Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicentre, phase 3, randomised controlled trial.

OBJECTIVE: To determine whether disrupting the renin angiotensin system with angiotensin receptor blockers will improve clinical outcomes in people with covid-19. DESIGN: CLARITY was a pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. SETTING: 17 hospital sites in India and Australia. PARTICIPANTS: Participants were at least 18 years old, previously untreated with angiotensin receptor blockers, with a laboratory confirmed diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection who had been admitted to hospital for management of covid-19. INTERVENTION: Oral angiotensin receptor blockers (telmisartan in India) or placebo (1:1) for 28 days. MAIN OUTCOME MEASURES: The primary endpoint was covid-19 disease severity using a modified World Health Organization Clinical Progression Scale (WHO scale) at day 14. Secondary outcomes were WHO scale scores at day 28, mortality, intensive care unit admission, and respiratory failure. Analyses were evaluated on an ordinal scale in the intention-to-treat population. RESULTS: Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomised: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met. CONCLUSIONS: In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan. TRIAL REGISTRATION: ClinicalTrials.gov NCT04394117.

Protocol for the Controlled evaLuation of Angiotensin Receptor blockers for COVID-19 respIraTorY disease (CLARITY): a randomised controlled trial.

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 solution for reducing COVID-19 respiratory outcomes. METHODS AND DISCUSSION: CLARITY is a pragmatic, adaptive, two-arm, multi-centre, comparative effectiveness phase III randomised controlled trial that examines whether ARBs reduce COVID-19 severity among high-risk patients. Recruiting in India and Australia, the trial will compare treatment with a maximum tolerated daily dose of an ARB to standard of care. Treatment allocation is blinded in India but open-label in Australia due to interruptions to placebo supply in the latter. The primary endpoint is a 7-point ordinal scale of clinical states, ranging from no limitation of activities (category 1) to death (category 7), assessed on day 14. Secondary outcomes include the 7-point scale assessed at day 28 and 28- and 90-day mortality. The design adapts the sample size based on accumulating data via frequent interim analyses and the use of predictive probability to determine whether the current sample size is sufficient or continuing accrual would be futile. The trial commenced recruitment on 18 August 2020. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04394117 . Registered on 19 May 2020. Clinical Trial Registry of India: CTRI/2020/07/026831).

Comparison between two different successful approaches to COVID-19 pandemic in India (Dharavi versus Kerala).

Various factors interplay when it comes to successful containment of pandemic. In last one year, we have witnessed various countries formulating and practicing their own unique ways to tackle coronavirus. We have seen the most developed countries failing terribly and unable to slow the COVID-19 spread, but at the same time also endorsed the comparatively less resourceful countries outperforming in terms of reduced disease morbidity and mortality. Current review is about two regions from India (Dharavi and Kerala) who were different in their approach as compared to rest of the country and were able to keep the COVID-19 cases to the minimum.

COVID-19 Pandemic and Children: A Review.

The severe respiratory disease COVID-19 (coronavirus disease 2019) was first reported in late December 2019 in Wuhan City, China. Soon thereafter, the World Health Organization (WHO) officially declared it a pandemic. The adult population is highly affected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); however, infants and children are also not spared. Transmission in the pediatric population appears to be primarily from COVID-19-positive adults, largely from family contacts through droplets, direct contacts, and aerosols. There is also evidence of fecal-oral route of transmission. The incubation period of COVID-19 in children ranges from 2 to 10 days. Most children are asymptomatic. The most common symptoms amongst symptomatic children are fever and cough. Shortness of breath, sore throat, rhinorrhea, conjunctivitis, fatigue, and headache are other common symptoms. Diarrhea, vomiting, and abdominal pain are the common gastrointestinal symptoms that may be present with or without respiratory symptoms. Very few children are likely to develop severe disease.Supportive care is the mainstay of treatment. Though data are limited, antiviral therapies such as remdesivir, favipiravir, lopinavir/ritonavir, and other drugs like hydroxychloroquine/chloroquine have been used for severe COVID-19 cases, with remdesivir showing the greatest promise. A few children may develop an exaggerated immune response, characterized by exaggerated cytokine release and manifests with features similar to Kawasaki disease. The syndrome has been referred to by many names including pediatric inflammatory multisystem syndrome (PIMS) and more recently, as multisystem inflammatory syndrome in children (MIS-C); this life-threatening condition often requires a multidisciplinary team effort and use of immunomodulators.