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1.
Trials ; 23(1): 361, 2022 Apr 27.
Article in English | MEDLINE | ID: covidwho-1817238

ABSTRACT

The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease) is a two-arm, multi-centre, randomised controlled trial being run in India and Australia that investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The trial was designed as a Bayesian adaptive sample size trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here, we describe the statistical analysis plan for the trial and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment.Trial registrationClinicalTrials.gov NCT04394117 . Registered on 19 May 2020Clinical Trial Registry of India CTRI/2020/07/026831Version and revisionsVersion 1.0. No revisions.


Subject(s)
COVID-19 , Respiratory Tract Diseases , Angiotensin Receptor Antagonists/adverse effects , Bayes Theorem , COVID-19/drug therapy , Data Interpretation, Statistical , Humans , Sample Size
2.
Heart Lung and Circulation ; 30:S244-S245, 2021.
Article in English | EMBASE | ID: covidwho-1734422

ABSTRACT

Background: Australia is experiencing ever more frequent weather/environmental challenges, including extreme heatwaves and bushfires. There are no proven interventions to reduce seasonal challenges to the cardiovascular health of vulnerable individuals. The REsilience to Seasonal ILlness and Increased Emergency admissioNs CarE (RESILIENCE) Trial will test the hypothesis that an individually-tailored intervention program will reduce re-hospitalisation risk and mortality in vulnerable individuals. Methods: We will recruit 300 medical patients admitted to the Austin Hospital (Melbourne, Australia), with chronic heart disease and multimorbidity and randomise (1:1) to standard care or the RESILIENCE program (RP). Applying a COVID-19 adapted protocol, the RP group will have their bio-behavioural profile and home environment assessed to determine their vulnerability to seasonal events. An individualised case-management program, including virtual clinic review with a nurse and physician, will be applied to promote seasonal resilience. The primary endpoint is all-cause days alive out of hospital during 12-month follow-up. Trial registered at ClinicalTrials.gov NCT04614428. Results: To date, 27 patients have been recruited and randomised. The mean age was 76±9 years and 11 (40%) were female. The most common comorbidities were hypertension (76 %), coronary artery disease (52 %), heart failure (52 %) and chronic kidney disease (52 %). Ten patients (37 %) have had a post-discharge home visit by the RP nurse and 5 (18 %) have attended the clinic. Conclusion: Recruitment is ongoing, and in the absence of further COVID-19 related lockdowns, all patients will be recruited over the next 12 months. Funding: MRFF-Keeping Australians Out of Hospital Grant

5.
Journal of Hypertension ; 39(SUPPL 1):e36-e37, 2021.
Article in English | EMBASE | ID: covidwho-1243515

ABSTRACT

Objective: Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of COVID-19 disease. However, the effect of RAS-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported Design and method: We examined how hypertension, its major metabolic cophenotypes and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterised by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model Results: Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis Conclusions: Our results indicate that neither hypertension nor antihypertensive treatment are likely to alter the expression of the key entry receptor for SARSCoV-2 in the human kidney. Our data further suggest that in the absence of SARSCoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

6.
Journal of Hypertension ; 39(SUPPL 1):e394, 2021.
Article in English | EMBASE | ID: covidwho-1240917

ABSTRACT

Objective: COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), utilises the catalytic site of membrane-bound angiotensin converting enzyme 2 (ACE2) for cell entry. It is thought that endocytosis of ACE2 results in a decrease in membrane bound ACE2 expression, and disruption of the local tissue renin angiotensin system protection. In this study, we hypothesised that SARS-CoV-2 infection would be associated with shedding of ACE2 leading to increased plasma ACE2 activity. Design and method: Australians aged >18 years (n=66) who had recovered from SARS-CoV-2 infection (positive result by PCR testing) and uninfected controls (n=70) were recruited. Serial samples were available in 23 recovered SARS-CoV-2 patients. Plasma ACE2 activity was measured using a fluorescent substrate-based assay and levels were compared using the Mann-Whitney or Kruskal-Wallis test. Serial ACE2 activity were analysed using the Friedman test for repeated measures. Post-hoc analysis was performed with a Bonferroni correction. Two-tailed P-values <0.05 were considered significant. Results: Controls and SARS-CoV-2 recovered patients were matched for age (mean±SD, 54±11 vs. 53±14 years, p=0.47) and gender (53% vs. 59% male, p=0.49). There were no significant differences (p>0.05) in the proportion of hypertension, obesity, diabetes, cardiovascular disease, or use of anti hypertensive, lipid lowering, and anti-platelet medications between the controls and SARSCoV-2 patients. Plasma ACE2 activity at median 35 days post-infection [interquartile range 30-38 days] was 97-fold higher in SARS-CoV-2 patients compared to controls (5.8 [2-11.3] vs. 0.06 [0.02-2.2] pmol/min/ml, p<0.0001). Plasma ACE2 activity was significantly different across disease severity (p=0.033), with severe COVID-19 associated with higher ACE2 activity compared to mild disease (11.2 [8.3-23.2] vs. 5.4 [1.8-9.0] pmol/min/ml, p=0.027). Men recovered from SARS-CoV-2 had higher ACE2 levels compared to women (9.2 [5.8-15.3] vs. 2.1 [0.2-5.1] pmol/min/ml, p<0.0001). In 23 patients who had serial blood samples at 63 [56-65] and 114 [111-125] days post infection, median ACE2 activity remained persistently elevated with no differences between time-points (p>0.05). Conclusions: Plasma ACE2 activity is elevated after SARS-CoV-2 infection and remains elevated post-infection. Our findings indicate the need for ongoing investigation to determine if ACE2 levels identify people at risk of prolonged illness following COVID-19.

7.
Journal of Hypertension ; 39(SUPPL 1):e205, 2021.
Article in English | EMBASE | ID: covidwho-1240912

ABSTRACT

Objective: Australia is experiencing ever more frequent/provocative weather and environmental challenges, including more extreme heatwaves and catastrophic bushfires. Concurrently, the annual challenge of wintry conditions to a population adapted to warmer conditions persists. Remarkably, however, there are no proven interventions to reduce seasonal challenges to the cardiovascular health of vulnerable individuals. In a world-first, the REsilience to Seasonal ILlness and Increased Emergency admissioNs CarE (RESILIENCE) Trial will test the hypothesis that an individually tailored, intervention program will reduce the risk of re-hospitalisation and mortality in vulnerable individuals. Design and method: 300 adult patients admitted to the Austin Hospital in Melbourne, Australia with heart disease and multimorbidity will be recruited and randomised (1:1) to standard care (SC) or the RESILIENCE program (RP) over 12-months. Applying a COVID-19 adapted protocol, the RP group will have their bio-behavioural profile and home environment assessed post-discharge, to determine their vulnerability to seasonal events. An individualised case-management program, including a virtual clinic review with a dedicated RP cardiac nurse and physician, will be applied to promote seasonal resilience. The primary end-point is all-cause days alive out of hospital (DAOH) during 12-month follow-up. Results: With study recruitment delayed due to COVID-19 restrictions, virtual screening of medical in-patients has confirmed the need and potential for the RP. Of 630 potential participants identified over a 6 week period, 196 patients (31%) met eligibility criteria-85 women and 79 men, mean (±SD) age 79 ± 11 years. Non-eligibility was largely due to non-chronic form of heart disease (34%), no comorbidity (23 %), and inability to give informed consent (15%). Conclusions: Preliminary data suggest that once commenced, we will rapidly recruit the requisite number of trial participants and depending on the results, we will be able to determine the cost-effectiveness of the RP to reduce seasonallyinduced admissions and mortality.

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