The INBUILD trial was a phase 3 clinical study that tested whether nintedanib, an antifibrotic drug already approved for idiopathic pulmonary fibrosis (IPF), could slow lung function decline in patients with other types of progressive fibrosing interstitial lung disease. The answer was yes: over 52 weeks, patients on nintedanib lost roughly 81 milliliters of lung capacity per year compared with about 188 milliliters per year in the placebo group, a difference of about 107 milliliters per year. That result, published in the New England Journal of Medicine in 2019, changed how clinicians think about fibrotic lung disease and led to new regulatory approvals and treatment guidelines worldwide.
The Problem INBUILD Set Out to Solve
Interstitial lung diseases are a broad family of conditions in which the tissue between the air sacs of the lungs becomes inflamed or scarred. The most well-known form, IPF, already had two approved antifibrotic treatments by the mid-2010s: nintedanib and pirfenidone. But many other interstitial lung diseases can also develop a progressive, scarring course. Conditions like chronic hypersensitivity pneumonitis, autoimmune-related lung disease, nonspecific interstitial pneumonia, and even sarcoidosis sometimes enter a phase where the lungs keep scarring despite standard treatment. When that happens, the outlook can be just as grim as untreated IPF, with irreversible loss of lung function, worsening quality of life, and shortened survival.1PubMed Central. Epidemiology and Prognosis of Progressive Pulmonary Fibrosis: A Literature Review
Before INBUILD, there was no large randomized trial showing that an antifibrotic drug could help these non-IPF patients once fibrosis started progressing. Clinicians often tried immunosuppressants or anti-inflammatory drugs, but for many patients the scarring continued regardless. The central question INBUILD asked was whether the progressive fibrotic behavior itself, rather than the specific diagnosis driving it, could be the treatment target.
How Nintedanib Works
Nintedanib blocks a family of receptor tyrosine kinases involved in fibrosis, particularly the receptors for platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF). In lab studies, this translated into interference with several key steps in the scarring process: the proliferation and migration of fibroblasts, their transformation into more aggressive cell types, and the deposition of excess extracellular matrix, the structural material that builds up as scar tissue. Animal studies showed both anti-fibrotic and anti-inflammatory effects in the lungs.2PubMed Central. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis
Because these pathways are common to fibrosis regardless of what initially triggers it, there was biological plausibility that nintedanib might work across different interstitial lung diseases. The lung does not have an unlimited repertoire for scarring; once fibrosis takes hold, the downstream machinery looks similar whether the initial insult was an autoimmune attack, a hypersensitivity reaction, or something entirely unknown. INBUILD was designed to test that hypothesis.
Trial Design and Who Was Enrolled
INBUILD was a double-blind, placebo-controlled trial conducted in 15 countries. Patients were randomly assigned to receive either nintedanib 150 mg twice daily or a matching placebo.3PubMed. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases Enrollment criteria were deliberately broad: any physician-diagnosed interstitial lung disease other than IPF was eligible, as long as the patient had fibrosing disease affecting more than 10 percent of the lung on high-resolution CT, reasonable baseline lung function (forced vital capacity at least 45 percent of predicted, diffusing capacity between 30 and 80 percent of predicted), and evidence of disease progression in the previous 24 months despite management deemed appropriate in clinical practice.
Progression could be demonstrated in several ways: a relative decline in FVC of at least 10 percent of predicted; a smaller FVC decline of 5 to 10 percent combined with worsening symptoms; a similar FVC decline combined with increased fibrosis on imaging; or worsening symptoms plus increased fibrosis on imaging.4PubMed Central. Effects of nintedanib by inclusion criteria for progression of interstitial lung disease This multi-criteria approach reflected real clinical practice, where progression does not always announce itself through a single clean measurement.
Because patients with a usual interstitial pneumonia (UIP) pattern on CT tend to decline faster, randomization was stratified by CT pattern: roughly two-thirds of the 663 enrolled patients showed a UIP-like fibrotic pattern, and about one-third showed other patterns. The underlying diagnoses were diverse. The largest groups were chronic hypersensitivity pneumonitis (about 26 percent), autoimmune interstitial lung diseases (about 26 percent), idiopathic nonspecific interstitial pneumonia (about 19 percent), and unclassifiable interstitial pneumonia (about 17 percent), with the remainder spread across other conditions.5Modern Rheumatology. Progressive fibrosing interstitial lung diseases: A new concept and indication of nintedanib
The Primary Result
The primary endpoint was the annual rate of decline in FVC over 52 weeks. In the overall population, the adjusted rate of FVC decline was about 81 milliliters per year in the nintedanib group versus about 188 milliliters per year in the placebo group, a difference of 107 milliliters per year in favor of nintedanib. The result was highly significant statistically.6Modern Rheumatology. Progressive fibrosing interstitial lung diseases: A new concept and indication of nintedanib To put that in perspective, 107 milliliters per year may sound small in absolute terms, but in a disease where cumulative lung function loss steadily narrows a patient’s capacity to breathe, slowing the decline by more than half is clinically meaningful. Patients are losing breathing reserve they cannot get back, so every milliliter preserved extends the window before disability becomes severe.
The effect was especially pronounced in patients with a UIP-like fibrotic pattern on CT. In that subgroup, the adjusted rate of decline was about 83 milliliters per year with nintedanib versus about 211 milliliters per year with placebo, a difference of about 128 milliliters per year.7Modern Rheumatology. Progressive fibrosing interstitial lung diseases: A new concept and indication of nintedanib The faster a patient’s lung function is declining, the more room there is for an antifibrotic to slow things down.
Did It Work Across Different Diagnoses?
One of the most important questions INBUILD had to answer was whether the drug’s benefit was limited to certain types of interstitial lung disease or whether it applied broadly. Overall, the relative effect of nintedanib on slowing FVC decline was consistent across subgroups based on diagnosis, CT pattern, and baseline disease severity, and between patients who were or were not taking glucocorticoids or disease-modifying antirheumatic drugs at enrollment.8PubMed Central. Key learnings from the INBUILD trial in patients with progressive pulmonary fibrosis A subgroup analysis of patients with autoimmune disease-related progressive fibrosis found no evidence of any difference in the drug’s effect between diagnoses.9PubMed Central. Nintedanib in Patients With Autoimmune Disease–Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the INBUILD Trial
That said, when a systematic review and meta-analysis looked at the data more granularly, the picture was not perfectly uniform. The benefit was statistically clear in connective tissue disease-related interstitial lung disease (about 106 milliliters per year preserved), idiopathic nonspecific interstitial pneumonia (about 142 milliliters per year), and occupational interstitial lung disease (about 253 milliliters per year). However, the benefit did not reach statistical significance for fibrotic hypersensitivity pneumonitis, fibrotic sarcoidosis, or unclassifiable fibrotic interstitial lung disease.10Oxford Academic. Nintedanib in Progressive Pulmonary Fibrosis: A Systematic Review and Meta-Analysis The numbers for sarcoidosis and unclassifiable disease had very wide confidence intervals, reflecting small subgroup sizes rather than necessarily indicating the drug does not work. Hypersensitivity pneumonitis is a trickier case: the trend favored nintedanib, but the data left open the possibility of no benefit. Clinicians treating patients with these specific diagnoses face the most uncertainty when deciding whether to prescribe nintedanib, and real-world experience is still accumulating.
Acute Exacerbations and Mortality
Beyond slowing the steady decline in lung function, the trial also looked at acute exacerbations, which are sudden, often devastating worsenings of lung disease that can land patients in the hospital or prove fatal. In the overall trial population, about 14 percent of patients on nintedanib had an acute exacerbation or died, compared with about 20 percent on placebo. Among patients with a UIP-like pattern, the difference was larger: 15 percent on nintedanib versus about 23 percent on placebo.11European Respiratory Journal. Nintedanib in progressive interstitial lung diseases: data from the whole INBUILD trial
Mortality was lower in the nintedanib group numerically, with about 11 percent dying on nintedanib versus about 14 percent on placebo over the trial period, but this difference did not reach statistical significance.12European Respiratory Journal. Nintedanib in progressive interstitial lung diseases: data from the whole INBUILD trial Fifty-two weeks is a relatively short window in which to demonstrate a survival benefit, and the trial was not specifically powered to detect one. A cost-effectiveness analysis that modeled outcomes over a longer horizon estimated that over ten years, nintedanib treatment would yield about 1.3 additional discounted life years and about 0.87 additional quality-adjusted life years per patient, at an incremental cost-effectiveness ratio of about €60,690 per quality-adjusted life year.13PubMed Central. Cost-Effectiveness of Nintedanib for Patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
What Patients Actually Felt
Lung function numbers matter, but what patients notice day to day matters just as much. INBUILD used a patient-reported outcome tool called the Living with Pulmonary Fibrosis (L-PF) questionnaire to track symptoms over the 52-week period. Scores worsened in both groups, as you would expect in a progressive disease, but the worsening was substantially smaller in the nintedanib group. The total symptom score increased by about 1.3 points in the nintedanib group versus about 5.3 in the placebo group. Dyspnea scores worsened by about 4.3 points on nintedanib versus 7.8 on placebo. For fatigue, the gap was even wider: a 0.7-point increase on nintedanib compared with 4.0 on placebo. Cough scores actually improved slightly in the nintedanib group while worsening in the placebo group.14European Respiratory Journal. Effects of nintedanib on symptoms in patients with progressive pulmonary fibrosis
These differences are not dramatic in isolation, but for patients already struggling to breathe, the cumulative effect of slower deterioration across multiple symptom domains adds up to a meaningful difference in daily life over months and years.
Safety and Side Effects
Nintedanib’s biggest drawback is gastrointestinal side effects, and INBUILD confirmed this in a non-IPF population. Diarrhea was reported in about 72 percent of patients on nintedanib versus about 26 percent on placebo. The diarrhea was severe enough to cause treatment discontinuation in about 6 percent of nintedanib patients. Nearly half (about 48 percent) of nintedanib patients needed at least one dose reduction or temporary treatment interruption, compared with about 16 percent on placebo.15PubMed Central. Safety and tolerability of nintedanib in patients with progressive fibrosing interstitial lung diseases: data from the randomized controlled INBUILD trial
These numbers sound alarming at first, but the dose-adjustment strategy is an expected part of treatment. Many patients can manage side effects with antidiarrheal medication, dietary changes, and temporary dose reductions without losing the overall benefit. The safety profile was consistent with what had already been seen in IPF trials, so clinicians were not facing unfamiliar risks.
Long-Term Data From the Extension Study
The original trial ran for 52 weeks. An open-label extension study called INBUILD-ON followed patients for additional time on nintedanib. The median exposure to nintedanib during the extension was 22 months. The safety profile remained consistent: diarrhea was still the most common adverse event, with about 90 percent of cases being mild or moderate. Adverse events led to treatment discontinuation at a rate of about 17 per 100 patient-years.16PubMed Central. Continued Treatment with Nintedanib in Patients with Progressive Pulmonary Fibrosis: Data from INBUILD-ON
The extension study also revealed an interesting pattern in lung function trajectories. Patients who had been on nintedanib from the start of the original trial continued to lose lung function at a rate consistent with what was seen during INBUILD itself, about 129 milliliters over 48 weeks in the extension. But patients who switched from placebo to nintedanib at the start of the extension showed a much smaller decline of only about 15 milliliters over the same period.17PubMed Central. Continued Treatment with Nintedanib in Patients with Progressive Pulmonary Fibrosis: Data from INBUILD-ON That difference probably reflects a selection effect: patients who had already been on placebo for a year and still survived with enough lung function to enter the extension may have had inherently slower-progressing disease. But the long-term data overall supported continued use of nintedanib beyond the initial trial period.
Using Nintedanib Alongside Immunomodulatory Drugs
A practical question for many patients is whether nintedanib can be combined with the immunosuppressive or immunomodulatory therapies already being used for conditions like rheumatoid arthritis-related lung disease or systemic sclerosis. A dedicated analysis of INBUILD data showed that nintedanib’s effect on slowing FVC decline was not influenced by whether patients were taking immunomodulatory therapies, and the combination was feasible.18PubMed Central. Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases This was reassuring, because many patients with autoimmune-driven interstitial lung disease are already on medications like mycophenolate or methotrexate and cannot simply stop them to start an antifibrotic.
How INBUILD Compared With IPF Trial Results
A natural question is whether nintedanib works as well in non-IPF progressive fibrosis as it does in IPF. A systematic review and meta-analysis of antifibrotic drugs in both IPF and non-IPF settings found no evidence of any difference in the standardized rate of FVC decline between the two groups. The effect size was virtually identical.19PubMed Central. Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both idiopathic pulmonary fibrosis (IPF) and non-IPF: a systematic review and meta-analysis This finding reinforced the idea that fibrosis, once it becomes self-sustaining, follows similar biological pathways regardless of what initially triggered it.
Pirfenidone, the other approved antifibrotic for IPF, has also been studied in non-IPF progressive fibrosis, though less extensively. A real-world comparative study found similar data in a progressive fibrosing interstitial lung disease subgroup, although the picture was more complicated in other subgroups and the evidence base is smaller.20Università di Siena Catalogo Ricerca. The impact of antifibrotic therapy in the management of idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases: a real-world comparative study of efficacy between pirfenidone and nintedanib INBUILD remains the definitive trial for nintedanib in this setting, and no equivalent large trial of pirfenidone in non-IPF progressive fibrosis has been completed.
Real-World Adherence Challenges
Trial results represent what happens under ideal conditions with motivated patients and close follow-up. Real-world use is messier. A study of antifibrotic treatment in Spain found that about 64 percent of nintedanib patients discontinued treatment during follow-up, compared with about 54 percent on pirfenidone. The main reason for stopping nintedanib was gastrointestinal side effects, while photosensitivity drove many pirfenidone discontinuations. Survival between the two groups was similar despite the difference in adherence.21BMJ Open Respiratory Research. Antifibrotic treatment adherence, efficacy and outcomes for patients with idiopathic pulmonary fibrosis in Spain: a real-world evidence study
These discontinuation rates highlight a gap between trial efficacy and clinical effectiveness. A drug that works well but that a substantial fraction of patients cannot tolerate long-term needs proactive management: early counseling about gastrointestinal side effects, prompt use of supportive medications, and willingness to adjust doses rather than abandon treatment entirely.
The Shift Toward Treating the Behavior, Not Just the Diagnosis
Perhaps the most significant legacy of INBUILD is conceptual rather than pharmacological. Before the trial, pulmonologists organized their thinking around individual diagnoses. Each interstitial lung disease had its own treatment approach, and there was no unifying framework for dealing with progressive fibrosis across different causes. INBUILD provided the evidence to support a new concept now codified as progressive pulmonary fibrosis (PPF), defined by clinical symptoms, lung function trajectory, and imaging changes rather than by the specific underlying condition.22PubMed Central. Progressive Pulmonary Fibrosis: Where Are We Now?
This phenotype-based approach has implications well beyond nintedanib. Researchers developing novel antifibrotic drugs are now thinking in terms of targeting fibrotic behavior rather than specific diagnoses, and several emerging therapies under investigation are conceptually aligned with this strategy.23PubMed Central. Most Promising Emerging Therapies for Pulmonary Fibrosis: Targeting Novel Pathways The shift means that a patient with, say, progressive lung scarring from scleroderma and a patient with progressive scarring from an unknown cause can both be evaluated for antifibrotic therapy under the same framework, rather than waiting for a disease-specific trial that might never come.
Biomarkers and the Search for Precision
INBUILD also generated data that could eventually help clinicians predict who will progress fastest and who responds best to treatment. A biomarker analysis from the trial found that a blood marker called soluble ICAM (s-ICAM) was the only one with a statistically significant association with both the rate of FVC decline and the risk of disease progression or death over 52 weeks. Higher baseline s-ICAM levels correlated with faster decline. Separately, nintedanib treatment was associated with decreases in several other markers, including KL-6, SP-D, CA-125, and CA19-9, with CA-125 showing the largest change. A mediation analysis suggested that the drug-related decrease in CA-125 accounted for about 16 percent of nintedanib’s overall effect on lung function.24European Respiratory Journal. Circulating biomarkers in subjects with progressive pulmonary fibrosis: data from the INBUILD trial
A separate pilot study in patients receiving nintedanib identified five additional proteins that changed significantly during 12 months of treatment, some decreasing and others increasing. Several of these showed increasing ability to distinguish fibrosis patients from healthy individuals over the course of treatment, suggesting potential as monitoring tools.25PubMed Central. Circulating biomarkers in patients with progressive fibrosing interstitial lung disease treated with nintedanib: a pilot study None of these markers is ready for routine clinical use yet, but they represent progress toward a future where a blood test might help guide treatment decisions rather than relying solely on lung function measurements and CT scans that capture damage only after it has occurred.