Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial.
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ABSTRACT:
SUBMITTER: Heaney LG
PROVIDER: S-EPMC7783382 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
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Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial.
Heaney Liam G LG Busby John J Hanratty Catherine E CE Djukanovic Ratko R Woodcock Ashley A Walker Samantha M SM Hardman Timothy C TC Arron Joseph R JR Choy David F DF Bradding Peter P Brightling Christopher E CE Chaudhuri Rekha R Cowan Douglas C DC Mansur Adel H AH Fowler Stephen J SJ Niven Robert M RM Howarth Peter H PH Lordan James L JL Menzies-Gow Andrew A Harrison Tim W TW Robinson Douglas S DS Holweg Cecile T J CTJ Matthews John G JG Pavord Ian D ID
The Lancet. Respiratory medicine 20200908 1
<h4>Background</h4>Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite sc ...[more]
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Project description:BackgroundPatients with difficult-to-control asthma consume 50-60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called 'T2-low asthma' and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy.Methods/designPatients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers.DiscussionMulti-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct.Trial registrationClinicalTrials.gov, NCT02717689 . Registered on 16 March 2016.
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Project description:BackgroundFractional exhaled nitric oxide (FeNO) is promising for diagnosing asthma and could replace bronchial provocation (BP). To date, cut-off values have been derived by post hoc analysis only. The aim was to validate the diagnostic accuracy for predefined FeNO cut-off values and the predictive value for responsiveness to inhaled corticosteroids (ICS).MethodsWe conducted a prospective, diagnostic, multicentre study with patients attending three private practices of pneumologists in Upper Bavaria, Germany, from July 3, 2020 to Jan 21, 2022. Index test was FENO measurement. Reference standard was Tiffeneau ratio (FEV1/VC) or airway resistance as assessed by whole body plethysmography, with additional BP or bronchodilation test. Follow-up was performed after 12 weeks. Analyses of Receiver Operating Characteristics curves were conducted to determine the diagnostic accuracy and predictive value of FeNO.Findings308 patients with complete follow-up were recruited, 186 (60·4%) were female, average age was 44·7 years, 161 (52·3%) had asthma. Regarding diagnostic accuracy, the area under the curve (AUC) was 0·718 (95% CI 0·661-0·775; p < 0·001). Sensitivity at FeNO >50 ppb was 0·24 (95% CI 0·18-0·32), specificity 0·99 (0·95-1·0), positive predictive value (PPV) 0·95 (0·84-0·99), negative predictive value (NPV) 0·54 (0·48-0·60). In 66 patients with ´wheezing´ and ´allergic rhinitis´, the sensitivity at FeNO >33 ppb was 0·49 (0·34-0·64), specificity 0·88 (0·64-0·99), PPV 0·92 (0·75-0·99), NPV 0·38 (0·23-0·54). In 68 patients with ICS medication, responsiveness was predicted at the cut-off >43 ppb, with a sensitivity of 0·55 (95%CI 0·36-0·74), specificity 0·82 (0·66-0·92), PPV 0·70 (0·47-0·87), NPV 0·71 (0·56-0·84).InterpretationFeNO measurement allows a valid ruling-in of an asthma diagnosis, whereas ruling-out of asthma is not possible. Enhanced probability of ICS responsiveness is also given with increased FeNO values.FundingCircassia Germany gave 25% discount on the purchase of three NIOX VERO devices.
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Project description:ObjectiveTo assess the efficacy and safety of modified-release (MR) versus immediate-release (IR) prednisone in newly diagnosed glucocorticoid (GC)-naïve patients with polymyalgia rheumatica (PMR).MethodsPatients were randomised to double-blind MR prednisone (taken at approximately 22:00) or IR prednisone (taken in the morning), 15 mg/day for 4 weeks. The primary end point was complete response rate (≥70% reduction in PMR visual analogue scale, duration of morning stiffness and C reactive protein (CRP) (or CRP <2× upper limit of normal (ULN))) at week 4. Non-inferiority was decided if the lower 95% confidence limit (MR vs IR prednisone) was above -15%. 400 patients were planned but only 62 were enrolled due to difficulties in recruiting GC-naïve patients with PMR with CRP ≥2×ULN.ResultsThe percentage of complete responders at week 4 was numerically greater for MR prednisone (53.8%) than for IR prednisone (40.9%). Non-inferiority of MR versus IR prednisone was not proven in the primary analysis on the per protocol population (N=48; treatment difference: 12.22%; 95% CI -15.82% to 40.25%). However, sensitivity analysis on the full analysis population showed an evident trend favouring MR prednisone (N=62; treatment difference: 15.56%; 95% CI -9.16% to 40.28%). Adverse events were generally mild and transient with no unexpected safety observations.ConclusionsThe study showed a clear trend for favourable short-term efficacy of MR prednisone versus IR prednisone in early treatment of PMR. Further studies are warranted.Trial registration numberEudraCT number 2011-002353-57; Results.
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Project description:BackgroundPatients with severe, uncontrolled asthma have a significant unmet need for new treatments that have broader effects on airway inflammation, and that provide greater improvements in asthma outcomes than currently approved biologics and standard-of-care therapies. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline disease phenotype. This article reports the design and objectives of the pivotal phase 3 NAVIGATOR study.MethodsNAVIGATOR (NCT03347279) is an ongoing randomized, double-blind, placebo-controlled trial in adults (18-80 years old) and adolescents (12-17 years old) with severe, uncontrolled asthma, who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids (N = 1061). The study population includes approximately equal proportions of patients with high (≥ 300 cells/μL) and low (< 300 cells/μL) blood eosinophil counts. The study comprises a 5-6-week screening period, a 52-week treatment period and a 12-week post-treatment follow-up period. All patients will receive their prescribed controller medications without change throughout the study. The primary efficacy endpoint is the annualized asthma exacerbation rate during the 52-week treatment period. Key secondary endpoints include the effect of tezepelumab on lung function, asthma control and health-related quality of life.DiscussionNAVIGATOR is evaluating the effect of tezepelumab in patients with a broad range of severe asthma phenotypes at baseline, including those with low blood eosinophil counts. The target sample size for NAVIGATOR (N = 1060) was achieved, and it is the largest clinical study of tezepelumab in severe, uncontrolled asthma to date. NAVIGATOR aims to further investigate the effect of tezepelumab on exacerbations and build on observations from the phase 2b PATHWAY study, and to demonstrate further the potential of tezepelumab to provide patients with severe, uncontrolled asthma with improvements in lung function, asthma control and health-related quality of life.Trial registrationNCT03347279 (ClinicalTrials.gov). Registered 20 November 2017.
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