INBUILD – Nintedanib in Progressive Fibrosing Interstitial Lung Diseases
Kevin R. Flaherty, M.D., Athol U. Wells, M.D., Vincent Cottin, M.D., et al., for the INBUILD Trial Investigators
N Engl J Med 2019; 381:1718-1727. [Full text]
Summary by Michelle Duong
Progressive fibrosing lung diseases, which includes idiopathic pulmonary fibrosis (IPF), are associated with significant morbidity and mortality owing to progressive decline in lung function, worsening of symptoms, and decreased quality of life. Given the clinical similarities of various fibrosing lung diseases, it has been hypothesized that there is a common pathophysiology contributing to progressive pulmonary fibrosis that would respond to similar treatment [1].
Nintedanib is a tyrosine kinase inhibitor, which inhibits multiple immune signaling pathways, and hence could play a role in lung fibrosis [2]. The INPULSIS trials showed that nintedanib reduces the decline in forced vital capacity (FVC) relative to placebo in patients with IPF [3]. The goal of the INBUILD trial was to investigate the efficacy of nintedanib in patients with progressive fibrosing interstitial lung diseases (ILD) not limited to IPF.
Patient population and Design
Eligible adults were ≥18 years of age with fibrosing lung disease features affecting >10% of lung volume on high resolution (HR) CT confirmed with central review, FVC of >45% of predicted, and DLCO of 30 to <80% of predicted. Radiographic features included reticular abnormalities with traction bronchiectasis, honeycombing, ground glass opacities, upper lung or peribronchovascular predominance, mosaic attenuation, air trapping, and centrilobular nodules. Participants also had to meet at least one of the following criteria for progression within 24 months prior to screening, despite standard treatment:
- ↓FVC of >10% of predicted
- ↓FVC of 5 to <10% of predicted and worsening of respiratory symptoms, or an increased extent of fibrosis on HRCT
- Worsening of respiratory symptoms and increased extend of fibrosis
Recruitment occurred between 2/2017-4/2018 in 15 countries. Patients were randomly assigned to receive oral nintedanib 150mg twice daily or placebo. Patients were followed for 52 weeks. Patients who experienced adverse events were permitted to interrupt treatment or reduce nintedanib dose to 100mg twice daily. Spirometry was done at baseline and at weeks 2, 4, 6, 12, 24, 36, and 52. Patients also completed the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire at baseline and week 52. This K-BILD questionnaire is a 15-item questionnaire regarding ILD patients’ health-related quality of life in regards to activity level, psychological factors, and respiratory symptoms [4].
The primary endpoint was the annual rate of decline in FVC. The secondary endpoints were absolute change from baseline in total score on the K-BILD questionnaire, time until first acute exacerbation of ILD or death over 52 weeks, and time until death over 52 weeks.
Results
1010 patients were assessed for eligibility and 663 underwent randomization to placebo (n = 331) and nintedanib (n=332). In the overall population, mean age was 66 years, mean FVC was 69% of predicted, and mean DLCO was 46% of predicted. The most prevalent etiologies of ILD were chronic hypersensitivity pneumonitis in 26% and autoimmune ILD in 26%. Baseline gender, age, smoking status, UIP prevalence, criteria met for disease progression, FVC, DLCO, and K-BILD scores were similar across both groups. Overall, 252 patients (76%) in nintedanib group and 282 patients (85%) in the placebo group completed 52 weeks of treatment.
The rate of FVC decline over the 52-week period was significantly less in the nintedanib group relative to the placebo group. In the overall population, the adjusted rate of decline in FVC over 52 weeks was -81 mL per year in the nintedanib group and -188mL per year in the placebo group (between-group difference 107 mL, 95% confidence interval, 65-149, P<0.001). This remained statistically significant even when stratified for UIP-like fibrosis and other fibrotic patterns.
The change in total score on the K-BILD questionnaire was not statistically significant between the two groups, even when stratified for fibrotic patterns. There was not a statistically significant difference between the patients in the nintedanib and placebo groups who had an acute ILD exacerbation or died over the 52-week study period.
Diarrhea was the most common adverse event, as reported by 67% of nintedanib patients and 24% of the placebo patients. Elevates transaminases (defined as liver enzymes that were at least three times the upper limit of normal) were more common in patients treated with nintedanib (14%) relative to placebo (2%), but reversed upon dose reduction or treatment interruption.
Discussion
The INBUILD trial demonstrated that patients with chronic progressive fibrosing ILD who received nintedanib had a slower disease progression as evidenced by the lower annual FVC decline over the 52-week study period. Nintedanib was associated with higher frequency of GI upset as an adverse effect. Of note, this slowing of disease progression was not associated with meaningful change in quality of life as measured by the K-BILD questionnaire.
One of the major limitations of this trial is that it lumps together many different patients with various forms of progressive fibrosing ILD [5]. The underlying etiology leading to ILD influences the survival. There are efficacious treatments for certain ILDs that would slow progression, such as changes in environmental exposures for hypersensitivity pneumonitis and use of disease-modifying modulating agents in autoimmune ILD. Furthermore, the gold standard for diagnosis is lung biopsy but the diagnoses in this trial were based on imaging findings [5]. Participant eligibility for inclusion and exclusion might have been altered based on pathology results, but this is more reflective of real world practice as lung biopsy for ILD is rare. Another limitation is that, while this was an international study spanning multiple continents, there was limited mention of the demographic breakdown and whether there was a difference in outcomes relative to race or location.
Despite its limitations, the INBUILD trial was the largest, double-blinded, placebo controlled RCT that evaluated the effect of nintedanib on other progressive fibrosing ILDs beyond IPF. In response to the limitations, the authors did a follow up analysis that further stratified the data based on ILD diagnoses of chronic hypersensitivity pneumonitis, autoimmune ILD, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs [6]. While the original study was not designed and therefore powered for such subgroup analyses, the authors did find that nintedanib reduced the rate of ILD progression as measured by FVC decline in patients with chronic progressive fibrosing ILD even when stratified for underlying ILD diagnoses [6].
For now, real world practice likely remains focusing on modifiable or underlying etiologies (i.e. hypersensitivity pneumonitis). Otherwise it often begins with a steroid sparing agent that is well tolerated, such as mycophenolate, with nintedanib reserved who have progression despite such treatment.
| F: Follow up | Yes |
| R: Randomization | Yes |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes |
| S: Source (funding) | Boehringer Ingelheim (pharma) |
- Wells AU, Brown KK, Flaherty KR, Kolb M, Thannickal VJ. What’s in a name? That which we call IPF, by any other name would act the same. Eur Respir J 2018;51(5):1800692-1800692.
- Wollin L, Wex E, Pautsch A, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2015;45:1434-1445.
- Richeldi L, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. The New England Journal of Medicine. 2014. 370(22):2071-2082.
- Patel AS, Siegert RJ, Brignall K, et al. The development and validation of the King’s Brief Interstitial Lung Disease (K-BILD) health status questionnaire. Thorax 2012;67:804-810.
- Raghu G, Fabre A, Kao JH, Huang HT, Li KJ. Correspondence: Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. New England Journal of Medicine. 2020. 382(8),779-781.
- Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al.. Nintedanib in Patients with Progressive Fibrosing Interstitial Lung Diseases-Subgroup Analyses by Interstitial Lung Disease Diagnosis in the INBUILD Trial: a Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Trial. Lancet Respir. Med. 2020; 8, 453–460. 10.1016/S2213-2600(20)30036-9
