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Cited by 141Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisChronic Obstructive Pulmonary Disease (COPD) ResearchPulmonary Hypertension Research and Treatments

Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis

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Flaherty, Kevin R., Fell, Charlene D., Huggins, J. Terrill, Nunes, Hilario, Sussman, Robert, Valenzuela, Claudia, Petzinger, Ute, Stauffer, John L. +3 more·2018·European Respiratory Journal
DOI 10.1183/13993003.00230-2018PMC PMC6092682
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Abstract

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.

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  • Background nintedanib was not allowed because previous small clinical trials assessing the combination of nintedanib and pirfenidone have shown high rates of adverse events and discontinuation that could have compromised study integrity.

    “Background nintedanib was not allowed because previous small clinical trials assessing the combination of nintedanib and pirfenidone have shown high rates of adverse events and discontinuation that could have compromised study integrity.17,18”

    From Deupirfenidone Compared with Pirfenidone and Placebo in Idiopathic Pulmonary Fibrosis (ELEVATE-IPF): a Phase 2b Randomized Placebo-Controlled Trial (2026) · cites this paper as [18]

    The Results report adverse events in 88 of 89 patients and discontinuation due to adverse events in 13 patients (15%). But the Discussion concludes that most patients tolerated the combination and that discontinuation rates were similar to those expected with either drug alone. The paper does not say these rates threatened another study’s integrity or explain a decision to prohibit background nintedanib. Page numbers were not provided in our copy. (LLM, conf=0.86)

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  1. [27]Lalla D, Bengston L, Raimundo K, et al. Pirfenidone and nintedanib compliance and persistence in a real world setting [poster presentation at the American Thoracic Society Conference 2017]. Am J Respir Crit Care Med 2017; 195: A5351.

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Authors
Flaherty, K. R., Fell, C. D., Huggins, J. T., Nunes, H., Sussman, R., Valenzuela, C., Petzinger, U., Stauffer, J. L., Gilberg, F., Bengus, M., & Wijsenbeek, M.
Affiliations
  • University of Michigan (US)
  • University of Calgary (CA)
  • Medical University of South Carolina (US)
  • Overlook Medical Center (US)
  • Hospital Universitario de La Princesa (ES)
  • Genentech (US)
  • F. Hoffmann-La Roche AG (CH)
  • Erasmus MC (NL)
ORCID
Venue
European Respiratory Journal
Publisher
European Respiratory Society (ERS)
Published
2018-06-25
Volume
52
Issue
2
Pages
1800230
ISSN
  • 0903-1936 (ISSN-L)
  • 1399-3003
DOI
10.1183/13993003.00230-2018
PMC
PMC6092682
OpenAlex
W2810699055
Cited by
141
References
27
Citations by year
2026: 13 · 2025: 14 · 2024: 24 · 2023: 20 · 2022: 15 · 2021: 16 · 2020: 15 · 2019: 21 · 2018: 3
FWCI
10.36
Type
journal article
Language
en
Update notices
correction (2018-10-04)
Open access
Licence
cc-by-nc
Locations
  • European Respiratory Journal (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
Funders
F. Hoffmann-La Roche
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
Keywords
idiopathic pulmonary fibrosis, nintedanib, pirfenidone, combination therapy, drug safety, tolerability, treatment-emergent adverse events, antifibrotic agents
MeSH terms
Aged, Anti-Inflammatory Agents, Non-Steroidal, Drug Therapy, Combination, Female, Humans, Indoles, Lung, Male, Middle Aged, Pyridones, Vital Capacity, Treatment Outcome, Internationality, Idiopathic Pulmonary Fibrosis

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