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1.
Am J Respir Crit Care Med ; 203(3): 296-306, 2021 02 01.
Article in English | MEDLINE | ID: mdl-32809843

ABSTRACT

Rationale: To examine the potential of TLR9 (Toll-like receptor 9) activation to modulate the type 2 immune response in asthma.Objectives: To evaluate efficacy and safety of AZD1419, an inhaled TLR9 agonist, in a phase 2a, randomized, double-blind trial.Methods: Adult patients with asthma with a history of elevated eosinophils (>250 cells/µl) were randomized 1:1 to receive 13 once-weekly doses of inhaled AZD1419 (1, 4, or 8 mg; n = 40) or placebo (n = 41). Inhaled corticosteroids and long-acting ß2-agonist were tapered down and then discontinued. The last four doses of AZD1419 were given without maintenance medication, followed by a 40-week observation period. Primary endpoint was time to loss of asthma control (LOC).Measurements and Main Results: AZD1419 induced a T-helper cell type 1-type IFN response with a sustained reduction in markers of type 2 inflammation. However, there were no statistically significant differences between AZD1419 and placebo for time to LOC, proportion of patients with LOC, changes in Asthma Control Questionnaire-five-item version, exacerbations, reliever use, FEV1, peak expiratory flow, or fractional exhaled nitric oxide (FeNO). LOC was predicted by an early rise in FeNO in 63% of patients. Despite withdrawal of maintenance treatment, 24 patients completed the study without LOC; AZD1419 n = 11, placebo n = 13. Adverse events were balanced across groups, with no deaths or serious adverse events judged as causally related to AZD1419.Conclusions: AZD1419 was safe and well tolerated but did not lead to improved asthma control, despite reducing markers of type 2 inflammation. Results suggest that a novel accelerated step-down approach based on FeNO is possible for patients with well-controlled asthma.


Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Oligonucleotides/therapeutic use , Toll-Like Receptor 9/therapeutic use , Administration, Inhalation , Adult , Aged , Anti-Asthmatic Agents/administration & dosage , Asthma/immunology , Double-Blind Method , Female , Humans , Immunologic Factors/therapeutic use , Male , Middle Aged , Toll-Like Receptor 9/agonists , Toll-Like Receptor 9/drug effects , Treatment Outcome
2.
Lancet Rheumatol ; 2(1): e31-e41, 2020 Jan.
Article in English | MEDLINE | ID: mdl-38258274

ABSTRACT

BACKGROUND: Glucocorticoids are highly effective and widely used anti-inflammatory drugs, but their use is limited by serious side-effects, including glucocorticoid-induced hyperglycaemia and diabetes. AZD9567 is a non-steroidal, selective glucocorticoid receptor modulator that aims to reduce side-effects. We aimed to assess the safety, tolerability, and pharmacokinetics of AZD9567 in healthy volunteers. METHODS: Two phase 1 clinical studies were done. First, a randomised, placebo-controlled, single-blind, single-ascending dose study was done in healthy men who received single oral doses of AZD9567 2 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 125 mg, or 155 mg, or prednisolone 60 mg (n=8 per dose group, randomly assigned [6:2] to receive active drug or placebo). Second, a randomised, active-controlled, single-blind, multiple-ascending dose study was done, in which men and women received oral AZD9567 or prednisolone once daily for 5 days. One cohort of volunteers with prediabetes received AZD9567 10 mg (n=7) or prednisolone 20 mg (n=2). All other cohorts comprised healthy volunteers, receiving AZD9567 20 mg, 40 mg, 80 mg, or 125 mg (n=7 per dose group), or prednisolone 5 mg (n=13), 20 mg (n=16), or 40 mg (n=13). Participants and study centre staff were masked to treatment assignment for each cohort, although data were unmasked for safety review between cohorts. The primary outcome of the single-ascending dose study was the safety, tolerability, and pharmacokinetics of single ascending doses of AZD9567; for the multiple-ascending dose study it was the safety and tolerability of AZD9567 following multiple ascending doses. As a secondary outcome, effects on glycaemic control were ascertained with oral glucose tolerance tests (OGTTs) done at baseline and on day 1 of the single-ascending dose study, and at baseline and on day 4 of the multiple-ascending dose study. These trials are registered at ClinicalTrials.gov, NCT02512575 and NCT02760316. FINDINGS: In the single-ascending dose study, between Nov 18, 2015, and Sept 26, 2016, 72 healthy white men were enrolled, and all completed the study. In the multiple-ascending dose study, between May 2, 2016, and Sept 13, 2017, 77 predominantly white male volunteers (including nine individuals with prediabetes and eight women) were enrolled and 75 completed the study. All doses of AZD9567 and prednisolone were well tolerated, with no serious adverse events or events suggesting adrenal insufficiency. In the single-ascending dose study, nine adverse events of mild intensity were reported (five with AZD9567 and four with placebo); no adverse event was reported by more than one person. In the multiple-ascending dose study, 44 adverse events of mild or moderate intensity were reported (18 with AZD9567 and 26 with prednisolone). The most common were headache and micturition. Apparent clearance, volume of distribution, and half-life of AZD9567 were consistent across doses and for single versus repeated dosing. In the multiple-ascending dose study, OGTTs showed no significant difference with AZD9567 doses up to 80 mg compared with prednisolone 5 mg in glucose area under the curve from 0 h to 4 h post-OGTT (AUC0-4h) from baseline to day 4; the increase in glucose AUC0-4h from baseline to day 4 was significantly lower with all AZD9567 doses versus prednisolone 20 mg (AZD9567 20 mg p<0·0001, 40 mg p=0·0001, 80 mg p=0·0001, and 125 mg p=0·0237). INTERPRETATION: AZD9567 appears to be safe and well tolerated in healthy, predominantly white male volunteers and shows promising initial evidence for improved post-prandial glucose control. Studies of longer duration, with a greater proportion of women and other ethnic groups, and in patients requiring anti-inflammatory treatment are needed to characterise the clinical efficacy and safety profile of AZD9567. FUNDING: AstraZeneca.

3.
Int J Chron Obstruct Pulmon Dis ; 13: 1009-1019, 2018.
Article in English | MEDLINE | ID: mdl-29628759

ABSTRACT

Background: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations. Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations. Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18-55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40-85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations. Results: The p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38ß isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout. Conclusion: Although p38α is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Benzamides/therapeutic use , Lung/drug effects , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrazines/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents/adverse effects , Benzamides/adverse effects , Cross-Over Studies , Disease Progression , Double-Blind Method , Female , Humans , Lung/enzymology , Lung/physiopathology , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/enzymology , Male , Middle Aged , Mitogen-Activated Protein Kinase 14/metabolism , Proof of Concept Study , Protein Kinase Inhibitors/adverse effects , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/enzymology , Pulmonary Disease, Chronic Obstructive/physiopathology , Pyrazines/adverse effects , Time Factors , Treatment Outcome , Young Adult
4.
Basic Clin Pharmacol Toxicol ; 121(4): 279-289, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28212463

ABSTRACT

AZD5423 is a novel, inhaled, selective glucocorticoid receptor modulator (SGRM), which in an allergen challenge model in asthma patients improved lung function and airway hyper-reactivity. In the current trial, AZD5423 was for the first time tested in patients with chronic obstructive pulmonary disease (COPD). In this double-blind, randomized and parallel group study, we examined airway and systemic effects of two doses of AZD5423, inhaled via Turbuhaler for 12 weeks, in 353 symptomatic patients with COPD (average pre-bronchodilator forced expiratory volume in one-second (FEV1) at screening was 50-52% of predicted normal). Pre-bronchodilator FEV1 was primary variable, with other lung function parameters plus symptoms and 24-hr plasma cortisol being secondary variables. Plasma concentrations of AZD5423 were also measured. Effects were compared against placebo and a reference glucocorticoid receptor agonist control. Neither AZD5423, at doses which have shown to be efficacious in allergen-induced asthma, nor the reference control, at double the approved dose, had any clinically meaningful effect in the patient population studied in regard to lung function or markers of inflammation. Both GR modulators were well tolerated and did suppress 24-hr cortisol. This study suggests that the selected population of patients with COPD does not respond to treatment with AZD5423 as regards lung function, while showing the expected systemic effects. It cannot be ruled out that a favourable lung function response of AZD5423 can be evoked using another experimental setting and/or within a different population of patients with COPD.


Subject(s)
Acetamides/administration & dosage , Anti-Asthmatic Agents/administration & dosage , Indazoles/administration & dosage , Lung/drug effects , Pulmonary Disease, Chronic Obstructive/drug therapy , Receptors, Glucocorticoid/drug effects , Acetamides/adverse effects , Acetamides/blood , Administration, Inhalation , Aged , Anti-Asthmatic Agents/adverse effects , Anti-Asthmatic Agents/blood , Double-Blind Method , Female , Forced Expiratory Volume , Humans , Indazoles/adverse effects , Indazoles/blood , Lung/metabolism , Lung/physiopathology , Male , Middle Aged , Nebulizers and Vaporizers , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/physiopathology , Receptors, Glucocorticoid/metabolism , Time Factors , Treatment Outcome , Vital Capacity
5.
Biomark Med ; 10(5): 513-24, 2016 05.
Article in English | MEDLINE | ID: mdl-27128658

ABSTRACT

In this perspective article, we discuss, from a statistician's perspective, how biomarkers can be useful in decision making in drug development with emphasis on early clinical development (Phase I and II) in chronic obstructive pulmonary disease. We illustrate with examples of how biomarkers can affect the very choice of treatment strategy: for example, targeting patients in early versus late phases of the disease or patients with particular extrapulmonary manifestations of chronic obstructive pulmonary disease. We also illustrate the use of biomarkers for establishing proof of mechanism in Phase I trials and how surrogate biomarkers can be used as end points in Phase II leading to shorter and more efficient proof-of-principle and dose-finding trials.


Subject(s)
Biomarkers/blood , Pulmonary Disease, Chronic Obstructive/diagnosis , Acetates/therapeutic use , Clinical Trials as Topic , Cluster Analysis , Endpoint Determination , Humans , Interleukin-6/blood , Lung/physiopathology , Prognosis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/pathology , Pyrazines/therapeutic use
7.
J Thorac Dis ; 7(4): 720-33, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25973239

ABSTRACT

BACKGROUND: To describe a study design that focuses on risk factors and patterns of chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: A 2-year, single centre, observational study was conducted in Guangzhou in China. The study enrolled 318 subjects with COPD aged 40-79 years, stratified into different but equally sized groups according to global initiative for chronic obstructive lung disease (GOLD) stage (including Stage 0) and 86 lung healthy controls. An assessment each year was scheduled including questionnaires, lung function testing, Chest X-ray and blood collection. A sub-group, called sub-group X, consisting of 203 subjects with COPD and 51 lung healthy controls, was selected to answer a symptom questionnaire daily (EXACT-PRO) via a BlackBerry Personal Digital Assistant (PDA) device. Upon an alert that indicated a change in daily symptom pattern, the patients were contacted by the clinic to decide whether they had experienced an exacerbation and should have an extra visit within 24-48 hours. At an extra visit, nasal and throat swabs, induced sputum and blood were collected. Air pollution, temperature and humidity were also monitored daily. A subset of sub-group X, called sub-group M that consisted of 52 COPD patients and 15 healthy controls was dedicated to measure muscle strength and a dexa scan. RESULTS: More than 78% of the enrolled patients completed the study successfully. There appeared a difference between the patient groups and the controls in gender, age, body mass index (BMI), forced expiratory volume in 1 second (FEV1), FEV1/FVC and smoking at baseline. In sub-group X 90 out of 203 (44.4%) selected COPD patients developed one or more exacerbations in the 2-year observation period. They were more severe COPD patients according to GOLD stage at study start. On average most exacerbations occurred in the month March and the least number of exacerbations occurred in October. CONCLUSIONS: This study with the obtained patient dataset will allow a better insight in many aspects of exacerbations in COPD (e.g., the identification, the risk factors, phenotypes and the biomarkers).

8.
Eur J Radiol ; 83(11): 2093-101, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25176287

ABSTRACT

OBJECTIVES: Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. MATERIALS AND METHODS: COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9µg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9µg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. RESULTS: OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. CONCLUSIONS: In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a ß2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.


Subject(s)
Adrenal Cortex Hormones/pharmacokinetics , Bronchodilator Agents/pharmacokinetics , Budesonide/pharmacokinetics , Formoterol Fumarate/pharmacokinetics , Magnetic Resonance Imaging , Pulmonary Disease, Chronic Obstructive/pathology , Adrenal Cortex Hormones/administration & dosage , Bronchodilator Agents/administration & dosage , Budesonide/administration & dosage , Drug Combinations , Feasibility Studies , Female , Forced Expiratory Volume/drug effects , Formoterol Fumarate/administration & dosage , Humans , Male , Middle Aged , Oxygen , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/physiopathology , Respiratory Function Tests
9.
Eur Respir J ; 43(5): 1306-15, 2014 May.
Article in English | MEDLINE | ID: mdl-24311762

ABSTRACT

Clear evidence for an association between systemic inflammation and increased arterial stiffness in patients with chronic obstructive pulmonary disease (COPD) is lacking. Moreover, the effects of pulmonary rehabilitation on arterial stiffness are not well studied. We aimed to 1) confirm increased arterial stiffness in COPD; 2) evaluate its correlates including systemic inflammation; and 3) study whether or not it is influenced by pulmonary rehabilitation. Aortic pulse-wave velocity (APWV) was determined in 168 healthy volunteers, and APWV and inflammatory markers were determined in 162 COPD patients during baseline evaluation of a pulmonary rehabilitation programme. A complete post-pulmonary rehabilitation dataset was collected in 129 patients. It was found that APWV was increased in COPD patients when compared with controls, blood pressure and age predicted baseline APWV, and systemic inflammatory markers were not independently related to APWV. Although baseline APWV was predictive for the change in APWV after pulmonary rehabilitation (r= -0.77), on average APWV did not change (10.7 ± 2.7 versus 10.9 ± 2.5 m·s(-1); p=0.339). Arterial stiffness in COPD is not related to systemic inflammation and does not respond to state-of-the-art pulmonary rehabilitation. These results emphasise the complexity of cardiovascular risk and its management in COPD.


Subject(s)
Arteries/physiopathology , Inflammation/physiopathology , Pulmonary Disease, Chronic Obstructive/physiopathology , Pulmonary Disease, Chronic Obstructive/rehabilitation , Vascular Stiffness , Aged , Cardiovascular Diseases/etiology , Cardiovascular Diseases/physiopathology , Female , Healthy Volunteers , Hemodynamics , Humans , Male , Middle Aged , Prospective Studies , Pulse Wave Analysis , Risk Factors , Software , Treatment Outcome
10.
C R Biol ; 327(3): 175-80, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15127888

ABSTRACT

Microchip arrays have become one of the most rapidly growing techniques for monitoring gene expression at the genomic level and thereby gaining valuable insight about various important biological mechanisms. Examples of such mechanisms are: identifying disease-causing genes, genes involved in the regulation of some aspect of the cell cycle, etc. In this article, we discuss the problem of estimating gene expression based on a proper statistical model. More precisely, we show how the model introduced by Li and Wong can be used in its full bivariate generality to provide a new measure of gene expression from high-density oligonucleotide arrays. We also present a second gene expression index based on a new way of reducing the model into a simpler univariate model. In both cases, the gene expression indices are shown to be unbiased and to have lower variance than the established ones. Moreover, we present a bootstrap method aiming at providing non-parametric confidence intervals for the expression index.


Subject(s)
Models, Statistical , Oligonucleotide Array Sequence Analysis/statistics & numerical data , Gene Expression , Mathematics
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