Icenticaftor, a CFTR Potentiator, in COPD: A Multicenter, Parallel-Group, Double-Blind Clinical Trial.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. Objectives: The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Methods: Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25 mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV1 after 12 weeks. Secondary endpoints included change from baseline in trough FEV1 and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24 weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24 weeks were assessed in exploratory and post hoc analyses, respectively. Measurements and Main Results: Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV1 was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24 weeks for trough FEV1, E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300 mg b.i.d. was consistently the most effective. Improvements for 300 mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. Conclusions: The primary endpoint was negative, as icenticaftor did not improve trough FEV1 over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV1; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).

Efficacy and safety of fevipiprant in patients with uncontrolled asthma: Two replicate, phase 3, randomised, double-blind, placebo-controlled trials (ZEAL-1 and ZEAL-2).

BACKGROUND: These studies assessed the efficacy and safety of fevipiprant, an oral antagonist of the prostaglandin D2 (PGD2) receptor (DP2), compared with placebo when added to standard-of-care (SoC) asthma therapy in patients with uncontrolled asthma. METHODS: ZEAL-1 (NCT03215758) and ZEAL-2 (NCT03226392) are two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies in which fevipiprant 150 mg once daily (o.d.) or placebo was added to SoC asthma therapy in patients aged ≥12 years with uncontrolled asthma. Primary endpoint: change from baseline in pre-dose forced expiratory volume in 1 s (FEV1) after 12 weeks' treatment. Key secondary endpoints: daytime asthma symptom score, short-acting ß-agonist (SABA) use and Asthma Quality-of-Life Questionnaire (AQLQ+12) score after 12-weeks treatment. FINDINGS: 662 patients in ZEAL-1 and 685 patients in ZEAL-2 completed the treatment period. In ZEAL-1, the least squares (LS) mean change from baseline in pre-dose FEV1 was 112 mL in fevipiprant vs 71 mL in placebo group (difference [∆]:41 mL; 95% CI: -6, 88; adjusted p-value 0·088). In ZEAL-2, the LS mean change in pre-dose FEV1 was 126 mL and 157 mL in the fevipiprant and placebo groups, respectively (∆:-31 mL; 95% CI: -80, 18; adjusted p-value 0·214). For both studies, there were no statistically significant differences in the key secondary objectives between the treatment groups. INTERPRETATION: The ZEAL studies did not demonstrate significant improvement in lung function or other clinical outcomes. These results suggest that DP2 receptor inhibition with fevipiprant is not effective in the studied patient population.

FLT3-ITD and CD135 Over-Expression are Frequent Findings of Poor Survival in Adult Patients with Acute Leukemias.

BACKGROUND: Fms-like tyrosine kinase 3 (FLT3) expression and mutation have been considered a poor prognostic factor in acute myeloid leukemia (AML). FLT3-ITD mutation is present in 30% of adult patients with AML and 2-5% in childhood acute lymphoblastic leukemia (ALL). The impact of these mutations on the prognosis of ALL patients, has not yet been established. Moreover, a limited number of publications regarding the level of expression of the FLT3 receptor (CD135) in both leukemias exist. This study aimed to analyze the clinical outcomes associated to the presence of FLT3-ITD mutation and the expression of CD135. METHODS: 82 adult patients with newly diagnosed acute leukemia (39 with AML and 43 with ALL) were included. Flow cytometry and RT-PCR were done to analyze the expression of CD135 and the presence of FLT3 ITD mutation, respectively. RESULTS: FLT3-ITD was present in 14 (36%) of AML and 15 (35%) of ALL patients. Disease free survival (DFS) and overall survival (OS) were lower in ALL patients having a CD135 expression >3000 cells/µL. There was a trend for poor OS in AML patients expressing FLT3 ITD. OS was worse in AML patients with high expression of CD135. CONCLUSION: A higher (35%) frequency of FLT3-ITD was found in adult ALL patients. The presence of FLT3-ITD was associated with a trend of poor OS in AML cases, and overexpression of CD135 was correlated with poor DFS in ALL cases and poor OS in both acute leukemias.

Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study.

INTRODUCTION: Hypertension in elderly people is characterised by elevated systolic blood pressure (SBP) and increased pulse pressure (PP), which indicate large artery ageing and stiffness. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is being developed to treat hypertension and heart failure. The Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study will assess the efficacy of LCZ696 versus olmesartan on aortic stiffness and central aortic haemodynamics. METHODS AND ANALYSIS: In this 52-week multicentre study, patients with hypertension aged ≥60 years with a mean sitting (ms) SBP ≥150 to <180 and a PP>60 mm Hg will be randomised to once daily LCZ696 200 mg or olmesartan 20 mg for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks. At 12-24 weeks, if the BP target has not been attained (msSBP <140 and ms diastolic BP <90 mm Hg), amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) can be added. The primary and secondary endpoints are changes from baseline in central aortic systolic pressure (CASP) and central aortic PP (CAPP) at week 12, respectively. Other secondary endpoints are the changes in CASP and CAPP at week 52. A sample size of 432 randomised patients is estimated to ensure a power of 90% to assess the superiority of LCZ696 over olmesartan at week 12 in the change from baseline of mean CASP, assuming an SD of 19 mm Hg, the difference of 6.5 mm Hg and a 15% dropout rate. The primary variable will be analysed using a two-way analysis of covariance. ETHICS AND DISSEMINATION: The study was initiated in December 2012 and final results are expected in 2015. The results of this study will impact the design of future phase III studies assessing cardiovascular protection. CLINICAL TRIALS IDENTIFIER: EUDract number 2012-002899-14 and ClinicalTrials.gov NCT01692301.

Performance in nondairy drinks of probiotic L. casei strains usually employed in dairy products.

The increase in vegetarianism as dietary habit and the increased allergy episodes against dairy proteins fuel the demand for probiotics in nondairy products. Lactose intolerance and the cholesterol content of dairy products can also be considered two additional reasons why some consumers are looking for probiotics in other foods. We aimed at determining cell viability in nondairy drinks and resistance to simulated gastric digestion of commercial probiotic lactobacilli commonly used in dairy products. Lactobacillus casei LC-01 and L. casei BGP 93 were added to different commercial nondairy drinks and viability and resistance to simulated gastric digestion (pH 2.5, 90 min, 37 °C) were monitored along storage (5 and 20 °C). For both strains, at least one nondairy drink was found to offer cell counts around 7 log orders until the end of the storage period. Changes in resistance to simulated gastric digestion were observed as well. Commercial probiotic cultures of L. casei can be added to commercial fruit juices after a carefull selection of the product that warrants cell viability. The resistance to simulated gastric digestion is an easy-to-apply in vitro tool that may contribute to product characterization and may help in the choice of the food matrix when no changes in cell viability are observed along storage. Sensorial evaluation is mandatory before marketing since the product type and storage conditions might influence the sensorial properties of the product due to the possibility of growth and lactic acid production by probiotic bacteria.

Efficacy and safety of a single-pill combination of amlodipine/valsartan in Asian hypertensive patients inadequately controlled with amlodipine monotherapy.

OBJECTIVE: The antihypertensive efficacy of amlodipine/valsartan combination has not been evaluated in Asian patients as previous large-scale studies enrolled very few patients. This multicentre, randomised, double-blind study assessed the efficacy and safety of a single-pill combination of amlodipine/valsartan versus amlodipine in Asian hypertensive patients. METHODS: After a 1-4-week washout period, patients (mean sitting diastolic BP [msDBP]: >or=95-<110 mmHg) were treated with amlodipine 5 mg for 4 weeks. Patients inadequately controlled on amlodipine (msDBP >or=90 and <110 mmHg) were randomised to receive amlodipine/valsartan 5/80 mg (n = 349) or amlodipine 5 mg (n = 349) for 8 weeks. Efficacy variables were change in msDBP, mean sitting systolic BP (msSBP) from baseline (at randomisation) to week 8 endpoint, and BP control rate (<140/90 mmHg) at week 8 endpoint. Safety assessments included monitoring and recording of adverse events (AEs). RESULTS: Baseline characteristics were comparable between the groups. Most patients were Chinese (86.4%), men (65.1%), with a baseline BP 139.5/94.5 mmHg. At week 8 endpoint, the least square mean reduction in BP was significantly greater with amlodipine/valsartan combination than amlodipine monotherapy (-11.4/-9.7 vs. -7.4/-7.1 mmHg; p < 0.0001) with a higher BP control rate (69.2 vs. 57.6%; p = 0.0013). Ambulatory BP monitoring in a subgroup of patients (n = 82), showed a significant 24-h mean BP reduction from baseline with amlodipine/valsartan (-7.3/-6.3 mmHg; p < 0.0001), whereas the reduction was not significant with amlodipine (-0.2/+0.3 mmHg; p > 0.05). The overall incidence of AEs was similar in both groups. Peripheral oedema occurred only in the amlodipine group n = 4 (1.1%) and not in the amlodipine/valsartan combination. Hypotension was reported in only one patient in the amlodipine/valsartan combination. Six patients (0.9%) experienced serious AEs, of which only one SAE, i.e. gastric ulcer, was reported to be related to amlodipine treatment. CONCLUSION: The single-pill combination of amlodipine/valsartan was efficacious and well-tolerated in Asian hypertensive patients who were inadequately controlled on amlodipine alone. As with all clinical trials, the entry criteria may limit the extrapolation of these results to a broader population. ClinicalTrials.gov Identifier: NCT00413049.