Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial

ObjectivesColchicine has been proposed as a COVID-19 treatment, but its effect on time to recovery is unknown. We aimed to determine whether colchicine is effective at reducing time to recovery and COVID-19 related hospitalisations/deaths among people in the community. DesignProspective, multicentre, open-label, multi-arm, adaptive Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE). SettingNational trial run remotely from a central trial site and at multiple primary care centres across the United Kingdom. ParticipantsAdults aged [≥]65, or [≥]18 years with comorbidities or shortness of breath, and unwell [≤]14 days with suspected COVID-19 in the community. InterventionsParticipants were randomised to usual care, usual care plus colchicine (500{micro}g daily for 14 days), or usual care plus other interventions. Main outcome measuresThe co-primary endpoints were time to first self-reported recovery, and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. The hypothesis for the time to recovery endpoint is evaluated first, and if superiority is declared on time to recovery, the hypothesis for the second co-primary endpoint of hospitalisation/death is then evaluated. To determine futility, we pre-specified a clinically meaningful benefit in time to first reported recovery as a hazard ratio of 1.2 or larger (equating to approximately 1.5 days benefit in the colchicine arm, assuming 9 days recovery in the usual care arm). ResultsThe trial opened on April 2, 2020, with randomisation to colchicine starting on March 04, 2021 and stopping on May 26, 2021, because the pre-specified time to recovery futility criterion was met. The primary analysis model included 2755 SARS-CoV-2 positive participants, randomised to colchicine (n=156), usual care (n=1145), and other treatments (n=1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.919 [95% credible interval 0.72 to 1.16] and an estimated increase of 1.14 days [-1.86 to 5.21] in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. Results were similar in comparisons with concurrent controls. COVID-19 related hospitalisations/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 [0.28 to 1.89] and an estimated difference of -0.4% [-2.7% to 2.4]. One serious adverse event occurred in the colchicine group and one in usual care. ConclusionsColchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community. Trial registrationISRCTN86534580.

Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial

BACKGROUNDInhaled budesonide has shown efficacy for treating COVID-19 in the community but has not yet been tested in effectiveness trials. METHODSWe performed a multicenter, open-label, multi-arm, adaptive platform randomized controlled trial involving people aged [≥]65 years, or [≥]50 years with comorbidities, and unwell [≤]14 days with suspected COVID-19 in the community (PRINCIPLE). Participants were randomized to usual care, usual care plus inhaled budesonide (800{micro}g twice daily for 14 days), or usual care plus other interventions. The co-primary endpoints are time to first self-reported recovery, and hospitalization/death related to COVID-19, both measured over 28 days from randomisation and analysed using Bayesian models. RESULTSThe trial opened on April 2, 2020. Randomization to inhaled budesonide began on November 27, 2020 and was stopped on March 31, 2021 based on an interim analysis using data from March 4, 2021. Here, we report updated interim analysis data from March 25, 2021, at which point the trial had randomized 4663 participants with suspected COVID-19. Of these, 2617 (56.1%) tested SARS-CoV-2 positive and contributed data to this interim budesonide primary analysis; 751 budesonide, 1028 usual care and 643 to other interventions. Time to first self-reported recovery was shorter in the budesonide group compared to usual care (hazard ratio 1.208 [95% BCI 1.076 - 1.356], probability of superiority 0.999, estimated benefit [95% BCI] of 3.011 [1.134 - 5.41] days). Among those in the interim budesonide primary analysis who had the opportunity to contribute data for 28 days follow up, there were 59/692 (8.5%) COVID-19 related hospitalizations/deaths in the budesonide group vs 100/968 (10.3%) in the usual care group (estimated percentage benefit, 2.1% [95% BCI -0.7% - 4.8%], probability of superiority 0.928). CONCLUSIONSIn this updated interim analysis, inhaled budesonide reduced time to recovery by a median of 3 days in people with COVID-19 with risk factors for adverse outcomes. Once 28 day follow up is complete for all participants randomized to budesonide, final analyses of time to recovery and hospitalization/death will be published. (Funded by the National Institute of Health Research/ United Kingdom Research Innovation [MC_PC_19079]; PRINCIPLE ISRCTN number, ISRCTN86534580.)

Asthma exacerbations and worsenings in patients aged 1-75 years with add-on tiotropium treatment.

This review explores the effect of tiotropium Respimat® add-on therapy on asthma exacerbations and worsenings, adverse events (AEs) related to exacerbations and symptoms and any effects on seasonality across the 10 UniTinA-asthma® clinical trials comprising over 6000 patients. When added on to inhaled corticosteroids ± additional therapies, tiotropium significantly reduced the risk of exacerbations and worsenings in adults with symptomatic severe asthma and provided a non-significant improvement in worsenings in adults with symptomatic moderate and mild asthma, which was significant for patients with moderate asthma receiving tiotropium 2.5 µg once daily vs. placebo. Trials in paediatric patients were not powered to assess exacerbations or worsenings, but when AEs related to asthma exacerbations and symptoms were grouped into a composite endpoint and pooled, tiotropium improved outcomes vs. placebo (rate ratio 0.76; 95% confidence interval 0.63, 0.93). The reduction in exacerbations with tiotropium is apparent across all patients during the observed seasonal peaks of these events.

Does Combined Anterior-Posterior Approach Improve Outcomes Compared with Posterioronly Approach in Traumatic Thoracolumbar Burst Fractures?: A Systematic Review

The aim of this systematic review was to evaluate the surgical, radiological, and functional outcomes of posterior-only versus combined anterior-posterior approaches in patients with traumatic thoracolumbar burst fractures. The ideal approach (anterior-only, posterior-only, or combined anterior-posterior) for the surgical management of thoracolumbar burst fracture remains controversial, with each approach having its advantages and disadvantages. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed (registration no., CRD42018115120). The authors reviewed comparative studies evaluating posterior-only approach compared with combined anterior-posterior approaches with respect to clinical, surgical, radiographic, and functional outcome measures. Five retrospective cohort studies were included. Postoperative neurological deterioration was not reported in either group. Operative time, estimated blood loss, and postoperative length of stay were increased among patients in the combined anterior-posterior group in one study and equivalent between groups in another study. No significant difference was observed between the two approaches with regards to long-term postoperative Cobb angle (mean difference, −0.2; 95% confidence interval, −5.2 to 4.8; p =0.936). Moreover, no significant difference in functional patient outcomes was observed in the 36item Short-Form Health Survey, Visual Analog Scale, and return-to-work rates between the two groups. The available evidence does not indicate improved clinical, radiologic (including kyphotic deformity), and functional outcomes in the combined anterior-posterior and posterior-only approaches in the management of traumatic thoracolumbar burst fractures. Further studies are required to ascertain if a subset of patients will benefit from a combined anterior-posterior approach.

Administration of tranexamic acid for victims of severe trauma within pre-hospital care ambulance services (PHCAS) in Malaysia

@#Introduction: Trauma is a Global threat and the 5th highest cause of all-cause mortality in Malaysia caused predominantly due to road traffic accidents. Majority of trauma victims are young adults aged between 21-40 years old. In Malaysia, 24 out of 100,000 population die annually due to trauma, rating us amongst the highest in South East Asia. These alarming figures justify aggressive preventive and mitigation strategies. The aim of this paper is to promote the implementation of evidence-based interventions that will reduce the rate of preventable death because of trauma. Tranexamic acid is one of the few interventions in the early management of severe trauma with level-one evidence. Tranexamic acid has been proven to reduce all causes of mortality and mortality due to bleeding. Evidence proves that it is most effective when administered early, particularly within the 1st hour of trauma. This proposed guideline is formulated based upon quality evidence from multicentre studies, clinical practices in other countries and consideration of the local demographic factors with the intent of enabling an easy and simple pathway to administer tranexamic acid early in the care of the severely injured. Conclusion: The guideline highlights select pre-hospital criteria’s and the methods for drug administration. The authors recognise that some variants may be present amongst certain institutions necessitating minor adaptations, nevertheless the core principles of advocating tranexamic acid early in the course of pre-hospital trauma should be adhered to.

Cost-effectiveness of tiotropium versus omalizumab for uncontrolled allergic asthma in US.

BACKGROUND: A significant minority of asthma patients remain uncontrolled despite the use of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA). A number of add-on therapies, including monoclonal antibodies (namely omalizumab) and more recently tiotropium bromide have been recommended for this subgroup of patients. The purpose of this study was to assess the cost-effectiveness of tiotropium versus omalizumab as add-on therapies to ICS + LABA for patients with uncontrolled allergic asthma. METHODS: A probabilistic Markov model of asthma was created. Total costs (in 2013 US $) and health outcomes of three interventions including standard therapy (ICS + LABA), add-on therapy with tiotropium, and add-on therapy with omalizumab, were calculated over a 10-year time horizon. Future costs and quality-adjusted life years (QALYs) were discounted at the rate of 3%. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at willingness-to-pay value of $50,000. RESULTS: The 10-year discounted costs and QALYs for standard therapy were $38,432 and 6.79, respectively. The corresponding values for add-on therapy with tiotropium and with omalizumab were $41,535 and 6.88, and $217,847 and 7.17, respectively. The incremental cost-effectiveness ratios (ICER) of add-on therapy with tiotropium versus standard therapy, and omalizumab versus tiotropium were $34,478/QALY, and $593,643/QALY, respectively. The model outcomes were most sensitive to the costs of omalizumab but were robust against other assumptions. CONCLUSIONS: Although omalizumab had the best health outcomes, add-on therapy with tiotropium was a cost-effective alternative to omalizumab and standard therapy for uncontrolled allergic asthma at willingness-to-pay of $50,000/QALY.

Predictors of inappropriate and excessive use of reliever medications in asthma: a 16-year population-based study.

BACKGROUND: Understanding factors associated with the inappropriate or excessive use of short-acting beta agonists (SABA) can help develop better policies. METHODS: We used British Columbian (BC)'s administrative health data (1997-2014) to create a retrospective cohort of asthma patients aged between 14 and 55 years. The primary and secondary outcomes were, respectively, inappropriate and excessive use of SABA based on a previously validated definition. Exposures were categorised into groups comprising socio-demographic variables, indicators of type and quality of asthma care, and burden of comorbid conditions. RESULTS: 343,520 individuals (56.3% female, average age 30.5) satisfied the asthma case definition, contributing 2.6 million person-years. 7.3% of person-years were categorised as inappropriate SABA use and 0.9% as excessive use. Several factors were associated with lower likelihood of inappropriate use, including female sex, higher socio-economic status, higher continuity of care, having received pulmonary function test in the previous year, visited a specialist in the previous year, and the use of inhaled corticosteroids in the previous year. An asthma-related outpatient visit to a general practitioner in the previous year was associated with a higher likelihood of inappropriate SABA use. Similar associations were found for excessive SABA use with the exception that visit to respirologist and the use of systemic corticosteroids were associated with increased likelihood of excessive use. CONCLUSIONS: Despite proven safety issues, inappropriate SABA use is still prevalent. Several factors belonging to patients' characteristics and type/quality of care were associated with inappropriate use of SABAs and can be used to risk-stratify patients for targeted attempts to reduce this preventable cause of adverse asthma outcomes.

Efficacy and safety of benralizumab in Japanese patients with severe, uncontrolled eosinophilic asthma.

BACKGROUND: In the Phase III CALIMA trial, benralizumab significantly reduced asthma exacerbations, increased lung function, and alleviated symptoms for patients with severe, uncontrolled eosinophilic asthma. The aim of this subgroup analysis was to evaluate the efficacy and safety of benralizumab for Japanese patients in the CALIMA trial. METHODS: CALIMA was a randomised, controlled trial of 1306 patients (aged 12-75 years; registered at ClinicalTrials.gov: NCT01914757) with severe asthma uncontrolled by medium- to high-dosage inhaled corticosteroids and long-acting ß2-agonists (ICS/LABA). Patients received 56 weeks' benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), or placebo Q4W. The primary analysis population was patients receiving high-dosage ICS/LABA with blood eosinophils ≥300 cells/µL. This subgroup analysis covered Japanese patients from this group. RESULTS: Of 83 patients randomised in Japan, 46 were receiving high-dosage ICS/LABA and had blood eosinophils ≥300 cells/µL. Compared with placebo, benralizumab reduced the annual rate of asthma exacerbations by 66% (Q4W; rate ratio 0.34, 95% CI, 0.11-0.99) and 83% (Q8W; rate ratio 0.17, 95% CI, 0.05-0.60); increased prebronchodilator FEV1 by 0.334 L (Q4W; 95% CI, 0.020-0.647) and 0.198 L (Q8W; 95% CI, -0.118 to 0.514); and decreased total asthma symptom score by 0.17 (Q4W; 95% CI, -0.82 to 0.48) and 0.24 (Q8W; 95% CI, -0.87 to 0.40). Percentages of adverse events were consistent with the overall CALIMA group. CONCLUSIONS: Benralizumab reduced annual asthma exacerbations and symptoms, increased lung function, and was well-tolerated by Japanese patients with severe, uncontrolled eosinophilic asthma.

The neglected burden of tuberculosis disease among health workers: a decade-long cohort study in South Africa.

BACKGROUND: Health workers (HWs) in resource-limited settings are at high-risk of exposure to tuberculosis (TB) at work. The aim of this study was to estimate the rate of TB disease among HWs in the Free State Province of South Africa between 2002 and 2012 and to compare demographic and clinical characteristics between HWs and the general population with TB. This study also explores the effect of occupational variables on risk of TB among HWs. METHODS: Probabilistic record linkage was utilized to identify HWs who were also registered as TB patients. This historical prospective cohort study calculated incidence rate ratios (IRR) for TB disease among HWs in Free State from 2002 to 2012. Generalized linear mixed-effects regression was used to model the association between sex, race, facility type, occupation, duration of employment, and the rate of TB. RESULTS: There were 2677 cases of TB diagnosed among HWs from 2002 to 2012 and 1280 cases were expected. The overall TB incidence rate in HWs during the study period was 1496·32 per 100,000 compared to an incidence rate of 719·37 per 100,000 in the general population during the same time period. IRR ranged from 1·14 in 2012 to 3·12 in 2005. HWs who were male, black, coloured and employed less than 20 years had higher risk of TB. Facility type and occupation were not associated with increased risk of TB when adjusted for other covariates. CONCLUSION: HWs in South Africa have higher rates of TB than the general population. Improved infection prevention and control measures are necessary in all high-burden TB healthcare settings.

In patients with severe uncontrolled asthma, does knowledge of adherence and inhaler technique using electronic monitoring improve clinical decision making? A protocol for a randomised controlled trial.

INTRODUCTION: Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes. METHODS AND ANALYSIS: This prospective, randomised, multicentre study will compare the impact of using information on adherence to influence asthma treatment. Patients with severe uncontrolled asthma will be included. Data on adherence, inhaler technique and electronically recorded peak expiratory flow rate will be used to promote adherence and guide a clinical decision protocol to guide management in the active group. The control group will receive standard inhaler and adherence education. Medications will be adjusted using a protocol based on Global Initiativefor Asthma (GINA) recommendations. The primary outcome is the between-group difference in the proportion of patients who have refractory disease and are prescribed appropriate medications at the end of 32 weeks. A co-primary outcome is the difference between groups in the rate of adherence to salmeterol/fluticasone inhaler over the last 12 weeks. Secondary outcomes include changes in symptoms, lung function, type-2 cytokine biomarkers and clinical outcomes between both groups. Cost-effectiveness and cost-utility analyses of the INCA device intervention will be performed. The economic impact of a national implementation of the INCA-SUN programme will be evaluated. ETHICS AND DISSEMINATION: The results of the study will be published as a manuscript in peer-reviewed journals. The study has been approved by the ethics committees in the five participating hospitals. TRIAL REGISTRATION: NCT02307669; Pre-results.

Quality of Life and Asthma Symptom Control: Room for Improvement in Care and Measurement.

BACKGROUND: The recent Global Initiative for Asthma management strategy recommends achieving symptom control and minimizing the future risk of poor outcomes as priorities for asthma management. OBJECTIVE: The objective was to quantify the association between symptom control and health-related quality of life in asthma. METHODS: In a prospectively recruited random sample of adults with asthma, we ascertained symptom control and measured health-related quality of life using a generic (EuroQol five-dimensional questionnaire [EQ-5D]) and a disease-specific (Asthma Quality of Life Questionnaire) instrument, to estimate EQ-5D and five-dimensional Asthma Quality of Life Questionnaire (AQL-5D) utilities, respectively. We measured the adjusted difference in utilities across symptom control levels and calculated the loss of predictive efficiency due to aggregating multiple symptoms into one symptom control variable. RESULTS: The final sample included 958 observations from 494 individuals (mean age at baseline 52.2 ± 14.5 years; 67.0% women). Asthma was symptomatically controlled, partially controlled, and uncontrolled in 269 (28.1%), 367 (38.3%), and 322 (33.6%) observations, respectively. A person with symptomatically uncontrolled asthma would gain 0.0512 (95% CI 0.0339-0.0686) in EQ-5D or 0.0802 (95% CI 0.0693-0.0910) in AQL-5D utilities by achieving symptom control. The loss of predictive efficiency was 55.4% and 27.6% for EQ-5D and AQL-5D utilities, respectively. CONCLUSIONS: Asthma symptom control status corresponds well with both generic and disease-specific quality-of-life measures. The trade-off, however, between ease of use and predictive power should be reconsidered in developing simplified measures of control. Our results have direct relevance in informing decision-analytic models of asthma and deducing the effect of interventions on quality of life through their impact on asthma control.

Quality assurance of spirometry in a population-based study -predictors of good outcome in spirometry testing.

BACKGROUND: The assurance of high-quality spirometry testing remains a challenge. METHODS: Spirometry training consisted of standardized coaching followed by certification for 35 spirometry-naïve and 9 spirometry-experienced research assistants. Spirometry was performed before and after bronchodilator (BD) in random population samples of 5176 people aged 40 years and older from 9 sites in Canada. using the hand-held EasyOne spirometer (ndd Medical Technologies Inc., Andover, MA, USA). Pulmonary function quality assurance with over reading was conducted centrally in Vancouver: spirograms were reviewed and graded according to ATS/ERS standards with prompt feedback to the technician at each site. Descriptive statistics were calculated for manoeuvre acceptability and repeatability variables. A logistic regression model was constructed for the predictors of spirometry quality success. RESULTS: 95% of test sessions achieved pre-determined quality standards for back extrapolated volume (BEV), time to peak flow (PEFT) and end of test volume (EOTV). The mean forced expiratory time (FET) was 11.2 seconds. Then, 90% and 95% of all manoeuvres had FEV1 and FVC that were repeatable within 150 ml and 200 ml respectively. Test quality was slightly better for post-BD test sessions compared with pre-BD for both groups of research assistants. Independent predictors of acceptable test quality included participant characteristics: female sex, younger age, greater BD responsiveness; but not study site or prior experience in completing spirometry by the technologist. CONCLUSIONS: Good quality spirometry tests are attainable in large multicenter epidemiological studies by trained research assistants, irrespective of their prior experience in spirometry.

Compliance with the Canadian Association of Emergency Physicians' asthma clinical practice guidelines at a tertiary care emergency department.

INTRODUCTION: Although evidence-based clinical practice guidelines (CPGs) exist, emergency department (ED) asthma management remains highly variable. Our objective was to compare asthma management at a tertiary care ED with that advised by the Canadian Association of Emergency Physicians' (CAEP) asthma CPG and current best practice. METHODS: This medical record study enrolled patients between the ages of 19 and 60 years with a previous diagnosis of asthma who were seen for an acute asthma exacerbation at the Vancouver General Hospital ED in 2008. Standard methodology guidelines for medical record review were followed, including explicitly defined criteria and determination of interrater reliability. Primary outcomes were the proportion of cases with the following: objective assessment of severity using peak expiratory flow (PEF), use of systemic corticosteroids (SCSs) in the ED and at discharge, prescription for any inhaled corticosteroids (ICSs), and documentation of outpatient follow-up. RESULTS: A total of 204 patient encounters were enrolled. Kappa values for interrater assessment ranged from 0.93 to 1.00. Compliance with primary outcomes was as follows: measurement of PEF, 90% (95% CI 85-94); use of SCSs in the ED, 64% (95% CI 57-71); prescription of SCSs at discharge, 59% (95% CI 51-67); prescription of any ICS at discharge, 51% (95% CI 41-61); and documentation of outpatient follow-up, 78% (95% CI 71-84). CONCLUSIONS: This study indicates an improvement in ED asthma care compared to previously published studies; however, discordance still exists between asthma management at a tertiary care ED and the CAEP asthma CPG and current best practice. Further research is warranted to understand the reasons for this finding.