Safety Of Nintedanib In Patients Research Articles

Design of a randomised controlled hybrid trial of nintedanib in patients with progressive myositis-associated interstitial lung disease.

The Myositis Interstitial Lung Disease Nintedanib Trial (MINT) is a hybrid trial, which is enrolling patients both at local sites and remotely via a decentralised site. The trial will investigate the efficacy and safety of nintedanib in patients with progressive myositis-associated interstitial lung disease (MA-ILD). MINT is an exploratory, prospective randomised placebo-controlled trial. Eligible patients will have myositis and evidence of fibrosing ILD on high-resolution computed tomography (HRCT), be taking standard of care medications for myositis, and meet criteria for ILD progression within the prior 24months based on decline in FVC, worsened fibrosis on HRCT, and/or worsened dyspnoea. Patients will be randomised 1:1 to receive nintedanib 150mg twice daily or placebo for 12weeks then open-label nintedanib for 12weeks. Patients will be enrolled at local sites and a decentralised site. Most study visits will be completed remotely using telemedicine or digital health technologies. The primary endpoint is the change in Living with Pulmonary Fibrosis (L-PF) questionnaire dyspnoea domain score at week 12. Other endpoints include changes in other L-PF questionnaire domains, lung function, imaging, and physical activity, and assessment of adverse events. Data collected using remote versus clinic enrolment, and using home versus clinic spirometry, will be compared. MINT is an innovative, hybrid trial that will evaluate the effects of nintedanib on symptoms, quality of life, and ILD progression in patients with progressive MA-ILD and provide valuable information on the utility of decentralised recruitment and remote data collection in clinical trials. Clinicaltrials.gov NCT05799755 (date of registration: 05/04/2023).

Safety and efficacy of nintedanib as second-line therapy for patients with differentiated or medullary thyroid cancer progressing after first-line therapy. A randomized phase II study of the EORTC Endocrine Task Force (protocol 1209-EnTF).

Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.

Efficacy and Safety of Nintedanib in Patients with Interstitial Lung Disease with or without Systemic Sclerosis: A Meta-Analysis.

Nintedanib is a potent intracellular inhibitor of tyrosine kinases and modulates the pathways involved in the development of fibrosis. We assessed nintedanib efficacy and safety in interstitial lung disease (ILD) patients. We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Register to identify available articles (up to April 2022). We conducted a meta-analysis of randomized controlled trials (RCTs) examining nintedanib efficacy and safety in patients with ILD with or without systemic sclerosis (SSc). Meta-analysis of five RCTs including 2,470 patients with ILD (1,343 nintedanib group and 1,127 controls) revealed that the annual rate of change in forced vital capacity (FVC) was significantly lower in the ILD group than in the control group (standardized mean difference [SMD] = 0.336; 95% confidence interval (CI) = 0.256-0.416, P<0.001). Stratification by disease type showed a low annual rate of change in FVC in patients with and without SSc (SMD = 0.389, 95% CI=0.294-0.478, P<0.001; SMD=0.177, 95% CI=0.013-0.340, P<0.00). The incidence of serious adverse events did not differ between the nintedanib and placebo groups; however, adverse events (AEs) and withdrawals due to AEs were significantly higher in the nintedanib group than in the placebo group (SMD =2.365, 95% CI=1.673-3.343, P<0.001; SMD =1.740, 95% CI= 1.385-2.185, P<0.001). Nintedanib is effective for ILD with or without SSc. However, it increased the incidence of AEs and withdrawals due to AEs.

Efficacy and safety of nintedanib in patients with non-small cell lung cancer, and novel insights in radiation-induced lung toxicity.

Nintedanib is a tyrosine kinase inhibitor of fibroblast growth factor-, vascular endothelial growth factor-, and platelet-derived growth factor receptors. These three receptors promote new blood vessel formation and maintenance, which is essential for tumor growth and spread. Several trials have shown that nintedanib plays a substantial role in treating patients with non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis. Recently, several clinical trials of nintedanib to treat NSCLC have been reported. In this review, we focus on our current understanding of nintedanib treatment for advanced NSCLC patients and summarize the literature on using nintedanib in radiation-induced lung toxicity and the efficacy and tolerability of nintedanib.

Nintedanib could potentially lead to improvements in anti-melanoma differentiation-associated 5 dermatomyositis-associated interstitial lung disease.

To determine the efficacy and safety of nintedanib in patients with anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis-associated interstitial lung disease (anti-MDA5+ DM-ILD). The study was a retrospective cohort design that evaluated patients with anti-MDA5+ DM who either received or did not receive nintedanib. Clinical symptoms, laboratory tests, and survival were compared in the two groups using a propensity score-matched analysis. The primary endpoint was mortality, while adverse events were recorded descriptively. After propensity score matching, 14 patients who received nintedanib (nintedanib+ group) and matched 56 patients who did not receive nintedanib (nintedanib- group) were enrolled. Compared with the nintedanib- group, the nintedanib+ group had a lower incidence of heliotrope and arthritis, higher lymphocyte counts, lower serum ferritin levels, and greater 12-month survival (all p<0.005). Although lung function, HRCT score, and lung VAS were not statistically different between the two groups, the longitudinal study showed significant improvement in HRCT scores (p=0.028) and pulmonary VAS (p=0.019) in the nintedanib+ group. Adverse events occurred in 28.6% of patients, with the most common adverse event with nintedanib being diarrhoea. Nintedanib may be effective for improving clinical symptoms, laboratory parameters, lung lesions, and survival in anti-MDA5+ DM. Diarrhoea was the most common adverse event associated with nintedanib, although the drug was well tolerated by most patients.

Efficacy and Safety of Nintedanib in Patients with Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD): A Real-World Single Center Experience.

Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) is a severe and fatal manifestation of systemic autoimmune disorders. Therapies rely on immunomodulators but their efficacy in ILD progression remains uncertain. Nintedanib, an antifibrotic agent that slows pulmonary function decline, has been approved for CTD-ILD treatment. The aim of this study was to assess the effectiveness and safety of nintedanib in CTD-ILD patients in a real-world data setting. A single-center, retrospective, and descriptive analysis of CTD-ILD patients treated with nintedanib from June 2019 to November 2022 was performed. The assessment of nintedanib treatment's efficacy was judged solely on the evolution of pulmonary function tests (PFTs), which were evaluated before and after treatment. Twenty-one patients (67% females, median age 64 years (IQR = 9) with CTD-ILD (systemic sclerosis n = 9, rheumatoid arthritis n = 5, dermatomyositis n = 4, juvenile rheumatoid arthritis n = 1, undifferentiated CTD n = 1, interstitial pneumonia with autoimmune features n = 1), 18 of whom were on concomitant immunosuppressives, had a median follow-up period of 10 months (IQR = 5). PFTs before and after treatment did not significantly differ. The mean FVC% difference was +0.9 (sd = 7.6) and the mean DLco% difference was +3.4 (sd = 12.6), suggesting numerical improvement of PFTs. The average percentage change was -0.3% and +7.6% for FVC% and DLco%, respectively, indicating stabilization of lung function. Our real-world data across a broad spectrum of CTD-ILD suggest that nintedanib could be beneficial in combination with immunosuppressives in slowing the rate of lung function decline.

A Narrative Review of Real-World Data on the Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis.

Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF) and other progressive fibrosing interstitial lung diseases. Placebo-controlled trials showed that the adverse event profile of nintedanib was characterised mainly by gastrointestinal events, particularly diarrhoea. We review the data from all published real-world studies of the safety of nintedanib in patients with IPF. These real-world data were consistent with the safety profile observed in clinical trials and described in the product label. The most common adverse events were diarrhoea, nausea and vomiting, but these infrequently led to permanent treatment discontinuation. Liver enzyme elevations were observed, supporting the recommendation for regular monitoring of liver enzymes, particularly in the first few months of treatment. Bleeding and cardiovascular adverse events were rarely reported. As in clinical trials, in real-world studies, reductions of the nintedanib dose, treatment interruptions and use of anti-diarrhoeal medications were frequently employed to manage adverse events. Few data are available on the use of nintedanib in patients who are elderly or have advanced disease, but there are some data to suggest a greater rate of treatment discontinuation in these patients. Effective management of adverse events associated with nintedanib is important to minimise their impact.

Observational, Multicenter Study on the Efficacy, Tolerability, and Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis Older than 80 Years

Background: Idiopathic pulmonary fibrosis (IPF) primarily affects old patients. Old age is a predictor of mortality. Nintedanib, the only antifibrotic drug approved in Italy for patients aged >80 years, can slow the progression of IPF by reducing the rate of decline in forced vital capacity (FVC) and the risk of exacerbations. Objectives: The primary aim of the study was to compare the decline of FVC after 12 months of nintedanib in patients aged >80 years versus younger patients. Differences related to other functional data, safety, tolerability, hospitalizations, exacerbations, and mortality were evaluated. Methods: An observational, retrospective, multicenter study was carried out in Italy. Results: 159 (122 [76.7%] males) patients were recruited: 106 (66.7%) aged ≤80 years and 53 (33.3%) aged >80 years. FVC decline after 12 months of therapy was not significantly different (−45 mL [−170; 75] vs. −20 mL [−138; 110] mL; p: 0.51). No differences were found for other functional data. Diarrhea was the most frequent adverse event (AE). Rate and type of any AEs, permanent/temporary dose reduction, or drug discontinuation were not significantly different between patients aged ≤80 vs. >80 years. Furthermore, acute exacerbations, hospitalization, and mortality were not significantly different. Conclusions: Nintedanib is effective and safe in patients with IPF aged >80 years, and no significant differences were found when clinical outcomes were compared with those of younger patients. Thus, older age should not be a barrier for the early prescription of antifibrotic treatment in IPF patients.

Nintedanib in Patients With Autoimmune Disease-Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the INBUILD Trial.

ObjectiveTo analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease–related interstitial lung diseases (ILDs) with a progressive phenotype.MethodsThe INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high‐resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol‐defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease–related ILDs.ResultsAmong 170 patients with autoimmune disease–related ILDs, the rate of decline in FVC over 52 weeks was −75.9 ml/year with nintedanib versus −178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively.ConclusionIn the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease–related ILDs, with AEs that were manageable for most patients.

Impact of lung function decline on time to hospitalisation events in systemic sclerosis-associated interstitial lung disease (SSc-ILD): a joint model analysis

BackgroundInterstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc. A decline in forced vital capacity (FVC) is an indicator of ILD progression and is associated with mortality in patients with SSc-associated ILD (SSc-ILD). However, the relationship between FVC decline and hospitalisation events in patients with SSc-ILD is largely unknown. The objective of this post hoc analysis was to investigate the relationship between FVC decline and clinically important hospitalisation endpoints.MethodsWe used data from SENSCIS®, a phase III trial investigating the efficacy and safety of nintedanib in patients with SSc-ILD. Joint models for longitudinal and time-to-event data were used to assess the association between rate of decline in FVC% predicted and hospitalisation-related endpoints (including time to first all-cause hospitalisation or death; time to first SSc-related hospitalisation or death; and time to first admission to an emergency room [ER] or admission to hospital followed by admission to intensive care unit [ICU] or death) during the treatment period, over 52 weeks in patients with SSc-ILD.ResultsThere was a statistically significant association between FVC decline and the risk of all-cause (n = 78) and SSc-related (n = 42) hospitalisations or death (both P < 0.0001). A decrease of 3% in FVC corresponded to a 1.43-fold increase in risk of all-cause hospitalisation or death (95% confidence interval [CI] 1.24, 1.65) and a 1.48-fold increase in risk of SSc-related hospitalisation or death (95% CI 1.23, 1.77). No statistically significant association was observed between FVC decline and admission to ER or to hospital followed by admission to ICU or death (n = 75; P = 0.15). The estimated slope difference for nintedanib versus placebo in the longitudinal sub-model was consistent with the primary analysis in SENSCIS®.ConclusionsThe association of lung function decline with an increased risk of hospitalisation suggests that slowing FVC decline in patients with SSc-ILD may prevent hospitalisations. Our findings also provide evidence that FVC decline may serve as a surrogate endpoint for clinically relevant hospitalisation-associated endpoints.Trial registrationClinicalTrials.govNCT02597933. Registered on 8 October 2015.

PRS3 Joint Modelling of Forced Vital Capacity Decline and Time to Hospitalization Outcomes in Systemic Sclerosis-Associated Interstitial Lung Disease

Joint modelling can be used to determine whether a biomarker can serve as a surrogate for a clinically important endpoint that may otherwise be difficult to measure, which is of particular relevance in rare diseases. We used this approach to assess the validity of forced vital capacity (FVC) decline as a surrogate endpoint for hospitalization-associated endpoints in systemic sclerosis-associated interstitial lung disease (SSc-ILD). Joint models for longitudinal and time-to-event data were applied to data from the Phase III SENSCIS® trial, which assessed the efficacy and safety of nintedanib in patients with SSc-ILD during the treatment period over 52 weeks. A joint model was fitted for each endpoint (time to first: "all-cause hospitalization or death”; “SSc-related hospitalization or death”; and “admission to emergency room [ER] or hospital followed by admission to intensive care unit [ICU] or death”). The “estimated slope” of FVC% predicted was the shared parameter, using all FVC values recorded during the SENSCIS® trial prior to hospitalization events. Independent implementations of the methodology with an available SAS macro and an R package were applied to validate the results. FVC decline had a statistically significant impact on the risk of all-cause and SSc-related hospitalizations or death (both P<0.0001). An FVC decrease of 5% corresponded with a 1.81-fold (95% confidence interval [CI] of hazard ratio [HR]: 1.42, 2.30) and 1.91-fold (95% CI of HR: 1.41, 2.60) increase in risk of “all-cause hospitalization or death” and “SSc-related hospitalization or death”, respectively. However, FVC decline did not impact the risk of “admission to ER or hospital followed by admission to ICU or death” (P=0.15). We found a consistent association between FVC decline and hospitalization-associated endpoints in patients with SSc-ILD. Our findings provide evidence that FVC decline may serve as a surrogate endpoint for clinically important hospitalization-associated endpoints.

Efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis who are elderly or have comorbidities

BackgroundIdiopathic pulmonary fibrosis (IPF) predominantly affects individuals aged > 60 years who have several comorbidities. Nintedanib is an approved treatment for IPF, which reduces the rate of decline in forced vital capacity (FVC). We assessed the efficacy and safety of nintedanib in patients with IPF who were elderly and who had multiple comorbidities.MethodsData were pooled from five clinical trials in which patients were randomised to receive nintedanib 150 mg twice daily or placebo. We assessed outcomes in subgroups by age < 75 versus ≥ 75 years, by < 5 and ≥ 5 comorbidities, and by Charlson Comorbidity Index (CCI) ≤ 3 and > 3 at baseline.ResultsThe data set comprised 1690 patients. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks versus placebo in patients aged ≥ 75 years (difference: 105.3 [95% CI 39.3, 171.2]) (n = 326) and < 75 years (difference 125.2 [90.1, 160.4]) (n = 1364) (p = 0.60 for treatment-by-time-by-subgroup interaction), in patients with < 5 comorbidities (difference: 107.9 [95% CI 65.0, 150.9]) (n = 843) and ≥ 5 comorbidities (difference 139.3 [93.8, 184.8]) (n = 847) (p = 0.41 for treatment-by-time-by-subgroup interaction) and in patients with CCI score ≤ 3 (difference: 106.4 [95% CI 70.4, 142.4]) (n = 1330) and CCI score > 3 (difference: 129.5 [57.6, 201.4]) (n = 360) (p = 0.57 for treatment-by-time-by-subgroup interaction). The adverse event profile of nintedanib was generally similar across subgroups. The proportion of patients with adverse events leading to treatment discontinuation was greater in patients aged ≥ 75 years than < 75 years in both the nintedanib (26.4% versus 16.0%) and placebo (12.2% versus 10.8%) groups. Similarly the proportion of patients with adverse events leading to treatment discontinuation was greater in patients with ≥ 5 than < 5 comorbidities (nintedanib: 20.5% versus 15.7%; placebo: 12.1% versus 10.0%).ConclusionsOur findings suggest that the effect of nintedanib on reducing the rate of FVC decline is consistent across subgroups based on age and comorbidity burden. Proactive management of adverse events is important to reduce the impact of adverse events and help patients remain on therapy.Trial registration: ClinicalTrials.gov NCT00514683, NCT01335464, NCT01335477, NCT02788474, NCT01979952.

Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial

Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial

Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial

In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients on stable treatment with mycophenolate for at least 6 months before randomisation could participate. The aim of this subgroup analysis was to examine the efficacy and safety of nintedanib by mycophenolate use at baseline. The SENSCIS trial was a randomised, double-blind, placebo-controlled trial, in which patients with SSc-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or placebo for at least 52 weeks. In a prespecified subgroup analysis, we analysed the primary endpoint of rate of decline in FVC over 52 weeks by mycophenolate use at baseline. In a post-hoc analysis, we analysed the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted at week 52 (proposed minimal clinically important difference estimate for worsening of FVC in patients with SSc-ILD) in subgroups by mycophenolate use at baseline. Adverse events were reported in subgroups by mycophenolate use at baseline. Analyses were done in all participants who received at least one dose of study drug. We analysed the annual rate of decline in FVC using a random coefficient regression model (with random slopes and intercepts) including anti-topoisomerase I antibody status, age, height, sex, and baseline FVC as covariates and terms for baseline-by-time, treatment-by-subgroup, and treatment-by-subgroup-by-time interactions. SENSCIS is registered with ClinicalTrials.gov, NCT02597933, and is now complete. Between Nov 30, 2015, and Oct 31, 2017, 819 participants were screened and 576 were enrolled, randomly assigned to, and treated with nintedanib (n=288) or placebo (n=288). 139 (48%) of 288 in the nintedanib group and 140 (49%) of 288 in the placebo group were taking mycophenolate at baseline. In patients taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -40·2 mL per year (SE 19·8) with nintedanib and -66·5 mL per year (19·3) with placebo (difference: 26·3 mL per year [95% CI -27·9 to 80·6]). In patients not taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -63·9 mL per year (SE 19·3) with nintedanib and -119·3 mL per year (19·0) with placebo (difference: 55·4 mL per year [95% CI 2·3 to 108·5]). We found no heterogeneity in the effect of nintedanib versus placebo on the annual rate of decline in FVC between the subgroups by mycophenolate use (p value for interaction=0·45). In a post-hoc analysis, the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted was lower with nintedanib than with placebo in both patients taking mycophenolate (40 [29%] of 138 vs 56 [40%] of 140; odds ratio 0·61 [0·37 to 1·01]) and those not taking mycophenolate (59 [40%] of 149 vs 70 [47%] of 148; 0·73 [0·46 to 1·16]) at baseline. The adverse event profile of nintedanib was similar between the subgroups. Diarrhoea, the most common adverse event, was reported in 106 (76%) of 139 patients in the nintedanib group and 48 (34%) of 140 in the placebo group among those taking mycophenolate at baseline, and in 112 (75%) of 149 in the nintedanib group and 43 (29%) of 148 in the placebo group among those not taking mycophenolate at baseline. Over the entire trial period, 19 patients died (ten in the nintedanib group and nine in the placebo group). One death in the nintedanib group was considered to be related to study drug. Nintedanib reduced the progression of interstitial lung disease both in patients with SSc-ILD who were and were not using mycophenolate at baseline, with no heterogeneity in its treatment effect detected between the subgroups. The adverse event profile of nintedanib was similar in the subgroups by mycophenolate use. Our findings suggest that the combination of mycophenolate and nintedanib offers a safe treatment option for patients with SSc-ILD. More data are needed on the benefits of initial combination therapy versus a sequential approach to treatment of SSc-ILD. Boehringer Ingelheim.

Efficacy and safety of nintedanib in Asian patients with systemic sclerosis-associated interstitial lung disease: Subgroup analysis of the SENSCIS trial.

In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% in comparison with placebo, with manageable adverse events in most patients. We analyzed the efficacy and safety of nintedanib in patients of Asian race. Patients with SSc-ILD were randomized to receive nintedanib or placebo. The outcomes over 52 weeks were analyzed in Asian versus non-Asian patients. Of the 288 patients in each treatment group, 62 (21.5%) in the nintedanib group and 81 (28.1%) in the placebo group were Asian; 90.2% of the Asian patients were enrolled in Asian countries. In the placebo group, the rate of FVC decline over 52 weeks was consistent between Asian and non-Asian patients (-99.9 and -90.6mL/year, respectively). The effect of nintedanib on reducing the rate of FVC decline over 52 weeks was consistent between Asian (difference, 44.3mL/year [95% CI: -32.8, 121.4]) and non-Asian patients (difference, 39.0mL/year [95% CI: -5.1, 83.1]) (treatment-by-time-by-subgroup interaction, p=0.91). Diarrhea was the most frequent adverse event and was reported in similar proportions of Asian and non-Asian patients in the nintedanib group (80.6% and 74.3%, respectively) and placebo group (28.4% and 32.9%, respectively). In patients with SSc-ILD, nintedanib had a consistent benefit on slowing the progression of SSc-ILD in Asian and non-Asian patients, with a similar adverse event profile. ClinicalTrials.gov NCT02597933.

Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Global Pharmacovigilance Data.

The safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) have been characterized using data from clinical trials. We further characterized the safety and tolerability of nintedanib in patients with IPF in clinical practice using the global pharmacovigilance database. The database included spontaneously reported adverse events and data collected via solicited reporting in patients treated with nintedanib from 15 October 2014 to 15 October 2018. Adverse events were coded using the Medical Dictionary for Regulatory Activities. Cumulative exposure to nintedanib was estimated on the basis of sales data. Cumulative exposure to nintedanib was estimated as 60,107 patient-years. Diarrhea was the most frequent event (301.6 events per 1000 patient-years). Most (97.0%) diarrhea events were non-serious. The median (25th, 75th percentile) time to onset of the first diarrhea event was 60 (11, 182) days. Elevated liver enzyme or bilirubin levels were reported at a rate of 31.5 events per 1000 patient-years. Bleeding was reported at a rate of 36.8 events per 1000 patient-years; 81.0% of events were non-serious. Major cardiovascular adverse events were reported at a rate of 13.4 events per 1000 patient-years and myocardial infarction at a rate of 4.3 events per 1000 patient-years. Gastrointestinal perforation was reported at a rate of 1.0 event per 1000 patient-years. On the basis of pharmacovigilance data collected over 4years, the safety profile of nintedanib in patients with IPF was consistent with that observed in clinical trials and described in the product label, with no new safety concerns observed.

THU0189 EFFICACY AND SAFETY OF NINTEDANIB IN PATIENTS WITH AUTOIMMUNE DISEASE-RELATED INTERSTITIAL LUNG DISEASE TREATED WITH DMARDS AND/OR GLUCOCORTICOIDS AT BASELINE

Background:In the INBUILD trial in patients with progressive fibrosing ILDs, nintedanib reduced the rate of decline in forced vital capacity (FVC) vs placebo over 52 weeks in the overall population and in the subgroup with autoimmune disease-related ILDs. Patients taking stable doses of medications to treat RA or CTD were eligible, but the protocol excluded enrolment of patients treated with azathioprine, cyclosporine, mycophenolate, tacrolimus, rituximab, cyclophosphamide, or oral glucocorticoids &gt;20 mg/day.Objectives:Assess the influence of DMARDs and/or glucocorticoids at baseline on the efficacy and safety of nintedanib in patients with progressive autoimmune disease-related ILDs.Methods:In patients with progressive autoimmune disease-related ILDs in the INBUILD trial, the rate of decline in FVC (mL/year) and adverse events (AEs) over 52 weeks of treatment (or until 28 days after last trial drug intake for patients who discontinued drug before week 52) were assessed in subgroups by use of DMARDs and/or glucocorticoids (any dose) at baseline (yes/no).Results:170 patients in the INBUILD trial (82 nintedanib, 88 placebo) had autoimmune disease-related ILDs (89 RA-ILD, 39 SSc-ILD, 19 MCTD-ILD, 23 other). The baseline characteristics of patients taking (n=131) and not taking (n=39) DMARDs and/or glucocorticoids are shown in the Table. All but 1 patient taking glucocorticoids at baseline was taking &lt;20 mg/day. The mean (SE) annual rate of decline in FVC in the placebo group was numerically greater in patients taking vs not taking DMARDs and/or glucocorticoids at baseline (Figure). The effect of nintedanib vs placebo on reducing the rate of decline in FVC was numerically more pronounced in patients taking vs not taking DMARDs and/or glucocorticoids at baseline, but the treatment-by-subgroup-by-time interaction p-values did not indicate heterogeneity in the effect of nintedanib between subgroups (Figure). In patients taking vs not taking DMARDs and/or corticosteroids at baseline, respectively, diarrhoea was reported in 59.4% and 77.8% of patients treated with nintedanib and 28.4% and 23.8% of patients treated with placebo. Serious AEs were more frequent in patients taking vs not taking DMARDs and/or glucocorticoids at baseline in both the nintedanib (39.1% vs 16.7%) and placebo (35.8% vs 19.0%) groups.Conclusion:In the INBUILD trial, the rate of FVC decline was numerically greater in placebo-treated patients who were taking DMARDs and/or glucocorticoids at baseline than in those who were not. The rate of FVC decline was slower in patients treated with nintedanib than placebo both in patients who were and were not taking DMARDs and/or glucocorticoids at baseline. Nintedanib had an acceptable safety profile both in patients who were and were not using DMARDs and/or glucocorticoids at baseline.DMARDs and/or glucocorticoids at baselineYes (n=131)No (n=39)Male, %51.930.8FVC, mL, mean (SD)2372 (718)2188 (619)ILD diagnosis, %RA-ILD60.325.6SSc-ILD15.348.7MCTD-ILD10.712.8Other13.712.8Biologic DMARDs, %15.3–Non-biologic DMARDs, %46.6–Glucocorticoids, %87.8–Most common biologic DMARDs, non-biologic DMARDs and glucocorticoids were abatacept (4.6%), hydroxychloroquine/hydroxychloroquine sulphate (19.8%) and prednisone (37.4%), respectively.Disclosure of Interests:Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly &amp; Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly &amp; Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB, Clive Kelly Consultant of: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, John Belperio: None declared, Alexandra James Employee of: Employee of Boehringer Ingelheim, Carl Coeck Employee of: Employee of Boehringer Ingelheim, Manuel Quaresma Employee of: Employee of Boehringer Ingelheim, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking

Efficacy and safety of nintedanib in patients with advanced idiopathic pulmonary fibrosis

BackgroundThe two 52-week INPULSIS trials investigated nintedanib versus placebo in patients with IPF, FVC ≥50% predicted and DLco 30–79% predicted. The 24-week INSTAGE trial investigated nintedanib plus sildenafil versus nintedanib alone in patients with IPF and DLco ≤35% predicted. We used data from INPULSIS and INSTAGE to compare the effects of nintedanib in patients with IPF with less versus more severe impairment in gas exchange at baseline.MethodsAnalyses were conducted in patients treated with nintedanib alone in the INPULSIS and INSTAGE trials and in patients treated with placebo in the INPULSIS trials. Outcomes included the rate of decline in FVC over 24 weeks, the proportions of patients who had a confirmed or suspected idiopathic acute exacerbation over 24 weeks, deaths over 24 weeks, and adverse events. Analyses were descriptive.ResultsIn total, 638 and 136 patients received nintedanib alone in the INPULSIS and INSTAGE trials, respectively, and 423 patients received placebo in the INPULSIS trials. Rates of FVC decline were − 52.3 and − 66.7 mL/24 weeks in patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and − 102.8 mL/24 weeks in patients treated with placebo in INPULSIS. Confirmed or suspected idiopathic acute exacerbations were reported in 0.6 and 3.7% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 2.1% of patients treated with placebo in INPULSIS. Deaths occurred in 2.0, 11.0 and 1.9% of patients in these groups, respectively. Diarrhoea adverse events were reported in 52.5 and 48.5% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 16.1% of patients treated with placebo in INPULSIS.ConclusionsBased on data from the INSTAGE and INPULSIS trials, nintedanib had a similar effect on FVC decline over 24 weeks, and a similar safety and tolerability profile, in patients with IPF and more versus less severe impairment in gas exchange. These data support the use of nintedanib in patients with IPF who have advanced disease.Trial registrationINPULSIS (NCT01335464 and NCT01335477); INSTAGE (NCT02802345).

Long-term treatment with nintedanib in Asian patients with idiopathic pulmonary fibrosis: Results from INPULSIS®-ON.

ABSTRACTBackground and objectiveThe efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) were investigated in the placebo‐controlled INPULSIS® trials. All patients who completed an INPULSIS® trial could receive open‐label nintedanib in the extension trial INPULSIS®‐ON.MethodsWe assessed the long‐term efficacy and safety of nintedanib in patients of Asian race who were treated in INPULSIS®‐ON. Analyses were descriptive.ResultsA total of 215 Asian patients were treated in INPULSIS®‐ON, of whom 121 continued nintedanib in INPULSIS®‐ON and 94 initiated nintedanib in INPULSIS®‐ON having received placebo in an INPULSIS® trial. At baseline of INPULSIS®‐ON, the mean (SD) age of Asian patients was 66.3 (7.5) years, 80.5% were males and mean (SD) forced vital capacity (FVC) was 78.9 (19.3) % predicted. Median total exposure to nintedanib in both INPULSIS® and INPULSIS®‐ON was 42.2 months; maximum exposure was 64.1 months. In INPULSIS®, the annual rate (SE) of decline in FVC over 52 weeks in Asian patients was −124 (20) mL/year in the nintedanib group and −218 (24) mL/year in the placebo group. In INPULSIS®‐ON, the annual rate (SE) of decline in FVC over 192 weeks in Asian patients was −127 (11) mL/year. Diarrhoea was reported in Asian patients at event rates of 58.8 and 82.5 events per 100 patient exposure–years in patients who continued and initiated nintedanib in INPULSIS®‐ON, respectively.ConclusionThe effect of nintedanib on slowing disease progression in Asian patients with IPF is sustained over the long term. Long‐term treatment with nintedanib has an acceptable safety and tolerability profile.

Nintedanib for Systemic Sclerosis–Associated Interstitial Lung Disease

BackgroundInterstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis–related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD.MethodsWe conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud’s symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George’s Respiratory Questionnaire (SGRQ) at week 52.ResultsA total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was −52.4 ml per year in the nintedanib group and −93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P=0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of −0.21 (95% CI, −0.94 to 0.53; P=0.58) and 1.69 (95% CI, −0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group.ConclusionsAmong patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.)