Comparison of Time to Clinical Improvement With vs Without ... · Prednisone 27 (7.9) 112 (5.7)...

Original Investigation | Infectious Diseases

Comparison of Time to Clinical Improvement With vs Without RemdesivirTreatment in Hospitalized Patients With COVID-19Brian T. Garibaldi, MD, MEHP; Kunbo Wang, MS; Matthew L. Robinson, MD; Scott L. Zeger, PhD; Karen Bandeen-Roche, PhD; Mei-Cheng Wang, PhD;G. Caleb Alexander, MD; Amita Gupta, MD; Robert Bollinger, MD, MPH; Yanxun Xu, PhD

Abstract

IMPORTANCE Clinical effectiveness data on remdesivir are urgently needed, especially amongdiverse populations and in combination with other therapies.

OBJECTIVE To examine whether remdesivir administered with or without corticosteroids fortreatment of coronavirus disease 2019 (COVID-19) is associated with more rapid clinicalimprovement in a racially/ethnically diverse population.

DESIGN, SETTING, AND PARTICIPANTS This retrospective comparative effectiveness researchstudy was conducted from March 4 to August 29, 2020, in a 5-hospital health system in theBaltimore, Maryland, and Washington, DC, area. Of 2483 individuals with confirmed severe acuterespiratory syndrome coronavirus 2 infection assessed by polymerase chain reaction, those whoreceived remdesivir were matched to infected individuals who did not receive remdesivir using time-invariant covariates (age, sex, race/ethnicity, Charlson Comorbidity Index, body mass index, anddo-not-resuscitate or do-not-intubate orders) and time-dependent covariates (ratio of peripheralblood oxygen saturation to fraction of inspired oxygen, blood pressure, pulse, temperature,respiratory rate, C-reactive protein level, complete white blood cell count, lymphocyte count,albumin level, alanine aminotransferase level, glomerular filtration rate, dimerized plasmin fragmentD [D-dimer] level, and oxygen device). An individual in the remdesivir group with k days of treatmentwas matched to a control patient who stayed in the hospital at least k days (5 days maximum) beyondthe matching day.

EXPOSURES Remdesivir treatment with or without corticosteroid administration.

MAIN OUTCOMES AND MEASURES The primary outcome was rate of clinical improvement(hospital discharge or decrease of 2 points on the World Health Organization severity score), and thesecondary outcome, mortality at 28 days. An additional outcome was clinical improvement and timeto death associated with combined remdesivir and corticosteroid treatment.

RESULTS Of 2483 consecutive admissions, 342 individuals received remdesivir, 184 of whom alsoreceived corticosteroids and 158 of whom received remdesivir alone. For these 342 patients, themedian age was 60 years (interquartile range, 46-69 years), 189 (55.3%) were men, and 276(80.7%) self-identified as non-White race/ethnicity. Remdesivir recipients had a shorter time toclinical improvement than matched controls without remdesivir treatment (median, 5.0 days[interquartile range, 4.0-8.0 days] vs 7.0 days [interquartile range, 4.0-10.0 days]; adjusted hazardratio, 1.47 [95% CI, 1.22-1.79]). Remdesivir recipients had a 28-day mortality rate of 7.7% (22 deaths)compared with 14.0% (40 deaths) among matched controls, but this difference was not statisticallysignificant in the time-to-death analysis (adjusted hazard ratio, 0.70; 95% CI, 0.38-1.28). The

(continued)

Key PointsQuestion Does time to clinical

improvement or time to death differ

among hospitalized patients treated

with vs without remdesivir (alone or

with corticosteroids) for coronavirus

disease 2019 outside of a clinical trial?

Findings In this multicenter

comparative effectiveness research

study that included 2483 consecutive

admissions with a high proportion of

non-White individuals, treatment with

remdesivir was associated with more

rapid clinical improvement than no

remdesivir receipt in propensity score–

matched controls. The addition of

corticosteroids to remdesivir was not

associated with improved time to death.

Meaning Remdesivir administration is

associated with more rapid clinical

improvement than no remdesivir receipt

among patients with coronavirus

disease 2019.

+ Supplemental content

Author affiliations and article information arelisted at the end of this article.

Open Access. This is an open access article distributed under the terms of the CC-BY License.

JAMA Network Open. 2021;4(3):e213071. doi:10.1001/jamanetworkopen.2021.3071 (Reprinted) March 24, 2021 1/14

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Abstract (continued)

addition of corticosteroids to remdesivir was not associated with a reduced hazard of death at 28days (adjusted hazard ratio, 1.94; 95% CI, 0.67-5.57).

CONCLUSIONS AND RELEVANCE In this comparative effectiveness research study of adultshospitalized with COVID-19, receipt of remdesivir was associated with faster clinical improvement ina cohort of predominantly non-White patients. Remdesivir plus corticosteroid administration didnot reduce the time to death compared with remdesivir administered alone.

JAMA Network Open. 2021;4(3):e213071. doi:10.1001/jamanetworkopen.2021.3071

Introduction

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continuesto progress, with more than 103 million global cases and more than 2.2 million deaths as of February2, 2021.1 While the world awaits the distribution of effective vaccines, a number of pharmacologicagents have been studied for treatment of coronavirus disease 2019 (COVID-19), the syndromecaused by SARS-CoV-2. Remdesivir, a nucleotide analogue prodrug with in vitro effects against abroad array of RNA viruses,2-4 has received considerable attention.3,5,6 Clinical trials assessing theeffectiveness of remdesivir have yielded conflicting results7-12; have not included a sufficient numberof patients from groups most affected by COVID-19, such as Black or Latinx individuals13; and havenot examined the coadministration of remdesivir with other drugs. The US Food and DrugAdministration (FDA) approved the use of remdesivir for the treatment of hospitalized patients withCOVID-1914 based mostly on the results of the Adaptive COVID-19 Treatment Trial (ACTT-1),11 whereasthe World Health Organization (WHO) recommended against the use of remdesivir15 based on resultsfrom the Solidarity trial.12

In addition to uncertainty about efficacy, there are concerns that the demand for remdesivir willoutpace supply, raising calls for a transparent and just distribution process.16 Black individuals andLatinx individuals have mortality rates that are 2.4 and 1.5 times as high as White individuals,respectively.17 However, only 11% to 20% of participants in remdesivir clinical trials were Blackpatients, and only 17% to 23% were Latinx patients.9,10 Because underrepresented minority groupsshoulder a disproportionate burden of morbidity and mortality from COVID-19,18 it is critical that weunderstand the effects of remdesivir in these populations.

The UK-based RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial showed thatdexamethasone administration compared with placebo led to a significant reduction in mortality rate(22.9% vs 25.7%).19 Trials examining the benefit of different corticosteroids were stopped early afterthe results of RECOVERY led to corticosteroids being considered the standard of care.20,21 Whetherthere is additional benefit from using both remdesivir and corticosteroids requires further evaluation.We used time-dependent propensity score matching to examine the association of remdesiviradministration with clinical improvement in patients admitted to our 5-hospital health system fromMarch 4 through August 29, 2020.

Methods

Study Design and ParticipantsThis comparative effectiveness study was conducted at 5 hospitals (Johns Hopkins Hospital,Baltimore, Maryland; Bayview Hospital, Baltimore, Maryland; Howard County General Hospital,Columbia, Maryland; Suburban Hospital, Bethesda, Maryland; and Sibley Hospital, Washington, DC)that comprise the Johns Hopkins Medicine System, with 2513 beds serving approximately 7 millionpersons. All patients consecutively admitted with SARS-CoV-2 infection confirmed by polymerase

JAMA Network Open | Infectious Diseases Remdesivir and Clinical Improvement in Hospitalized Patients With COVID-19




chain reaction testing from nasal, oropharyngeal, or bronchoalveolar lavage samples between March4 and August 29, 2020, were eligible. This study was conducted according to the InternationalSociety for Pharmacoeconomics and Outcomes Research (ISPOR) reporting guideline for comparativeeffectiveness research.22 The hospital institutional review boards approved this study as minimal riskand waived informed consent requirements. No one received compensation or was offered anyincentive for participating in this study.

Data CollectionThe data used were part of JH-CROWN: The COVID Precision Medicine Analytics PlatformRegistry.23,24 Some patients were included in a previous description of the cohort.24 Race andethnicity were derived from patient-reported values in the electronic health record.

Eligibility Criteria and Administration of RemdesivirThe health system remdesivir policy followed the guidance from the US FDA initial Emergency UseAuthorization.25 Patients prescribed remdesivir were required to have significant illness (oxygensaturation �94% breathing ambient air or requiring supplemental oxygen, mechanical ventilation,or extracorporeal membrane oxygenation) and have an alanine aminotransferase level less than 5times the upper reference limit. Patients who were intubated at the end of a 5-day treatment couldreceive an additional 5 days if they had not improved. Treatment was stopped if the alanineaminotransferase level increased more than 5 times the upper reference limit or if there were othersigns or symptoms of liver toxicity. Physicians were encouraged to stop remdesivir if the creatinineclearance decreased by more than 50% with no alternative explanation. Patients who received atleast 1 dose of remdesivir outside of a clinical trial were considered to have been treated withremdesivir.

OutcomesThe primary outcome of interest was time to clinical improvement from the start of remdesivir, acomposite outcome defined as discharged alive from the hospital without worsening of WHO diseaseseverity score or at least a 2-point decrease in WHO severity score during hospitalization within 28days or maximum follow-up.26 Failure of clinical improvement was censored at the last day offollow-up or 28 days, whichever came first. Death was also censored at 28 days. The secondaryoutcome was time to death from the first remdesivir treatment day. Patients who were dischargedalive were censored at 28 days to account for death and discharge being competing risks, aspreviously described.27 An additional secondary outcome was the time to clinical improvement or todeath following administration of both corticosteroids and remdesivir.

Statistical AnalysisCox proportional hazards regression models were applied to estimate the association betweenremdesivir treatment and outcomes of interest. A set of demographic characteristics, clinicalvariables (including admission hospital), and laboratory results were included in the Cox proportionalhazards regression models based on clinical interest and knowledge (Table). To account for thenonrandomized assignments of remdesivir and different timing of initial administration, we usedtime-dependent propensity score matching to create pairs of individuals, with 1 patient treated andthe other patient being the most similar patient eligible for treatment at the time of initiation.Beginning from day 0, sequential 1:1 greedy matching without replacement was conducted.Propensity scores were calculated from a time-dependent Cox proportional hazards regressionmodel using the time to first receipt of remdesivir as the outcome, in which the propensity score at agiven hospitalization day is the hazard of exposure to remdesivir treatment on that day. Analyseswere performed on the matched sets.28,29 Patients were included in matching if their admissiondates were later than the earliest admission date (April 27, 2020) among patients in the remdesivirtreatment group. In addition, a time constraint was imposed so that a patient in the remdesivir group




https://www.equator-network.org/reporting-guidelines/good-research-practices-for-comparative-effectiveness-research-defining-reporting-and-interpreting-nonrandomized-studies-of-treatment-effects-using-secondary-data-sources-the-ispor-good-research-pr/

Table. Characteristics of Patients Before and After Propensity Score Matching

Characteristic

All patientsa Propensity score–matched patientsb

All remdesivir(n = 342)

All control(n = 1957)

Absolute standardizeddifference

Matched remdesivir(n = 285)

Matched control(n = 285)


Demographic characteristics

Sex, No. (%)

Male 189 (55.3) 1004 (51.3)0.079

160 (56.1) 158 (55.4)0.014

Female 153 (44.7) 953 (48.7) 125 (43.9) 127 (44.6)

Race/ethnicity, No. (%)

Black 124 (36.3) 715 (36.5) 0.006 95 (33.3) 100 (35.1) 0.037

Latinx 114 (33.3) 519 (26.5) 0.149 98 (34.4) 86 (30.2) 0.090

White 66 (19.3) 534 (27.3) 0.190 59 (20.7) 66 (23.2) 0.059

Otherc 38 (11.1) 189 (9.7) 0.048 33 (11.6) 33 (11.6) 0

Age, median (IQR), y 60 (46-69) 60 (44-74) 0.025 60 (48-70) 62 (51-75) 0.167

BMI, median (IQR) 30.1 (25.7-36.0) 28.2 (24.1-33.2) 0.225 29.8 (25.9-34.7) 29.6 (25.4-35.0) 0.070

DNR or DNI, No. (%) 61 (17.8) 435 (22.2) 0.110 59 (20.7) 69 (24.2) 0.084

Oxygen devices, No. (%)

No supplemental oxygen 16 (4.7) 907 (46.3) 1.088 16 (5.6) 15 (5.3) 0.015

Nasal cannula or face mask 210 (61.4) 819 (41.8) 0.399 189 (66.3) 173 (60.7) 0.117

High-flow nasal cannula 60 (17.5) 79 (4.0) 0.446 38 (13.3) 50 (17.5) 0.117

Noninvasive positive-pressureventilation

5 (1.5) 34 (1.7) 0.022 5 (1.8) 5 (1.8) 0

Mechanical ventilator 51 (14.9) 105 (5.4) 0.320 37 (13.0) 39 (13.7) 0.021

Vital signs, mean (SD)

Temperature, °C 37.9 (0.9) 37.6 (0.9) 0.246 37.8 (0.8) 37.9 (0.9) 0.090

Pulse, beats/min 97.6 (18.0) 96.9 (19.5) 0.039 96.4 (19.6) 97.7 (18.7) 0.064

Systolic BP, mm Hg 109.1 (17.4) 110.1 (19.3) 0.057 106.2 (16.5) 107.6 (17.6) 0.086

Diastolic BP, mm Hg 60.9 (10.9) 61.2 (12.0) 0.025 58.7 (10.3) 58.3 (10.9) 0.040

SpO2:FIO2 ratio, mean (SD) 355.9 (115.3) 420.1 (108.6) 0.573 345.8 (108.1) 334.5 (122.6) 0.098

Laboratory results, mean (SD)

Estimated glomerular filtrationrate, mL/min/1.73 m2

81.5 (30.3) 77.4 (36.1) 0.124 85.9 (29.9) 79.7 (34.9) 0.192

C-reactive protein, mg/dL 11.1 (8.1) 8.8 (8.5) 0.285 11.5 (8.5) 12.1 (10.4) 0.055

Absolute lymphocyte count, /μL 1100 (600) 1300 (2000) 0.137 1100 (700) 1000 (600) 0.124

Platelet count, ×103/μL 215 900 (91 200) 217 200 (93 300) 0.015 233 200 (102 700) 225 300 (98 300) 0.078

White blood cell count, cells/μL 7900 (5300) 8100 (6900) 0.037 8200 (6300) 8200 (4400) 0.000

Hemoglobin, g/dL 12.6 (2) 12.2 (2.2) 0.202 12.1 (1.9) 12 (2.3) 0.053

Albumin, g/dL 3.4 (0.6) 3.5 (0.6) 0.134 3.2 (0.6) 3.1 (0.6) 0.100

Alanine aminotransferase, U/L 44.7 (36.1) 50.4 (164.1) 0.047 44.5 (38.4) 41.8 (39.9) 0.068

D-dimer, μg/mL FEU 2 (4.2) 2.1 (4.2) 0.019 2.3 (4.7) 2.2 (4.1) 0.028

Past diagnoses, No. (%)d

Hypertension 152 (44.4) 906 (46.3) 0.037 131 (46.0) 131 (46.0) 0

Coronary artery disease 92 (26.9) 599 (30.6) 0.082 82 (28.8) 107 (37.5) 0.187

Congestive heart failure 45 (13.2) 292 (14.9) 0.051 39 (13.7) 59 (20.7) 0.187

Chronic kidney disease 28 (8.2) 236 (12.1) 0.129 27 (9.5) 34 (11.9) 0.080

Diabetes 111 (32.5) 536 (27.4) 0.111 97 (34.0) 93 (32.6) 0.030

Asthma 29 (8.5) 164 (8.4) 0.004 23 (8.1) 22 (7.7) 0.013

COPD or chronic lung disease 59 (17.3) 307 (15.7) 0.042 49 (17.2) 39 (13.7) 0.097

Cancer 23 (6.7) 190 (9.7) 0.109 22 (7.7) 25 (8.8) 0.038

Liver disease 13 (3.8) 99 (5.1) 0.061 13 (4.6) 14 (4.9) 0.017

AIDS/HIV 3 (0.9) 26 (1.3) 0.043 2 (0.7) 5 (1.8) 0.096

Transplant 8 (2.3) 34 (1.7) 0.043 8 (2.8) 4 (1.4) 0.098

(continued)




with k days of treatment was matched to a patient in the control group who stayed in the hospital atleast k days (5 days maximum) beyond the matching day. The last condition avoided matches inwhich the control patient was healthy enough to be discharged soon after the matched day becausethose patients would not be similar to patients who started remdesivir (eMethods in theSupplement). Data were analyzed using R, version 3.6.2 (R Foundation for Statistical Computing).

Sensitivity AnalysesThe analyses were repeated using the same propensity score–matching method but with thefollowing conditions: (1) excluding remdesivir-treated patients who also received corticosteroids; (2)applying the ACTT-111 inclusion/exclusion criteria to select qualified patients for matching; (3)decreasing the number of days that matched controls had to remain in the hospital after the matchedday from a maximum of 5 days to either 4 or 3 days; and (4) categorizing clinical improvement usinga 1-point decrease in WHO severity score instead of a 2-point decrease.

Combination of Remdesivir With CorticosteroidsWe compared outcomes among patients who received corticosteroids plus remdesivir to patientswho received remdesivir alone. Because the sample sizes for the 2 groups were similar and exposureto corticosteroids was time variant, marginal structural Cox proportional hazards regression modelswere used to adjust for the nonrandomized administration of corticosteroids and to analyze theassociation of corticosteroids with outcomes of interest in patients who had exposure to remdesivir.The same set of time-dependent and time-invariant covariates were included in the model. Theinverse probability treatment weighting method was applied for parameter estimation27,30

(eMethods in the Supplement).

Table. Characteristics of Patients Before and After Propensity Score Matching (continued)

Characteristic

All patientsa Propensity score–matched patientsb

All remdesivir(n = 342)

All control(n = 1957)


Matched remdesivir(n = 285)

Matched control(n = 285)


Charlson Comorbidity Index,score, No. (%)

0 142 (41.5) 794 (40.6) 0.019 111 (38.9) 102 (35.8) 0.065

1-4 191 (55.8) 1089 (55.6) 0.004 166 (58.2) 176 (61.8) 0.072

≥5 9 (2.6) 74 (3.8) 0.065 8 (2.8) 7 (2.5) 0.022

Concomitant medications, No. (%)

Hydroxychloroquine 3 (0.9) 399 (20.4) 0.667 3 (1.1) 7 (2.5) 0.107

Azithromycin 153 (44.7) 706 (36.1) 0.177 121 (42.5) 124 (43.5) 0.021

Dexamethasone 157 (45.9) 155 (7.9) 0.948 132 (46.3) 46 (16.1) 0.689

Prednisone 27 (7.9) 112 (5.7) 0.086 22 (7.7) 15 (5.3) 0.100

Methylprednisolone 20 (5.8) 88 (4.5) 0.061 14 (4.9) 23 (8.1) 0.128

Hydrocortisone 12 (3.5) 62 (3.2) 0.019 10 (3.5) 15 (5.3) 0.086

Heparin 292 (85.4) 1358 (69.4) 0.389 242 (84.9) 220 (77.2) 0.198

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BP, blood pressure; COPD, chronic obstructive pulmonary disease;D-dimer, dimerized plasmin fragment D; DNI, do not intubate; DNR, do not resuscitate; FEU, fibrinogen-equivalent unit; IQR, interquartile range; SpO2:FIO2, ratio of peripheral bloodoxygen saturation to fraction of inspired oxygen.

SI conversion factors: To convert C-reactive protein to milligrams per liter, multiply by 10; lymphocyte count and white blood cell count to ×109/L, by 0.001; platelet count to ×109 perliter, by 1.0; hemoglobin to g/L, by 10.0; albumin to grams per liter, by 10; alanine aminotransferase to microkatals per liter, by 0.0167; D-dimer to nanomoles per liter, by 5.476.a Data shown are from day 0 of hospital admission.b Data shown are from the day of remdesivir treatment initiation.c Comprised non-White, non-Black, and non-Latinx patients.d Only the Charlson Comorbidity Index was used in the Cox proportional hazards models. Individual comorbidities are shown but were not used in matching.






Results

PatientsOf 2483 patients admitted to the Johns Hopkins Health System with COVID-19 between March 4 andAugust 29, 2020, 184 were excluded. The reasons for exclusion included death or hospital dischargewithin 24 hours of admission (n = 168), participation in randomized clinical trials of remdesivir(n = 12), and being treated with remdesivir at the date of censoring (n = 4) (Figure 1). Among theremaining 2299 patients, 342 (14.9%) received remdesivir. Of those receiving remdesivir, the medianage was 60 years (interquartile range [IQR], 46-69 years); 153 (44.7%) were women, and 189(55.3%) were men; and 276 (80.7%) self-identified as non-White individuals. The percentage ofpatients who stopped treatment early was 2.9%. In addition, 303 patients (88.6%) received a 5-daycourse, 33 patients (9.6%) did not complete 5 days of treatment, and 6 patients (1.8%) receivedmore than 5 days of treatment. The median time from admission to treatment initiation was 1.1 days(IQR, 0.8-2.4 days). After time-dependent propensity score matching, 285 patients (83.3%) in theremdesivir group were matched successfully and were selected for primary statistical analyses. Ofthose patients, 59 (20.7%) self-identified as being non-Latinx White, 95 (33.3%) non-Latinx Black,and 98 (34.4%) Latinx race/ethnicity. The Table shows the demographic and clinical characteristics ofremdesivir recipients and controls before (day 0) and after (day 1 of treatment) propensity scorematching.

Figure 1. Description of Patients Included in the Analysis

2483 Patients admitted to JHHS(March 4 to August 29, 2020)

2315 Patients in study

1:1 Time-dependent propensity score matching

342 Treatment patients

57 Treatment patients removedNo match

570 Propensity score–matched patientsincluded in analyses on efficacy ofremdesivir

12 ExcludedInvolved in clinical trial

4 ExcludedStill on treatment at the time of analysis

358 Received at least 1treatment of remdesivir

1957 Control patients

1117 Admitted after April 27 840 Admitted before April 27

168 ExcludedDeath or discharge within24 h after admission

JHHS indicates the Johns Hopkins Health System.




Time to Clinical ImprovementOf 570 matched individuals (285 remdesivir and 285 matched controls), 236 (82.8%) patients whoreceived remdesivir and 213 (74.7%) controls achieved clinical improvement before 28 days, with amedian time to clinical improvement of 5.0 days (IQR, 4.0-8.0 days) for remdesivir recipients and 7.0days (IQR, 4.0-10.0 days) for controls. In Cox proportional hazards regression models, remdesivirtreatment was associated with significantly shortened time to clinical improvement (adjusted hazardratio [aHR], 1.47 [95% CI, 1.22-1.79]) (Figure 2A). Patients treated with remdesivir and breathingambient air or nasal cannula oxygen reached clinical improvement faster than matched controls(median, 5 days [IQR, 4.0-7.0 days] vs 6 days [IQR, 4.0-9.0 days]; aHR, 1.41 [95% CI, 1.12-1.79]); thosewith severe disease (requiring higher levels of respiratory support) also benefitted in the time toclinical improvement from remdesivir treatment (median, 8.0 days [IQR, 6.0-13.0 days] vs 9.0 days[IQR, 5.5-16.0 days]; aHR, 1.59 [95% CI, 1.02-2.49]) (Figure 2B and C).

Time to DeathRemdesivir recipients had a 28-day mortality rate of 7.7% (22 deaths) compared with 14.0% (40deaths) for matched controls, but this difference was not statistically significant in the time-to-deathanalysis (aHR, 0.70; 95% CI, 0.38-1.28) (Figure 3A). The median time to death was 8.6 days (IQR,

Figure 2. Time to Clinical Improvement

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aHR, 1.41; 95% CI, 1.12-1.79

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aHR, 1.42; 95% CI, 1.15-1.74

+

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Cumulative incidence curves for time to clinical improvement are shown for the entire remdesivir and matched control cohort (A); patients with severe disease (requiring high-flownasal cannula, noninvasive ventilation, mechanical ventilation, extracorporeal membrane oxygenation, or vasopressors) (B); patients with mild to moderate disease (on ambient air ornasal cannula oxygen) (C); and patients who would have met Adaptive COVID-19 Treatment Trial 1 (ACTT-1) study criteria (D). aHR indicates adjusted hazard ratio.




6.1-14.2 days) for remdesivir recipients and 8.2 days (IQR, 4.8-13.8 days) for controls. There was nosignificant mortality benefit associated with remdesivir treatment for patients with mild to moderatedisease (aHR, 0.27; 95% CI, 0.06-1.27) or for patients with severe disease (aHR, 0.78; 95% CI, 0.33-1.84) (Figure 3B and C).

Sensitivity AnalysesWe considered only 306 remdesivir recipients who met inclusion criteria for ACTT-1 for the sensitivityanalysis (eFigure 1 in the Supplement). Of them, 252 (82.4%) were successfully matched with controlpatients who also satisfied the criteria (eTable 1 in the Supplement). The median time to clinicalimprovement was 5.0 days (IQR, 4.0-8.0 days) for remdesivir recipients and 6.0 days (IQR, 4.0-10.0days) for matched controls; remdesivir administration was associated with shortened time to clinicalimprovement (aHR, 1.42; 95% CI, 1.15-1.74) (Figure 2D). The mortality rate at 28 days was 6.3% (16deaths) in the remdesivir group vs 13.1% (33 deaths) in controls, but this difference was notstatistically significant (aHR, 0.51; 95% CI, 0.25-1.04) (Figure 3D). The median time to death was 9.1days (IQR, 6.9-17.8 days) and 9.6 days (IQR, 6.7-14.7 days) for remdesivir recipients and controlpatients.

Figure 3. Patient Survival

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Kaplan-Meier survival curves are shown for the entire remdesivir and matched control cohort (A); patients with severe disease (requiring high-flow nasal cannula, noninvasiveventilation, mechanical ventilation, extracorporeal membrane oxygenation, or vasopressors) (B); patients with mild to moderate disease (on ambient air or nasal cannula oxygen) (C);and patients who would have met Adaptive COVID-19 Treatment Trial 1 (ACTT-1) study criteria (D). aHR indicates adjusted hazard ratio.






The results were sensitive to the requirement that controls be selected from among patientswho remained hospitalized for the same duration of treatment as their matched counterpart (up to 5days). Although remdesivir administration was still associated with a significant decrease in the timeto clinical improvement if the requirement was reduced to 4 days (aHR, 1.25; 95% CI, 1.03-1.50), theestimated aHR decreased to 1.07 (95% CI, 0.89-1.28) if the required period of hospitalization waslowered to 3 days or less. This finding occurred because 87 patients in the control group had theirevent within 4 days of matching (78 discharged from the hospital, and 9 improved) compared with26 patients in the treatment group (23 discharged, and 3 improved).

We repeated the time-to-improvement analyses using a 1-point improvement in the WHOseverity score, and the results did not appreciably change (eMethods in the Supplement). Weexcluded 184 patients who received remdesivir plus corticosteroids (and their matched controls)from our initial analyses. Remdesivir alone still had a significant association with time to clinicalimprovement (aHR, 1.94; 95% CI, 1.44-2.63) (Figure 4A) and no significant association with mortality(aHR, 1.13; 95% CI, 0.39-3.29) (Figure 4C). These results remained unchanged if we only removedpatients who received dexamethasone from the analysis (time to clinical improvement: aHR, 1.71[95% CI, 1.30-2.26]; time to death: aHR, 1.32 [95% CI, 0.51-3.41]).

Figure 4. Clinical Improvement, Mortality, and Survival Rates by Receipt of Remdesivir Alone or Plus Corticosteroids

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A, Time to clinical improvement for patients who received remdesivir, excluding patients who also received corticosteroids. B, Adjusted cumulative improvement curve for patientswho received remdesivir plus corticosteroids vs those who received remdesivir alone, adjusted using marginal structural Cox models. C, Kaplan-Meier survival curves for patients whoreceived remdesivir, excluding patients who also received corticosteroids. D, Adjusted survival curve for patients who received remdesivir plus corticosteroids vs those who receivedremdesivir alone, adjusted using marginal structural Cox proportional hazards regression models. aHR indicates adjusted hazard ratio.





Combination of Remdesivir With CorticosteroidsWe compared 184 patients who received remdesivir plus corticosteroids with 158 patients whoreceived remdesivir alone (eTable 2 and eFigure 2 in the Supplement). Combination therapy wasassociated with longer time to clinical improvement in the marginal structural Cox proportionalhazards regression model (aHR, 0.77; 95% CI, 0.62-0.97) (Figure 4B). Unadjusted 28-day mortalityrates were similar (15 deaths [8.2%] for the combination vs 10 deaths [6.3%] for remdesivir alone)(eTable 2 in the Supplement). The median time to death was increased for patients who receivedcombination therapy (15.0 days; IQR, 9.0-21.0 days) compared with remdesivir alone (6.5 days; IQR,6.0-7.8 days). A marginal structural Cox proportional hazards regression model did not show asignificant reduction in the hazard of death for patients who received remdesivir and corticosteroidscompared with remdesivir alone (aHR, 1.94; 95% CI, 0.67-5.57) (Figure 4D). In total, 68 individuals(37%) in the remdesivir and corticosteroid group had severe disease compared with 41 individuals(26%) in the remdesivir group. The sample sizes were too small to evaluate whether combinedtherapy was associated with benefits for patients with severe disease. If the analysis was restrictedto only patients who received dexamethasone as the corticosteroid, the combination ofdexamethasone and remdesivir was not associated with reduced mortality compared withremdesivir alone (aHR, 1.47; 95% CI, 0.46-4.67).

Reasons for Stopping Remdesivir EarlyOf 33 patients (9.6%) who did not complete at least 5 days of remdesivir administration, 21 weredischarged from the hospital, and 2 died before completing treatment. For the remaining patients,treatment was stopped for the following reasons: increased levels of liver enzyme or bilirubin (n = 4),kidney failure of unclear cause (n = 2), nausea (n = 1), epistaxis and tachycardia (n = 1), neck andmouth itching (n = 1), and transition to comfort care (n = 1). The incidence of liver enzyme levelsabove 200 U/L (ie, alanine aminotransferase or aspartate aminotransferase; to convert tomicrokatals per liter, multiply by 0.0167), bilirubin levels above 2 mg/dL (to convert to micromolesper liter, multiply by 17.104), and estimated glomerular filtration rate less than 30 mL/min/1.73 m2 areshown in eTable 3 in the Supplement.

Discussion

Optimal implementation of therapeutics to decrease COVID-19 morbidity and mortality is a globalpriority. Remdesivir has been the subject of controversy since ACTT-1, sponsored by the NationalInstitutes of Health, showed a shortened time to clinical improvement, but the larger Solidarity study,sponsored by the WHO, did not show a mortality benefit. Although the results of Solidarity likelyindicate that remdesivir alone does not have a robust mortality benefit for patients with COVID-19,remdesivir may still have an important role to play in reducing duration and severity of illness, bothimportant outcomes when hospitals are overwhelmed with patients having COVID-19.31 In ourretrospective multicenter study, receipt of remdesivir was associated with a significantly shorter timeto clinical improvement. The mortality rate was lower in the remdesivir group, but the results werenot statistically significant. The magnitude and direction of these associations were similar to thoseshown in ACTT-1.32

Our study included a much higher percentage of patients from underrepresented minoritygroups than previous remdesivir clinical trials. Approximately 80% of patients in our cohort werenon-White individuals compared with 30% to 47% in clinical trials.9,10,32 Because underrepresentedminority groups have shouldered a disproportionate burden during the COVID-19 pandemic but havenot been widely represented in clinical trials,13 our results provide important evidence that receiptof remdesivir is associated with decreased time to clinical improvement in these populations.

The vast majority of patients in the remdesivir group received 5 days of therapy, which supportsrecommendations for an initial 5-day course for most patients. Although ACTT-1 used a 10-daytreatment course, a comparison of 5 days vs 10 days showed similar efficacy,9 and an open-label







study found that a 5-day course, but not a 10-day course, was associated with a significantimprovement in disease severity.10 Our finding that a 5-day treatment course was associated with aclinical benefit is important, particularly given reports of both US and global shortages of remdesivirand the potential for even greater supply constraints moving forward.33

Our cohort included several groups of individuals who were not eligible to receive remdesivir inprior clinical trials, including 9 patients who were pregnant, 2 patients who were younger than 18years, and 16 patients who showed evidence of chronic kidney disease at baseline. Inclusion of thesepatients was not associated with an increased incidence of significant adverse effects as evidencedby the small percentage of patients in our cohort who stopped treatment early (2.9%) comparedwith ACTT-1 (9%).

We also took into account the increased use of dexamethasone (and corticosteroids in general)after the RECOVERY trial.19 Removing patients who also received corticosteroids did not appreciablychange the overall association of remdesivir with time to clinical improvement.

Although there was no significant reduction in the hazard of death for patients who receivedboth remdesivir and corticosteroids, our low baseline mortality rate (6.3% for remdesivir-onlypatients) compared with the RECOVERY trial (26% for controls)19 and small numbers of events mayhave prevented us from detecting a benefit. The increased median time to death and the highernumber of severely ill patients in the combination group suggest that the combination group wasmore severely ill and may have derived some benefit from the addition of corticosteroids that wasnot accounted for in the marginal structural model.

In ACTT-1, patients breathing ambient air or nasal cannula oxygen benefitted from treatmentwith remdesivir, whereas patients receiving higher levels of respiratory support, such as mechanicalventilation, did not benefit.32 Although our study showed a significant association of remdesivir withtime to clinical improvement in both groups, the 95% CI in the severely ill group approached 1,suggesting perhaps a more robust benefit for patients with mild to moderate disease. By contrast,the RECOVERY trial showed that only patients receiving supplemental oxygen or additionalrespiratory support benefitted from dexamethasone, whereas patients breathing ambient air didnot.19 Although ACTT-4 will provide some insight into the effectiveness of remdesivir combined withdexamethasone, the comparator group will be remdesivir in combination with baricitinib, and theresults will not be available for several months.34 The combination of corticosteroids and remdesivirin specific target populations and the timing of coadministration warrant additional study.

LimitationsOur study has limitations. The time-dependent propensity score method produced matched sets inwhich patients were very similar on measured confounders. However, there could be unmeasuredvariables that biased our treatment effect estimates. It is possible that there was a secular trend inthe quality of COVID-19 patient care as our health system gained experience; thus, we limited ourmatched control group to the period when remdesivir was available. We required controls to remainhospitalized for the same amount of time as patients who received remdesivir treatment, notexceeding 5 days. This criterion was a prespecified analysis design to avoid bias from matchingcontrols with different disease severity that could not be controlled for by the measurementconfounders. However, our findings were sensitive to this restriction being reduced to 3 or fewerdays. This protocol is consistent with ACTT-1, which excluded patients expected to be dischargedfrom the hospital within 3 days of randomization.32 Among the unmatched control patients, 596experienced their outcome within 5 days of admission, with 578 (97%) being discharged from thehospital. The matching assignment is therefore unlikely to bias the results toward the null hypothesis.We were likely underpowered to detect a mortality difference between patients receiving remdesivirand matched controls. There was a trend toward a reduction in mortality associated with remdesiviradministration that was similar in magnitude to that shown in ACTT-1, but neither study resultreached statistical significance.




Conclusions

This study suggests that remdesivir was associated with a significant decrease in the time to clinicalrecovery among patients admitted to the hospital for treatment of COVID-19. These results providefurther evidence that remdesivir may be effective in reducing the duration of COVID-19 illness, thata 5-day treatment course may be sufficient, and that patients with milder disease likely benefit most.The inclusion of a larger proportion of patients from underrepresented minority groups providesmuch-needed evidence suggesting the effectiveness of remdesivir administration in these groups.The combination of remdesivir and corticosteroids was not associated with reduced mortality,suggesting that additional studies assessing patients with COVID-19 are warranted.

ARTICLE INFORMATIONAccepted for Publication: February 4, 2021.

Published: March 24, 2021. doi:10.1001/jamanetworkopen.2021.3071

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Garibaldi BTet al. JAMA Network Open.

Corresponding Author: Brian T. Garibaldi, MD, MEHP, Division of Pulmonary and Critical Care Medicine, JohnsHopkins University School of Medicine, 1830 E Monument St, Fifth Floor, Baltimore, MD 21205 ([email protected]).

Author Affiliations: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School ofMedicine, Baltimore, Maryland (Garibaldi); Department of Applied Mathematics and Statistics, Johns HopkinsUniversity, Baltimore, Maryland (K. Wang, Xu); Division of Infectious Disease, Johns Hopkins University School ofMedicine, Baltimore, Maryland (Robinson, Gupta, Bollinger); Division of Biostatistics, Johns Hopkins BloombergSchool of Public Health, Baltimore, Maryland (Zeger, Bandeen-Roche, M.-C. Wang); Center for Drug Safety andEffectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Alexander); Division ofBiostatistics and Bioinformatics at The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins UniversitySchool of Medicine, Baltimore, Maryland (Xu).

Author Contributions: Dr Garibaldi and Mr. K. Wang contributed equally to this article and are considered co–firstauthors. Dr Garibaldi had full access to all of the data in the study and takes responsibility for the integrity of thedata and the accuracy of the data analysis.

Concept and design: Garibaldi, K. Wang, Robinson, Zeger, Bandeen-Roche, Gupta, Bollinger, Xu.

Acquisition, analysis, or interpretation of data: Garibaldi, K. Wang, Robinson, Zeger, M.-C. Wang, Alexander, Gupta,Bollinger, Xu.

Drafting of the manuscript: Garibaldi, K. Wang, Xu.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Garibaldi, K. Wang, Robinson, Zeger, Bandeen-Roche, M.-C. Wang, Xu.

Obtained funding: Garibaldi.

Administrative, technical, or material support: Garibaldi, Robinson, Gupta, Bollinger.

Supervision: Garibaldi.

Conflict of Interest Disclosures: Dr Garibaldi reported receiving personal fees from Janssen Research andDevelopment LLC and from the US Food and Drug Administration (FDA) Pulmonary-Asthma Drug AdvisoryCommittee outside the submitted work. Dr Bandeen-Roche reported receiving grants from the National Institutesof Health (NIH) during the conduct of the study. Dr Alexander reported being a past Chair of the US FDA Peripheraland Central Nervous System Advisory Committee; being a co-founding principal and equity holder in MonumentAnalytics; and receiving personal fees from IQVIA and OptumRx. Dr Gupta reported receiving grants from the NIHoutside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by funding from John Hopkins inHealth, the Johns Hopkins PrecisionMedicine initiative through JH-CROWN, and the coronavirus disease 2019 (COVID-19) Administrative Supplementfor the US Departmentof Health and Human Services (HHS) Region 3 Treatment Center from the Office of theAssistant Secretary for Preparedness and Response (to Drs Garibaldi, Robinson, Gupta, and Xu and Mr K. Wang).





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mailto:[email protected]

mailto:[email protected]

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; anddecision to submit the manuscript for publication.

Additional Contributions: The authors thank the Johns Hopkins Health System and its surrounding communitiesfor working together to provide outstanding patient care and to keep one another safe during theseextraordinary times.

Additional Information: The data used for this publication were part of JH-CROWN: The COVID PrecisionMedicine Analytics Platform (PMAP) Registry, which is based on contributions from many patients and clinicians.

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SUPPLEMENT.eMethods.eFigure 1. Exclusion Details Under ACTT-1 CriteriaeFigure 2. Timing of Remdesivir and Corticosteroid CoadministrationeTable 1. Characteristics of Patients That Satisfied ACTT-1 Criteria, Before and After Propensity Score MatchingeTable 2. Characteristics of Remdesivir Patients Stratified by Corticosteroid UseeTable 3. Adverse EventseReferences.





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