Efficacy and safety of ipratropium bromide/albuterol compared with albuterol in patients with moderate-to-severe asthma: a randomized controlled trial

Abstract Background Many patients with asthma require frequent rescue medication for acute symptoms despite appropriate controller therapies. Thus, determining the most effective relief regimen is important in the management of more severe asthma. This study’s objective was to evaluate whether ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI) provides more effective acute relief of bronchospasm in moderate-to-severe asthma than albuterol hydrofluoroalkaline (ALB-HFA) alone after 4 weeks. Methods In this double-blind, crossover study, patients who had been diagnosed with asthma for ≥1 year were randomized to two sequences of study medication “as needed” for symptom relief (1–7 day washout before second 4-week treatment period): CVT-MDI/ALB-HFA or ALB-HFA/CVT-MDI. On days 1 and 29 of each sequence, 6-hour serial spirometry was performed after administration of the study drug. Co-primary endpoints were FEV 1 area under the curve (AUC 0–6 ) and peak (post-dose) forced expiratory volume in 1 s (FEV 1 ) response (change from test day baseline) after 4 weeks. The effects of “as needed” treatment with ALB-HFA/CVT-MDI were analyzed using mixed effect model repeated measures (MMRM). Results A total of 226 patients, ≥18 years old, with inadequately controlled, moderate-to-severe asthma were randomized. The study met both co-primary endpoints demonstrating a statistically significant treatment benefit of CVT-MDI versus ALB-HFA. FEV 1 AUC 0-6h response was 167 ml for ALB-HFA, 252 ml for CVT-MDI (p <0.0001); peak FEV 1 response was 357 ml for ALB-HFA, 434 ml for CVT-MDI (p <0.0001). Adverse events were comparable across groups. Conclusions CVT-MDI significantly improved acute bronchodilation over ALB-HFA alone after 4 weeks of “as-needed” use for symptom relief, with a similar safety profile. This suggests additive bronchodilator effects of β 2 -agonist and anticholinergic treatment in moderate-to-severe, symptomatic asthma. Trial registration ClinicalTrials.gov No.: NCT00818454; Registered November 16, 2009

Estimation of the Prevalence of Progressive Fibrosing Interstitial Lung Diseases: Systematic Literature Review and Data from a Physician Survey

Some patients with interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis exhibit a progressive clinical phenotype. These chronic progressive fibrosing ILDs have a variety of underlying diseases, and their prevalence is currently unknown. Here we carry out the first systematic review of literature on the prevalence of fibrosing ILDs and progressive fibrosing ILDs using data from physician surveys to estimate frequency of progression among different ILDs. We searched MEDLINE and Embase for studies assessing prevalence of ILD, individual ILDs associated with fibrosis and progressive fibrosing ILDs. These were combined with data from previously published physician surveys to obtain prevalence estimates of each chronic fibrosing ILD with a progressive phenotype and of progressive fibrosing ILDs overall. We identified 16 publications, including five reporting overall ILD prevalence, estimated at 6.3\u201376.0 per 100,000 people in Europe (four studies) and 74.3 per 100,000 in the USA (one study). In total, 13\u201340% of ILDs were estimated to develop a progressive fibrosing phenotype, with overall prevalence estimates for progressive fibrosing ILDs of 2.2\u201320.0 per 100,000 in Europe and 28.0 per 100,000 in the USA. Prevalence estimates for individual progressive fibrosing ILDs varied up to 16.7 per 100,000 people. These conditions represent a sizeable fraction of chronic respiratory disorders and have a high unmet need

Study design of a randomised, placebo-controlled trial of nintedanib in children and adolescents with fibrosing interstitial lung disease

Childhood interstitial lung disease (chILD) comprises >200 rare respiratory disorders, with no currently approved therapies and variable prognosis. Nintedanib reduces the rate of forced vital capacity (FVC) decline in adults with progressive fibrosing interstitial lung diseases (ILDs). We present the design of a multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial of nintedanib in patients with fibrosing chILD (1199-0337 or InPedILD; ClinicalTrials.gov: NCT04093024). Male or female children and adolescents aged 6–17 years (≥30; including ≥20 adolescents aged 12–17 years) with clinically significant fibrosing ILD will be randomised 2:1 to receive oral nintedanib or placebo on top of standard of care for 24 weeks (double-blind), followed by variable-duration nintedanib (open-label). Nintedanib dosing will be based on body weight-dependent allometric scaling, with single-step dose reductions permitted to manage adverse events. Eligible patients will have evidence of fibrosis on high-resolution computed tomography (within 12 months of their first screening visit), FVC ≥25% predicted, and clinically significant disease (Fan score of ≥3 or evidence of clinical progression over time). Patients with underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk are ineligible. The primary endpoints are pharmacokinetics and the proportion of patients with treatment-emergent adverse events at week 24. Secondary endpoints include change in FVC% predicted from baseline, Pediatric Quality of Life Questionnaire, oxygen saturation, and 6-min walk distance at weeks 24 and 52. Additional efficacy and safety endpoints will be collected to explore long-term effects

Computed tomographic biomarkers in idiopathic pulmonary fibrosis: The future of quantitative analysis

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Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases

A proportion of patients with fibrosing interstitial lung diseases (ILDs) develop a progressive phenotype characterised by decline in lung function, worsening quality of life and early mortality. Other than idiopathic pulmonary fibrosis (IPF), there are no approved drugs for fibrosing ILDs and a poor evidence base to support current treatments. Fibrosing ILDs with a progressive phenotype show commonalities in clinical behaviour and in the pathogenic mechanisms that drive disease worsening. Nintedanib is an intracellular inhibitor of tyrosine kinases that has been approved for treatment of IPF and has recently been shown to reduce the rate of lung function decline in patients with ILD associated with systemic sclerosis (SSc-ILD). In vitro data demonstrate that nintedanib inhibits several steps in the initiation and progression of lung fibrosis, including the release of pro-inflammatory and pro-fibrotic mediators, migration and differentiation of fibrocytes and fibroblasts, and deposition of extracellular matrix. Nintedanib also inhibits the proliferation of vascular cells. Studies in animal models with features of fibrosing ILDs such as IPF, SSc-ILD, rheumatoid arthritis-ILD, hypersensitivity pneumonitis and silicosis demonstrate that nintedanib has anti-fibrotic activity irrespective of the trigger for the lung pathology. This suggests that nintedanib inhibits fundamental processes in the pathogenesis of fibrosis. A trial of nintedanib in patients with progressive fibrosing ILDs other than IPF (INBUILD) will report results in 2019

Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria

RATIONALE: In the absence of a surgical lung biopsy, patients diagnosed with idiopathic pulmonary fibrosis (IPF) in clinical practice could participate in the INPULSIS® trials of nintedanib if they had honeycombing and/or traction bronchiectasis plus reticulation, without atypical features of usual interstitial pneumonia (UIP), on high-resolution computed tomography (HRCT). Thus the patients in these trials represented patients with definite UIP and a large subgroup of patients with possible UIP. OBJECTIVE: We investigated the potential impact of diagnostic subgroups on the progression of IPF and effect of nintedanib. METHODS: Post-hoc subgroup analysis of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy versus patients without either, using pooled data from the INPULSIS® trials. MEASUREMENTS AND MAIN RESULTS: 723 (68.1%) patients had honeycombing and/or biopsy and 338 (31.9%) had no honeycombing or biopsy. In these subgroups, respectively, the adjusted annual rate of decline in forced vital capacity (FVC) in patients treated with placebo was -225.7 mL/year and -221.0 mL/year, and the nintedanib versus placebo difference in adjusted annual rate of decline in FVC was 117.0 mL/year (95% CI: 76.3, 157.8) and 98.9 mL/year (95% CI: 36.4, 161.5). There was no significant treatment-by-subgroup interaction (p=0.8139). Adverse events were similar between subgroups. CONCLUSION: Patients with IPF diagnosed in clinical practice who have possible UIP with traction bronchiectasis on HRCT and have not undergone surgical lung biopsy have disease that progresses in a similar way, and responds similarly to nintedanib, as patients with honeycombing on HRCT and/or confirmation of UIP by biopsy. Clinical trial registration available at www.clinicaltrials.gov, IDs NCT01335464 and NCT01335477

The natural history of progressive fibrosing interstitial lung diseases

We used data from the INBUILD and INPULSIS trials to investigate the natural history of progressive fibrosing interstitial lung diseases (ILDs). Subjects in the two INPULSIS trials had a clinical diagnosis of idiopathic pulmonary fibrosis (IPF) while subjects in the INBUILD trial had a progressive fibrosing ILD other than IPF and met protocol-defined criteria for ILD progression despite management. Using data from the placebo groups, we compared the rate of decline in forced vital capacity (FVC) (mL·year−1) and mortality over 52 weeks in the INBUILD trial with pooled data from the INPULSIS trials. The adjusted mean annual rate of decline in FVC in the INBUILD trial (n=331) was similar to that observed in the INPULSIS trials (n=423) (−192.9 mL·year−1 and −221.0 mL·year−1, respectively; nominal p-value=0.19). The proportion of subjects who had a relative decline in FVC >10% predicted at Week 52 was 48.9% in the INBUILD trial and 48.7% in the INPULSIS trials, and the proportion who died over 52 weeks was 5.1% in the INBUILD trial and 7.8% in the INPULSIS trials. A relative decline in FVC >10% predicted was associated with an increased risk of death in the INBUILD trial (hazard ratio 3.64) and the INPULSIS trials (hazard ratio 3.95). These findings indicate that patients with fibrosing ILDs other than IPF, who are progressing despite management, have a subsequent clinical course similar to patients with untreated IPF, with a high risk of further ILD progression and early mortality

No relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone

Nintedanib and pirfenidone are approved treatments for idiopathic pulmonary fibrosis (IPF). This open-label, two-group trial investigated the pharmacokinetic drug-drug interaction between these two drugs in patients with IPF.Subjects not treated with antifibrotics at screening (Group 1, n=20) received a single nintedanib dose (150 mg) followed by pirfenidone (titrated to 801 mg thrice-daily) for 3 weeks, with a further single nintedanib dose (150 mg) on the last day (day 23). Subjects treated with pirfenidone at screening (Group 2, n=17) continued to receive pirfenidone alone (801 mg thrice-daily) for 7 days, then co-administered with nintedanib (150 mg twice-daily) for a further 7 days, before single doses of both treatments on day 16.In Group 1, adjusted geometric mean (gMean) ratios (with/without pirfenidone) were 88.6% and 80.6% for nintedanib area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax), respectively. In Group 2, gMean ratios (with/without nintedanib) were 97.2% and 99.5% for pirfenidone AUC and Cmax, respectively. For all parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. Both treatments were well tolerated.These data indicate there is no relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when co-administered in IPF patients

Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria

Rationale: In the absence of a surgical lung biopsy, patients diagnosed with idiopathic pulmonary fibrosis (IPF) in clinical practice could participate in the INPULSIS trials of nintedanib if they had honeycombing and/or traction bronchiectasis plus reticulation, without atypical features of usual interstitial pneumonia (UIP), on high-resolution computed tomography (HRCT). Thus, the patients in these trials represented patients with definite UIP and a large subgroup of patients with possible UIP. Objectives: To investigate the potential impact of diagnostic subgroups on the progression of IPF and the effect of nintedanib. Methods: We conducted a post hoc subgroup analysis of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy versus patients without either, using pooled data from the INPULSIS trials. Measurements and Main Results: Seven hundred twenty-three (68.1%) patients had honeycombing and/or biopsy, and 338 (31.9%) patients had no honeycombing or biopsy. In these subgroups, respectively, the adjusted annual rate of decline in FVC in patients treated with placebo was 2225.7 and 2221.0 ml/yr, and the nintedanib versus placebo difference in the adjusted annual rate of declineinFVCwas117.0ml/yr(95%confidenceinterval,76.3-157.8) and 98.9 ml/yr (95% confidence interval, 36.4-161.5). There was no significant treatment-by-subgroup interaction (P = 0.8139). Adverse events were similar between the subgroups. Conclusions: Patients with IPF diagnosed in clinical practice who had possible UIP with traction bronchiectasis on HRCT and had not undergonesurgicallungbiopsyhaddiseasethatprogressedinasimilar way, and responded similarly to nintedanib, to that of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy