Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial (preprint)

Background: Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic and haemodynamic effects. Methods: In this randomised, controlled, open-label trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus empagliflozin 10mg once daily for 28 days or until discharge using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. On 3 March the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on 7 March. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: Between 8 July 2021 and 6 March 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Overall, 289 (14%) patients allocated to empagliflozin and 307 (14%) patients allocated to usual care died within 28 days (rate ratio 0.96; 95% confidence interval [CI] 0.82-1.13; p=0.64). There was no evidence of significant differences in duration of hospitalisation (median 8 days vs. 8 days) or the proportion of patients discharged from hospital alive within 28 days (79% vs. 78%; rate ratio 1.03; 95% CI 0.96-1.10; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (16% vs. 17%; risk ratio 0.95; 95% CI 0.84-1.08; p=0.44). Interpretation: In adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.

A case control investigation of COVID-19 associated Mucormycosis in India (preprint)

Background: Increased occurrence of mucormycosis in India during the second wave of the COVID-19 pandemic in early 2021 in India subsequently prompted us to undertake a multi-site case-control investigation. The objectives were to examine the monthly trend of Covid-19 Associated Mucormycosis (CAM) cases among in-patients and to identify factors associated with it.Methods: Eleven study sites were involved across India and archived records since 1st January till 30th September, 2021 were used for trend analysis. The cases and controls were enrolled during 15th June 2021 to 30th September 2021. Data were collected using a semi-structured questionnaire. Among 1211 enrolled participants, 336 were CAM cases and 875 were COVID-19 positive non-mucormycosis controls. Results: Admitted CAM-case number reached highest point in May 2021 after a month of peak admission for COVID-19. Odds of developing CAM increased with the history of working in a dusty environment (adjusted odds ratio; aOR 3.24, 95%CI: 1.34, 7.82), diabetes mellitus (aOR: 31.83, 95%CI: 13.96, 72.63), longer duration of hospital stay (aOR: 1.06, 95%CI: 1.02, 1.11) and use of methyl prednisolone (aOR: 2.71, 95%CI: 1.37, 5.37) following adjustment for age, gender, occupation, education, type of houses used for living, requirement of ventilatory support and route of steroid administration. Higher proportion of CAM cases required supplemental oxygen compared to the controls; use of non-rebreather mask (NRBM) was associated as a protective factor against mucormycosis compared to face masks (aOR: 0.18, 95%CI: 0.08, 0.41). Genomic sequencing of archived respiratory samples showed similar presence of Delta and Delta derivates in both cases and controls.Conclusions: Appropriate management of hyperglycemia, judicious use of steroids and use of NRBM during oxygen supplementation among COVID-19 patients bear the potential to reduce the risk of occurrence of mucormycosis. Avoiding exposure to dusty environment would add to prevention efforts.  

Vaccination saves lives: How do patients with chronic diseases and severe COVID-19 fare? Analysis from India’s National Clinical registry for COVID-19 (preprint)

Objectives This study aims to describe the demographic and clinical profile and ascertain the determinants of outcome among hospitalised COVID-19 adult patients enrolled in the National Clinical Registry for COVID-19 (NCRC). Methods NCRC is an on-going data collection platform operational in 42 hospitals across India. Data of hospitalized COVID-19 patients enrolled in NCRC between 1 st September 2020 to 26 th October 2021 were examined. Results Analysis of 29,509 hospitalised, adult COVID-19 patients [mean (SD) age: 51.1 (16.2) year; male: 18752 (63.6%)] showed that 15678 (53.1%) had at least one comorbidity. Among 25715 (87.1%) symptomatic patients, fever was the commonest symptom (72.3%) followed by shortness of breath (48.9%) and dry cough (45.5%). In-hospital mortality was 14.5% (n=3957). Adjusted odds of dying were significantly higher in age-group ≥60 years, males, with diabetes, chronic kidney diseases, chronic liver disease, malignancy, and tuberculosis, presenting with dyspnea and neurological symptoms. WHO ordinal scale 4 or above at admission carried the highest odds of dying [5.6 (95% CI: 4.6, 7.0)]. Patients receiving one [OR: 0.5 (95% CI: 0.4, 0.7)] or two doses of anti-SARS CoV-2 vaccine [OR: 0.4 (95% CI: 0.3, 0.7)] were protected from in-hospital mortality. Conclusions WHO ordinal scale at admission is the most important independent predictor for in-hospital death in COVID-19 patients. Anti-SARS-CoV2 vaccination provides significant protection against mortality.

Analysis of predictors and outcomes of COVID-19 patients requiring ICU admission from COVID 19 (preprint)

BackgroundSevere Corona virus disease (COVID-19) is associated with high mortality. Although single centre intensive care units (ICU) have reported clinical characteristics and outcomes, no large scale multicentric study from India has been published. The present retrospective, multi-centre study was aimed to describe the predictors and outcomes of COVID-19 patients requiring ICU admission from COVID-19 Registry of Indian council of Medical Research (ICMR), India.MethodsProspectively collected data from multiple participating institutions was entered in the electronic National Clinical Registry of COVID 19. We enrolled patients aged>18 years with COVID-19 pneumonia requiring ICU admission between March 2020 and August 2021. Exclusion criteria were negative RT PCR, death within 24 hours of ICU admission, or patients with incomplete data in the registry Their demographic characteristics, laboratory variables, ICU severity indices, treatment strategies and outcomes were analysed.ResultsA total of 5865 patients, with mean age 56±15 years, with 3840/5865 (65.4%) men, were enrolled in the ICMR registry.. Overall mortality was 2535/5865 (43.5%). Non-survivors were older than survivors (58.2±15.4 years vs 53.6 ±14.7 years; P=0.001). Non-survivors had multiple comorbidities (n=1951, 52.9%) with hypertension (47.2%) and diabetes (45.6%) being the most common, higher creatinine (1.6 ± P=0.001, high D-dimer (1.56 vs 1.37, P=0.001), higher CT severity index (16.8±5.2 vs 13.5 ±5.47 ) compared to  survivors. Non survivors had longer hospital and ICU stay (P=0.001). On multivariate regression analysis, high NLR (HR 1.017, 95% CI 1.005- 1.029, P=0.001), high CRP (HR 1.008, 95% CI 1.006- 1.010, P=0.001), high D dimer ((HR 1.089, 95% CI 1.065- 1.113, P=0.001) were associated with mechanical ventilation while younger age, (HR 0.974, CI 0.965-0.983, p=0.001), high D dimer (HR-1.014, CI 1.001-1.027, P=0.035) and use of prophylactic LMWH (HR 0.647, CI 0.527-0.794, p=0.001) were independently associated with mortality. ConclusionIn this large retrospective study of 5865 critically ill COVID 19 patients admitted to ICU, overall mortality was 2535/5865 (43.5%). Age, high D dimer, CT Severity score and use of prophylactic LMWH were independently associated with mortality. 

Delta Variant SARS-CoV-2 infections in pediatric cases during the second wave in India (preprint)

The aim of this study was to identify the SARS-CoV-2 lineages circulating in the pediatric population of India during the second wave of the pandemic. Clinical and demographic details linked with the nasopharyngeal/oropharyngeal swabs (NPS/OPS) collected from SARS-CoV-2 cases (n=583) aged 0-18 year and tested positive by real-time RT-PCR were retrieved from March to June 2021.Symptoms were reported among 37.2% of patients and 14.8% reported to be hospitalized. The E gene CT value had significant statistical difference at the point of sample collection when compared to that observed in the sequencing laboratory. Out of these 512 sequences 372 were VOCs, 51 were VOIs. Most common lineages observed were Delta, followed by Kappa, Alpha and B.1.36, seen in 65.82%, 9.96%, 6.83% and 4.68%, respectively in the study population. Overall, it was observed that Delta strain was the leading cause of SARS-CoV-2 infection in Indian children during the second wave of the pandemic. We emphasize on the need of continuous genomic surveillance in SARS-CoV-2 infection even amongst children.

Assessing of the Factors Associated with Mortality Among the Patients of PLACID Trial (A Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease) (preprint)

Background: Large data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analyzed the factors associated with mortality in a cohort of moderately ill COVID-19 patients enrolled in a multicentre randomized trial on convalescent plasma.Methods: Demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic records. Factors associated with mortality were explored using univariate and multivariable Cox regression analysis and expressed as hazard ratio (HR) with 95% confidence intervals (CI).Findings: The mean (SD) age of the cohort (n=451) was 51±12·4 years; 76·7% were male. Admission SOFA score was 2·4±1·1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98·9%, 8·4% and 4·0% respectively. The 28 day all-cause mortality was 14·4%. Median time from symptom onset to hospital admission was similar (p=1.0) in survivors (4 days; IQR 3-7) and non survivors (4 days; IQR 3-6). Patients with two or more co-morbidities had 2·25 (95%CI:1·17–4·32, p=0·014) times risk of death. When compared with survivors, admission IL-6 levels were higher (p<0.001) in non survivors and increased further on Day 3. On multivariable regression analysis, severity of illness (HR 1·21, 95%CI:1·07-1·36, p=0·002), PaO2/FiO2 ratio<100 (3·37, 1·54-7·41,p=0·002), Neutrophil Lymphocyte ratio (NLR)>10 (9·38, 3·67-24·0,p<0·001), D-dimer>1·0mg/l (2·51,1·14-5·51,p=0·022), ferritin>500ng/ml (2·66,1·46-4·85,p=0·001) and LDH≥450 IU/L (2·96,1·61-5·45,p=0·001) were significantly associated with death.Interpretation: In this cohort of moderately ill COVID-19 patients, severity of illness, underlying co-morbidities and higher levels of inflammatory markers were significantly associated with death.Trial Registration: The trial protocol was registered with the Clinical Trial Registry of India (CTRI/2020/04/024775).Funding: This study was funded by Indian Council of Medical Research, an autonomous government funded medical research council.Declaration of Interests: No other author has any competing financial or non-financial interest.Ethics Approval Statement: Ethical approval was obtained from the ICMR Central Ethics Committee on Human Research 326 (CECHR-002/2020) as well as from the Institutional Review Boards (IRB) /Institutional Ethics 327 Committees of all the participating hospitals.

Convalescent plasma in the management of moderate COVID-19 in India: An open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial) (preprint)

ObjectivesConvalescent plasma (CP) as a passive source of neutralizing antibodies and immunomodulators is a century-old therapeutic option used for the management of viral diseases. We investigated its effectiveness for the treatment of COVID-19. DesignOpen-label, parallel-arm, phase II, multicentre, randomized controlled trial. SettingThirty-nine public and private hospitals across India. ParticipantsHospitalized, moderately ill confirmed COVID-19 patients (PaO2/FiO2: 200-300 or respiratory rate > 24/min and SpO2 [≤] 93% on room air). InterventionParticipants were randomized to either control (best standard of care (BSC)) or intervention (CP + BSC) arm. Two doses of 200 mL CP was transfused 24 hours apart in the intervention arm. Main Outcome MeasureComposite of progression to severe disease (PaO2/FiO2< 100) or all-cause mortality at 28 days post-enrolment. ResultsBetween 22nd April to 14th July 2020, 464 participants were enrolled; 235 and 229 in intervention and control arm, respectively. Composite primary outcome was achieved in 44 (18.7%) participants in the intervention arm and 41 (17.9%) in the control arm [aOR: 1.09; 95% CI: 0.67, 1.77]. Mortality was documented in 34 (13.6%) and 31 (14.6%) participants in intervention and control arm, respectively [aOR) 1.06 95% CI: -0.61 to 1.83]. InterpretationCP was not associated with reduction in mortality or progression to severe COVID-19. This trial has high generalizability and approximates real-life setting of CP therapy in settings with limited laboratory capacity. A priori measurement of neutralizing antibody titres in donors and participants may further clarify the role of CP in management of COVID-19. Trial registrationThe trial was registered with Clinical Trial Registry of India (CTRI); CTRI/2020/04/024775.