Abstract
<title>Abstract</title> <p> Background Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease associated with relentless decline in lung function, impaired quality of life, and high mortality despite currently available antifibrotic therapies. Although pirfenidone and nintedanib slow disease progression, tolerability issues, particularly gastrointestinal adverse effects with high-dose pirfenidone, frequently limit treatment adherence. The OPTIMA-IPF (Optimizing Antifibrotic Therapy in Idiopathic Pulmonary Fibrosis) Study evaluated whether combining low-dose pirfenidone with nintedanib provides superior long-term clinical efficacy and tolerability compared with high-dose pirfenidone or nintedanib monotherapy. Methods The OPTIMA-IPF Study was a prospective, randomized, single-centre comparative study with 36 months of follow-up (Institutional Review Board approval VCC:012/2022). Eighty-four patients with IPF diagnosed according to ATS/ERS clinical-radiological criteria were equally allocated to three treatment groups (n = 28 each): high-dose pirfenidone (1,800–2,400 mg/day according to tolerance), nintedanib (100 mg three times daily), or combination therapy comprising nintedanib (100 mg three times daily) plus low-dose pirfenidone (400 mg three times daily). All participants had baseline forced vital capacity (FVC) > 50% predicted and received standard supportive care, including influenza and pneumococcal vaccination. Clinical assessment was performed monthly, pulmonary function testing every six months, and high-resolution computed tomography annually. Primary analyses compared exercise capacity, pulmonary function, radiological progression, exacerbation frequency, adverse events, and mortality after 36 months using chi-square, one-way ANOVA, and paired <italic>t</italic> -tests. Results The combination therapy group demonstrated significantly greater preservation of exercise capacity, with superior 6-minute walk distance and faster recovery of heart rate and oxygen saturation compared with both monotherapy groups (p = 0.0017 and p = 0.0038, respectively). Radiological progression was significantly reduced, with fewer patients demonstrating worsening fibrosis, central extension of disease, and extensive reticulation or honeycombing (p = 0.0019, p = 0.0060, and p = 0.0012, respectively). Lung function outcomes also differed significantly among treatment groups, with combination therapy achieving the highest proportion of patients with stable or improved FVC and the lowest proportion experiencing > 10% FVC decline (p = 0.0089). Annual exacerbation rates requiring hospitalization were significantly lower in the combination group (p = 0.0004). High-dose pirfenidone was associated with significantly greater nausea, vomiting, weight loss, anorexia, and treatment intolerance, whereas gastrointestinal adverse events were substantially less frequent with combination therapy and nintedanib alone. During follow-up, disease-related mortality occurred in five patients receiving pirfenidone and three patients each receiving nintedanib monotherapy and combination therapy. Conclusions The OPTIMA-IPF Study demonstrates that combining low-dose pirfenidone with nintedanib provides clinically meaningful long-term benefits over high-dose pirfenidone and offers incremental advantages over nintedanib monotherapy by improving functional capacity, preserving lung function, reducing radiological progression and exacerbation risk, while maintaining superior gastrointestinal tolerability. These findings suggest that low-dose pirfenidone may serve as an effective adjunct to nintedanib, improving treatment adherence and potentially optimizing long-term outcomes in patients with idiopathic pulmonary fibrosis. </p>