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.

Serum anti-Spike antibody titers before and after heterologous booster with mRNA-1273 SARS-CoV-2 vaccine following two doses of inactivated whole-virus CoronaVac vaccine (preprint)

BackgroundThe inactivated whole-virus vaccine CoronaVac (SinoVac) is the COVID-19 vaccine most administered worldwide. However, data on its immunogenicity and reactogenicity to heterologous boosting with mRNA vaccines are lacking. MethodsIn a cohort of hospital staff in Jakarta, Indonesia, who received two-dose CoronaVac six months prior (median 190 days, IQR165-232), we measured anti-Spike IgG titers on paired serum samples taken before and 28 days after a 100g mRNA-1273 (Moderna) booster. We performed correlations and multivariable ordinal regressions. FindingsAmong 304 participants, the median age was 31 years (range 21-59), 235 (77.3%) were women, 197 (64.8%) had one or more previous SARS-CoV-2 infections (including 155 [51.0%] who had a post-CoronaVac breakthrough infection. Pre-boost IgG titers correlated negatively with the time since the latest documented "virus exposure" (either by the second CoronaVac or SARS-CoV-2-infection whichever most recent). Previous SARS-CoV-2 infection and a longer time interval between second vaccine and mRNA-1273 boost were associated with a higher pre-boost IgG titer. Post-booster, the median IgG titer increased 9.3-fold, from 250 (IQR32-1389) to 2313 (IQR1226-4324) binding antibody units (BAU/mL) (p<0.001). All participants, including seven whose pre-boost IgG was below assay detection limits, became seropositive and all reached a substantial post-boost titer ([≥]364 BAU/mL). Post-boost IgG was not associated with pre-boost titer or previous SARS-CoV-2 infection. Booster reactogenicity was acceptable, with 7.9% of participants experiencing short-lived impairment of activities of daily living (ADL). InterpretationA heterologous, high-dose mRNA-1273 booster after two-dose CoronaVac was highly immunogenic and safe, including in those most in need of improved immunity. FundingWellcome Trust, UK Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe inactivated whole-virus vaccine CoronaVac (SinoVac) is the COVID-19 vaccine most administered worldwide, at around 2 billion doses in 54 countries. Concerns that CoronaVac has lower immunogenicity than virus vector or mRNA vaccines, with pronounced decreases of neutralising antibody titres within a few months, and reduced effectiveness in the older population, highlight the urgent need for immunogenic, safe and well-tolerated booster schedules, especially with Omicron rapidly emerging. We used the terms "SARS-CoV-2", "COVID-19", "vaccine", "booster" to search PubMed and medRxiv up to Dec 22th, 2021, with no language or date restrictions, to identify clinical trials and real-world studies reporting on the immune responses and reactogenicity to a "third booster" of currently approved COVID-19 vaccines. Previous research reported that neutralising antibody responses elicited by all currently approved vaccines (mRNA, adenovirus-vectored, inactivated, and protein subunit) declined to varying degrees after 6-8 months after full-schedule vaccination. Several clinical trials have evaluated heterologous ("mix and match") vaccination schedules, demonstrating robust immune responses in adults. After two-dose CoronaVac, BNT162b2 (Pfizer-BioNTech) boost was significantly more immunogenic than a homologous booster against wild-type and Variants of Concern (VOCs) Beta, Gamma and Delta, and AZD1222 boost increased spike RBD-specific IgG 9-10-fold, with high neutralizing activity against the wild type and VOCs. Compared to previous SARS-CoV-2 variants, current vaccine boosters appeared to neutralise Delta to a slightly lesser degree, and Omicron to a substantially lesser degree, although preliminary data from Moderna found that the authorised dose (50g) of the mRNA-1273 boost increased antibodies 37-fold and the high-dose (100g) boost 83-fold. Added value of this studyTo our knowledge, this study is the first to provide critical real-world evidence that heterologous boosting with high-dose mRNA-1273 vaccine after CoronaVac is highly immunogenic, safe and well-tolerated in adults. After a primary course of two-dose CoronaVac, we found that a high-dose (100g) mRNA-1273 booster was immunogenic for all participants in a highly exposed cohort of hospital staff in Jakarta, Indonesia, in the context of Delta predominance, particularly for those with the lowest pre-boost antibody levels. All participants became seropositive and all reached a substantial post-boost titer ([≥]364 BAU/mL), up to a median 9.3-fold increase. Booster reactogenicity was acceptable, with 7.9% of participants experiencing short-lived impairment of activities of daily living Implications of all the available evidenceThe study findings contribute to informing policy makers on flexible options in deploying COVID-19 vaccines in mix-and-match schedules, with particular relevance for countries that are largely dependent on inactivated vaccines. Further trials are warranted that assess clinical endpoints of optimized doses of mRNA-1273 booster, and variant-specific or multivalent vaccines in response to decreased protection against emerging SARS-CoV-2 VOCs.

Pandemic inequity in a megacity: a multilevel analysis of individual, community, and health care vulnerability risks for COVID-19 mortality in Jakarta, Indonesia (preprint)

Background The 33 recognized megacities comprise approximately 7% of the global population, yet account for 20% COVID-19 deaths. The specific inequities and other factors within megacities that affect vulnerability to COVID-19 mortality remain poorly defined. We assessed individual, community-level and health care factors associated with COVID-19-related mortality in a megacity of Jakarta, Indonesia, during two epidemic waves spanning March 2, 2020, to August 31, 2021. Methods This retrospective cohort included all residents of Jakarta, Indonesia, with PCR-confirmed COVID-19. We extracted demographic, clinical, outcome (recovered or died), vaccine coverage data, and disease prevalence from Jakarta Health Office surveillance records, and collected sub-district level socio-demographics data from various official sources. We used multi-level logistic regression to examine individual, community and sub-district-level health care factors and their associations with COVID-19-mortality. Findings Of 705,503 cases with a definitive outcome by August 31, 2021, 694,706 (98.5%) recovered and 10,797 (1.5%) died. The median age was 36 years (IQR 24-50), 13.2% (93,459) were <18 years, and 51.6% were female. The sub-district level accounted for 1.5% of variance in mortality (p<0.0001). Individual-level factors associated with death were older age, male sex, comorbidities, and, during the first wave, age <5 years (adjusted odds ratio (aOR) 1.56, 95%CI 1.04-2.35; reference: age 20-29 years). Community-level factors associated with death were poverty (aOR for the poorer quarter 1.35, 95%CI 1.17-1.55; reference: wealthiest quarter), high population density (aOR for the highest density 1.34, 95%CI 1.14-2.58; reference: the lowest), low vaccine coverage (aOR for the lowest coverage 1.25, 95%CI 1.13-1.38; reference: the highest). Interpretation In addition to individual risk factors, living in areas with high poverty and density, and low health care performance further increase the vulnerability of communities to COVID-19-associated death in urban low-resource settings.

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

Background: Colchicine has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory actions. Methods: In this randomised, controlled, open-label trial, several possible treatments were 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 colchicine twice daily for 10 days or until discharge (or one of the other treatment arms) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: Between 27 November 2020 and 4 March 2021, 5610 patients were randomly allocated to receive colchicine and 5730 patients to receive usual care alone. Overall, 1173 (21%) patients allocated to colchicine and 1190 (21%) patients allocated to usual care died within 28 days (rate ratio 1.01; 95% confidence interval [CI] 0.93-1.10; p=0.77). Consistent results were seen in all pre-specified subgroups of patients. There was no significant difference in duration of hospitalisation (median 10 days vs. 10 days) or the proportion of patients discharged from hospital alive within 28 days (70% vs. 70%; rate ratio 0.98; 95% CI 0.94-1.03; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (25% vs. 25%; risk ratio 1.02; 95% CI 0.96-1.09; p=0.47). Interpretation: In adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.

Excess mortality during the first ten months of COVID-19 epidemic at Jakarta, Indonesia (preprint)

Excess mortality during the COVID-19 epidemic is an important measure of health impacts. We examined mortality records from January 2015 to October 2020 from government sources at Jakarta, Indonesia: 1) burials in public cemeteries; 2) civil death registration; and 3) health authority death registration. During 2015-2019, an average of 26,342 burials occurred each year from January to October. During the same period of 2020, there were 42,460 burials, an excess of 61%. Burial activities began surging in early January 2020, two months before the first official laboratory confirmation of SARS-CoV-2 infection in Indonesia in March 2020. Analysis of civil death registrations or health authority death registration showed insensitive trends during 2020. Burial records indicated substantially increased mortality associated with the onset of and ongoing COVID-19 epidemic in Jakarta and suggest that SARS-CoV-2 transmission may have been initiated and progressing at least two months prior to official detection. Article summary lineAnalysis of civil records of burials in Jakarta, Indonesia showed a 61% increase during 2020 compared to the previous five years, a trend that began two months prior to first official confirmation of SARS-CoV-2 transmission in the city.

Clinical characteristics and mortality associated with COVID-19 in Jakarta, Indonesia: a hospital-based retrospective cohort study (preprint)

BackgroundData on COVID-19-related mortality and associated factors from low-resource settings are scarce. This study examined clinical characteristics and factors associated with in-hospital mortality of COVID-19 patients in Jakarta, Indonesia, from March 2 to July 31, 2020. MethodsThis retrospective cohort included all hospitalised patients with PCR-confirmed COVID-19 in 55 hospitals. We extracted demographic and clinical data, including hospital outcomes (discharge or death). We used Cox regression to examine factors associated with mortality. FindingsOf 4265 patients with a definitive outcome by July 31, 3768 (88%) were discharged and 497 (12%) died. The median age was 46 years (IQR 32-57), 5% were children, and 31% had at least one comorbidity. Age-specific mortalities were 11% (7/61) for <5 years; 4% (1/23) for 5-9; 2% (3/133) for 10-19; 2% (8/638) for 20-29; 3% (26/755) for 30-39; 7% (61/819) for 40-49; 17% (155/941) for 50-59; 22% (132/611) for 60-69; and 34% (96/284) for [≥]70. Risk of death was associated with higher age; pre-existing hypertension, cardiac disease, chronic kidney disease or liver disease; clinical diagnosis of pneumonia; multiple (>3) symptoms; and shorter time from symptom onset to admission. Patients <50 years with >1 comorbidity had a nearly six-fold higher risk of death than those without (adjusted hazard ratio 5{middle dot}50, 95% CI 2{middle dot}72-11{middle dot}13; 27% vs 3% mortality). InterpretationOverall mortality was lower than reported in high-income countries, probably due to younger age distribution and fewer comorbidities. However, deaths occurred across all ages, with >10% mortality among children <5 years and adults >50 years.