Abnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown ...improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF.
In an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker.
Of the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (-0·06 L, 95% CI -0·11 to -0·01) than did those not taking anti-acid treatment (-0·12 L, -0·17 to -0·08; difference 0·07 L, 95% CI 0-0·14; p=0·05).
Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed.
National Institutes of Health.
The purpose of this study was to determine whether noninvasive fractional flow reserve derived from computed tomography (FFR
) predicts coronary revascularization and outcomes and whether its ...addition improves efficiency of referral to invasive coronary angiography (ICA) after coronary computed tomography angiography (CTA).
FFR
may improve the efficiency of an anatomic CTA strategy for stable chest pain.
This observational cohort study included patients with stable chest pain in the PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) trial referred to ICA within 90 days after CTA. FFR
was measured at a blinded core laboratory, and FFR
results were unavailable to caregivers. We determined the agreement of FFR
(positive if ≤0.80) with stenosis on CTA and ICA (positive if ≥50% left main or ≥70% other coronary artery), and predictive value for a composite of coronary revascularization or major adverse cardiac events (death, myocardial infarction, or unstable angina). We retrospectively assessed whether adding FFR
≤0.80 as a gatekeeper could improve efficiency of referral to ICA, defined as decreased rate of ICA without ≥50% stenosis and increased ICA leading to revascularization.
FFR
was calculated in 67% (181 of 271) of eligible patients (mean age 62 years; 36% women). FFR
was discordant with stenosis in 31% (57 of 181) for CTA and 29% (52 of 181) for ICA. Most patients undergoing coronary revascularization had an FFR
of ≤0.80 (91%; 80 of 88). An FFR
of ≤0.80 was a significantly better predictor for revascularization or major adverse cardiac events than severe CTA stenosis (HR: 4.3 95% confidence interval CI: 2.4 to 8.9 vs. 2.9 95% CI: 1.8 to 5.1; p = 0.033). Reserving ICA for patients with an FFR
of ≤0.80 could decrease ICA without ≥50% stenosis by 44%, and increase the proportion of ICA leading to revascularization by 24%.
In this hypothesis-generating study of patients with stable chest pain referred to ICA from CTA, an FFR
of ≤0.80 was a better predictor of revascularization or major adverse cardiac events than severe stenosis on CTA. Adding FFR
may improve efficiency of referral to ICA from CTA alone.
Abstract Background The oral vasopressin-2 receptor antagonist tolvaptan causes aquaresis in patients with volume overload, potentially facilitating decongestion and improving the clinical course of ...patients with acute heart failure (AHF). Objectives To address the acute use of tolvaptan to improve congestion in AHF, we conducted the Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure (TACTICS-HF, NCT01644331) study. Methods TACTICS-HF randomized patients within 24 hours of AHF presentation in a prospective, double blind, placebo-controlled trial. Patients were eligible regardless of ejection fraction, and were randomized to either 30 mg of tolvaptan or placebo given at 0, 24, and 48 hours, with a fixed-dose furosemide regimen as background therapy. The primary endpoint was the proportion of patients considered responders at 24 hours. Secondary endpoints included symptom improvement, changes in renal function, and clinical events. Results A total of 257 patients were randomized. Dyspnea relief by Likert scale was similar between tolvaptan and placebo at 8 hours (25% moderately or markedly improved for tolvaptan vs. 28% placebo, p=0.59) and at 24 hours (50% tolvaptan vs. 47% placebo, p=0.80). Need for rescue therapy was also similar at 24 hours (21% tolvaptan, 18% placebo, p=0.57). The proportion defined as responders at 24 hours (primary study endpoint) was 16% for tolvaptan and 20% for placebo (p=0.32). Tolvaptan resulted in greater weight loss and net fluid loss compared to placebo, but tolvaptan-treated patients were more likely to experience worsening renal function during treatment. There were no differences in in-hospital or post-discharge clinical outcomes. Conclusions In patients hospitalized with AHF, dyspnea, and congestion, the addition of tolvaptan to a standardized furosemide regimen did not improve the number of responders at 24 hours despite greater weight loss and fluid loss.
Mortality is an impractical primary endpoint for clinical trials in patients with idiopathic pulmonary fibrosis who have mild-to-moderate physiological impairment because event rates are low. Change ...in forced vital capacity (FVC) is widely accepted as a surrogate for mortality and is the most common primary endpoint in clinical trials for this disorder. Use of hospital admission as a predictor for mortality, independent of FVC decline, has not been well defined. We aimed to ascertain the independent and combined association of hospital admission and at least a 10% decrease in FVC with all-cause mortality.
We did a pooled cohort study of 517 patients with idiopathic pulmonary fibrosis from three IPFnet multicentre randomised controlled trials. We compared the incidence of non-elective hospital admission and a 10% or greater reduction in FVC across strata of baseline physiological impairment. We used Cox proportional-hazards models to assess the risk of all-cause mortality associated with these surrogate events, occurring up to a predefined landmark timepoint. The three studies are registered at ClinicalTrials.gov, numbers NCT00650091, NCT00517933, and NCT00957242.
Seven patients died before the landmark timepoint. Of the 510 patients remaining, 38 (7%) were admitted to hospital up to the predefined timepoint and 58 (11%) had a categorical decrease in FVC of at least 10%. Most patients admitted to hospital did not have a 10% or greater decrease in FVC (30 vs eight). Both surrogate events were associated with subsequent time to death from any cause (hazard ratio HR for admission 4·05, 95% CI 1·36-12·11 vs HR for 10% or greater decline in FVC 4·68, 1·83-11·99). When causes of hospital admission were considered, only respiratory events were associated with mortality (5·97, 1·81-19·74).
Hospital admission might be an appropriate component of a clinically meaningful composite endpoint that improves the feasibility of clinical trials in idiopathic pulmonary fibrosis. Further studies are needed to refine the most appropriate definition of hospital admission for future trials.
US National Heart, Lung, and Blood Institute (NHLBI), and The Cowlin Family Fund at the Chicago Community Trust.
BACKGROUND The feasibility of an interventional clinical trial in idiopathic pulmonary fibrosis (IPF) using death and hospitalization as primary end points is an area of uncertainty. Using data from ...a large well-characterized clinical trial population, this article aims to illustrate the impact of cohort enrichment and study duration on sample size requirements for IPF clinical trials in which death alone or death plus hospitalization serve as the primary end point. METHODS Event rate estimates for death and hospitalization were determined from patients enrolled in National Institutes of Health-sponsored IPF Clinical Research Network clinical trials. Standard equations were applied to estimate the total sample size required for varying gender, age, and pulmonary function (GAP) stage-based cohorts. RESULTS Risk estimates for death and hospitalization in the clinical trial cohort were substantially lower than those published. An IPF trial with death as its primary end point enrolling subjects designated as GAP stage 1 and 2 over 1 year with a minimum follow-up of 1 year would require an estimated 7,986 subjects to achieve 90% power for a hazard ratio of 0.70. Alternatively, an IPF trial with death plus hospitalization as its primary end point enrolling subjects with GAP stage 2 and 3 over 2 years with a minimum follow-up of 1 year would require an estimated 794 subjects for the same power and hazard ratio. CONCLUSIONS Study design decisions, in particular cohort enrichment strategies, have a substantial impact on sample size requirements for IPF clinical trials using time-to-event primary end points such as death and death plus hospitalization.
Immunotherapy is an effective treatment for a subset of cancer patients, and expanding the benefits of immunotherapy to all cancer patients will require predictive biomarkers of response and ...immune-related adverse events (irAEs). To support correlative studies in immunotherapy clinical trials, we are developing highly validated assays for quantifying immunomodulatory proteins in human biospecimens.
Here, we developed a panel of novel monoclonal antibodies and incorporated them into a novel, multiplexed, immuno-multiple reaction monitoring mass spectrometry (MRM-MS)-based proteomic assay targeting 49 proteotypic peptides representing 43 immunomodulatory proteins.
The multiplex assay was validated in human tissue and plasma matrices, where the linearity of quantification was >3 orders of magnitude with median interday CVs of 8.7% (tissue) and 10.1% (plasma). Proof-of-principle demonstration of the assay was conducted in plasma samples collected in clinical trials from lymphoma patients receiving an immune checkpoint inhibitor. We provide the assays and novel monoclonal antibodies as a publicly available resource for the biomedical community.
Abstract Immunotherapies are revolutionizing cancer care, but many patients do not achieve durable responses and immune-related adverse events are difficult to predict. Quantifying the hundreds of ...proteins involved in cancer immunity has the potential to provide biomarkers to monitor and predict tumor response. We previously developed robust, multiplexed quantitative assays for immunomodulatory proteins using targeted mass spectrometry, providing measurements that can be performed reproducibly and harmonized across laboratories. Here, we expand upon those efforts in presenting data from a multiplexed immuno-oncology (IO)-3 assay panel targeting 43 peptides representing 39 immune- and inflammation-related proteins. A suite of novel monoclonal antibodies was generated as assay reagents, and the fully characterized antibodies are made available as a resource to the community. The publicly available dataset contains complete characterization of the assay performance, as well as the mass spectrometer parameters and reagent information necessary for implementation of the assay. Quantification of the proteins will provide benefit to correlative studies in clinical trials, identification of new biomarkers, and improve understanding of the immune response in cancer.
Live virus vaccines provide significant protection against many detrimental human and animal diseases, but reversion to virulence by mutation and recombination has reduced appeal. Using severe acute ...respiratory syndrome coronavirus as a model, we engineered a different transcription regulatory circuit and isolated recombinant viruses. The transcription network allowed for efficient expression of the viral transcripts and proteins, and the recombinant viruses replicated to WT levels. Recombinant genomes were then constructed that contained mixtures of the WT and mutant regulatory circuits, reflecting recombinant viruses that might occur in nature. Although viable viruses could readily be isolated from WT and recombinant genomes containing homogeneous transcription circuits, chimeras that contained mixed regulatory networks were invariantly lethal, because viable chimeric viruses were not isolated. Mechanistically, mixed regulatory circuits promoted inefficient subgenomic transcription from inappropriate start sites, resulting in truncated ORFs and effectively minimize viral structural protein expression. Engineering regulatory transcription circuits of intercommunicating alleles successfully introduces genetic traps into a viral genome that are lethal in RNA recombinant progeny viruses.
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