Background The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis (IPF) at risk of poor outcomes from pulmonary hypertension, whether already present or likely to develop, is uncertain. We aimed to assess the efficacy and safety of sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeks in 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 at 56 university clinics, research hospitals, and tertiary sites in Canada,

We assessed safety and tolerability of treatment with pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1) in patients with idiopathic pulmonary fibrosis (IPF).This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day−1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither.89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs.Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF.

Combination treatment with sildenafil and pirfenidone may warrant investigation of the treatment of patients with advanced IPF and pulmonary vascular involvement leading to PH.

Background Patients with interstitial lung disease (ILD) require regular physician visits and referral to specialist ILD clinics. Difficulties or delays in accessing care can limit opportunities to monitor disease trajectory and response to treatment, and the COVID-19 pandemic has added to these challenges. Therefore, home monitoring technologies, such as home handheld spirometry, have gained increased attention as they may help to improve access to care for patients with ILD. However, while several studies have shown that home handheld spirometry in ILD is acceptable for most patients, data from clinical trials are not sufficiently robust to support its use as a primary endpoint. This review discusses the challenges that were encountered with handheld spirometry across three recent ILD studies, which included home spirometry as a primary endpoint, and highlights where further optimisation and research into home handheld spirometry in ILD is required. Abstract body Rate of decline in forced vital capacity (FVC) as measured by daily home handheld spirometry versus site spirometry was of primary interest in three recently completed studies: STARLINER (NCT03261037), STARMAP and a Phase II study of pirfenidone in progressive fibrosing unclassifiable ILD (NCT03099187). Unanticipated practical and technical issues led to problems with estimating FVC decline. In all three studies, cross-sectional correlations for home handheld versus site spirometry were strong/moderate at baseline and later timepoints, but longitudinal correlations were weak. Other issues observed with the home handheld spirometry data included: high within-patient variability in home handheld FVC measurements; implausible longitudinal patterns in the home handheld spirometry data that were not reflected in site spirometry; and extreme estimated rates of FVC change. Conclusions Home handheld spirometry in ILD requires further optimisation and research to ensure accurate and reliable FVC measurements before it can be used as an endpoint in clinical trials. Refresher training, automated alerts of problems and FVC changes, and patient support could help to overcome some practical issues. Despite the challenges, there is value in incorporating home handheld spirometry into clinical practice, and the COVID-19 pandemic has highlighted the potential for home monitoring technologies to help improve access to care for patients with ILD.

There is a need for clinical trial end-points to better assess how patients feel and function, so that interventions can be developed which alleviate symptoms and improve quality of life. Use of 6-min walk test (6MWT) outcomes as a primary end-point in interstitial lung disease (ILD) trials is growing, particularly for drugs targeting concurrent pulmonary hypertension. However, 6MWT outcomes may be influenced differentially by interstitial lung and pulmonary vascular components of ILD, making interpretation complicated. We propose that using 6MWT outcomes, including 6-min walk distance or oxygen desaturation, as primary end-points should depend upon the study population (how advanced the ILD is; whether vasculopathy is significant), the degree of disease progression, and, importantly, the effect of study treatment expected. We argue that the 6MWT as a single outcome measure is suitable as a primary end-point if the treatment goal is to improve functional performance or prevent disease progression within a study population of patients with advanced ILD or those with ILD and co-existent vasculopathy. In addition, we discuss the potential of composite primary end-points incorporating 6MWT outcomes, outlining important considerations to ensure that they are appropriate for the study population and treatment goals.