Left ventricular dysfunction in an idiopathic pulmonary fibrosis patient on nintedanib.
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ABSTRACT:
SUBMITTER: Imai R
PROVIDER: S-EPMC7017142 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
Publications
Left ventricular dysfunction in an idiopathic pulmonary fibrosis patient on nintedanib.
Imai Ryosuke R Tomishima Yutaka Y
Respirology case reports 20200213 2
Nintedanib, a tyrosine kinase inhibitor, is approved for the treatment of idiopathic pulmonary fibrosis. We report a case of left ventricular dysfunction in a patient with idiopathic pulmonary fibrosis treated with nintedanib, which recovered after cessation of nintedanib. Nintedanib may induce left ventricular dysfunction, and early recognition is important since this condition is potentially reversible. ...[more]
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Project description:BackgroundNintedanib slows disease progression in patients with Idiopathic Pulmonary Fibrosis (IPF) by reducing decline in Forced Vital Capacity (FVC). The effects of nintedanib on abnormalities on high-resolution computed tomography scans have not been previously studied.ObjectiveWe conducted a Phase IIIb trial to assess the effects of nintedanib on changes in Quantitative Lung Fibrosis (QLF) score and other measures of disease progression in patients with IPF.Methods113 patients were randomized 1:1 to receive nintedanib 150 mg bid or placebo double-blind for ≥6 months, followed by open-label nintedanib. The primary endpoint was the relative change from baseline in QLF score (%) at month 6. Analyses were descriptive and exploratory.ResultsAdjusted mean relative changes from baseline in QLF score at month 6 were 11.4% in the nintedanib group (n=42) and 14.6% in the placebo group (n=45) (difference 3.2% [95% CI: -9.2, 15.6]). Adjusted mean absolute changes from baseline in QLF score at month 6 were 0.98% and 1.33% in these groups, respectively (difference 0.35% [95% CI: -1.27, 1.96]). Adjusted mean absolute changes from baseline in FVC at month 6 were -14.2 mL and -83.2 mL in the nintedanib (n=54) and placebo (n=54) groups, respectively (difference 69.0 mL [95% CI: -8.7, 146.8]).ConclusionExploratory data suggest that in patients with IPF, 6 months' treatment with nintedanib was associated with a numerically smaller degree of fibrotic change in the lungs and reduced FVC decline versus placebo. These data support previous findings that nintedanib slows the progression of IPF.
| S-EPMC7539538 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a rare lung disease characterised by progressive loss of lung function, dyspnoea and cough. IPF has a variable clinical course but a poor prognosis. Nintedanib, a tyrosine kinase inhibitor, is one of two drugs approved for the treatment of IPF. In clinical trials, nintedanib slowed disease progression by reducing the rate of decline in forced vital capacity (FVC) in patients with IPF and mild or moderate lung function impairment. The effect of nintedanib was consistent across patient subgroups defined by baseline characteristics including FVC % predicted, diffusion capacity of the lung for carbon monoxide % predicted and the presence of emphysema. Recently, it has been shown that the rate of decline in FVC and the treatment effect of nintedanib are the same in patients with preserved lung volume (FVC >90% predicted) as in patients with greater impairment in FVC, supporting the value of early treatment of IPF. The adverse events most commonly associated with nintedanib, both in clinical trials and real-world clinical practice, are mild gastrointestinal events, particularly diarrhoea. Side effects are manageable in a majority of patients through symptomatic treatment, dose reductions and treatment interruptions, enabling most patients to stay on treatment in the long term.
| S-EPMC5531305 | biostudies-literature
Project description:BackgroundPhase 3 trials have shown that nintedanib reduces the decline in forced vital capacity (FVC) in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF) with acceptable safety profiles; however, its effects on advanced IPF are unclear. We investigated the efficacy and safety of nintedanib in patients with advanced IPF.MethodsProspective data were obtained from 108 IPF patients administered at least one dose of nintedanib. Of these patients, 47.2% had advanced IPF (FVC < 50% predicted, or diffusing capacity < 30% predicted).ResultsThe median treatment duration was 42.2 weeks. Nintedanib significantly reduced the decline rate in both FVC (- 0.55% [before] vs. -0.32% [after] predicted/month, p = 0.020) and total lung capacity (TLC) (- 0.35% vs. -0.06% predicted/month, p < 0.001) in all patients. A significant improvement in FVC decline rate after treatment was also observed in the advanced group (- 0.77% vs. -0.22% predicted/month, p = 0.003), but not in the non-advanced group (- 0.41% vs. -0.33% predicted/month, p = 0.564). Adverse events occurred in 97.2% of the cohort, including diarrhoea (50.0%) and anorexia (45.4%). Following adjustment for treatment duration, no inter-group difference in odds ratio was observed for the occurrence of adverse events. However, the advanced group showed a higher frequency of treatment interruption (68.0% vs. 40.0%), mainly as a result of disease progression (47.1% vs. 36.4%).ConclusionsThe efficacy and safety profiles of nintedanib in the advanced group were comparable to those in the non-advanced group except for a higher frequency of discontinuation, which may be due to the advanced status itself.
| S-EPMC6194688 | biostudies-literature
Project description:BackgroundTwo antifibrotic drugs, nintedanib and pirfenidone, are available for treatment of idiopathic pulmonary fibrosis (IPF). Although efficacy and adverse events have been well studied, little is known about patient experiences with these drugs. We aimed to systematically and quantitatively evaluate patient expectations, experiences, and satisfaction with nintedanib and pirfenidone. Furthermore, we assessed which factors were associated with overall patient satisfaction with medication.MethodsOutpatients with IPF prospectively completed the Patient Experiences and Satisfaction with Medication (PESaM) questionnaire before start, and after three and 6 months of antifibrotic treatment, as part of a randomized eHealth trial (NCT03420235). The PESaM questionnaire consists of an expectation module, a validated generic module evaluating patient experiences and satisfaction concerning the effectiveness, side-effects, and ease of use of a medication, and a disease-specific module about IPF. Satisfaction was scored on a scale from - 5 (very dissatisfied) to + 5 (very satisfied).ResultsIn total, 90 patients were included, of whom 43% used nintedanib and 57% pirfenidone. After 6 months, the mean overall score for satisfaction with medication was 2.1 (SD 1.9). No differences were found in experiences and satisfaction with medication, and the number and severity of side-effects between nintedanib and pirfenidone. Perceived effectiveness of medication was rated as significantly more important than side-effects and ease of use (p = 0.001). Expectations of patients regarding effectiveness were higher than experiences after 6 months. Self-reported experience with effectiveness was the main factor associated with overall medication satisfaction.ConclusionsPatient experiences and satisfaction with antifibrotic treatment were fairly positive, and similar for nintedanib and pirfenidone. Systematic evaluation of patient expectations, experiences, and satisfaction with medication could enhance shared-decision making and guide drug treatment decisions in the future.Trial registrationNCT03420235 .
| S-EPMC7376884 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterised by dyspnea and loss of lung function.Using pooled data from the replicate, randomized, 52-week, placebo-controlled INPULSIS(®) trials, we characterized the safety and tolerability of nintedanib 150 mg twice daily in patients with IPF and described how adverse events were managed during these trials.One thousand and sixty- one patients were treated (nintedanib 638; placebo 423). Higher proportions of patients in the nintedanib group than the placebo group had ? 1 dose reduction to 100 mg bid (27.9% versus 3.8%) or treatment interruption (23.7% versus 9.9%). Adverse events led to permanent treatment discontinuation in 19.3% and 13.0% of patients in the nintedanib and placebo groups, respectively. Diarrhea was the most frequent adverse event, reported in 62.4% of patients in the nintedanib group versus 18.4% in the placebo group; however, only 4.4% of nintedanib-treated patients discontinued trial medication prematurely due to diarrhea. Monitoring of liver enzymes before and periodically during nintedanib treatment was recommended so that liver enzyme elevations could be managed through dose reduction or treatment interruption.Nintedanib had a manageable safety and tolerability profile in patients with IPF. Recommendations for adverse event management minimized permanent treatment discontinuations in the INPULSIS(®) trials.clinicaltrials.gov NCT01335464 and NCT01335477.
| S-EPMC4581488 | biostudies-literature
Project description:RATIONALE:There is no consensus as to when treatment for idiopathic pulmonary fibrosis (IPF) should be initiated. Some physicians prefer not to treat patients with preserved lung volume. OBJECTIVE:To investigate whether patients with IPF and preserved lung volume receive the same benefit from nintedanib as patients with more impaired lung volume. METHODS:Post hoc subgroup analyses of pooled data from the two replicate phase III INPULSIS trials by baseline FVC % predicted (?90%, >90%). RESULTS:At baseline, 274 patients had FVC >90% predicted and 787 patients had FVC ?90% predicted. In patients treated with placebo, the adjusted annual rate of decline in FVC was consistent between patients with FVC >90% predicted and FVC ?90% predicted (-224.6?mL/year and -223.6?mL/year, respectively). There was no statistically significant difference between these subgroups in the effect of nintedanib on annual rate of decline in FVC, change from baseline in St George's Respiratory Questionnaire total score or time to first acute exacerbation. In patients with baseline FVC >90% predicted and ?90% predicted, respectively, the adjusted annual rate of decline in FVC with nintedanib was -91.5?mL/year (difference vs placebo: 133.1?mL/year (95% CI 68.0 to 198.2)) and -121.5?mL/year (difference vs placebo: 102.1?mL/year (95% CI 61.9 to 142.3)). Adverse events associated with nintedanib were similar in both subgroups. CONCLUSIONS:Patients with IPF and preserved lung volume (FVC >90% predicted) have the same rate of FVC decline and receive the same benefit from nintedanib as patients with more impaired lung volume. TRIAL REGISTRATION NUMBER:NCT01335464 and NCT01335477.
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Project description:Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and is characterized by a poor prognosis, with an estimated 5-year survival of approximately 20%. Progressive and irreversible lung functional impairment leads to chronic respiratory insufficiency with a severely impaired quality of life. In the last 2 decades, novel treatments for IPF have been developed as a consequence of an increasing understanding of disease pathogenesis and pathobiology. In IPF, injured dysfunctional alveolar epithelial cells promote fibroblast recruitment and proliferation, resulting in scarring of the lung tissue. Recently, pirfenidone and nintedanib have been approved for the treatment of IPF, having shown efficacy to slow functional decline and disease progression. This article focuses on the pharmacologic characteristics and clinical evidence supporting the use of nintedanib, a potent small-molecule tyrosine kinase inhibitor, as therapy for IPF. After introducing the mechanism of action and pharmacokinetics, an overview of the safety and efficacy results from the most recent clinical trials of nintedanib in IPF is presented.
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Project description:We assessed safety and tolerability of treatment with pirfenidone (1602-2403 mg·day-1) and nintedanib (200-300 mg·day-1) in patients with idiopathic pulmonary fibrosis (IPF).This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day-1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602-2403 mg·day-1) and nintedanib (200-300 mg·day-1). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither.89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs.Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF.
| S-EPMC6092682 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal progressive disease with a median survival of 2-5 years. Nintedanib is a small tyrosine kinase inhibitor that reduces IPF progression, significantly slowing the annual decline in Forced Vital Capacity (FVC). Very little data is available on the molecular mechanisms of this treatment in IPF, despite a growing interest in the definition of IPF pathogenesis and target therapy. A functional proteomic approach was applied to the analysis of serum samples from IPF patients in order to highlight differential proteins potentially indicative of drug-induced molecular pathways modifications and response to therapy. Twelve serum samples were collected from six IPF patients in care at Siena Regional Referral Center for Interstitial Lung Diseases (ILDs) and treated with nintedanib for one year. Serum samples were analyzed at baseline (T0 before starting therapy) and after one year of treatment (T1) and underwent differential proteomic and bioinformatic analysis. Proteomic analysis revealed 13 protein species that were significantly increased after one year of treatment. When the targets of nintedanib (VEGFR, FGFR and PDGFR) were added, enrichment analysis extracted molecular pathways and process networks involved in cell differentiation (haptoglobin and albumin), coagulation (antithrombin III), epithelial mesenchymal transition, cell proliferation and transmigration. PI3K and MAPK induced up-regulation of apolipoprotein C3. Proteomic study found 13 protein species up-regulated in IPF patients after one year of nintedanib treatment. Haptoglobin, a central hub of our analysis was validated by 2D-WB and ELISA as theranostic marker in a more numerous populations of patients.
| S-EPMC7287088 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix (ECM) proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and transforming growth factor-? are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials.
| S-EPMC4416110 | biostudies-literature