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. [1-3]

References:

[1] National Institutes of Health (NIH). COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. Available at https://www.covid19treatmentguidelines.nih.gov/. Last Updated December 16, 2021. Accessed January 7, 2022.
[2] Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Clin Infect Dis. 2020;ciaa478. doi:10.1093/cid/ciaa478.
[3] Society of Critical Care Medicine. The Surviving Sepsis Campaign COVID-19 guidelines. Available https://sccm.org/SurvivingSepsisCampaign/Guidelines/COVID-19. January 29, 2021. Accessed January 7, 2022.

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:

  1. Not hospitalized and no limitations of activities
  2. Not hospitalized, with limitation of activities, home oxygen requirement, or both
  3. Hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection-control or other nonmedical reasons)
  4. Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related to Covid-19 or to other medical conditions)
  5. Hospitalized, requiring any supplemental oxygen
  6. Hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices
  7. Hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
  8. 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%)

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

  1. Not hospitalized, no limitations on activities

  2. Not hospitalized, limitation on activities

  3. Hospitalized, not requiring supplemental oxygen

  4. Hospitalized, requiring supplemental oxygen

  5. Hospitalized, on non-invasive ventilation or high flow oxygen devices

  6.  Hospitalized, on invasive mechanical ventilation or ECMO

  7. 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

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:

1, death

2, hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation

3, hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices

4, hospitalized, requiring low-flow supplemental oxygen

5, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related or not to COVID-19)

6, hospitalized, not requiring supplemental oxygen or ongoing medical care

7, 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

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;

 

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 

4

5

6

7

 


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)

 

82 

10 (9 - 13)

1.51 (1.10–2.08)

 

73

18 (13 - 21)

Mortality over first 14 days

Hazard ratio (95% CI)

No. of deaths by day 14

 


0.54 (0.23–1.28)

8



15

 

0.21 (0.02 - 1.8)

1

 

5

Mortality over entire trial period

Hazard ratio (95% CI)

No. of deaths by day 28

 

0.65 (0.39–1.09)

24

 

37

 

0.55 (0.22 - 0.38)

7

 

-

13

Ordinal score at day 15 (±2 days)

1

2

3

Odds ratio (95% CI)

 


177 (34.4)

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)

0

2.2 (1.4–3.6)

 


17 (15.0)

24 (21.2)

0

-

Median time to improvement by one category on the ordinal scale

Rate ratio (95% CI) 

6


1.21 (1.06 - 1.39)

8


-

   

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.