According to the results of an international, single-arm, open-label, phase 4 study (ClinicalTrials.gov Identifier: NCT02598193) published in the European Respiratory Journal, combination therapy with pirfenidone and nintedanib was safe and tolerated by the majority of patients with idiopathic pulmonary fibrosis (IPF).
Both pirfenidone and nintedanib have shown efficacy and have been approved as monotherapy for IPF, and both agents received conditional recommendation for use in IPF in the 2015 update of the American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) clinical practice guidelines. However, neither agent stops or reverses the disease. As it is believed that these agents have differing mechanisms of action, with evidence suggesting that they may target different aspects of the fibrotic cascade involved in IPF, it has been suggested that combination therapy may benefit patients with IPF.
To investigate the safety and tolerability of the combination of pirfenidone (1602-2403 mg/d) and nintedanib (200-300 mg/d), researchers enrolled 89 patients with a forced vital capacity (FVC) ≥50% and carbon monoxide diffusing capacity (DLco) ≥30% in the 24-week trial. Before nintedanib was initiated, patients had received pirfenidone for ≥16 weeks and were stabilized on ≥1602 mg/d for ≥28 days. The primary end point was the proportion of patients who completed 24 weeks of combination therapy.
A total of 73 patients completed the trial, and 69 met the primary end point. However, 16 patients discontinued treatment prematurely, 13 as the result of treatment-emergent adverse events (TEAEs). A total of 74 patients had 418 treatment-related TEAEs; the most common were diarrhea, nausea, and vomiting. The median TEAE duration was 1.9 weeks, 0.4 weeks, and 0.5 weeks for TEAEs related to pirfenidone, nintedanib, and the combination therapy, respectively. In the 13 patients who discontinued treatment, TEAEs were attributed to nintedanib alone in 10 patients, both pirfenidone and nintedanib in 1 patient, and unrelated to either treatment in 2 patients.
In addition, 18 patients (20%) experienced severe (grade ≥3) TEAEs; in 6 patients (7%) this was considered related to the study treatment. In the study, 2 patients experienced 1 serious TEAE each, both attributed to nintedanib alone: 1 patient had a transient ischemic attack but continued on the combination therapy without dose modification, and 1 patient experienced deep vein thrombosis and discontinued nintedanib but continued pirfenidone therapy. No fatal TEAEs occurred during the study.
The study was limited by the lack of a control or comparator group and the small sample size. Furthermore, only patients who tolerated pirfenidone were included in the study, which could have introduced bias towards patients less likely to experience TEAEs. Patients with more advanced disease were also excluded from the study.
Disclosures: This trial was funded by F. Hoffmann-La Roche, Ltd, and several authors received financial support from various pharmaceutical companies.
Flaherty KR, Fell CD, Huggins JT, et al. Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis [published online June 25, 2018]. Eur Respir J. doi:10.1183/13993003.00230-2018