Dataset Information

Parametric Time-to-Event Model for Acute Exacerbations in Idiopathic Pulmonary Fibrosis.

ABSTRACT: We describe a parametric time-to-event model for idiopathic pulmonary fibrosis (IPF) exacerbations and identify predictors of exacerbation risk using data obtained for the tyrosine-kinase inhibitor nintedanib in two phase III studies (INPULSIS-1/2). Parametric survival analysis was performed on time to first exacerbation (censoring on day 372), with univariate analysis to select statistically significant covariates (P = 0.05). Multivariate covariate models were developed using stepwise covariate modeling with forward inclusion (P = 0.05) and backward elimination (P = 0.01). Sixty-three first exacerbation events were reported across 1,061 subjects in the INPULSIS studies. Baseline and decline of forced vital capacity (FVC)/percent-predicted FVC (%pFVC), supplemental oxygen use, baseline CO diffusing capacity and age were statistically significant in the univariate analysis. The final covariate model included decline in FVC to week 52, baseline %pFVC, supplemental oxygen use, and age. The developed model may be used to identify patients at high risk of IPF exacerbations and accelerate development of novel treatments.

SUBMITTER: Tang F

PROVIDER: S-EPMC7020291 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Parametric Time-to-Event Model for Acute Exacerbations in Idiopathic Pulmonary Fibrosis.

Tang Fei F Weber Benjamin B Stowasser Susanne S Korell Julia J

CPT: pharmacometrics & systems pharmacology 20200125 2

We describe a parametric time-to-event model for idiopathic pulmonary fibrosis (IPF) exacerbations and identify predictors of exacerbation risk using data obtained for the tyrosine-kinase inhibitor nintedanib in two phase III studies (INPULSIS-1/2). Parametric survival analysis was performed on time to first exacerbation (censoring on day 372), with univariate analysis to select statistically significant covariates (P = 0.05). Multivariate covariate models were developed using stepwise covariate ...[more]

PMID: 31919989

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Project description:BackgroundSevere acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days. Recent evidence suggests autoantibodies may be involved in IPF progression. Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments. We conducted a pilot trial to test the hypothesis that autoantibody-targeted therapies may also benefit AE-IPF patients.MethodsEleven (11) critically-ill AE-IPF patients with no evidence of conventional autoimmune diseases were treated with therapeutic plasma exchanges (TPE) and rituximab, supplemented in later cases with intravenous immunoglobulin (IVIG). Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively. Outcomes among the trial subjects were compared to those of 20 historical control AE-IPF patients treated with conventional glucocorticoid therapy prior to this experimental trial.ResultsNine (9) trial subjects (82%) had improvements of pulmonary gas exchange after treatment, compared to one (5%) historical control. Two of the three trial subjects who relapsed after only five TPE responded again with additional TPE. The three latest subjects who responded to an augmented regimen of nine TPE plus rituximab plus IVIG have had sustained responses without relapses after 96-to-237 days. Anti-HEp-2 autoantibodies were present in trial subjects prior to therapy, and were reduced by TPE among those who responded to treatment. Conversely, plasma MMP7 levels were not systematically affected by therapy nor correlated with clinical responses. One-year survival of trial subjects was 46+15% vs. 0% among historical controls. No serious adverse events were attributable to the experimental medications.ConclusionThis pilot trial indicates specific treatments that reduce autoantibodies might benefit some severely-ill AE-IPF patients. These findings have potential implications regarding mechanisms of IPF progression, and justify considerations for incremental trials of autoantibody-targeted therapies in AE-IPF patients.Trial registrationClinicalTrials.gov NCT01266317.

Project description:BackgroundGiven the broad definition of an acute exacerbation of IPF, it is likely that acute exacerbations are heterogeneous in their aetiology, severity and clinical course. We used pooled data from the INPULSIS® trials of nintedanib versus placebo to investigate whether acute exacerbations reported as serious adverse events were associated with higher mortality than those reported as non-serious adverse events and to assess the effect of nintedanib on these types of events.MethodsAdverse events considered by an investigator to be an acute exacerbation were adjudicated as a confirmed acute exacerbation, suspected acute exacerbation, or not an acute exacerbation. Time to first investigator-reported acute exacerbation or confirmed/suspected acute exacerbation reported as a serious adverse event or non-serious adverse event over the 52-week treatment period was assessed post-hoc. Deaths were assessed based on data collected over the 52-week treatment period.ResultsOf 63 patients who had ≥1 investigator-reported acute exacerbation, 48 (76.2%) had a first acute exacerbation reported as a serious adverse event. Thirty-six (3.4%) patients had ≥1 confirmed/suspected acute exacerbation, of whom 31 had a first event reported as a serious adverse event. Investigator-reported acute exacerbations reported as serious adverse events occurred in 23 patients in the nintedanib group and 26 in the placebo group. Confirmed/suspected acute exacerbations reported as serious adverse events occurred in 10 and 21 patients in these groups, respectively. Nintedanib significantly reduced the risk of a first acute exacerbation reported as a serious adverse event (HR 0.57 [95% CI: 0.32, 0.99]; p = 0.0476) and the risk of a first confirmed/suspected acute exacerbation reported as a serious adverse event (HR 0.30 [95% CI: 0.14, 0.64]; p = 0.0019) versus placebo. A higher proportion of patients with investigator-reported acute exacerbations reported as serious adverse events died than patients with acute exacerbations reported as non-serious adverse events (61.2% versus 7.1%).ConclusionDifferent severities of acute exacerbation of IPF may exist. Acute exacerbations reported as serious adverse events in the INPULSIS® trials were associated with high mortality. Nintedanib significantly reduced the risk of acute exacerbations reported as serious adverse events.Trial registrationClinicalTrials.gov NCT01335464 and NCT01335477 .

Dataset Information

Parametric Time-to-Event Model for Acute Exacerbations in Idiopathic Pulmonary Fibrosis.

Publications

Parametric Time-to-Event Model for Acute Exacerbations in Idiopathic Pulmonary Fibrosis.

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