Note: Most studies of COVID-19 use AZM with HCQ.
- Mycobacterial (nontuberculous) infection
- STIs and various bacterial infections1
- Induction of IFN-stimulated genes, attenuating viral replication2
- Enhanced neutrophil activation3
- Attenuation of inflammatory cytokines (IL-6 and IL-8) in epithelial cells and inhibition of fibroblast growth factor in airway smooth muscle cells2
- AZM has primarily been studied for the treatment of COVID-19 in combination with HCQ. The RECOVERY trial includes an AZM monotherapy arm, which is currently enrolling
Please see the description of the combination therapy study results in the Hydroxychloroquine Plus Azithromycin section below and in Hydroxychloroquine Plus Azithromycin.
- Extra-intestinal amebiasis
- Increases endosomal pH, inhibiting fusion of SARS-CoV-2 and the host cell membranes4
- Inhibits glycosylation of the cellular ACE2 receptor, which may interfere with binding of SARS-CoV to the cell receptor5
- Immunomodulatory effects
High-Dose vs. Low-Dose CQ:7
- A randomized, double-blind, Phase 2b study compared two different CQ regimens, CQ 600 mg twice daily for 10 days (high dose) vs. CQ 450 mg twice daily for 1 day followed by 450 mg for 4 days (low dose), in hospitalized adults with suspected cases of severe COVID-19 (respiratory rate >24 breaths/min, heart rate >125 bpm, oxygen saturation <90%, and/or shock). All patients received ceftriaxone plus AZM; 89.6% of patients received oseltamivir. Of note, both AZM and oseltamivir can increase the QTc interval.
- The primary outcome for this analysis was mortality at 13 days after treatment initiation. The planned study sample size was 440 participants, which was sufficient to show a reduction in mortality by 50% with high-dose CQ. The study was stopped by the study’s DSMB after 81 patients were enrolled.
- 41 and 40 patients were randomized into the high-dose and low-dose CQ arms, respectively.
- The overall fatality rate was 27.2%.
- Mortality by Day 13 was higher in the high-dose arm than in the low-dose arm (death occurred in 16 of 41 patients [39%] vs. in 6 of 40 patients [15%], respectively; P = 0.03). This difference was no longer significant when controlled by age (OR 2.8: 95% CI, 0.9–8.5).
- Overall, QTcF >500 ms occurred more frequently among patients in the high-dose arm (18.9% of patients) than in the low-dose arm (11.1% of patients). Among those with confirmed COVID-19, QTcF >500 ms was also more frequent in the high-dose arm (24.1% of patients) than in the low-dose arm (3.6% of patients).
- 2 patients in the high-dose arm experienced ventricular tachycardia before death.
- Limitations: More older patients and more patients with history of heart disease were randomized to the high-dose arm than to the low-dose arm.
- Interpretation: Despite the small number of patients enrolled, this study raises concerns about an increased risk of mortality when high-dose CQ (600 mg twice daily) is administered in combination with AZM and oseltamivir.
CQ vs. LPV/r:8
- In a small randomized controlled trial in China, 22 hospitalized patients with COVID-19 (none critically ill) were randomized to receive oral CQ 500 mg twice daily or LPV/r 400 mg/100 mg twice daily for 10 days. Patients with a history of heart disease (chronic disease and a history of arrhythmia), or kidney, liver, or hematologic diseases were excluded from participation. The primary study outcome was a neagative SARS-CoV-2 PCR test result at Days 10 and 14. Secondary outcomes included improvement of lung CT scan at Days 10 and 14, discharge at Day 14, and clinical recovery at Day 10, as well as safety (which was determined by evaluating study drug-related AEs).
- Ten patients received CQ and 12 patients received LPV/r. At baseline, patients had good SpO2 levels (97% to 98%).
- Compared to the LPV/r-treated patients, the CQ-treated patients had a shorter duration from symptom onset to initiation of treatment (2.5 days vs. 6.5 days, P < 0.001).
- Though not statistically significant, patients in the chloroquine arm were younger (median age 41.5 years vs. 53.0 years; P = 0.09). Few patients had comorbidities.
- At Day 10, 90% of the CQ-treated patients and 75% of the LPV/r-treated patients had a negative SARS-CoV-2 PCR test result. At Day 14, the percentages for the CQ-treated patients and the LPV/r-treated patients were 100% and 91.2%, respectively.
- At Day 10, 20% of the CQ-treated patients and 8.3% of the LPV/r-treated patients had CT scan improvement. At Day 14, the percentages for the CQ-treated patients and the LPV/r-treated patients were 100% and 75%, respectively.
- At Day 14, 100% of the CQ-treated patients and 50% of the LPV/r-treated patients were discharged from the hospital.
- The risk ratios of these outcome data cross 1, and the results were not statistically significant.
- Both drugs were generally well-tolerated.
- The trial sample size was very small, and the participants were fairly young.
- The CQ-treated patients were younger and had fewer symptoms prior to treatment initiation; these variables that could have affected the study protocol-defined outcomes.
- Patients who had chronic comorbidities and who were critically ill were excluded from the study.
- Interpretation: In this small randomized controlled trial, CQ and LPV/r showed similar efficacy in treating COVID-19.
- Lupus erythematosus
- Rheumatoid arthritis9
- Increases the endosomal pH, inhibiting fusion of SARS-CoV-2 and the host cell membranes4
- May block the transport of SARS-CoV-2 from early endosomes to endolysosomes in vitro, which may be required to release the viral genome6
- Immunomodulatory effects
New York Department of Health Study on HCQ With or Without AZM:
A retrospective, multicenter, observational study in New York evaluated the use of HCQ with and without AZM in a random sample of 1,438 inpatients with COVID-19. Patients were categorized into 4 treatment groups: HCQ plus AZM, HCQ alone, AZM alone, or neither drug. The primary outcome measure was in-hospital mortality, and the secondary outcome measure was cardiac arrest and arrhythmia or QT prolongation on an ECG.
- Patients in the 3 treatment groups had more severe disease at baseline than those who received neither drug.
- In adjusted analyses, patients who received 1 of the 3 treatment regimens did not show a decreased in-hospital mortality rate when compared with those who received neither drug.
- Patients who received HCQ plus AZM had a greater risk of cardiac arrest than patients who received neither drug (OR 2.13; 95% CI, 1.12–4.05).
Despite the large size of this study, it suffers from the inherent limitations of an observational study. These include residual confounding from confounding variables that were unrecognized and/or unavailable for analysis.
Despite the limitations discussed above, these findings suggest that although HCQ and AZM are not associated with an increased risk of in-hospital death, the combination of HCQ and AZM may be associated with an increased risk of cardiac arrest.
Observational Study of HCQ at a Large Medical Center in New York City:10
- This observational study evaluated 1,376 consecutive adults with COVID-19 who were admitted to a large New York City hospital (after excluding 70 patients who died or who were transferred within 24 hours after presenting to the emergency department). The study assessed the time from study baseline (24 hours after patients arrived at the emergency department) to intubation or death based on whether the patient received HCQ at baseline or during follow-up. Patients who received HCQ were prescribed a twice-daily dose of HCQ 600 mg on the first day and 400 mg daily for 4 additional days; this was based on the clinical guidance of the hospital.
- 811 patients (58.5%) received HCQ and 565 (41.1%) did not.
- Patients who received HCQ were older and more likely to have hypertension (49.1% vs. 6.7%) and to be on systemic steroids (26.6% vs. 10.1%) than those who did not receive HCQ.
- Patients who received HCQ were more likely to receive concomitant AZM (59.9% vs. 22.5%) and/or other antibiotics (74.5% vs. 54.0%) than those who did not receive HCQ.
- Patients who received HCQ had higher levels of inflammatory markers.
- HCQ-treated patients had more severe hypoxia, with a lower PaO2/FiO2 ratio at baseline than patients who did not receive HCQ (median of 233 mm Hg vs. 360 mm Hg).
Most patients (85.9%) received HCQ within 48 hours of presentation.
Using propensity scores to adjust for major predictors of respiratory failure and inverse probability weighting, the study demonstrated that HCQ use was not associated with intubation or death (HR 1.04; 95% CI, 0.82–1.32).
There was also no association between concomitant use of AZM and the composite endpoint of intubation or death (HR 1.03; 95% CI, 0.81–1.31).
- Despite the large size of this study, it suffers from the inherent limitations of an observational study. These include residual confounding from confounding variables that were unrecognized and/or unavailable for analysis.
- The use of HCQ for treatment of COVID-19 was not associated with harm or benefit in a large observational study.
Retrospective Observational Cohort from the United States Veterans Health Administration
This study has not been peer reviewed11
- An observational, retrospective cohort study analyzed data from patients with confirmed COVID-19 who were hospitalized at the United States Veterans Health Administration medical centers between March 9–April 11, 2020. Patients were categorized as having received either HCQ, HCQ plus AZM, or no HCQ. Doses and duration of HCQ or AZM use were not specified. All patients also received standard supportive management for COVID-19. The primary endpoints were death and the need for mechanical ventilation. Associations between treatment and outcomes were determined using propensity score adjustment, including demographic data, comorbidity data, and clinical data (including predictors of COVID-19 disease severity). Patients were included in the analysis if BMI, vital signs, and discharge disposition were noted in their medical records.
- 368 patients were eligible for analysis. These patients were categorized into 3 treatment groups: HCQ (n = 97), HCQ plus AZM (n = 113), or no HCQ (n = 158). The median ages for the patients in each group were 70, 68, and 69 years, respectively. All patients were male.
- 70 patients died; 35 of those who died (50%) were not receiving mechanical ventilation.
- No difference was observed between the groups in the risk of mechanical ventilation.
- The risk of death from any cause was higher in the HCQ group than in the no HCQ group (adjusted HR 2.61; 95% CI, 1.10–6.17; P = 0.03). The no HCQ group and the HCQ plus AZM group had similar risks of death from any cause (adjusted HR 1.14; 95% CI, 0.56–2.32, P = 0.72).
- There was no between-group difference in the risk of death after ventilation.
- The patient population was entirely male.
- The dose and duration of administration for HCQ and AZM were not included in the report. Patients were included if they received a single dose of either or both drugs.
- Propensity score adjustment was used to account for differences between the groups, however the possibility of residual confounding cannot be excluded, as patients who were more ill may have been more likely to receive HCQ.
- No imaging data were presented; the severity of chest X-ray findings could predict worse outcomes.
- The use of other antiviral or immunomodulatory agents were not reported.
- The reason for the high mortality rate among patients who did not receive mechanical ventilation is not clear, especially as most of these patients appear to have had mild or moderate disease at admission.
- Interpretation: This study showed no beneficial effect of HCQ plus AZM for the treatment of COVID-19 and a possible association between the use of HCQ and an increased risk of mortality; however, residual confounding may have affected the study results.
Randomized, Controlled Trial of HCQ vs. SOC for Mild or Moderate COVID-19:12
- This multicenter, randomized, open-label trial compared HCQ 1,200 mg once daily for 3 days followed by HCQ 800 mg once daily for the rest of the treatment duration (2 weeks for patients with mild or moderate COVID-19 [99% of the patients] and 3 weeks for 2 patients with severe disease) and SOC.
- The primary outcome was a negative PCR test result within 28 days. Secondary outcomes were alleviation of symptoms (resolution of fever, SpO2 >94% on room air, resolution of respiratory symptoms), improvement in markers of inflammation (including CRP levels), and improvement of lung lesions on a chest X-ray within 28 days.
- 75 patients were enrolled in each study arm. Patients were randomized at a mean of 16.6 days after symptom onset.
- The HCQ arm and the SOC arm had similar negative PCR conversion rates within 28 days (85.4% of participants vs. 81.3% of participants, respectively) and similar times to negative PCR conversion (median of 8 days vs. 7 days, respectively).
- There was no difference in the probability of symptom alleviation between the groups in the intention-to-treat analysis.
- AEs occurred in 30% of the participants in the HCQ arm (most commonly diarrhea) and in 9% of the participants in the SOC arm.
- It is unclear how the overall rate of symptom alleviation was calculated.
- The duration of HCQ use (2 weeks) was longer than in most other observational cohort studies or clinical trials for the treatment of COVID-19.
- The study did not reach the target sample size.
- Interpretation: This study demonstrated no difference in viral clearance between HCQ and SOC.
Observational Cohort of HCQ vs. No HCQ:13
- This observational, retrospective cohort study analyzed data for adult patients who were hospitalized for COVID-19 pneumonia at 4 French tertiary care centers over a 2-week period (March 17–31, 2020). Patients aged 18 to 80 years were eligible if they had PCR-confirmed SARS-CoV-2 infection and required oxygen by mask or nasal cannula. Exclusion criteria included HCQ initiation before hospitalization, receipt of another experimental COVID-19 treatment within 48 hours, organ failure that required immediate admission to the ICU or continuous care unit, admission with ARDS that required noninvasive ventilation with continuous positive airway pressure or mechanical ventilation, discharge from the ICU to standard care, or if a decision was made to limit or stop active treatments prescribed at admission. Patients in 1 treatment arm received a daily dose of HCQ 600 mg within 48 hours of admission; patients in the other arm did not receive HCQ during the same period. The decision to use HCQ to treat a patient was based on local medical consensus and prescriber opinion and was reportedly independent of patient characteristics. Patients were followed from baseline until death, loss to follow-up, or the end of the follow-up period on April 24, 2020. The primary outcome was survival without transfer to the ICU at Day 21. An inverse probability of treatment weighting approach was used to “emulate” randomization.
- Of the 181 patients who were eligible for the analysis, 84 participants received HCQ within 48 hours, 8 received HCQ beyond 48 hours, and 89 participants did not receive HCQ.
- Comorbidities were less common in the HCQ group; overall initial COVID-19 severity was well balanced across the treatment arms.
- In the HCQ group, 18% of the patients received concomitant AZM and 52% of the patients received amoxicillin/clavulanic acid.
- In the inverse probability of treatment weighted analysis, there was no difference in the primary outcome (survival rates without ICU transfer at Day 21) between the HCQ group (76% of participants) and the non-HCQ group (75% of participants). Similarly, there was no difference between the groups in the secondary outcomes of survival rate and survival rate without ARDS at Day 21.
- Among the 84 patients who received HCQ within 48 hours, 8 patients (10%) experienced ECG changes that required treatment discontinuation at a median of 4 days from the start of dosing, including 7 patients with a QTc that prolonged >60 ms and 1 patient with new onset, first-degree AV block. None of these patients received AZM.
- Limitations: This was a retrospective, nonrandomized study.
- Interpretation: In this retrospective study, there was no difference in the rates of clinically important outcomes between patients who received HCQ within 48 hours of hospital admission and those who did not.
A Case Series of HCQ vs. Control:14
- In a case series from France, 26 hospitalized adults with either asymptomatic SARS-CoV-2 infection or upper or lower respiratory tract infection received HCQ 200 mg 3 times daily for 10 days. These patients were compared to 16 control individuals (i.e., those who refused treatment, did not meet eligibility criteria, or were from a different clinic).
- 6 patients in the HCQ group were excluded from the analysis for the following reasons:
- 1 patient died,
- 3 patients were transferred to the ICU,
- 1 patient stopped the study drug due to nausea, and
- 1 patient withdrew from the study.
- 6 patients also received AZM.
- By Day 6, NP PCRs were negative in 14 of 20 HCQ-treated patients (70%) and 2 of 16 controls (12.5%).
- Among the HCQ patients, 8 of 14 (57.1%) who received only HCQ and 6 of 6 (100%) who received HCQ and AZM had negative NP PCRs by Day 6.
- Clinical outcomes for all patients were not reported for all patients.
- The sample size of the series is small.
- The criteria for enrollment of cases and controls is unclear.
- Asymptomatic individuals were enrolled.
- Exclusion of 6 HCQ-treated patients includes 1 death and 3 ICU transfers.
- No clinical outcomes were reported; thus, the clinical significance of a negative PCR is unknown.
- The reason for the addition of AZM for some patients is unclear.
- Interpretation: Methodologic problems with this case series limit the ability to draw conclusions regarding the efficacy of HCQ with or without AZM.
|Hydroxychloroquine Plus Azithromycin
||See the Azithromycin and Hydroxychloroquine sections above.
||See the Azithromycin and Hydroxychloroquine sections above.
Case Series of HCQ Plus AZM:15
- In a case series of 80 hospitalized patients with COVID-19 (including 6 patients from a previous study),14 patients were treated with HCQ 200 mg 3 times daily for 10 days plus AZM 500 mg for once daily for 1 day followed by AZM 250 mg once daily for 4 days. Mean time from symptom onset to treatment was about 5 days. The outcomes that were evaluated included the need for oxygen therapy or ICU transfer after ≥3 days of therapy, SARS-CoV-2 level as determined by PCR, SARS-CoV-2 culture (in a subset of patients; a convenience sample), and length of stay in the infectious diseases ward.
- 1 patient died (1.2%), 3 required ICU transfer (3.8%), and 12 required oxygen therapy (15%).
- 65 patients (81.2%) were discharged to their homes or transferred to other units for continuing treatment; 14 patients (17.4%) remained hospitalized at the time the study results were published.
- SARS-CoV-2 NP PCR was negative in 83% of patients by Day 7 and in 93% of patients by Day 8.
- In the subset of patients who had respiratory sample viral cultures performed at Day 5, results were negative for 97.5% of the samples.
- The trial lacked a control group, which is particularly important because many people with mild disease improve in the absence of treatment.
The trial lacked complete or longer-term follow-up.
- Interpretation: The multiple issues with trial design and the lack of a control group limit the usefulness of this study for informing recommendations.
Small Prospective Case Series of HCQ Plus AZM:16
- A prospective case series from France assessed 11 consecutive hospitalized patients with COVID-19.
- 8 of the 11 patients had significant comorbid conditions: obesity (n = 2), solid cancer (n = 3), hematological cancer (n = 2), and HIV infection (n = 1).
- 10 of 11 patients were receiving supplemental oxygen at treatment initiation.
- All patients were treated with HCQ 600 mg once daily for 10 days and AZM 500 mg once daily for 1 day followed by AZM 250 mg once daily for 4 days.
- Within 5 days, the condition of 3 patients worsened, including 1 patient who died and 2 patients who were transferred to the ICU.
- HCQ was discontinued in 1 patient due to QTc prolongation.
- Qualitative NP PCR remained positive at Days 5 and 6 after treatment initiation in 8 of 10 patients.
- Limitations: This is a case series that included a small number of patients.
- Interpretation: In this small case series, most patients who received HCQ plus AZM did not have rapid viral clearance.
Case Series of Changes in QTc Interval in Patients Who Received HCQ Plus AZM:17
- A case series in the United States reported changes in QTc interval in 84 patients with COVID-19 who received the combination of HCQ (400 mg twice daily for 1 day, followed by 200 mg twice daily for 4 days) and AZM (500 mg once daily for 5 days).
- 84 patients were enrolled; 74% were male, with a mean age of 63 ± 15 years. 65% had HTN, mean serum creatinine was 1.4 mg/dL at baseline, 13% required vasopressors, and 11% had CAD.
- Some participants were receiving concomitant drugs that had the potential to prolong the QTc interval; 11% of participants were receiving neuropsychiatric drugs and 8% of participants were receiving levofloxacin, LPV/r, or tacrolimus.
- 4 patients died, without arrhythmia.
- The mean baseline QTc was 435 ± 24 ms and the mean maximum QTc was 463 ± 32 ms.
- The mean time to maximum QTc was 3.6 ± 1.6 days. ECG follow-up was done for a mean of 4.3 days.
- 9 patients (11%) developed QTc >500 ms; the QTc increased by 40 to 60 ms and >60 ms in 18% and 12% of patients, respectively.
- This was a descriptive case series.
- Interpretation: This case series demonstrated that HCQ plus AZM can prolong QTc and that the use of this combination warrants careful monitoring.
HIV Protease Inhibitors
Note: LPV/r and DRV/c have been studied in patients with COVID-19.
- No data on in vitro activity of LPV/r against SARS-CoV-2
- Possible inhibition of SARS-CoV-2 protease 3CLpro18
- In vitro data does not support the use of DRV/c for the treatment of COVID-1919
LPV/r Pharmacokinetics in Patients With COVID-19:
In a case series, 8 patients with COVID-19 were treated with LPV/r 400 mg/100 mg orally twice daily and had plasma trough levels of LPV drawn and assayed by liquid chromatography-tandem mass spectrometry.20
- The median plasma LPV concentration was 13.6 μg/mL.
- After correcting for protein binding, trough levels would need to be approximately 60-fold to 120-fold higher to achieve the in vitro EC50 for SARS-CoV-2.
- Only the trough levels of LPV were quantified.
- No data are available on effective LPV concentrations for SARS-CoV-2 in vivo.
- The plasma drug concentrations that were achieved using typical doses of LPV/r are far below the levels that may be needed to inhibit SARS-CoV-2.
Randomized Controlled Trial of LPV/r vs. SOC:
- In a clinical trial that randomized 199 patients to receive LPV/r 400 mg/100 mg PO twice daily for 14 days or to SOC, patients who were randomized to the LPV/r arm did not have a shorter time to clinical improvement.
- There was a lower, but not statistically significant, mortality rate for the LPV/r group (19.2%) than for the SOC group (25.0%), and a shorter ICU stay for those in the LPV/r group than those in the SOC group (6 days vs. 11 days; difference of -5 days; 95% CI, -9 to 0 days).
- The duration of hospital stays and time to clearance of viral RNA from respiratory tract samples did not differ between the LPV/r and SOC arms.
- Nausea, vomiting, and diarrhea were all more frequent in the LPV/r-treated group.
The study was powered only to show a fairly large effect.
- The study was not blinded, which may have affected the assessments of clinical improvement.
- The study was underpowered to show small effects.
- Interpretation: A moderate-sized randomized trial failed to find a virologic or clinical benefit of LPV/r over SOC.
LPV/r Plus IFN Beta-1b Plus Ribavirin for COVID-19:
- Also see Interferons for a description of this trial and its results.
- An open-label, Phase 2 clinical trial randomized 127 participants with COVID-19 2:1 to receive either a 14-day course of a combination therapy that included IFN beta-1b 8 million international units administered subcutaneously on alternating days (1–3 doses, depending on time from symptom onset) plus LPV/r 400 mg/100 mg orally every 12 hours and ribavirin 400 mg orally every 12 hours, or a 14-day course of LPV/r 400 mg/100 mg every 12 hours alone.21
- In the combination therapy group, those who were admitted <7 days after symptom onset (n = 52) received triple-drug therapy; however, IFN beta-1b was not included in the regimen for those who were admitted ≥7 days after symptom onset (n = 34) because of concerns regarding its potential for inflammatory effects. The study population consisted of patients who were hospitalized in Hong Kong; the median age was 52 years and the median time from symptom onset to enrollment was 5 days. Only 12% to 14% of participants were on supplemental oxygen, and only 1 participant was mechanically ventilated.
- Patients in the combination therapy group showed faster viral clearance and more rapid clinical improvement than those in the control group.
Participants in both arms received LPV/r, so it is impossible to determine whether LPV/r contributed to the observed treatment effects. However, the possibility that LPV/r may have contributed to the effectiveness of the combination therapy also cannot be ruled out.
- The positive clinical impact of the combination therapy was limited to those who were hospitalized <7 days from symptom onset.
- Most participants in this study had mild illness, and only slightly more than 10% were on supplemental oxygen. For this reason, the study has limited applicability to hospitalized patients in the United States.
- This study neither supports nor refutes the use of LPV/r with or without ribavirin in patients with COVID-19. See the Interferons section for further discussion.
LPV/r vs. Umifenovir vs. SOC
- In a trial of 86 hospitalized patients with mild-to-moderate COVID-19, 34 patients were randomized to receive LPV/r, 35 patients received the broad-spectrum antiviral umifenovir (trade name Arbidol; not available in the United States), and 17 patients received SOC.22
- Results (Comparison of LPV/r to SOC):
- The time to a negative SARS-CoV-2 nucleic acid pharyngeal swab was similar for patients receiving LPV/r (mean 9 days [SD 5.0]) and for those receiving SOC (mean 9.3 days [SD 5.2]).
- Progression to severe illness occurred among 6 patients (18%) in the LPV/r arm and 2 patients (12%) who received SOC.
- 2 patients became critically ill; both were randomized to receive LPV/r.
- The trial had small sample size.
- The study was not blinded.
- The effectiveness of umifenovir in treating COVID-19 is unknown.
- Interpretation: The small sample size limits the usefulness of this trial.
LPV/r vs. CQ:
- A small randomized study in China compared LPV/r to CQ. Please refer to the CQ section for the study description.
- Binds to the viral RNA-dependent RNA polymerase, inhibiting viral replication through premature termination of RNA transcription
- Has demonstrated in vitro activity against SARS-CoV-24
- In a rhesus macaque model of SARS-CoV-2 infection, RDV treatment was initiated soon after inoculation; RDV-treated animals had lower lung virus levels and less lung damage than the control animals.23
Multinational Randomized Controlled Trial of RDV vs. Placebo in Hospitalized Patients:24
- ACTT is an NIH-sponsored, multinational, randomized, double-blind placebo-controlled trial in hospitalized adults with COVID-19. Participants were randomized 1:1 to receive IV RDV or placebo for 10 days. The primary study endpoint was time to clinical recovery, which was defined as either discharge from the hospital or hospitalization for infection control purposes only. Severity of illness at baseline and at Day 15 was assessed using an ordinal scale:
- Not hospitalized, no limitations
- Not hospitalized, with limitations
- Hospitalized, no active medical problems
- Hospitalized, not on oxygen
- Hospitalized, on oxygen
- Hospitalized, on high-flow oxygen or noninvasive mechanical ventilation
- Hospitalized, on mechanical ventilation or ECMO
- Study Population: The study population consisted of hospitalized patients aged ≥18 years with laboratory-confirmed SARS-CoV-2 infection. Patients were enrolled if they met at least 1 of the following conditions:
- The patient had pulmonary infiltrates, as determined by radiographic imaging,
- SpO2 was ≤94% on room air,
- The patient required supplemental oxygen,
- The patient was on mechanical ventilation, or
- The patient was on ECMO.
- The study excluded individuals who had ALT or AST levels >5 times the ULN, those who had an eGFR <30 mL/min, and those who were pregnant or breastfeeding.
- Preliminary Results:
- Of 1,063 enrolled participants, 1,059 had preliminary results available for analysis (n = 538 for the RDV group; n = 521 for the placebo group).
- The mean age was 58.9 years; 64.3% of participants were male, 53.2% were white, and 79.8% were enrolled in North America.
- 52.1% of participants had 2 or more comorbidities; 37% were obese (mean BMI 30.6 kg/m2)
- The median time from symptom onset to randomization was 9 days (IQR 6–12 days).
- At the time of the preliminary analysis, 391 RDV recipients and 340 placebo recipients had completed the study through Day 29, recovered, or died.
- 8 RDV recipients and 9 placebo recipients terminated the study prior to Day 29.
- At the time of this preliminary analysis, 132 RDV recipients and 169 placebo recipients had not recovered and had not completed the Day 29 follow-up visit.
- RDV significantly reduced time to recovery compared to placebo (median time to recovery 11 days vs. 15 days, respectively; recovery rate ratio 1.32; 95% CI, 1.12–1.55; P < 0.001).
- Clinical improvement based on the ordinal scale was significantly higher in patients who received RDV than in those who received placebo at Day 15 (OR 1.50; 95% CI, 1.18–1.91, P < 0.001).
- The benefit of RDV on reducing time to recovery was clearest in the subgroup of hospitalized patients who required supplemental oxygenation at study enrollment (ordinal scale 5, n = 421; recovery rate ratio 1.47; 95% CI, 1.17–1.84). In a post-hoc analysis of 14-day survival, remdesivir appeared to confer a survival benefit in this subgroup (HR 0.22; 95% CI, 0.08–0.58).
- In patients who required high-flow oxygen or noninvasive ventilation at study enrollment (ordinal scale 6, n = 197), there was no observed difference between the remdesivir and placebo groups in time to recovery (recovery rate ratio 1.20; 95% CI, 0.79–1.81). In a post-hoc analysis of 14-day survival, there was no evidence that remdesivir had an impact on the mortality rate in this subgroup (HR 1.12; 95% CI, 0.53–2.38).
- Among the patients who were on mechanical ventilation or ECMO at enrollment (ordinal scale 7, n = 272), there was no observed difference between the RDV and placebo groups in time to recovery (recovery rate ratio 0.95; 95% CI, 0.64–1.42). In a post-hoc analysis of 14-day survival, there was no evidence that remdesivir had an impact on the mortality rate in this subgroup (HR 1.06; 95% CI, 0.59–1.92).
- Among the patients who were classified as having mild to moderate disease at enrollment, there was no difference in the median time to recovery between the RDV and placebo groups (n = 119; recovery rate ratio 1.09; 95% CI, 0.73–1.62). Mild to moderate disease was defined as SpO2 >94% and respiratory rate <24 breaths/min without supplemental oxygen.
- The mortality estimate by Day 14 was lower in the RDV arm than in the placebo arm (7.1% vs. 11.9%, respectively), but the difference was not statistically significant (HR 0.70; 95% CI, 0.47–1.04).
- The use of RDV was associated with shorter time to recovery regardless of the duration of symptoms prior to randomization (≤10 days vs. >10 days).
- The percentages of participants with serious AEs were similar in the RDV and placebo groups (21.1% vs. 27.0%, respectively).
- Transaminase elevations occurred in 4.1% of RDV recipients and 5.9% of placebo recipients.
- Limitations: At the time of publication, the full dataset was not available for analysis.
- Interpretation: In patients with severe COVID-19, RDV reduced the time to clinical recovery. The benefit of RDV was most apparent in hospitalized patients who required only supplemental oxygen. There was no observed benefit of RDV in those who were on high-flow oxygen, noninvasive ventilation, mechanically ventilation or ECMO, but the study was not powered to detect differences in subgroups. There was no observed benefit of RDV in patients with mild or moderate COVID-19, but the number of participants in these categories was relatively small.
Multinational Randomized Trial of Different Durations of RDV Treatment in Hospitalized Patients:25
- This was a manufacturer-sponsored, multinational, randomized, open-label trial in hospitalized adolescents and adults with COVID-19. Participants were randomized 1:1 to receive either 5 days or 10 days of IV RDV. The primary study endpoint was clinical status at Day 14, which was assessed using a 7-point ordinal scale:
- Hospitalized, on invasive mechanical ventilation or ECMO
- Hospitalized, on noninvasive ventilation or high-flow oxygen devices
- Hospitalized, requiring low-flow supplemental oxygen
- Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care for COVID-19 or for other reasons
- Hospitalized, not requiring supplemental oxygen or ongoing medical care (other than the care that was specified in the protocol for RDV administration)
- Not hospitalized
- Study Population: The study enrolled hospitalized patients aged ≥12 years with RT-PCR-confirmed SARS-CoV-2 infection and radiographic evidence of pulmonary infiltrates. Patients in this study had either SpO2 ≤94% on room air or were receiving supplemental oxygen. The study excluded patients who were receiving mechanical ventilation or ECMO or who had multiorgan failure, an ALT or AST level >5 times ULN, or an estimated CrCl <50 mL/min. Patients were also excluded if they had received an agent with putative anti-SARS-CoV-2 activity within 24 hours of starting treatment in the trial.
- Of 402 randomized participants, 397 began 5 days (n = 200) or 10 days (n = 197) of RDV treatment.
- In the 5-day group, the median age was 61 years; 60% of participants were male, and 71% were white. In the 10-day group, the median age was 62 years; 68% of participants were male, and 70% were white. The frequency of coexisting conditions was similar in both groups.
- The median time from symptom onset to first dose of RDV was 8 days in the 5-day group and 9 days in the 10-day group. The median duration of hospitalization before the first RDV dose was 2 days in both groups.
- At baseline, patients in the 10-day group had worse clinical status (based on the ordinal scale distribution) than those in the 5-day group (P = 0.02).
- A few patients were on mechanical ventilation: 4 patients (2%) were assigned to the 5-day group, and 9 patients (5%) were assigned to the 10-day group. Although mechanical ventilation was an exclusion criterion for enrollment, some patients were intubated between screening and treatment initiation; others were protocol deviations.
- 172 participants (86%) in the 5-day group completed a median of 5 days of treatment, and 86 (44%) in the 10-day group completed a median 9 days of treatment.
- 65% of patients in the 5-day group and 54% of those in the 10-day group had a 2-point improvement in clinical status on the ordinal scale.
- After adjusting for imbalances in the baseline clinical status, the Day 14 distribution in clinical status on the ordinal scale was similar in the 5-day and 10-day groups (P = 0.14)
- The time to clinical improvement of at least 2 levels on the ordinal scale (median day of 50% cumulative incidence) was similar in the 5-day and 10-day groups (10 days vs. 11 days, respectively).
- The median durations of hospitalization among patients who were discharged on or before Day 14 were similar in the 5-day group (7 days; IQR 6–10 days) and 10-day group (8 days; IQR 5–10 days).
- By Day 14, 120 patients (60%) in the 5-day group had been discharged and 16 patients (8%) had died; in the 10-day group, 103 patients (52%) had been discharged and 21 patients (11%) had died.
- Serious AEs were more common in the 10-day group (35%) than in the 5-day group (21%); 4% of patients in the 5-day group and 10% of patients in the 10-day group stopped treatment because of AEs.
- This was an open-label trial without a placebo control group, so the clinical benefit of RDV could not be assessed.
- There were baseline imbalances in the clinical statuses of participants in the 5-day and 10-day groups. At the start of the study, more patients in the 10-day group than in the 5-day group were receiving noninvasive ventilation or high-flow oxygen (30% vs. 24%, respectively), and fewer patients in the 10-day group than in the 5-day group were not receiving supplemental oxygen (11% vs. 17%, respectively).
- Interpretation: In hospitalized patients with COVID-19 who were not on mechanical ventilation or ECMO, RDV treatment for 5 or 10 days had similar clinical benefit. Because this trial only evaluated a few patients who were on mechanical ventilation, the appropriate duration of RDV treatment for critically ill patients is still unclear.
Randomized Controlled Trial of RDV vs. Placebo for Severe COVID-19 in China:26
- This was a multicenter, double-blind, randomized, placebo-controlled trial that evaluated patients with severe COVID-19 in China. Patients were randomized 2:1 to receive IV RDV or normal saline placebo for 10 days. Concomitant use of LPV/r, corticosteroids, and interferons was allowed. The primary study endpoint was time to clinical improvement, defined as improvement on an ordinal scale or discharged alive from the hospital, whichever came first. The planned sample size was 453 patients.
- The study enrolled hospitalized adults with laboratory-confirmed COVID-19 whose time from symptom onset to randomization was <12 days, whose O2 saturation was ≤94% on room air or whose PaO2/FiO2 was <300 mmHg, and who had radiographically confirmed pneumonia.
- Between February 6-March 12, 2020, 237 hospitalized patients were enrolled and randomized to receive RDV (n = 158) or placebo (n = 79). The study was stopped before target enrollment was reached due to control of the COVID-19 outbreak in China.
- The participants’ median age was 65 years; 56% of the participants in the RDV arm and 65% in the placebo arm were male.
- There were more patients with HTN, DM, or CAD in the RDV arm than in the placebo arm.
- At Day 1, 83% of the patients required supplemental oxygen by nasal cannula or mask; only 1 patient required mechanical ventilation or ECMO.
- The median time from symptom onset to randomization was 9 days in the RDV group and 10 days in the placebo group.
- 65% of the participants in the RDV group and 68% of participants in the placebo group received corticosteroids.
- 28% of the participants in the RDV group and 29% of the participants in the placebo group received LPV/r.
- 29% of participants in the RDV arm, and 38% of participants in the placebo arm received IFN alfa-2b.
- Study Endpoints:
- There was no difference in the time to clinical improvement between the RDV and placebo groups (a median of 21 days vs. 23 days, respectively; HR 1.23; 95% CI, 0.87–1.75).
- For patients who started RDV or placebo within 10 days of symptom onset, faster time to clinical improvement was seen in the RDV arm than in the placebo arm (median of 18 days vs. 23 days, respectively; HR 1.52; 95% CI, 0.95–2.43); however, this was not statistically significant
- The 28-day mortality rate was similar for the 2 study arms (14% of participants in the RDV arm vs 13% in the placebo arm).
- There was no difference between the groups in SARS-CoV-2 viral load at baseline, and the rate of decline over time was similar between the 2 groups.
- The number of participants who experienced AEs was similar between the 2 groups (66% of participants in the RDV arm vs. 64% in the placebo arm).
- More participants in the RDV arm discontinued therapy due to AEs (12% of participants in the RDV arm vs. 5% in the placebo arm).
- The study was terminated early; as a result, the sample size did not have sufficient power to detect differences in clinical outcomes.
- The use of concomitant medications (i.e., corticosteroids, LPV/r, IFNs) may have obscured the effects of RDV.
- Interpretation: There was no difference in time to clinical improvement, 28-day mortality, or rate of viral clearance between RDV-treated and placebo-treated patients.
Uncontrolled Case Series from RDV Compassionate Use Program:
- In an uncontrolled case series of 53 hospitalized patients with COVID-19, most patients needed less oxygen support after receiving compassionate use RDV. There was no comparison group, however, so it is not possible to assess whether the use of RDV led to the improvement was the result of using RDV.27