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Background: There is limited information on effectiveness of COVID-19 therapies in immunocompromised patients, who are at higher risk of hospitalizations, complications, and mortality due to COVID-19. We examined hospital all-cause mortality for early RDV use vs. no RDV use among immunocompromised COVID-19 patients across several distinct dominant variants of concern (VOC) periods: pre-Delta (Dec'20-Apr'21), Delta (May-Nov'21) and Omicron (Dec'21-Apr'22). Method(s): Using the Premier Healthcare Database, we identified adults with an immunocompromised condition (cancer, solid organ and hematopoietic stem cell transplant, hematologic malignancies, primary immunodeficiencies, asplenia, bone marrow failure/aplastic anemia, severe combined immunodeficiencies or HIV), hospitalized with a primary diagnosis of COVID-19. Patients treated with RDV in first 2 days of admission vs. those not treated with RDV during the hospitalization were matched using 1:1 preferential withinhospital propensity matching with replacement. Patients were excluded if discharged within 3 days of RDV initiation. Cox Proportional Hazards Model was used to examine time to 14-and 28-day mortality. Result(s): Overall (Dec'20-Apr'22), 14,169 RDV-treated patients were matched to 5,341 unique non-RDV patients. Post-matching balance was achieved with 59% being 65+ years, 40.5% with no supplementary oxygen charges, 39% received low-flow oxygen, 19% on high-flow oxygen/non-invasive ventilation and 1.5% on invasive mechanical ventilation/ECMO at baseline. During the study period, unadjusted mortality rate was significantly lower for RDV patients at 14 days (11% [95% CI: 11%-12%] vs 15% [15%-16%];p< .0001) and 28 days (18% [17%-18%];p< .0001 vs 22% [22%-23%];p< .0001) as compared to patients that did not receive RDV. After adjusting for baseline and clinical covariates, 14-day results showed that RDV had significantly lower mortality risk compared to non-RDV across all VOC periods [overall (30% lower risk), pre-delta (41%), Delta (23%), Omicron (25%)]. Similarly, 28-day results showed that RDV had significantly lower mortality risk compared to non-RDV across all VOC periods [overall (25%), pre-delta (35%), Delta (21%), Omicron (16%)] (Fig). Conclusion(s): Timely initiation of RDV in first two days of hospital admission demonstrated significant mortality reduction in immunocompromised patients hospitalized with primary diagnosis of COVID-19. RDV demonstrated consistent benefit in an immunocompromised cohort across all variant periods of the pandemic.
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Background: Clinical management of COVID-19 based on oxygenation requirements continues to change over time as variants of concern (VOC) evolve. We examine hospital all-cause mortality for early hospital RDV use vs. no RDV use across dominant VOC periods: pre-Delta (Dec'20-Apr'21), Delta (May-Nov'21) and Omicron (Dec'21-Apr'22). Method(s): We examined adults with a primary discharge diagnosis of COVID-19 (ICD-10: U07.1) using the Premier Healthcare Database. Patients treated with RDV in the first 2 days of admission vs. those not treated with RDV during the hospitalization were matched using a 1:1 preferential within-hospital propensity matching with replacement. Patients were excluded if discharged within 3 days of RDV initiation. Time to mortality at 14-and 28-days was examined for patients with no supplemental oxygen charges (NSOc), low-flow oxygen (LFO), high-flow oxygen/non-invasive ventilation (HFO/NIV) and invasive mechanical ventilation/ECMO (IMV/ECMO) at baseline. Baseline was defined as first 2 days of hospitalization. Result(s): 164,791 RDV-treated patients were matched to 48,473 unique non-RDV patients. Post-matching balance was achieved across groups with different baseline oxygenation levels and VOC periods. In the matched weighted cohort, 35% required NSOc, 41% LFO, 21% HFO/NIV and 3% IMV/ECMO. During the overall study period (Dec'20-Apr'22), unadjusted mortality rate was significantly lower for RDV patients across all oxygenation levels at 14 days (NSOc: 5.4% vs. 7.3%, LFO: 6.4% vs. 8.8%, HFO/NIV: 16.8% vs. 19.4%, IMV/ECMO: 27.8% vs. 35.3%) and 28 days (NSOc: 8.0% vs. 9.8%, LFO: 9.8% vs. 12.3%, HFO/ NIV: 25.8% vs. 28.3%, IMV/ECMO: 41.4% vs. 50.6%). After adjusting for baseline and clinical covariates, 14-day mortality results showed that RDV significantly lower risk compared to non-RDV across all oxygenation levels at baseline [NSO (26%), LFO (28%), HFO/NIV (17%), IMV/ ECMO (27%)]. Similarly, 28-day mortality results showed that RDV significantly lower risk compared to non-RDV across all oxygenation levels at baseline [NSO (19%), LFO (21%), HFO/NIV (12%), IMV/ECMO (26%)]. This lower mortality risk associated with RDV was consistently observed across all variant periods (Figure). Conclusion(s): Timely initiation of RDV within first two days of hospital admission demonstrated significant mortality reduction in patients hospitalized for a primary diagnosis of COVID-19 across all oxygenation levels. Remdesivir demonstrated consistent benefit across all variant periods of the pandemic to-date.
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Background: There is limited data on the association between COVID-19 therapy and hospital readmissions, including during evolution of the pandemic over time. We examine all cause 30-day readmissions after a COVID-19 hospitalization among remdesivir (RDV)-treated vs non-RDV treated patients across different dominant variants of concern (VOC) periods: pre-Delta (May'20-Apr'21), Delta (May-Nov'21) and Omicron (Dec'21-Apr'22). Method(s): Using the Premier Healthcare Database, we examined adults hospitalized with a primary diagnosis of COVID-19 (ICD-10:U07.1) who were discharged alive from the COVID-19 hospitalization. All-cause readmission to the same hospital was examined using multivariate logistic regression. The model adjusted for: age, corticosteroids use, VOC period, Charlson comorbidity index, maximum oxygenation requirements and ICU admission during COVID-19 hospitalization. Result(s): In the study period (May'20-Apr'22), 440,601 patients with a primary diagnosis of COVID-19 were discharged alive, of which 53% received RDV. As compared to non-RDV, RDV patients were younger (median[IQR]: 62[51-73] vs 64[52-76]), with a lower proportion with no supplementary oxygen charges (30% vs 52%), a higher proportion with low-flow oxygen (46% vs 36%), highflow oxygen/non-invasive ventilation (20% vs 10%), and invasive mechanical ventilation/ECMO (4% vs 2%). Among RDV-treated, the all-cause 30-day readmission was 6.3% compared to 9.1% (p< .0001) in non-RDV treated. Lower readmission for RDV vs non-RDV was seen in Pre-delta (6.3% vs 9.3%;p< .0001), Delta (5.1% vs 7.8%;p< .0001), and Omicron (8.7% vs 9.9%;p< .0001) (Fig). After adjusting for age and characteristics at index hospitalization including corticosteroid, RDV patients had significantly lower likelihood of all-cause 30-day readmission (OR[95% CI]:0.73[0.72-0.75]) as compared to non-RDV. Significantly Lower odds of 30-day readmission for RDV vs non-RDV patients were observed in Pre-delta (0.69[0.67-0.71]), Delta (0.72[0.68-0.76]) and Omicron-(0.87[0.83-0.92]) (Fig). Similarly, RDV-related reduction in readmissions was also seen for COVID-19 related readmissions. Conclusion(s): RDV use during the COVID-19 hospitalization was associated with significantly lower likelihood of all-cause 30-day readmission across the VOC periods of the pandemic May 2020 till April 2022. The lower rate of hospital re-admission for RDV-treated patients was observed despite the RDV group having higher supplemental oxygen requirement during their index COVID-19 hospitalization.
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Methods: This retrospective study included adults with COVID-19 (ICD-10: U07.1) and pneumonia (ICD-10 subcodes within J11.x - J16.x, J18.x) May 2020-December 2021 in the Premier Healthcare Database, analyzing severity, treatment patterns and clinical outcomes. Result(s): Between May 2020 and December 2021: N=338,930 patients in 856 hospitals 79% of patients received any dexamethasone(DEX);>50% received any remdesivir(RDV) Combination therapy use increased: DEX+RDV only from <1% of patients to 29%;DEX+RDV with baricitinib or tocilizumab from <1% to 19% RDV initiation in the first 2 days of hospitalization increased 41% to 88% Overall all-cause mortality increased 19% to 24% with large differences between severity subgroups: in December 2021, 20%, 32%, 46% and 60%, respectively, in no supplementary oxygen(NSOc), low-flow(LFO), highflow/non-invasive(HFO/NIV) and invasive mechanical ventilation/ECMO(IMV/ECMO) Overall median hospital LOS and ICU LOS remained between 6-10 days, with notable variation by severity subgroup and over time Overall ICU use was 35%-38%, with large differences by severity subgroups: in December 2021, 28%, 47%, 67% and 94%, respectively, in NSOc, LFO, HFO/NIV and IMV/EC Conclusion(s): COVID-19 can result in severe outcomes;understanding treatment and severity trends can improve prognosis.
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Introduction: Trials of remdesivir (RDV) for COVID-19 have provided evidence for regulatory approval. This is the first meta-analysis (MA) to evaluate the real-world effectiveness of RDV in patients hospitalized with COVID-19. Objective(s): To synthesize RDV observational data. Method(s): A systematic literature review identified observational studies of RDV. Outcomes were all-cause mortality and progression to invasive mechanical ventilation (IMV) assessed at early (day 14/15) and late (day 28/29/30) timepoints. MAs were conducted using standard random effects models;analyses were performed with R statistical software. Result(s): Of 1,069 studies identified, 29 met inclusion criteria for mortality data, 18 were excluded for low quality based on the ROBINS-I tool;11 studies from the United Kingdom, European Union, United States and Japan were included in the MA (N=166,399 patients). RDV was associated with a significant improvement in mortality at early (5 studies;risk ratio [RR] 0.71, 95% confidence interval [CI] 0.64-0.79) and late (10 studies, RR 0.82, 95%CI 0.71-0.95;Figure) timepoints. No significant effect was shown on the proportion of patients requiring IMV (evaluable only in the 3 studies denoted by asterisk in Figure, RR 1.07, 95%CI 0.84-1.34). Results were robust to scenario analyses. Conclusion(s): In a real-world setting, RDV is effective in reducing mortality in hospitalized COVID-19 patients.
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Purpose: To characterize demographics, treatment patterns, and outcomes among 3,998 transplant patients hospitalized for COVID-19 over 16 months of the pandemic (May '20-Aug '21). Method(s): Adult patients in a transplant cohort (TC) and non-transplant cohort (NTC) hospitalized with COVID-19 (ICD-10: U07.1) were compared in the Premier Healthcare Database from May '20-Aug '21. Baseline measures in first two days, demographics, comorbidity, COVID-19 treatments and immunosuppressants were analyzed. Outcomes included mortality (discharge status expired or hospice) and hospital and ICU LOS. Result(s): 3,998 TC patients were hospitalized for COVID-19 in 587 US hospitals. Compared to NTC, TC were younger (61 vs 64 yrs;p<.0001), less likely to be white (59% vs 67%;p<.0001), obese (24% vs 33%;p<.0001) or have COPD (17% vs 24%;p<.0001). TC had higher rates hypertension (84% vs 69%;p<.0001), renal disease (80% vs 22%, p<.0001), diabetes (48% vs 29%;p<.0001) and chronic heart failure (23% vs 18%;p<.0001). During hospitalization, a lower proportion of TC needed any oxygen therapy compared to NTC (p<.05). Compared to NTC, fewer TC received remdesivir (RDV) (44% vs 48%;p<.0001), but more received corticosteroids (87% vs 78%;p<.0001), anticoagulants (44% vs 29%;p<.0001) and convalescent plasma (18% vs 16%;p=0.007). In TC, 44% received MMF, 73% calcineurin inhibitors and 5% mTOR. Use of MMF did not change over time (43% May-Jul 2020;43% Aug- Dec 2020;45% 2021). TC had higher ICU admission rates (31% vs 28%;p.001), but similar hospital LOS and ICU LOS compared to NTC. All-cause mortality in NTC (15% overall;16% May-Jul 2020;16% Aug-Dec 2020;14% 2021) was not significantly different than TC over time (16% overall;13% May-Jul 2020;16% Aug-Dec 2020;16% 2021). Conclusion(s): Very few large studies have assessed COVID-19 management in transplant patients over time. All-cause mortality was comparable in both cohorts despite TC immunosuppression. RDV use was lower in TC. Uncertainty around MMF use in COVID-19 patients did not impact reported use of MMF. Further analyses are needed to evaluate confounding factors (medication sequence, time since transplant, disease severity) and impact of external factors such as earlier testing and treatment for COVID-19, vaccination, and new variants. (Table Presented).
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Background. Remdesivir (RDV) reduced time to recovery and mortality in some subgroups of hospitalized patients in the NIAID ACTT-1 RCT compared to placebo. Comparative effectiveness data in clinical practice are limited. Methods. Using the Premier Healthcare Database, we compared survival for adult non-mechanically ventilated hospitalized COVID-19 patients between Aug-Nov 2020 and treated with RDV within 2 days of hospitalization vs. those who did not receive RDV. Preferential within-hospital propensity score matching with replacement was used. Patients were matched on baseline O2 and 2-month admission period and were excluded if discharged within 3 days of RDV initiation (to exclude anticipated discharges/transfers within 72 hrs consistent with ACTT-1 study). Time to 14- and 28-day mortality was examined separately for patients on high-flow/non-invasive ventilation (NIV), low-flow, and no supplemental O2 using Cox Proportional Hazards models. Results. RDV patients (n=27,559) were matched to unique non-RDV patients (n=15,617) (Fig 1). The two groups were balanced;median age 66 yrs and 73% white (RDV);68 yrs and 74% white (non-RDV), and 55% male. At baseline, 21% required high-flow O2, 50% low-flow O2, and 29% no O2, overall. Mortality in RDV patients was 9.6% and 13.8% on days 14 and 28, respectively. For non-RDV patients, mortality was 14.0% and 17.3% on days 14 and 28, respectively. Kaplan-Meier curves for time to mortality are shown in Fig 2. After adjusting for baseline and clinical covariates, RDV patients on no O2 and low-flow O2 had a significantly lower risk of death within 14 days (no O2, HR: 0.69, 95% CI: 0.57-0.83;low-flow, HR: 0.67, 95% CI: 0.59-0.77) and 28 days (no O2, HR: 0.80, 95% CI: 0.68-0.94;low-flow, HR: 0.76, 95% CI: 0.68-0.86). Additionally, RDV patients on high-flow O2/NIV had a significantly lower risk of death within 14 days (HR: 0.81, 95% CI: 0.70-0.93);but not at 28 days (Fig 3). Conclusion. In this large study of patients in clinical care hospitalized with COVID-19, we observed a significant reduction of mortality in RDV vs. non-RDV treated patients in those on no O2 or low-flow O2. Mortality reduction was also seen in patients on high-flow O2 at day 14, but not day 28. These data support the use of RDV early in the course of COVID-19 in hospitalized patients.
ABSTRACT
Background. Remdesivir (RDV) is a potent nucleotide prodrug inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase that has demonstrated efficacy in the treatment of patients hospitalized with moderate to severe COVID-19. This Phase 3 (GS-US-540-9012) double-blind, placebo-controlled study compared the efficacy and safety of 3 days of RDV to standard of care in non-hospitalized, high-risk participants with confirmed COVID-19. Methods. Participants were randomly assigned 1:1 to receive intravenous (IV) RDV (200 mg on day 1, 100 mg on days 2 to 3) or placebo. The primary efficacy endpoint was composite COVID-19 hospitalization or all-cause death by day 28 and compared using Cox proportional hazards model with baseline stratification factors as covariates. The primary safety endpoint was proportion of participants with treatment-emergent adverse events. Study enrollment was terminated early for administrative reasons in light of the evolving pandemic. Results. 562 patients underwent randomization and started their assigned treatment (279, RDV;283, placebo). Baseline demographics and characteristics were balanced across arms. Overall, 52% were male, 44% were Hispanic/Latino ethnicity and 30% were ≥ 60 years old. The most common comorbidities were diabetes mellitus (62%), obesity (56%;median BMI, 30.7), and hypertension (48%). Median baseline SARS-CoV-2 RNA nasopharyngeal viral load was 6.2 log10 copies/mL. Treatment with RDV significantly reduced COVID-19 hospitalization or all-cause death by day 28 (HR, 0.13;95% CI, 0.03 - 0.59;p = 0.008;Table 1) compared to placebo. Participants receiving RDV also had significantly lower risk for COVID-19-related medically attended visits or all-cause death by day 28 compared to placebo (HR, 0.19;95% CI, 0.07 - 0.56;p = 0.002;Table 1). No deaths occurred in either arm by day 28. There was no difference between arms in time-weighted average change in nasopharyngeal viral loads from baseline up to day 7. The proportion of patients with AEs was similar between arms (Table 1);the most common AEs in the RDV arm were nausea (11%), headache (6%), and diarrhea (4%). Conclusion. A 3-day course of IV RDV was safe, well tolerated and highly effective at preventing COVID-19 related hospitalization or death in high-risk non-hospitalized COVID-19 patients.
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Objectives: In this comparative effectiveness study, we compare the survival outcomes for hospitalized COVID-19 patients treated with remdesivir (RDV) upon admission vs. those not treated with RDV. Methods: We used the Premier Healthcare Database to examine patients hospitalized between Aug-Nov 2020 and treated with RDV within 2 days of hospitalization vs. those who did not receive RDV during their hospitalization. Preferential within-hospital propensity score matching with replacement was used. Patients were matched on baseline oxygen requirement and 2-month admission period and were excluded if discharged within 3 days of RDV initiation (to exclude anticipated discharges/transfers within 72 hrs consistent with ACTT-1 study). Cox Proportional Hazards models were used to examine 14- and 28-day mortality overall and for patients on no supplemental oxygen (NSO), low-flow oxygen (LFO), high-flow oxygen/non-invasive ventilation (HFO/NIV) and invasive mechanical ventilation/ECMO (IMV/ECMO) separately. Results: RDV patients (n=28,855) were matched to unique non-RDV patients (n=16,687). The two groups were balanced. At baseline, 28% required NSO, 48% LFO, 20% HFO/NIV and 4% IMV/ECMO. Mortality in RDV patients was 10.6% and 15.4% on days 14 and 28, respectively. For non-RDV patients, mortality was 15.4% and 19.1% on days 14 and 28, respectively. After adjusting for baseline and clinical covariates, RDV patients had significantly lower risk of mortality at 14-days (HR[95% CI]: 0.76[0.70−0.83]) and 28-days (0.89[0.82−0.96]). This mortality benefit was also seen for NSO, LFO and IMV/ECMO patients at 14-days (NSO: 0.69[0.57−0.83], LFO: 0.68[0.80−0.77], IMV/ECMO: 0.70[0.58−0.84]) and 28-days (NSO: 0.80[0.68−0.94], LFO: 0.77[0.68−0.86], IMV/ECMO: 0.81[0.69−0.94]). Additionally, HFO/NIV RDV patients had a significantly lower risk of mortality at 14-days (0.81[0.70−0.93]);but not at 28-days. Conclusions: In this observational study, treatment with RDV was associated with statistically significant reduction in mortality among hospitalized COVID-19 patients. These results complement the findings from the ACTT-1 and contribute to the growing body of evidence on the survival benefits of RDV.
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Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a myeloid cell growth factor and pro-inflammatory cytokine, may drive the overactive host immune response in COVID-19. We conducted a clinical trial assessing the anti-GM-CSF monoclonal antibody gimsilumab for hyperinflammatory COVID-19 pneumonia (BREATHE). Here, we report a pre-specified subgroup analysis demonstrating a signal of benefit in patients invasively ventilated at baseline. Methods: BREATHE (NCT04351243) was a double-blind, randomized, placebo-controlled trial at 21 US locations. Patients were randomized 1:1 to receive two doses of IV gimsilumab or placebo one week apart. The study included hospitalized COVID-19 patients with hyperinflammation (CRP ≥50 mg/L or ferritin ≥1,000 ng/mL) and pre-ARDS lung injury or ARDS. The primary endpoint was all cause mortality at day 43, and key secondary outcomes assessed ventilator use and hospitalization length. Results: 225 patients were randomized and dosed. 41 patients were invasively ventilated at baseline. Steroid use and baseline characteristics were generally balanced across study arms in this subgroup. Ventilated patients treated with gimsilumab demonstrated improvements over placebo on the primary and key secondary endpoints (Table 1). Contrasting the placebo group, gimsilumabtreated patients did not experience a sharp rise in NT-proBNP, a marker of heart failure, through day 43 (Figure 1). Conclusions: GM-CSF inhibition may be therapeutic in ventilated COVID-19 patients through a neurohormonal mechanism. More studies are needed to assess the role of GM-CSF in COVID-19-associated cardiomyopathy, volume status, and ARDS.
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Background: Remdesivir (RDV), an RNA-dependent RNA polymerase inhibitor of SARS-CoV-2, and its intravenous formulation excipient, cyclodextrin, are renally cleared. We sought to characterize whether RDV was associated with worsening renal function in hospitalized patients with moderate COVID-19. Methods: We conducted an open-label, phase 3 trial (NCT04252664) involving hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, oxygen saturation >94% on room air and eGFR ≥50 mL/ min/1.73m2. Patients were randomly assigned 1:1:1 to receive up to 5d or 10d of RDV with standard of care (SoC), or SoC alone. Also included in this analysis were patients who enrolled in an extension phase of the trial, receiving 10d of RDV. RDV was dosed intravenously at 200 mg on d1 and 100 mg daily thereafter. Acute kidney injury (AKI) was defined as an increase in serum creatinine from baseline and classified as Stage 1 (increase > 0.3 and % change ≤25%, or % change >25% and ≤ 100%), Stage 2 (% change >100% and ≤200%), Stage 3 (% change >200%). For AKI development (ever/never for stage 1 or greater), age-adjusted risk ratios (RR) and 95% Wald confidence intervals (CI) were reported. Results: 1005 patients (822 [83%] RDV, 183 [17%] SoC) with creatinine values collected through d14 were evaluated. Baseline patient demographics, creatinine, and eGFR were mostly similar between RDV vs SoC arms. Worsening renal function was observed less frequently in patients receiving RDV vs SOC (7% vs 10%, p=0.03, Table). After adjustment for age, there was no significant association of RDV with risk of AKI relative to SoC (RR=0.66;95% CI 0.40, 1.09). Most AKI events were observed in patients with baseline eGFR >90 mL/min, with few events occurring in patients with a baseline eGFR 50-59 mL/min. In patients who developed Stage 3 AKI, those treated with RDV (n=2, 0.2%) returned to baseline creatinine values while those on SOC (n=4, 2%) remained elevated to d14. No difference in AKI between treatment arms was observed in patients with a history of chronic kidney disease (CKD;RDV: n=6 [12%] vs SOC: n=2 [40%] p=0.14). Older age, history of CKD, and eGFR status at baseline were independently associated with worsening renal function. Conclusion: AKI events were observed less frequently in patients with moderately severe COVID-19 patients treated with RDV compared to SoC.
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Background: Patients with underlying medical conditions have a greater risk of developing severe COVID-19. Unlike vaccine-derived immunity which develops over time, administration of neutralizing monoclonal antibodies is an immediate, passive humoral immunotherapy, with the potential to reduce disease progression, emergency room visits, hospitalizations, and death. Methods: In this phase 3 portion of the BLAZE-1 trial, a high-risk ambulatory cohort of 1035 patients with mild-to-moderate COVID-19 were randomly assigned 1:1 to receive a single intravenous infusion of a neutralizing monoclonal antibody combination treatment consisting of 2800mg bamlanivimab+2800mg etesevimab together, or placebo, within 3 days of laboratory diagnosis. The primary outcome was overall patient clinical status, measured by the proportion of patients who experienced COVID-19-related hospitalization or death by any cause by Day 29. Results: 1035 patients were randomized and infused (mean age [SD];53.8 years [16.8], female (52%)). A 70% reduction in COVID-19-related hospitalization and death by any cause by Day 29 was observed in patients who received the bamlanivimab+etesevimab combination treatment (11/518 arm total) compared to those who received placebo (36/517 arm total) (Δ[95% CI]=-4.8[-7.4,-2.3])(p=0.0004). No deaths were observed among patients who received the combination treatment, 10 deaths were reported in the placebo group, at least 8 designated COVID-19-related. A significantly greater reduction in log10(viral load) from baseline at Day 7 was observed amongst patients who received bamlanivimab+etesevimab compared to placebo (Δ[95% CI]=-1.20[-1.46,-0.94])(p<0.00000001). The median time to sustained symptom resolution was shorter for those who received the combination treatment (days [95% CI]=8[7.0,8.0]) compared to those who received placebo (days [95% CI]=9[8.0,10.0])(p=0.007). Similar rates of adverse events were observed between placebo (60/517,11.6%) and combination treatment groups (69/518,13.3%). Conclusion: 2800mg bamlanivimab+2800mg etesevimab neutralizing monoclonal antibody combination therapy significantly reduced COVID-19- related hospitalizations and deaths amongst high-risk ambulatory patients and accelerated the decline in viral load and disease symptoms over time. This study confirms that early intervention with bamlanivimab + etesevimab greatly improves the clinical outcomes for high-risk ambulatory patients, and links reduction in nasopharyngeal viral load to clinically meaningful benefits.
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Background: Remdesivir (RDV), a RNA polymerase inhibitor with potent in vitro activity against SARS-CoV-2, is the only treatment with demonstrated efficacy in shortening the duration of COVID-19. Here we report regional differences in clinical outcomes of severe COVID-19 patients treated with RDV, as part of an open-label, randomized phase-3 trial establishing RDV treatment duration. Methods: Hospitalized patients with oxygen saturation ≤94%, a positive SARS-CoV-2 PCR in the past 4 days and radiographic evidence of pneumonia were randomized 1:1 to receive 5d or 10d of intravenous RDV. We compared d14 clinical outcomes of patients from different geographical areas, as measured by mortality rates, change in clinical status from baseline (BL) on a 7-point ordinal scale and change in O2 requirements from BL. Based on previous analyses in compassionate use data showing region as an important predictor of outcome, Italy was examined separately from other regions. Results: 397 patients were treated with RDV, of which 229 (58%) were in the US, 77 (19%) Italy, 61 (15% in Spain), 12 (3%) Republic of Korea, 9 (2%) Singapore, 4 (1%) Germany, 4 (1%) Hong Kong and 1 (< 1%) Taiwan. BL clinical status was worse in Italy compared to other regions (72% vs 17% requiring high-flow oxygen delivery or higher), and Italian patients were more likely to be male than patients from other regions (69% vs 63%). Overall results showed 5d RDV was as effective as 10d. Mortality at d14 was higher in Italy (18%) compared to all other countries except Italy (7%). Similarly, clinical improvement at d14, measured as ≥2-point increase in the ordinal scale, was lower in Italian patients (39%) compared to all other countries combined (64%). (Fig.1). Conclusion: Overall, our results demonstrate significant geographical differences in the clinical course of severe COVID-19 patients treated with RDV. We observed worse outcomes, such as increased mortality and lower rate of clinical improvement, in patients from Italy compared to other regions. (Table Presented).
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Background: Remdesivir (RDV) shortens time to recovery time in patients with severe COVID-19. Its effect in patients with moderate COVID-19 remains unclear. Methods: We conducted an open-label, phase 3 trial (NCT04252664) involving hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, and oxygen saturation >94% on room air. Patients were randomly assigned 1:1:1 to receive up to 5d or 10d of RDV with standard of care (SoC), or SoC alone;patients could be discharged prior to completing per-protocol assigned treatment duration. RDV was dosed intravenously at 200 mg on d1, 100 mg daily thereafter. Patients were evaluated daily while hospitalized, and via telephone if discharged. The primary endpoint was clinical status on d11 assessed on a 7-point ordinal scale. Results regarding the primary endpoint are expected to be published before IDWeek 2020;we plan to present d28 results at the meeting. Results: In total, 584 patients underwent randomization and started their assigned treatment (191, 5d RDV;193, 10d RDV;200, SoC). By d11, 3 2 point improvement on the ordinal scale occurred in 70% of patients in the 5d arm, 65% in the 10d arm, and 61% in the SoC arm. Patients in the 5d RDV arm were significantly more likely to have an improvement in clinical status than those receiving SoC (odds ratio [OR], 1.65;95% confidence interval [CI], 1.09-2.48;P=0.017);OR of improvement for the 10d RDV arm compared to SoC was 1.31 (95% CI, 0.88-1.95];p=0.183). This improvement in the 5-day arm over the SOC arm was noted from d6 through d11. We observed a peak of discharges corresponding with the assigned treatment duration of RDV, with increased discharges at d6 in the 5-day arm and at d11 in the 10-day arm. A worsening of clinical status of ≥ 1 point in the ordinal scale was observed more commonly in the SoC am (n=19, 10%) versus the 5d RDV (n=7, 4%) and 10d RDV (n=9, 5%). Conclusion: RDV for up to 5 days was superior to SoC in improving the clinical status of patients with moderate COVID-19 by d11. We will report d28 outcomes at the meeting. (Table Presented).