Phase 2B Study of Inhaled RVT-1601 for Chronic Cough in Idiopathic Pulmonary Fibrosis: A Multicenter, Randomized, Placebo-controlled Study (SCENIC Trial).

Rationale: Chronic cough remains a major and often debilitating symptom for patients with idiopathic pulmonary fibrosis (IPF). In a phase 2A study, inhaled RVT-1601 (cromolyn sodium) reduced daytime cough and 24-hour average cough counts in patients with IPF. Objectives: To determine the efficacy, safety, and optimal dose of inhaled RVT-1601 for the treatment of chronic cough in patients with IPF. Methods: In this multicenter, randomized, placebo-controlled phase 2B study, patients with IPF and chronic cough for ⩾8 weeks were randomized (1:1:1:1) to receive 10, 40, and 80 mg RVT-1601 three times daily or placebo for 12 weeks. The primary endpoint was change from baseline to end of treatment in log-transformed 24-hour cough count. Key secondary endpoints were change from baseline in cough severity and cough-specific quality of life. Safety was monitored throughout the study. Measurements and Main Results: The study was prematurely terminated owing to the impact of the coronavirus disease (COVID-19) pandemic. Overall, 108 patients (mean age 71.0 years, 62.9% males) received RVT-1601 10 mg (n = 29), 40 mg (n = 25), 80 mg (n = 27), or matching placebo (n = 27); 61.1% (n = 66) completed double-blind treatment. No statistically significant difference was observed in the least-square mean change from baseline in log-transformed 24-hour average cough count, cough severity, and cough-specific quality of life score between the RVT-1601 groups and the placebo group. The mean percentage change from baseline in 24-hour average cough count was 27.7% in the placebo group. Treatment was generally well tolerated. Conclusions: Treatment with inhaled RVT-1601 (10, 40, and 80 mg three times a day) did not provide benefit over placebo for the treatment of chronic cough in patients with IPF.

A New Perspective for Isolated Coronary Artery Ectasia: Cystatin C.

Introduction The pathophysiology of isolated coronary artery ectasia (iCAE) has not been clearly identified, although multiple abnormalities, including arteritis, endothelial dysfunction, and vascular destruction, have been reported. In this study, we aimed to analyze serum cystatin C concentrations in patients with iCAE and controls. Methods Forty-seven patients with iCAE (mean age: 55.9 ± 11.5) and 32 individuals with normal coronary angiography (mean age: 57.8.1 ± 9.6) were included in the study. Plasma cystatin C levels were measured by using the principle of particle-enhanced turbidimetric immunoassay (PETIA). Results Serum cystatin C concentrations were significantly lower in patients with iCAE compared with the control group (0.98 ± 0.17 mg/L versus 1.17 ± 2.6 mg/L, p-value = 0.001). A significantly positive relationship was found between serum cystatin C levels and creatinine and high-sensitivity C-reactive protein (hs-CRP) levels in both groups (r-value = 0.288, p-value = 0.005, r-value = 0.143, p-value = 0.007, respectively). In multivariate logistic regression analysis, serum cystatin C level found to be a significant predictor for the presence of iCAE (OR: 0.837, CI: 95% (0.341 - 1.637), p-value = 0.013). Receiver operating characteristic (ROC) analysis determined that a cystatin C value < 1.02 mg/L had a sensitivity of 56% and a specificity of 78% for the prediction of ectasia. Conclusion We conclude that cystatin C independently can be a useful predictor for the presence of iCAE.

Successful cryoablation of atrial fibrillation from jugular approach in patient with interrupted inferior vena cava and azygos continuation.

We herein report successful cryoablation of paroxysmal atrial fibrillation via right jugular vein in a patient with interrupted inferior vena cava. We preferred cryoablation instead of radiofrequency ablation in the treatment of our patient. For stronger support in aiming the Brockenbrough needle toward the septum, we manuallly curved the needle with a 120° angle about 6 cm proximal to the tip. After successful transseptal puncture, we performed balloon dilatation in the septal puncture zone to facilitate passage. Cryoablation has theoretical advantage, particularly in challenging anatomies, in which it eliminates the need for point-by-point ablation around the pulmonary vein.

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.

BACKGROUND: Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. METHODS: This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. FINDINGS: Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48-0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78-2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. INTERPRETATION: This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation. FUNDING: Patara Pharma.

Transcatheter closure of atrial septal defect with atrial septal occluder in a patient with nickel allergy.

Presently described is transcatheter closure of atrial septal defect with atrial septal occluder (ASO) device in a patient with nickel allergy. Patients with metal allergy who will undergo nitinol device implantation should be tested for possible nickel hypersensitivity. ASO device and treatment strategy (percutaneous or surgical) should be selected according to allergy test result.

Hourglass-shaped right ventricle and localized constrictive pericarditis.

Constrictive pericarditis is characterized by thick pericardial fibrosis and frequent calcification that progressively impairs diastolic filling of the heart. The diagnosis of constrictive pericarditis has been challenging even though multiple diagnostic modalities have been developed. The diagnosis of constructive pericarditis is especially difficult in localized constrictive pericarditis which is extremely rare. We report a case of localized constrictive pericarditis with a 3D multislice cardiac computed tomography (CT) finding of the constrictive band causing strangulation and hourglass shaping of the right ventricle.

Evaluation of Tp-Te Interval and Tp-Te/QT Ratio in Patients with Coronary Slow Flow Tp-Te/QT Ratio and Coronary Slow Flow.

OBJECTIVE: Coronary slow flow (CSF) phenomenon is described by angiographically normal coronary arteries with delayed opacification of the distal vasculature. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-Te) may correspond to the transmural dispersion of the repolarization and that increased Tp-Te interval and Tp-Te/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate the ventricular repolarization by using Tp-Te interval and Tp-Te/QT ratio in patients with CSF. MATERIALS AND METHODS: This study included 50 CSF patients (40 male, mean age 48.6±12.5 years) and 40 control individuals (23 male, mean age 47.8±12.5 years). Tp-Te interval and Tp-Te/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared in groups. RESULTS: Baseline characteristics of the study groups were comparable. In electrocardiographic parameters analysis, QT and corrected QT were similar in CSF patients compared to the controls (357±35.2 vs 362±38.0 milliseconds and 419±25.8 vs 430±44.2 milliseconds, all p value >0.05). Tp-Te interval, Tp-Te/QT and Tp-Te/QTc ratio were significantly higher in CSF patients (85±13.7 vs 74±9.9 milliseconds and 0.24±0.03 vs 0.20±0.02 and 0.20±0.03 vs 0.17±0.02 all p value <0.001). CONCLUSION: Our study revealed that QTd, Tp-Te interval and Tp-Te/QT ratio are prolonged in patients with CSF.

The effect of varenicline on Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio in healthy smokers and nonsmokers.

BACKGROUND: Varenicline could affect the T wave and QT interval. The interval from the peak to the end of the electrocardiographic (ECG) T wave (Tp-e) may correspond to the transmural dispersion of repolarization, and increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. In this study, we assessed the effects of varenicline on Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio. METHODS: Thirty healthy volunteers (15 healthy non-smokers [NS] and 15 healthy smokers [S]) were included in the randomized, double-blind, placebo-controlled, crossover study. Varenicline (2 mg single dose) or placebo was administered in two different testing sessions (5 days after the first period, performed the second period). Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were assessed in the supine position and during handgrip exercise before and after the participants were given placebo or varenicline. Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were calculated from continuous ECG recordings and averages were used in the final analysis. RESULT: There were no statistically significant differences among any of the Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio before and after placebo administration in both groups (S and NS). In the S group, Tp-e and QTc interval, and Tp-e/QT and Tp-e/QTc ratio were significantly increased after varenicline administration (Tp-e: 64.28 ± 8.78 vs. 70.42 ± ± 13.12; p = 0.02, QTc: 409.57 ± 28.17 vs. 425.28 ± 32.79; p = 0.02, Tp-e/QT: 0.18 ± 0.02 vs. 0.19 ± 0.03; p = 0.04, Tp-e/QTc: 0.17 ± 0.02 vs. 0.19 ± 0.02; p = 001) but these parameters were not changed in the NS group. CONCLUSIONS: Tp-e and QTc interval, and Tpe/QT and Tpe/QTc ratio were increased after varenicline administration in smokers.

Effects of off-pump versus on-pump coronary artery bypass grafting: apoptosis, inflammation, and oxidative stress.

BACKGROUND: It has been suggested that off-pump coronary artery bypass grafting (CABG) surgery reduces myocardial ischemia-reperfusion injury, postoperative systemic inflammatory response, and oxidative stress. The aim of this study was to measure serum malondialdehyde (MDA), high-sensitivity C-reactive protein (hs-CRP), M30, and M65 levels and to investigate the relationship between M30 levels and oxidative stress and inflammation in patients undergoing on-and off-pump CABG surgery. METHODS: Fifty patients were randomly assigned to on-pump or off-pump CABG surgery (25 patients off-pump and 25 on-pump CABG surgery), and blood samples were collected prior to surgery, and 30 minutes, 60 minutes, 6 hours, and 24 hours after CABG surgery. RESULTS: Compared to the on-pump group, serum MDA levels at 30 minutes, 60 minutes, 6 hours, and 24 hours after the CABG surgery were significantly lower in the off-pump group (P=.001, P=.001, P=.001, and P=.001, respectively). Serum M30 levels were found to be elevated in both groups, returning to baseline at 24 hours. When compared to baseline, the hs-CRP level reached its peak at 24 hours at 13.28±5.32 mg/dL in the on-pump group, and 15.44±4.02 mg/dL in the off-pump group. CONCLUSION: CABG surgery is associated with an increase in inflammatory markers and serum M30 levels, indicating epithelial/endothelial apoptosis in the early period.