Comparative efficacy and safety of monotherapy and combination pharmacotherapies for idiopathic pulmonary fibrosis: a network meta-analysis of randomized controlled trials.

BACKGROUND

Idiopathic pulmonary fibrosis (IPF) is a fatal, progressive fibrosing lung disease. While novel agents and combinations are emerging, head-to-head trials are scarce, underscoring the need for robust comparative evidence to guide treatment prioritization.

METHODS

We conducted a systematic review and network meta-analysis (NMA) of IPF RCTs in adults, searching PubMed, Embase, Cochrane Library, and Web of Science through 1 December 2025. Eligible studies compared pharmacotherapies (mono/combination) with placebo or active comparators and reported prespecified outcomes. Primary outcomes were forced vital capacity (FVC) change and disease progression; secondary outcomes included all-cause mortality, adverse events (AEs), serious AEs (SAEs), and DLCO change. Risk of bias was assessed via RoB 2, with frequentist random-effects NMA for continuous/binary outcomes and a random-effects model for disease progression. Treatment rankings used SUCRA, and evidence certainty was evaluated via GRADE with CINeMA.

RESULTS

Thirty-five reports (8,983 participants, 21 strategies) were included. RoB 2 ratings were low (19 studies) or raised some concerns (16). For FVC preservation, recombinant human pentraxin-2 (RHP) (SMD = 0.72, 95% CI: 0.23-1.20), rentosertib (SMD = 0.63, 95% CI:0.04-1.22), and nintedanib (SMD = 0.50, 95% CI:0.27-0.73) showed the highest statistical probability of benefit versus placebo, though these rankings are based primarily on low-certainty indirect comparisons. For disease progression, pirfenidone, pamrevlumab, and nerandomilast showed favorable but imprecise effects. No regimen significantly reduced all-cause mortality or showed clear AE/SAE differences versus placebo, with wide uncertainty in comparisons. Evidence certainty was mostly low to very low, driven by imprecision and indirect comparisons in star-shaped networks.

CONCLUSIONS

RHP, rentosertib, and nintedanib showed consistent signals for preserving FVC versus placebo. However, comparative effects on progression, mortality, and safety remain uncertain due to sparse data and limited head-to-head evidence. Large, well-designed trials with harmonized endpoints and longer follow-up are needed to validate these exploratory rankings and define optimal treatment sequencing and combinations.

REGISTRATION: PROSPERO CRD420261289653.