Please summarize any guidelines and literature surrounding the use of remdesivir in COVID-19 patients.

Comment by InpharmD Researcher

The role of remdesivir in COVID-19 has been assessed through numerous studies. Results from these studies have suggested a variety of potential effects of remdesivir on clinical patient outcomes. Some studies have found an overall benefit, including a reduction in mortality, lower risk of hospitalization, decreased need for mechanical ventilation, and faster clinical improvement. Other studies have found a benefit only when remdesivir was used in combination therapy. Finally, some studies have concluded that remdesivir failed to provide improved outcomes at all. Guidelines currently recommend the use of remdesivir only for specific patients at high risk of disease progression.

Background

Per National Institutes of Health guidelines, routine use of remdesivir for the treatment of COVID-19 in hospitalized patients who do not require supplemental oxygen is not recommended, but remdesivir may be considered in patients at high risk of disease progression. Remdesivir monotherapy or in combination with dexamethasone is recommended in patients who require supplemental oxygen, including through a high-flow device or noninvasive ventilation. The Panel recommends against initiating remdesivir monotherapy in patients who require mechanical ventilation or extracorporeal membrane oxygenation. The Infectious Diseases Society of America panel recently updated its recommendations on the use of remdesivir for ambulatory patients. For ambulatory patients with mild to moderate COVID-19 at high risk for progression to severe disease, remdesivir may be initiated if the symptom onset occurs within seven days. Specifically, the dosing used in this setting is remdesivir 200 mg on day one followed by 100 mg on days two and three. According to the Surviving Sepsis Campaign COVID-19 guidelines, the ideal window of starting remdesivir should be within 72 hours of a positive SARS-CoV-2 serology test. [1], [2], [3]

Literature Review

A search of the published medical literature revealed 11 studies investigating the researchable question:

Please summarize any guidelines and literature surrounding the use of remdesivir in COVID-19 patients.

Level of evidence

A - Multiple high-quality studies with consistent results Read more→

Please see Tables 1-11 for your response.

Remdesivir for the Treatment of Covid-19 — Final Report (ACTT-1)
Design	Double-blind, randomized, multi-national placebo-controlled trial N=1062
Objective	To observe the use of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.
Study Groups	Remdesivir (n=541) Placebo (n=521)
Methods	Inclusion criteria: Patients with severe COVID-19 pneumonia (required mechanical ventilation, required supplemental oxygen, SPo2 < 94%, or they had tachypnea.) Exclusion criteria: Other experimental treatment or off-label medication use from day 1 through day 29. Patients in the remdesivir group received remdesivir 200 mg loading dose on day 1 followed by 100 mg maintenance dose daily on days 2 to 10 or until discharge or death. Both groups received supportive therapy according to the specific institutions. The study was expanded to 73 sites across ten countries (54 being in the United States).
Duration	Recruitment period: February 21, 2020 to April 19, 2020. Follow-up: day 29
Outcome Measures	Primary outcome: Time to recovery during the 28 days after enrollment determined by meeting category 1, 2, or 3 on 8-point ordinal scale Secondary outcome: 8-point ordinal scale: Not hospitalized and no limitations of activities Not hospitalized, with limitation of activities, home oxygen requirement, or both Hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection-control or other nonmedical reasons) Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related to Covid-19 or to other medical conditions) Hospitalized, requiring any supplemental oxygen Hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices Hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Death
Baseline Characteristics		Remdesivir (n=541)	Placebo (n=521)
	Received treatment as assigned	531 (98.2%)	517 (99.2%)
	Age, years	58.6 ± 14.6	59.2 ± 15.4
	Male	352 (65.1%)	332 (63.7%)
	White Black Hispanic/Latino Asian	279 (51.6%) 109 (20.1%) 134 (24.8%) 79 (14.6%)	287 (55.1%) 117 (22.5%) 116 (22.3%) 56 (10.7%)
	Median time (interquartile range [IQR]) from symptom onset to randomization	9 (6 to 12)	9 (7 to 13)
	Ordinal scale score 4 5 6 7 missing baseline score	75 (13.9%) 232 (42.9%) 95 (17.6%) 131 (24.2%) 8 (1.5%)	63 (12.1%) 203 (39.0%) 98 (18.8%) 154 (29.6%) 3 (0.6%)
Results	Endpoint	Remdesivir (n=541)	Placebo (n=521)
	Number of recoveries	399	352
	Median time to recovery, days	10 (9 to 11)	15 (13 to 18)
	Rate ratio for recovery (95% confidence interval [CI]; p-value)	1.29 (1.12 to 1.49; p<0.001)
	Deaths by day 15	35	61
	Hazard ratio for mortality through day 15 (95% CI)	0.55 (0.36 to 0.83)
	Deaths by day 29	59	77
	Hazard ratio for mortality through day 29 (95% CI)	0.73 (0.52 to 1.03)
	Ordinal score at day 15 (± 2 days) 1 2 3 4 5 6 7 8	157 (29.0%) 117 (21.6%) 14 (2.6%) 38 (7.0%) 58 (10.7%) 28 (5.2%) 95 (17.6%) 34 (6.3%)	115 (22.1%) 102 (19.6%) 8 (1.5%) 33 (6.3%) 60 (11.5%) 24 (4.6%) 121 (23.2%) 58 (11.1%)
	Odds ratio (95% CI)	1.5 (1.2 to 1.9)
Adverse Events	Serious Adverse Events: 131 out of 532 remdesivir patients (24.6%) 163 out of 516 placebo patients (31.6%)
Adverse Events	Percentage that Discontinued due to Adverse Events besides death: 52 remdesivir patients 70 placebo patients
Study Author Conclusions	Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.
InpharmD Researcher Critique	Patients had a median time to recovery of 10 days which indicates that patients in the remdesivir group generally received treatment for 10 days. However, there were a notable number of patients who also discontinued therapy from the remdesivir group during the treatment. While there were no notable treatment-related adverse events, it is difficult to conclude on the efficacy and safety due to the variability in study protocol.

References:

Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19 - Final report. N Engl J Med. 2020 Oct 8:NEJMoa2007764. doi: 10.1056/NEJMoa2007764.

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial
Design	Phase 3, open-label, adaptive, multicentre, randomized, controlled trial N= 832
Objective	To further document clinical outcomes, virological kinetics, treatment pharmacokinetics, and related safety data, and the preliminary analyses are reported here for remdesivir compared with control
Study Groups	Remdesivir (n= 414) Placebo (n= 418)
Inclusion Criteria	18 years or older who were admitted for laboratory-confirmed COVID-19 infection, and illness of any duration of at least one of the following: clinical assessment (evidence of rales or crackles), oxygen saturation of ≤94%, requirement of supplemental oxygen, high-flow oxygen devices, non-invasive ventilation, or mechanical ventilation
Exclusion Criteria	Liver enzymes more than five times the upper limit of normal, stage 4 severe chronic kidney disease or requiring dialysis, or if the patient was transferred within 72 hours to another hospital not enlisted in the study
Methods	Participants were randomized 1:1 to receive either standard of care or standard of care plus remdesivir (a loading dose of 200 mg on day 1 followed by a 100 mg, 1-h infusion once-daily for a total duration of 10 days). Remdesivir cessation was allowed after 5 days if the participant was discharged from the hospital. In critically ill participants with acute respiratory distress syndrome requiring intensive care unit admission, dexamethasone could be used at the clinician's discretion (20 mg once daily for 5 days, followed by 10 mg once daily for 5 days). Other supportive treatments, such as immunomodulatory agents, were allowed in all groups per the investigator's discretion.
Duration	March 22, 2020 to January 21, 2021 Treatment: up to 10 days Follow-up: up to 29 days
Outcome Measures	Primary outcome: clinical status at day 15 as measured on the seven-point ordinal scale of the WHO Master Protocol Not hospitalized, no limitations on activities Not hospitalized, limitation on activities Hospitalized, not requiring supplemental oxygen Hospitalized, requiring supplemental oxygen Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, on invasive mechanical ventilation or ECMO Death Secondary outcome: clinical status and change from baseline of the clinical status at days 3, 5, 8, 11, and 29
Baseline Characteristics		Remdesivir (n= 414)	Control (n= 418)
	Age, years	63 (55-73)	64 (54-72)
	Female	123 (30%)	130 (31%)
	White	244 (68%)	255 (70%)
	Median days from symptom onset to randomization (IQR)	9 (7-11)	9 (7-12)
	COVID-19 severity at randomization Moderate Severe	253 (61%) 161 (39%)	251 (60%) 167 (40%)
	IQR: interquartile range
Results		Remdesivir (n= 414)	Control (n= 418)	OR/HR (95% CI)	p-value
	7-point ordinal scale at day 15 1 2 3 4 5 6 7	61 (15%) 129 (31%) 50 (12%) 76 (18%) 15 (4%) 62 (15%) 21 (5%)	73 (18%) 132 (32%) 29 (7%) 67 (16%) 14 (3%) 79 (19%) 24 (6%)	OR 0.98 (0.77 to 1.25)	0.85
	7-point ordinal scale at day 29 1 2 3 4 5 6 7	109 (26%) 156 (38%) 47 (11%) 36 (9%) 6 (2%) 26 (6%) 34 (8%)	122 (29%) 119 (28%) 50 (12%) 41 (10%) 7 (2%) 41 (10%) 38 (9%)	OR 1.11 (0.87 to 1.42)	0.39
	Days to hospital discharge within 29 days (IQR)	15 (10-29)	13 (8-29)	HR 0.94 (0.80 to 1.11)	0.49
	Death by day 28	34 (8%)	37 (9%)	OR 0.93 (0.57 to 1.52)	0.77

Adverse Events	Common Adverse Events: Not disclosed
Adverse Events	Serious Adverse Events: Acute respiratory distress syndrome (9%), Acute respiratory failure (7%), Arrhythmia (3%)
Study Author Conclusions	No clinical benefit was observed from the use of remdesivir in patients who were admitted to the hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support.
InpharmD Researcher Critique	This was an open-label study with no placebo control. This might have introduced bias in the follow-up and management of patients, and in the evaluation of endpoints whose assessment includes elements of subjectivity. The study was conducted in France, Belgium, Austria, Portugal, and Luxembourg and during a time where various treatments were considered the standard of care, which also may have confounded results. Additionally, it is possible the Delta variant may have been prevalent during the tail end of the study.

References:

Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial [published online ahead of print, 2021 Sep 14]. Lancet Infect Dis. 2021;S1473-3099(21)00485-0. doi:10.1016/S1473-3099(21)00485-0.

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19
Design	Randomized, open-label, multinational, phase 3 trial N= 397
Objective	To describe the results of an open-label, randomized, multicenter trial evaluating the efficacy and safety of treatment with remdesivir for 5 or 10 days in patients with severe Covid-19 disease
Study Groups	5-day group (n= 200) 10-day group (n= 197)
Methods	Inclusion criteria: > 12 years age, confirmed SARS-CoV-2 by PCR within 4 days of randomization, pulmonary infiltrates with either oxygen saturation < 94%. Exclusion criteria: Mechanical ventilation or ECMO at screening, signs of multiorgan failure, AST/ALT > 5x ULN, CrCl < 50 mL/min, concurrent therapy with other agents with activity against COVID-19 Patients were randomized to receive remdesivir IV 200 mg on day 1 and 100 mg once daily on subsequent days. Fifty-five hospitals were included, which comprised of 8 different countries. The protocol was amended on March 15, 2020, after enrollment began to lower the age from 18 to 12 years and eliminated the required temperature of at least 36.6°C at screening. The primary outcome was also changed to assess the clinical status on a 7-point ordinal scale on day 14.
Duration	March 6 to March 2020
Outcome Measures	Primary outcome: Clinical status based on the 7-point ordinal scale at day 14. Secondary outcome: Clinical improvement, recovery, and modified recovery Clinical improvement: Improvement at least 2 points from baseline Recovery: Improvement from baseline score of 2 to 5 to a score of 6 or 7. Modified recovery: Improvement from baseline score of 2 to 4 to a score of 5 to 7 or from a score to 5 to a score of 6 or 7).
Baseline Characteristics		5-day group (n= 200)	10-day group (n= 197)
	Median age, years (IQR)	61 (50 to 69)	62 (50 to 71)
	Male	120 (60%)	133 (68%)
	White Black Asian Other	142 (71%) 21 (10%) 20 (10%) 17 (8%)	134 (70%) 23 (12%) 25 (13%) 10 (5%)
	Median body mass index (IQR)	29 (25 to 34)	29 (25 to 33)
	Comorbid conditions of interest Diabetes Hypertension Hyperlipidemia Asthma	47 (24%) 40 (20%) 100 (505) 27 (14%)	43 (22%) 49 (25%) 98 (50%) 22 (11%)
	Clinical status on 7-point ordinal scale 2 3 4 5	4 (2%) 49 (24%) 113 (56%) 34 (17%)	9 (5%) 60 (30%) 107 (54%) 21 (11%)
	Median symptom duration before remdesivir (IQR)	8 (5 to 11)	9 (6 to 12)
Results	Endpoint	5-day group (n=200)	10-day group (n=197)	p-value Baseline-adjusted difference (95% CI)
	7-point scale* 1 2 3 4 5 6 7	16 (8%) 16 (8%) 9 (4%) 19 (10%) 11 (6%) 9 (4%) 120 (60%)	21 (11%) 33 (17%) 10 (5%) 14 (7%) 13 (7%) 3 (2%) 103 (52%)	p= 0.14
	Time to clinical improvement, days (median of 50% cumulative incidence)	10	11	0.79 (0.61 to 1.01)
	Clinical improvement Day 5 Day 7 Day 11 Day 14	33 (16%) 71 (36%) 116 (58%) 129 (64%)	29 (15%) 54 (27%) 97 (49%) 107 (54%)	0.2% (-7.0 to 7.5) -5.0% (-14.0 to 4.0) -4.8% (-14.1 to 4.6) -6.5% (15.7 to 2.8)
	Time to recovery, days (median of 50% cumulative incidence)	10	11	0.81 (0.64 to 1.04)
	Recovery Day 5 Day 7 Day 11 Day 14	32 (16%) 71 (36%) 115 (58%) 129 (64%)	27 (14%) 51 (26%) 97 (49%) 106 (54%)	0.1% (-7.0 to 7.1) -6.0% (-14.8 to 2.7) -3.7% (-12.8 to 5.5) -6.3% (-15.4 to 2.8)
	Time to modified recovery, days (median of 50% cumulative incidence)	9	10	0.82 (0.64 to 1.04)
	Modified recovery Day 5 Day 7 Day 11 Day 14	51 (26%) 84 (42%) 128 (64%) 140 (70%)	41 (21%) 69 (35%) 106 (54%) 116 (59%)	-2.3% (-10.5 to 5.9) -3.4% (-12.6 to 5.8) -5.7 (-14.6 to 3.2) -6.7% (-15.3 to 1.9)
	*7-point scale 1: Death 2: Hospitalized, invasive mechanical ventilation or ECMO 3: Hospitalized, non-invasive ventilation or high-flow oxygen 4: Hospitalized, low-flow supplemental oxygen 5: Hospitalized, no oxygen but requiring ongoing medical care 6: Hospitalized, No oxygen or medical care needed 7: Not hospitalized
Adverse Events	Any adverse events: 5-day group: 141/200 (70%): Nausea was highest (10%), followed by acute respiratory failure (6%) and ALT increase (6%) 10-day group: 145/197 (74%): Acute respiratory failure was highest (11%), followed by nausea (9%) and ALT increase (8%) but also acute kidney injury (8%)
	Serious Adverse Events: 5-day group: 42/200 (21%): Acute respiratory failure was highest (5%), followed by a number of others that occurred between 1-2% (other respiratory events, viral pneumonia, septic shock) 10-day group: 68/197 (35%): Acute respiratory failure was highest (9%), followed by respiratory failure (5%) and other events that occurred between 1-3% (other respiratory events, viral pneumonia, septic shock.)
	Percentage that Discontinued due to Adverse Events: 5-day group: 4% 10-day group: 10%
Study Author Conclusions	In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined.
InpharmD Researcher Critique	The study excluded those in severe medical status (those requiring mechanical ventilation or ECMO, multiorgan failure), so the benefit in those with severe COVID-19 is unknown. Along with the other studies, the protocol was adapted shortly after beginning to include a larger group along with altering the primary outcome. Uniquely, this study was double-blinded.

References:

Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020;383(19):1827-1837.

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19
Design	Randomized, open-label trial N= 596
Objective	To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on the clinical status on day 11 after initiation of treatment
Study Groups	10-day Remdesivir (n= 197) 5-day Remdesivir (n= 199) Standard of care (n= 200)
Methods	Inclusion criteria: Patients age > 12 years with confirmed SARS-CoV-2 infection within 4 days of randomization with diagnosed moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation > 94%). Exclusion criteria: Alanine aminotransferase or aspartate aminotransferase > 5x ULN or CrCL < 50 mL/min. Patients were randomized (1:1:1) to receive remdesivir 200 mg IV on day 1 followed by 100 mg IV once daily for subsequent days for either 10 days or 5 days. Discharge was based on physician's personal judgment. Patients were ranked on the 7-point ordinal scale. Patients who continued to be hospitalized beyond 14 days had their worst score documented.
Duration	Study enrollment: March 15, 2020, to April 18, 2020 Duration: 14 days or hospital discharge
Outcome Measures	Primary endpoint: Clinical status assessed by the 7-point ordinal scale on day 11 of study ranked from worst to best status: death hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices hospitalized, requiring low-flow supplemental oxygen hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related or not to COVID-19) hospitalized, not requiring supplemental oxygen or ongoing medical care not hospitalized Secondary endpoint: Clinical improvement defined as at least 2 point improvement from baseline on 7-point ordinal scale, recovery defined as improvement from baseline score of 2 to 5 to a 6 or 7 or a baseline score of 6 to a 7.
Baseline Characteristics		10-day Remdesivir (n=197)	5-day Remdesivir (n=199)	Standard of care (n=200)
	Age, years	56	58	57
	Women	75 (39%)	77 (40%)	75 (38%)
	White Black Asian Other	107 (57%) 37 (20%) 31 (16%) 13 (7%)	109 (59%) 35 (19%) 34 (18%) 8 (4%)	112 (58%) 27 (14%) 37 (19%) 17 (9%)
	Day 1 status: 7-point scale Class 3 Class 4 Class 5 Class 6	1 (1%) 23 (12%) 163 (84%) 6 (3%)	2 (1%) 29 (15%) 160 (84%) 0	2 (1%) 36 (18%) 160 (80%) 2 (1%)
	Coexisting conditions Cardiovascular diasease Hypertension Diabetes Asthma	111 (58%) 85 (44%) 85 (44%) 31 (16%)	111 (58%) 82 (43%) 71 (37%) 22 (12%)	107 (58%) 81 (41%) 76 (38%) 28 (14%)
	Concomitant medications Steroids Hydroxychloroquine/chloroquine Lopinavir-ritonavir Tocilizumab Azithromycin	29 (15%) 22 (11%) 11 (6%) 1 (1%) 41 (21%)	33 (17%) 16 (8%) 10 (5%) 1 (1%) 35 (18%)	38 (19%) 89 (45%) 43 (22%) 10 (5%) 62 (31%)
	Duration of symptoms before first dose, median days (interquartile range)	8 (5 to 11)	8 (5 to 11)	9 (6 to 11)
Results	Endpoint	10-day Remdesivir (n=197)	5-day Remdesivir (n=199)	Standard of care (n=200)
	Day 11 clinical status: 7-point ordinal scale Class 1 Class 2 Class 3 Class 4 Class 5 Class 6 Class 7	2 (1%) 1 (1%) 0 12 (6%) 44 (23%) 9 (5%) 125 (65%)	0 0 5 (3%) 7 (4%) 38 (20%) 7 (4%) 134 (70%)	4 (2%) 4 (2%) 7 (4%) 11 (6%) 46 (23%) 8 (4%) 120 (60%)
	Difference in clinical status distribution vs standard care, odds ratio (95% CI)	N/A*	1.65 (1.09 to 2.48)	1 [reference]
	p-value	p=0.18	p=0.02	-
	Clinical improvement Day 5 Day 7 Day 11 Difference in % vs standard of care Day 14 Day 28	72 (37%) 92 (48%) 126 (65%) 4.8% (-5.0 to 14.4) 148 (77%) 174 (90%)	61 (32%) 106 (56%) 134 (70%) 9.7% (0.1 to 19.1) 146 (76%) 171 (90%)	66 (33%) 94 (47%) 121 (61%) - 135 (68%) 166 (83%)
	Recovery Day 5 Day 7 Day 11 Difference in % vs standard of care Day 14 Day 28	74 (38%) 94 (49%) 132 (68%) 4.4% (-5.0 to 13.8) 153 (79%) 178 (92%)	67 (35%) 114 (60%) 141 (74%) 9.8% (0.3 to 19.0) 153 (80%) 175 (92%)	71 (36%) 101 (51%) 128 (64%) - 145 (73%) 170 (85%)
	* The 10-day remdesivir group did not meet the proportional odds assumption. In this scenario, the p-value was derived using the Wilcoxon rank sum test which showed non-significance.
Adverse Events	Any adverse events: n=113 (59%) 10-day remdesivir group; n=98 (51%) 5-day remdesivir group; n=93 (47%) standard care group. Difference between 5-day group and standard care was non-significant (4.8%; 95% CI -5.2% to 13.7%) Difference between 10-day group and standard care was significant (12.0%; 95% CI 1.6% to 21.8%) More common events versus standard care were nausea, hypokalemia, and headache. Serious adverse events did not differ significantly between groups. No deaths were attributable to the remdesivir treatment.
Study Author Conclusions	Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.
InpharmD Researcher Critique	As mentioned in the conclusion, the clinical importance of improving ordinal scales remains uncertain. The study was an open-label design which may have led to bias. The authors noted that discharge rates typically peaked at the completion of remdesivir infusions. The study was also multi-centered but did not stratify based on clinical sites. Different clinical sites could vary in discharge protocols and do not necessarily mean patients have recovered fully (especially when ER vacancies are in limited supply). There was no standardized method to determine patient discharge besides the physician's personal judgment. The ordinal scales also differ from the other clinical trial in this inquiry [Table 1]. Overall, the study shows plausibility but needs to be verified in well-controlled studies.

References:

Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(11):1048–1057. doi:10.1001/jama.2020.16349

Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19 (ACTT-2)

Design

Double-blind, multicenter, randomized, placebo-controlled trial

N= 1,033

Objective

To evaluate whether the combination of baricitinib plus remdesivir was superior to remdesivir alone

Study Groups

Baricitinib + remdesivir (n= 515)

Placebo + remdesivir (n= 518)

Inclusion Criteria

Age ≥ 18 years, admitted with COVID-19 symptoms, laboratory-confirmed SARS-CoV-2 infection, current illness with one of the following indicators radiographic infiltrates by imaging, OR SpO2 ≤ 94% on room air, OR requiring supplemental oxygen, requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

Exclusion Criteria

Pregnancy and breastfeeding, alanine transaminase (ALT) or aspartate transaminase (AST) > 5 times the upper limit of normal (ULN), estimated glomerular filtration rate (eGFR) < 30 ml/min or on hemodialysis, neutropenia (absolute neutrophil count < 1000 cells/microliter), lymphopenia (absolute lymphocyte count <200 cells/microliter), received ≥ 3 doses of remdesivir, other immunosuppressants four weeks before study entry

Methods

Enrolled patients were randomized (1:1) to receive either remdesivir and baricitinib or remdesivir and placebo. Remdesivir was administered 200-mg intravenously on day 1, followed by 100-mg daily from day 2 to day 10 or until hospital discharge or death. Baricitinib was given 4-mg or 2-mg (eGFR < 60 ml/minute) daily either by mouth or through a nasogastric tube for 14 days or until the hospital discharge.

All COVIDd-19 patients received venous thromboembolism prophylaxis and stand supportive care based on hospital policies. However, no other experimental or off-label treatments for COVID-19 were not allowed, including glucocorticoids, unless for other clinically validated indications.

Duration

Enrollment: May 8, 2020, to July 1, 2020, from 67 sites in eight countries

Follow-up: daily during hospitalization day 1 through day 29 or until discharge or death

Outcome Measures

Primary outcome: time to recovery defined as the first day when a patient achieved category 1, 2, or 3 on the eight-category ordinal scale

Secondary outcomes: clinical status at day 15; time to improvement by one or two categories; time to discharge; the number of days of receipt of supplemental oxygen, noninvasive ventilation or high-flow oxygen, and invasive ventilation or ECMO up to day 29; the incidence and duration of new use of oxygen, new use of non-invasive ventilation or high-flow oxygen, and new use of invasive ventilation or ECMO; duration of hospitalization; mortality at 14 and 28 days after

Safety outcomes: grade 3 and 4 adverse events and serious adverse events, discontinuation or temporary suspension of trial-product administration, and changes in the laboratory values

Recovered	Ordinal scale	Definition
	1	Not hospitalized, no limitations on activities
	2	Not hospitalized, limitation on activities and/or requiring home oxygen
	3	Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care
Population Enrolled	4	Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care
	5	Hospitalized, requiring supplemental oxygen
	6	Hospitalized, on non-invasive ventilation or high flow oxygen devices
	7	Hospitalized, on mechanical ventilation or ECMO
	8	Death

Baseline Characteristics

Baricitinib + remdesivir

(n = 515)

Placebo + remdesivir

(n = 518)

Mean age, years

55 ± 15.4

55.8 ± 16

Female

196 (38.1%)

185 (35.7%)

Race/Ethnic group*

Asian

Black

White

Hispanic or Latino

49 (9.5%)

77 (15%)

251 (48.7%)

263 (51.1%)

52 (10%)

79 (15.3%)

245 (47.3%)

268 (51.7%)

Median time (IQR) from symptom onset to randomization — days

8 (5–10)

8 (5–11)

Disease severity

Moderate

Severe

358 (69.5%)

157 (30.5%)

348 (67.2%)

170 (32.8%)

Score on the ordinal scale

70 (13.6%)

288 (55.9%)

103 (20%)

54 (10.5%)

72 (13.9%)

276 (53.3%)

113 (21.8%)

57 (11%)

Plus-minus values are means ± SD. Percentages may not total 100 because of rounding. Covid-19 denotes coronavirus disease 2019, ECMO extracorporeal membrane oxygenation, IQR interquartile range.

*Race and ethnic group were reported by the patients. With respect to “other” races, the categories used when data on race were reported included American Indian or Alaska Native and Native Hawaiian or other Pacific Islander.

Results

Baricitinib + remdesivir

(n = 515)

Placebo + remdesivir

(n = 518)

Ordinal Score 6 at Baseline

Baricitinib

(n = 103)

Placebo

(n = 113)

Recovery

No. of recoveries

Median time to recovery (95% CI), days

Rate ratio (95% CI)

433

7 (6 - 8)

1.16 (1.01–1.32 [P = 0.03])

406

8 (7 - 9)

10 (9 - 13)

1.51 (1.10–2.08)

18 (13 - 21)

Mortality over first 14 days

Hazard ratio (95% CI)

No. of deaths by day 14

0.54 (0.23–1.28)

0.21 (0.02 - 1.8)

Mortality over entire trial period‡

Hazard ratio (95% CI)

No. of deaths by day 28

0.65 (0.39–1.09)

0.55 (0.22 - 0.38)

Ordinal score at day 15 (±2 days)

Odds ratio (95% CI)

177 (34.4)

8 (1.6)

1.3 (1.0–1.6)

165 (31.9)

163 (31.5)

3 (0.6)

27 (26.2)

30 (29.1)

2.2 (1.4–3.6)

17 (15.0)

24 (21.2)

Median time to improvement by one category on the ordinal scale

Rate ratio (95% CI)

1.21 (1.06 - 1.39)

Incidence of new use of oxygen

Difference (95% CI)

22.9%

- 17.4% (- 31.6 to -2.1)

40.3%

New use of mechanical ventilation of ECMO

Difference (95% CI)

10%

- 5.2% (- 9.5 to -0.5)

15.2%

Progression to death or noninvasive or invasive ventilation

Rate ratio (95% CI)

22.5%

0.77 (0.6 - 0.98)

28.4%

Progression to death or invasive ventilation

Rate ratio (95% CI)

12.2%

0.69 (0.5 - 0.95)

17.2%

Adverse Events

Treatment associated grade 3 or 4 adverse events: 25 vs. 28

Hyperglycemia (4.9% vs. 7.9%), anemia (5.9% vs. 5.9%), decreased lymphocyte count (4.5% vs. 6.9%), and acute kidney injury (3% vs. 5.3%)

Treatment associated serious adverse events: 6 vs. 5

New infection (5.9% vs. 11.2%), acute respiratory failure (3.6% vs. 2.6%), pulmonary embolism (1% vs. 0.4%)

Percentage that Discontinued due to Adverse Events: cause not reported, baricitinib plus remdesivir group (8.5%), remdesivir (13.1%)

Study Author Conclusions

Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events.

InpharmD Researcher Critique

Based on the study results, the authors identified the specific patient population who would benefit the most from the combination therapy with baricitinib, those on high-flow or noninvasive ventilation.

Limitations of the study include a lack of power to find a significant difference in 28-day mortality between the two groups. At the study enrollment, patients were not allowed to receive glucocorticosteroids for COVID-19 treatment, which provided limited data on the combination therapy plus steroids. Of note, approximately 10% of patients eventually received a corticosteroid post-randomization (baricitinib plus remdesivir group [10.9%] versus remdesivir [12.9%]) but this subset of patients were not analyzed separately.

References:

Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021;384(9):795-807. doi:10.1056/NEJMoa2031994

Comparison of Time to Clinical Improvement With vs Without Remdesivir Treatment in Hospitalized Patients With COVID-19
Design	Multicenter, retrospective, comparative study N=2,299
Objective	To examine whether remdesivir administered with or without corticosteroids for the treatment of coronavirus disease 2019 (COVID-19) is associated with more rapid clinical improvement in a racially/ethnically diverse population
Study Groups	All patients All remdesivir (n=342) All control (n=1,957) Propensity score-matched patients* Matched remdesivir (n=285) Matched control (n=285) *Those who received remdesivir were matched to infected individuals who did not receive remdesivir using time-invariant covariates (e.g., age, sex, race/ethnicity) and time-dependent covariates (e.g., blood pressure, pulse, temperature, respiratory rate, C-reactive protein level).
Inclusion Criteria	Hospitalized patients with confirmed COVID-19, significant illness (oxygen saturation ≤94% breathing ambient air or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation), and alanine aminotransferase level less than 5 times the upper reference limit.
Exclusion Criteria	Death or hospital discharge within 24 hours of admission, participation in randomized clinical trials of remdesivir, or being treated with remdesivir at the date of censoring.
Methods	Data were collected from the electronic health record from a 5-hospital health system in the United States. Patients received a 5-day treatment and could receive 5 more days of therapy if they were intubated and had not improved. Treatment was stopped if ALT levels increased more than 5 times the upper limit of normal, if other signs or symptoms of liver toxicity were present, or in the physician's discretion if the creatinine clearance decreased by more than 50% with no alternative explanation. Outcomes of patients receiving corticosteroids plus remdesivir were compared to patients receiving remdesivir alone using time-dependent and time-invariant covariates.
Duration	March 4, 2020, to August 29, 2020.
Outcome Measures	Primary outcomes: Time to clinical improvement (composite of discharged alive from the hospital without worsening of World Health Organization [WHO] disease severity score or ≥ 2-point decrease in World Health Organization (WHO) severity score during hospitalization within 28 days or maximum follow-up). Secondary outcome: Time to death from the first remdesivir treatment day, time to clinical improvement, or death following administration of both corticosteroids and remdesivir.
Baseline Characteristics		All patients		Propensity score-matched patients
		All remdesivir (n=342)	All control (n=1,957)	Matched remdesivir (n=285)	Matched control (n=285)
	Median age, years	60 (46-69)	60 (44-74)	60 (48-70)	62 (51-75)
	Median body mass index	30.1 (25.7-36)	28.2 (24.1-33.2)	29.8 (25.9-34.7)	29.6 (25.4-35)
	Male	189 (55.3%)	1,004 (51.3%)	160 (56.1%)	158 (55.4%)
	Race Black Latinx White Other	124 (36.3%) 114 (33.3%) 66 (19.3%) 38 (11.1%)	715 (36.5%) 519 (26.5%) 534 (27.3%) 189 (9.7%)	95 (33.3%) 98 (34.4%) 59 (20.7%) 33 (11.6%)	100 (35.1%) 86 (30.2%) 66 (23.2%) 33 (11.6%)
	Concomitant Medications Hydroxychloroquine Azithromycin Dexamethasone Prednisone Methylprednisolone Hydrocortisone Heparin	3 (0.9%) 153 (44.7%) 157 (45.9%) 27 (7.9%) 20 (5.8%) 12 (3.5%) 292 (85.4%)	399 (20.4%) 706 (36.1%) 155 (7.9%) 112 (5.7%) 88 (4.5%) 62 (3.2%) 1,358 (69.4%)	3 (1.1%) 121 (42.%) 132 (46.3%) 22 (7.7%) 14 (4.9%) 10 (3.5%) 242 (84.9%)	7 (2.5%) 124 (43.5%) 46 (16.1%) 15 (5.3%) 23 (8.1%) 15 (5.3%) 220 (77.2%)
Results	Endpoint	Matched remdesivir (n=285)	Matched control (n= 285)	Adjusted hazard ratio (aHR) (95% confidence interval [CI])
	Median time to clinical improvement, days	5 (4-8)	7 (4-10)	1.47 (1.22-1.79)
	Median time to death, days Mild-moderate disease Severe disease	8.6 (6.1-14.2) - -	8.2 (4.8-13.8) - -	- 0.27 (0.06-1.27) 0.78 (0.33-1.84)
	28-day mortality rate	22 (7.7%)	40 (14%)	0.70 (0.38-1.28)
		Remdesivir plus corticosteroids (n=184)	Remdesivir alone (n=158)	aHR (95% CI)
	Median time to death, days	15 (9-21)	6.5 (6-7.8)	1.94 (0.67-5.57)
	Unadjusted 28-day mortality rates	15 (8.2%)	10 (6.3%)	-
	Combination therapy of remdesivir with a corticosteroid resulted in a longer time to clinical improvement (aHR, 0.77; 95% CI, 0.62-0.97).
Adverse Events	Common Adverse Events: ALT or aspart aminotransferase (AST) > 200 international units (11.2% vs 12.6%), bilirubin > 2 mg/dL (3.9% vs 6.3%), estimated glomerular filtration rate (eGFR) < 30 mL/min (10.9% vs 24.9%)
	Serious Adverse Events: N/A
	Percentage that Discontinued due to Adverse Events: Treatment was stopped in 10 patients due to increased levels of liver enzyme or bilirubin (n=4), kidney failure of unclear cause (n=2), nausea (n=1), epistaxis and tachycardia (n=2), neck and mouth itching (n=1).
Study Author Conclusions	The receipt of remdesivir was associated with faster clinical improvement in a cohort of predominantly non-White patients. Remdesivir plus corticosteroid administration did not reduce the time to death compared with remdesivir administered alone.
InpharmD Researcher Critique	This study does involve racially and ethnically diverse populations, unlike the other clinical trials, and its study objective was to investigate whether remdesivir plus/minus corticosteroids for the treatment of COVID-19 brings out clinical improvements in a racially/ethnically diverse population; however, the study results were not stratified by the racial makeup. The authors generously concluded that remdesivir showed clinical benefits in a cohort of predominantly non-White patients. Strengths of this analysis include adjustments for confounding variables via propensity-score matching; however, unmeasured variables may still bias the treatment effect estimates. The authors mentioned that the study was likely underpowered to detect a mortality difference between the patients receiving remdesivir and matched controls.

References:

Garibaldi BT, Wang K, Robinson ML, et al. Comparison of time to clinical improvement with vs without remdesivir treatment in hospitalized patients with COVID-19. JAMA Netw Open. 2021;4(3):e213071. doi: 10.1001/jamanetworkopen.2021.3071.

Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients
Design	Double-blind, randomized, placebo-controlled trial N= 562
Objective	To evaluate the efficacy and safety of a 3-day course of remdesivir in high-risk, nonhospitalized patients with Covid-19
Study Groups	Remdesivir (n= 279) Placebo (n= 283)
Inclusion Criteria	SARS-CoV-2 infection confirmed by a molecular diagnostic assay within 4 days before screening; at least one ongoing symptom consistent with Covid-19, with onset of the first symptom within 7 days before randomization; 12 years of age or older and had at least one preexisting risk factor for progression to severe Covid-19 (hypertension, cardiovascular or cerebrovascular disease, diabetes mellitus, obesity, immune compromise, chronic mild or moderate kidney disease, chronic liver disease, chronic lung disease, current cancer, or sickle cell disease) or were 60 years of age or older, regardless of whether they had other risk factors.
Exclusion Criteria	Concurrent or anticipated use of supplemental oxygen or hospital care at the time of screening, previous hospitalization for Covid-19, previous treatment for Covid-19 (including investigational agents), SARS-CoV-2 vaccine recipients.
Methods	Nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days were randomized (1:1) to receive either intravenous (IV) remdesivir (200 mg on day 1 followed by 100 mg on days 2 and 3) or a placebo.
Duration	From September 18, 2020, through April 8, 2021
Outcome Measures	Primary outcome: composite of hospitalization related to Covid-19 or death from any cause by day 28. Secondary outcomes: composite of Covid-19–related medically attended visits or death from any cause by days 14 and 28, Covid-19–related hospitalization by days 14 and 28
Baseline Characteristics		Remdesivir (n= 279)	Placebo (n=283)
	Age, years ≥60 years < 18 years	50 ± 15 83 (29.7%) 3 (1.1%)	51 ± 15 87 (30.7%) 5 (1.8%)
	Female	131 (47%)	138 (48.8%)
	White	228 (81.7%)	224 (79.2%)
	Body Mass Index (BMI), kg/m²	31.2 ± 6.7	30.8 ± 5.8
	Coexisting conditions Diabetes mellitus Obesity Hypertension Chronic lung disease Current cancer Cardiovascular or cerebrovascular disease Immune compromise Chronic kidney disease, mild or moderate Chronic liver disease	173 (62.0%) 154 (55.2%) 138 (49.5%) 67 (24.0%) 12 (4.3%) 20 (7.2%) 14 (5.0%) 7 (2.5%) 1 (0.4%)	173 (61.1%) 156 (55.1%) 130 (45.9%) 68 (24.0%) 18 (6.4%) 24 (8.5%) 9 (3.2%) 11 (3.9%) 1 (0.4%)
	Residence in skilled nursing facility	8 (2.9)	7 (2.5)
	Median duration of symptoms before first infusion (IQR), days	5 (3–6)	5 (4–6)
	Median time since RT-PCR confirmation of SARS-CoV-2 (IQR), days	2 (1–3)	3 (1–4)
	Mean SARS-CoV-2 RNA nasopharyngeal viral load, log₁₀ copies/mL‡	6.31 ± 1.75	6.28 ± 1.79
	‡ Data are shown for the virologic analysis set: 215 of 279 patients (77.1%) in the remdesivir group and 213 of 283 patients (75.3%) in the placebo group.
Results	Endpoint	Remdesivir (n= 279)	Placebo (n= 283)	Hazard ratio (95% CI)
	Primary efficacy endpoint
	Covid-19–related hospitalization or death from any cause by day 28†	2 (0.7%)	15 (5.3%)	0.13 (0.03 to 0.59); p= 0.008
	Secondary efficacy endpoint
	Covid-19–related hospitalization or death from any cause by day 14	2 (0.7%)	15 (5.3%)	0.13 (0.03 to 0.59)
	Covid-19–related medically attended visit or death from any cause‡
	Day 14	2/246 (0.8%)	20/252 (7.9%)	0.10 (0.02 to 0.43)
	Day 28	4/246 (1.6%)	21/252 (8.3%)	0.19 (0.07 to 0.56)
	Death from any cause by day 28	0	0	n/a
	Hospitalization for any cause by day 28§	5 (1.8%)	18 (6.4%)	0.28 (0.10 to 0.75)
	Time-weighted average change in nasopharyngeal SARS-CoV-2 viral load from baseline to day 7, log₁₀ copies/mL	−1.24	−1.14	0.07 (−0.10 to 0.24)¶
	Alleviated baseline Covid-19 symptoms, according to FLU-PRO Plus questionnaire‖
	Questionnaire completed before infusion on day 1	23/66 (34.8%)	15/60 (25.0%)	1.41 (0.73 to 2.69)**
	Questionnaire completed on day 1, either before or after infusion§	61/169 (36.1%)	33/165 (20.0%)	1.92 (1.26 to 2.94)**
	† Of the eight patients who were adolescents, none had a Covid-19–related hospitalization or death from any cause by day 28. ‡ Data are shown for patients who underwent randomization, received at least one infusion of remdesivir or placebo, and met eligibility criteria as defined in protocol amendment 2 or later. § The analysis was conducted post hoc. ¶ The value is the least-squares mean. ‖ On the FLU-PRO (Influenza Patient-Reported Outcome) Plus questionnaire, which was adapted for patients with Covid-19, alleviation of Covid-19 symptoms was defined as mild or absent symptoms. ** The value is the rate ratio.
Adverse Events	Common Adverse Events (at least >5%): Nausea. (10.8%), headache (5.7%) and cough (3.6%)
	Serious Adverse Events: 5 of 279 remdesivir-treated patients (1.8%) vs. 19 of 283 placebo-treated patients (6.7%)
	Percentage that Discontinued due to Adverse Events: Not disclosed.
Study Author Conclusions	Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo.
InpharmD Researcher Critique	The trial was conducted primarily in the United States (94.5%), and only 8 patients (1.4%) were adolescents. Given this trial excluded patients who had received SARS-CoV-2 vaccines, the findings may not be generalizable to the vaccinated population. Less than half of the planned enrollment was achieved due to premature termination of the trial (administration issues), and the effect of remdesivir on emerged B.1.617.2 (delta) variant of SARS-CoV2 is unknown.

References:

Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe covid-19 in outpatients [published online ahead of print, 2021 Dec 22]. N Engl J Med. 2021;10.1056/NEJMoa2116846. doi:10.1056/NEJMoa2116846

Remdesivir Treatment in Hospitalized Patients With Coronavirus Disease 2019 (COVID-19): A Comparative Analysis of In-hospital All-cause Mortality in a Large Multicenter Observational Cohort
Design	Multicenter, observational, retrospective cohort study N= 45,542
Objective	To compare 14- and 28-day mortality among hospitalized patients with COVID-19 with and without remdesivir (RDV) treatment
Study Groups	Non-RDV (n= 16,687) RDV (n= 28,855)
Inclusion Criteria	Adult (≥18 years) patients hospitalized with a primary or secondary discharge diagnosis of COVID-19 (International Classification of Diseases, 10th revision, Clinical Modification: U07.1)
Exclusion Criteria	Pregnant; length of stay longer than 100 days; incomplete data; transferred to or from another hospital; transferred from a hospice; elective procedures; discharged or died during the baseline period; received RDV through a clinical trial or who were first administered RDV after the baseline period
Methods	The Premier Healthcare Database was utilized to identify eligible patients who received RDV within two days of hospitalization vs. those not receiving RDV during their hospitalization. Preferential within-hospital propensity score matching with replacement was used with a ratio up to 1:10 (1 RVD patients matched to 1 to 10 non-RVD patients) based on various patients' characteristics. More specifically, patients were also matched on baseline oxygenation level (no supplemental oxygen charges [NSO], low-flow oxygen [LFO], high-flow oxygen/noninvasive ventilation [HFO/NIV], and invasive mechanical ventilation/extracorporeal membrane oxygenation [IMV/ECMO]).
Duration	August 1, 2020, to November 30, 2020
Outcome Measures	14-day and 28-day all-cause inpatient mortality (defined as a discharge status of “expired” or “hospice”)
Baseline Characteristics	Propensity Score-matched Patients	No RDV (n= 28,855)	RDV (n= 28,855)	SMD
	Age, years 50–64 65–74 75–84	8,261.4 (28.6%) 7,514.3 (26.0%) 6,265.5 (21.7%)	8,806.0 (30.5%) 7,300.0 (25.3%) 5,617.0 (19.5%)	0.17 - - -
	Female	12,944.5 (44.9%)	12,820.0 (44.4%)	0.01
	White	21,209.7 (73.5%)	21,017.0 (72.8%)	0.03
	Comorbidities Obesity COPD Cardiovascular disease (including hypertension) Diabetes Renal disease Cancer Immunosuppressive condition	11,410.3 (39.5%) 8,449.5 (29.3%) 24,046.2 (83.3%) 12,807.9 (44.4%) 6,817.5 (23.6%) 1,178.1 (4.1%) 1,263.0 (4.4%)	11,782.0 (40.8%) 7,859.0 (27.2%) 22,825.0 (79.1%) 12,381.0 (42.9%) 4,970.0 (17.2%) 1,094.0 (3.8%) 1,181.0 (4.1%)	- 0.03 0.05 0.11 0.03 0.16 0.01 0.01
	Baseline severity IMV/ECMO HFO/NIV LFO NSO	1,296.0 (4.5%) 5,781.0 (20.0%) 13,808.0 (47.9%) 7,970.0 (27.6%)	1,296.0 (4.5%) 5,781.0 (20.0%) 13,808.0 (47.9%) 7,970.0 (27.6%)	0.00 - - - -
	Medication use Anticoagulants Corticosteroids Convalescent plasma	4,718.3 (16.4%) 27,933.4 (96.8%) 9,598.9 (33.3%)	4,280.0 (14.8%) 27,692.0 (96.0%) 9,088.0 (31.5%)	- 0.04 0.04 0.04
	COPD, chronic obstructive pulmonary disease; HFO/NIV, high-flow oxygen/noninvasive ventilation; ICU, intensive care unit; IMV/ECMO, invasive mechanical ventilation/extracorporeal membrane oxygenation; LFO, low-flow oxygen; NSO, no supplemental oxygen charges; RDV, remdesivir; SMD, standardized mean difference
Results	Endpoint	Non-RDV	RDV	p-value
	Mortality rate 14-day 28-day	15.4% 19.1%	10.6% 15.4%	< 0.0001 - -
	Mortality rate with baseline severity NSO 14-day 28-day LFO 14-day 28-day HFO/NIV 14-day 28-day IMV/ECMO 14-day 28-day	- - 9.1% 11.5% - 12% 15.1% - 25.7% 30.8% - 43.8% 55.8%	- - 5.4% 8% - 7.4% 10.7% - 20.5% 29.4% - 32.3% 48.4%	- < 0.0001 - - < 0.0001 - - 0.1859 - - < 0.0001 - -
	Patients Requiring NSO (ie, Without Charges for Supplemental Oxygen) at Baseline: After adjusting for baseline and clinical covariates, there was a significant reduction in mortality among RDV-treated patients compared with non-RDV group (14-day adjusted hazard ratio [aHR]: 0.69; 95% confidence interval [CI] 0.57 to 0.83; 28-day aHR: 0.80; 95% CI 0.68 to 0.94). Patients Requiring LFO at Baseline: Mortality at day 14 (aHR: 0.81; 95% CI 0.70 to 0.93); no significant difference between the 2 groups at 28 days (aHR: 0.97; 95% CI 0.84 to 1.11) Patients Requiring HFO/NIV at Baseline: Mortality at day 14 (aHR: 0.81; 95% CI 0.70 to 0.93); no significant difference between the 2 groups at 28 days (aHR: 0.97; 95% CI 0.84 to 1.11) Patients Requiring IMV/ECMO at Baseline: Significant difference in mortality (14-day aHR: 0.70; 95% CI 0.58 to 0.84; 28-day aHR: 0.81; 95% CI 0.69 to 0.94)
Adverse Events	Not reported
Study Author Conclusions	In summary, in this retrospective comparative effectiveness study of more than 100,000 adults hospitalized with COVID-19 in the United States, treatment initiation with RDV upon hospital admission was associated with significant survival benefits at 14 and 28 days. These benefits were most apparent among patients receiving NSO, LFO, or IMV/ECMO at baseline. Although unmeasured confounding cannot be excluded, these findings provide further support that RDV antiviral therapy is a foundational treatment approach for COVID-19.
InpharmD Researcher Critique	Given the retrospective nature of the study design, certain variables might not be adjusted, which could potentially confound the study outcomes. Additionally, as the data was gathered during the early phase of the pandemic, protocols and treatment guidelines might have evolved and were not reflective of current practice.

References:

Mozaffari E, Chandak A, Zhang Z, et al. Remdesivir treatment in hospitalized patients with COVID-19: a comparative analysis of in-hospital all-cause mortality in a large multi-center observational cohort. Clin Infect Dis. 2021 Oct 1:ciab875. doi: 10.1093/cid/ciab875

Improved Survival Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Treated With Remdesivir and Dexamethasone. A Nationwide Population-Based Cohort Study
Design	Multicenter, retrospective, cohort study N=2,747
Objective	To compare the effectiveness of standard of care alone versus standard of care plus remdesivir and dexamethasone in patients hospitalized with COVID-19
Study Groups	Standard of care (n= 1,053) Standard of care (SOC) + dexamethasone + remdesivir (n= 1,694)
Inclusion Criteria	Confirmed SARS-CoV-2 infection with a new-onset pulmonary radiographic infiltrate; oxygen saturation ≤ 94%; need of supplemental oxygen; symptom duration of < 10 days (which was later extended to 12 days)
Exclusion Criteria	Evidence of multiorgan failure; receiving more than one pressor for septic shock; plasma alanine transaminase 5 times above the upper limit of normal; renal failure or dialysis or continuous veno-venous hemofiltration; pregnant or lactating women; history of hypersensitivity to remdesivir
Methods	Two population-based nationwide cohorts in Denmark hospitalized with COVID-19 compared individuals using the original standard of care and compared them to individuals receiving standard of care + dexamethasone and remdesivir.
Duration	February through December 2020 The standard of care cohort: February through May 2020 The standard of care + Dexamethasone and Remdesivir cohort: June through December 2020
Outcome Measures	Death in 30 days, need for mechanical ventilation
Baseline Characteristics		SOC (n= 1,053)	SOC + Dexamethasone and Remdesivir (n= 1,694)	p-value
	Age, years	71 (57 to 80)	69 (57 to 79)	0.20
	Female	45%	36.7%	0.001
	Coexisting Comorbidities Hypertension Diabetes Cardiovascular disease Chronic obstructive pulmonary disease Malignancy Other	38.9% 19.8% 27.4% 14.6% 12.1% 35.9%	36.8% 22.7% 26.3% 13.0% 10.2% 47.7%	0.27 0.09 0.53 0.25 0.13 <0.001
	Symptom duration, days (Interquartile Range [IQR])	7 (3 to 10)	6 (3 to 9)	<0.001
	Supplemental O2	44.6%	95%	<0.001

Results	Endpoint	SOC (n= 1,053)	SOC + Dexamethasone and Remdesivir (n= 1,694)	p-value
	Time to discharge, days (IQR)	6 (2 to 13)	7 (5 to 11)	<0.001
	Time to death, days (IQR)	8 (5 to 13)	14 (8 to 20)	<0.001
	Deceased ≤ 30 days	19.7%	12.6%	<0.001
	Required mechanical ventilation ≤24 hours ≤30 days	2.8% 14.6%	1.2% 9.0%	0.004 <0.001

Adverse Events	Not disclosed
Study Author Conclusions	Individuals with COVID-19 who received remdesivir and dexamethasone in addition to standard of care had reduced 30-day mortality and need of MV compared to individuals receiving standard of care alone.
InpharmD Researcher Critique	One strength is the population-based nationwide design with complete follow-up; however, the study was limited to Denmark and due to the retrospective nature of the study, confounding variables may have impacted the outcomes. Additionally, the population was not evenly distributed between the two cohorts.

References:

Benfield T, Bodilsen J, Brieghel C, et al. Improved survival among hospitalized patients with coronavirus disease 2019 (COVID-19) treated with remdesivir and dexamethasone. A nationwide population-based cohort study. Clinical Infectious Diseases. 2021 Dec 6;73(11):2031-2036.

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19
Design	Independent, add-on, randomized-controlled trial N= 181
Objective	To evaluate remdesivir and hydroxychloroquine effects on all-cause, in-hospital mortality, degree of respiratory failure and inflammation, and viral clearance in the oropharynx
Study Groups	Remdesivir + standard of care (SOC) (n= 42) Hydroxychloroquine + SOC (n= 52) Standard of care (n= 87)
Inclusion Criteria	Adults aged ≥ 18 years with PCR-confirmed SARS-CoV-2 infection; admitted to the hospital ward or intensive care unit (ICU) with no anticipated transfer to a nonstudy hospital within 72 hours of inclusion
Exclusion Criteria	Severe comorbid conditions were life expectancy was less than 3 months, aspartate aminotransferase or alanine aminotransferase levels more than 5 times the upper limit of normal, rate-corrected QT interval > 470 ms
Methods	Patients were randomized and placed into 3 different study groups: 1. Local SOC 2. SOC plus hydroxychloroquine 800 mg by mouth twice daily on day 1, then 400 mg twice daily up to 9 days 3. SOC plus remdesivir 200 mg by intravenous route once daily, then 100 mg once daily up to 9 days All above treatments were discontinued upon hospital discharge.
Duration	March 28 and October 4, 2020 Follow-up: 3 months
Outcome Measures	Primary outcome: study treatment vs. SOC all-cause, in-hospital mortality Secondary outcomes: patients on invasive mechanical ventilation, time to first receipt of mechanical ventilation, duration of mechanical ventilation, and duration of treatment at an ICU
Baseline Characteristics		Remdesivir + SOC (n= 42)	SOC (n= 57)(Remdesivir Control)	HCQ + SOC (n= 52)	SOC (n= 54 (HCQ Control)
	Mean age, years	59.7 ± 16.5	58.1 ± 15.7	60.3 ± 13.3	59.2 ± 16.4
	Female	13 (31%)	14 (24.6%)	21 (40.4)	20 (37%)
	Mean BMI, kg/m²	28 ± 5	28 ± 4	28 ± 5	27 ± 4
	Mean symptom duration before admission, days	7.5 ± 6.1	7.2 ± 3.5	8.4 ± 4.3	8.6 ± 5.3
	Comedications Steroids ACE Inhibitors	1 (2.4%) 2 (4.9%)	2 (3.6%) 4 (7.1%)	2 (3.8%) 1 (1.9%)	4 (7.4%) 7 (13%)
	Comorbidity Ever smoking Hypertension Diabetes Obese (BMI > 30 kg/m²)	16 (39%) 15 (36.6%) 9 (22%) 11 (28.9%)	27 (47.4%) 14 (24.6%) 9 (15.8%) 9 (15.8%)	18 (34.6%) 17 (32.7%) 7 (13.5%) 16 (32.7%)	21 (38.9%) 18 (33.3%) 8 (14.8%) 11 (22%)
	Mean viral load (oropharynx), log10 count/1000 cells	1.6 ± 1.6	2.3 ± 1.8	2.3 ± 1.5	2 ± 1.5
Results	Endpoint	Treatment + SOC (95% CI), %	SOC (95% CI), %	Relative Risk (95% CI)*	Hazard Ratio (95% CI)**	Estimated Marginal Risk Difference (95% CI)
	Remdesivir vs. its SOC Mortality 28-day mortality 60-day mortality Admission to ICU Mechanical ventilation Time to ventilation	7.1 (1.8 to 17.5) 2.4 (0.1 to 10.1) 7.1 (1.8 to 17.5) 19.0 (9.2 to 32.6) 9.5 (3.1 to 20.8) -	7.0 (2.2 to 15.6) 5.3 (1.3 to 13.1) 5.3 (1.3 to 13.1) 19.3 (10.5 to 30.8) 7.0 (2.2 - 15.6) -	1.0 (0.2 to 4.6) - - - - 1.4 (0.4 to 5.8)	1.0 (0.4 to 2.9) - - - - 1.3 (0.5 to 3.4)	- -2.9 (-10.3 to 4.5) 1.9 (-7.8 to 11.6) -0.3 (-15.9 to 15.4) 2.5 (-8.6 to 13.6) -
	HCQ vs. its SOC Mortality 28-day mortality 60-day mortality Admission to ICU Mechanical ventilation Time to ventilation	7.5 (2.4 to 16.7) 7.5 (2.4 to 16.7) 7.5 (2.4 to 16.7) 22.6 (12.8 to 35) 15.1 (7.2 to 26.3) -	3.6 (0.6 to 10.6) 1.8 (2.4 to 16.7) 1.8 (2.4 to 16.7) 16.1 (8.1 to 27.1) 10.7 (4.4 to 20.5) -	2.2 (0.4 to 10.8) - - - - 2.1 (0.7 to 6.2)	3.1 (0.3 to 34.4) - - - - 3.0 (0.6 to 16.3)	- 5.8 (-2.2 to 13.7) 5.8 (-2.2 to 13.7) 6.6 (-8.2 to 21.4) 4.4 (-8.2 to 17.0) -
Adverse Events	Common Adverse Events: N/A
	Serious Adverse Events: prolonged rate-corrected QT interval (2 patients in HCQ group), respiratory/thoracic/mediastinal disorders, respiratory failure
	Percentage that Discontinued due to Adverse Events: 2 patients in HCQ group withdrew from treatment due to prolonged rate-corrected QT interval
Study Author Conclusions	Despite the early emergence of reports that both remdesivir and HCQ effectively exerted strong antiviral activities against SARS-CoV-2 in preclinical models, our results show no antiviral effects of these drugs in hospitalized patients. It has been claimed that these antiviral drugs, particularly remdesivir, could be important in the early stages of COVID-19, before clinical progression to a state of hyperinflammation. However, we found no significant antiviral effects of remdesivir or HCQ, even in patients with symptom duration less than 7 days or baseline CRP and ferritin levels below median levels in the patient cohort. Moreover, the presence of SARS-CoV-2 antibodies or high or low viral load at hospital admission did not influence the potential antiviral effects of these drugs.
InpharmD Researcher Critique	Baseline characteristics of patients were well balanced but had a higher percentage of men (65.7%). The study included a population consisting of hospitalized and ICU patients, making the study more generalizable. Given the median duration of hospital stay of about 5-6 days, most patients did not receive the entire 10-day course of remdesivir, the treatment design. Additionally, discharge was based on the treating physician's discretion, which might be subjective to variation in discharging criteria.

References:

Barratt-Due A, Olsen IC, Nezvalova-Henriksen K, et al. Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial. Ann Intern Med. 2021;174(9):1261-1269. doi:10.7326/M21-0653

Successful early treatment combining remdesivir with high-titer convalescent plasma among COVID-19-infected hematological patients
Design	Retrospective, observational, cohort study N=32
Objective	To assess the efficacy of early combination therapy of remdesivir and high-titer convalescent plasma (CP) in hematological patients
Study Groups	Pneumonia cohort (n=18) No Pneumonia cohort (n=14)
Methods	Inclusion criteria: hematological patients diagnosed with COVID-19 and subsequently treated with a remdesivir and high-titer CP combination Exclusion criteria: N/A All patients were given intravenous remdesivir 200 mg on the first day then administered 100 mg daily for a total of 5 days. Two units of high-titer convalescent plasma (CP) were given per one treatment cycle. Many of the patients went through retreatment because of either prolonged SARS-CoV-2 positivity or repositivity.
Duration	Study duration: December 30, 2020 to March 29, 2021 Treatment duration: 5 days
Outcome Measures	Primary outcome: Highest degree of severity on treatment during the first treatment cycle. Disease severity was assessed according to adapted definitions: Asymptomatic or Presymptomatic: Positive SARS-CoV-2 test; no symptoms Mild Illness: Mild symptoms (e.g., fever, cough, or chage in taste or smell no dyspnea) Moderate Illness: Clinical or radiographic evidence of lower respiratory tract disease oxygen saturation ≥94% Severe Illness: Oxygen saturation <94% respiratory rate ≥30 breaths/min; lung infiltrates >50% Critical Illness: Resipatory failure, shock, and multiorgan dysfunction or failure
Baseline Characteristics		Pneumonia (n=18)	No pneumonia (n=14)	p-value
	Age, median years (range)	62 (44-86)	56 (25-77)	0.303
	Male	10 (56%)	9 (64%)	0.725
	SARS-CoV-2 RT-PCR positive test	15 (83%)	8 (57%)	0.132
	SARS-CoV-2 antigen-positive test	3 (17%)	6 (43%)	0.132
	Active hematological disease	14 (78%)	10 (71%)	0.704
	COVID-19 severity at the time of the start of therapy Asymptomatic Mild Moderate Severe Critical	1 (6%) 2 (11%) 0 15 (83%) 0	4 (29%) 8 (57%) 1 (7%) 1 (7%) 0	<0.001
Results		Pneumonia (n=18)	No pneumonia (n=14)	p-value
	COVID-19 severity on treatment during the first treatment cycle Asymptomatic Mild Moderate Severe Critical	0 0 2 (11%) 11 (61%) 5 (28%)	2 (14%) 8 (57%) 0 4 (29%) 0	<0.001
	Total length of hospitalization during first treatment cycle, median (range)	15 (6-91)	12 (5-26)	0.574
Adverse Events	No patients developed direct adverse reactions requiring treatment reduction
Study Author Conclusions	While robust data on remdesivir and CP treatment in this specific group of patients are not yet available for literature, published case reports and our substantial actual clinical records indicate remarkable efficacy of high-titer CP/remdesivir combination initiated immediately following COVID-19 diagnosis. We believe that this treatment strategy is especially effective in patients who have not yet developed pneumonia.
InpharmD Researcher Critique	The trial had a very small sample size and no comparator group. However, the study's strength is the fact that it focuses on a specific population time composed of hematological patients.

References:

Weinbergerova B, Mayer J, Kabut T, et al. Successful early treatment combining remdesivir with high‐titer convalescent plasma among COVID‐19‐infected hematological patients. Hematological Oncology. 2021;39(5):715-720.