mortalityoccurred in 22 (25%) patients in the sildenafil group and 26 (29%) in the placebo group.Interpretation Addition of sildenafil to pirfenidone did not provide a treatment benefit versus pirfenidone plusplacebo up to 52 weeks in patients with advanced IPF and risk of pulmonary hypertension. No new safety signalswere identified with either treatment. Although the absence of a beneficial treatment effect suggests that sildenafil isnot an appropriate treatment in the overall population, further research is required to establish if specific subgroupsof patients with IPF might benefit from sildenafil.

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