Abstract:Background
SARS-CoV-2 binds to membrane-bound angiotensin-converting enzyme 2 (ACE2) which may result in downregulation of membrane-bound ACE2. ACE2 is a key regulator of the renin-angiotensin system (RAS) and is responsible for degrading angiotensin II and thereby counteracting its pro-inflammatory, pro-fibrotic effects mediated through the angiotensin II type 1 receptor (AT1R). As AT1R is directly blocked by angiotensin receptor blockers (ARBs), these agents may offer a safe, low-cost solutio… Show more
“…Additional eligibility criteria identify participants who are at high risk of severe disease, including requirement for hospital admission due to COVID-19 or, for those who are managed in the community and have at least one of the following risk factors: aged ≥60 years, body mass index ≥30kg/m 2 , diagnosis of diabetes (HbA1c ≥7% and/or use of glucose-lowering medication), history of cardiovascular disease ∗ , history of chronic respiratory disease ∗ or current treatment with immunosuppressive therapy ( ∗ as defined by the treating clinician). Additional inclusion and exclusion criteria are defined in the trial protocol [ 11 ]. Fig.…”
Section: Methodsmentioning
confidence: 99%
“…The final study report will follow the Consolidated Standards of Reporting Trials guidelines for reporting on randomised controlled adaptive trials [ 8 – 10 ]. The study protocol has been accepted for publication [ 11 ].…”
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.
“…Additional eligibility criteria identify participants who are at high risk of severe disease, including requirement for hospital admission due to COVID-19 or, for those who are managed in the community and have at least one of the following risk factors: aged ≥60 years, body mass index ≥30kg/m 2 , diagnosis of diabetes (HbA1c ≥7% and/or use of glucose-lowering medication), history of cardiovascular disease ∗ , history of chronic respiratory disease ∗ or current treatment with immunosuppressive therapy ( ∗ as defined by the treating clinician). Additional inclusion and exclusion criteria are defined in the trial protocol [ 11 ]. Fig.…”
Section: Methodsmentioning
confidence: 99%
“…The final study report will follow the Consolidated Standards of Reporting Trials guidelines for reporting on randomised controlled adaptive trials [ 8 – 10 ]. The study protocol has been accepted for publication [ 11 ].…”
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.
“…Bayesian adaptive sample sizes have been employed when there is uncertainty around the distribution of the primary outcome and around the potential treatment effect sizes as they offer more flexibility than their standard frequentist counterparts. 10,15 They allow for sample size reassessment through Bayesian monitoring during the accrual phase where the trial may stop early for efficacy or futility (using a GST approach 9,10 ), or may continue recruiting if an indeterminant result has been obtained after accrual of the initial planned sample size. 15 Multi-arm multistage (MAMS) trials are a natural extension to GSTs offering more gains in efficiency by concurrently comparing multiple experimental arms, usually against a common control arm, and may also permit head-to-head comparisons.…”
Section: Bayesian Adaptive Sample Size and Multi-arm Multistage Designsmentioning
The use of Bayesian adaptive designs for clinical trials has increased in recent years, particularly during the COVID‐19 pandemic. Bayesian adaptive designs offer a flexible and efficient framework for conducting clinical trials and may provide results that are more useful and natural to interpret for clinicians, compared to traditional approaches. In this review, we provide an introduction to Bayesian adaptive designs and discuss its use in recent clinical trials conducted in respiratory medicine. We illustrate this approach by constructing a Bayesian adaptive design for a multi‐arm trial that compares two non‐invasive ventilation treatments to standard oxygen therapy for patients with acute cardiogenic pulmonary oedema. We highlight the benefits and some of the challenges involved in designing and implementing Bayesian adaptive trials.
“… 66 Besides, currently a phase 3 study is being conducted in India and Australia to investigate if Ang II receptor blockers can reduce COVID‐19 severity among patients at high risk. 68 …”
Section: Enzymes Are Entrance Tickets For Sars‐cov‐2 To Invade the Hu...mentioning
The rising pandemic caused by a coronavirus, resulted in a scientific quest to discover some effective treatments against its etiologic agent, the severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). This research represented a significant scientific landmark and resulted in many medical advances. However, efforts to understand the viral mechanism of action and how the human body machinery is subverted during the infection are still ongoing. Herein, we contributed to this field with this compilation of the roles of both viral and human enzymes in the context of SARS‐CoV‐2 infection. In this sense, this overview reports that proteases are vital for the infection to take place: from SARS‐CoV‐2 perspective, the main protease (M
pro
) and papain‐like protease (PL
pro
) are highlighted; from the human body, angiotensin‐converting enzyme‐2, transmembrane serine protease‐2, and cathepsins (CatB/L) are pointed out. In addition, the influence of the virus on other enzymes is reported as the JAK/STAT pathway and the levels of lipase, enzymes from the cholesterol metabolism pathway, amylase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and glyceraldehyde 3‐phosphate dehydrogenase are also be disturbed in SARS‐CoV‐2 infection. Finally, this paper discusses the importance of detailed enzymatic studies for future treatments against SARS‐CoV‐2, and how some issues related to the syndrome treatment can create opportunities in the biotechnological market of enzymes and the development of new drugs.
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