Skip to main content

Our take —

In this randomized, placebo-controlled trial, the use of hydroxychloroquine within 4 days of COVID-19 exposure did not reduce incidence of illness consistent with COVID-19 or confirmed COVID-19 infection.

Study design

Randomized Controlled Trial

Study population and setting

821 persons with household or occupational exposure to someone with confirmed SARS-CoV-2 infection in the United States and Canada (“exposure” = contact with distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield [high-risk exposure] or while wearing a face mask but no eye shield [moderate-risk exposure]). Participants were recruited through social media and traditional media platforms. Study participants were randomized to either hydroxychloroquine or placebo in a 1:1 ratio within 4 days of exposure.

Summary of Main Findings

87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed COVID-19 contact. The population was generally healthy and not at increased risk for severe COVID-19. The incidence of new illness compatible with COVID-19 did not differ between those receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); absolute difference −2.4 percentage points (95% confidence interval, −7.0 to 2.2; P=0.35). Side effects were more common among participants receiving hydroxychloroquine compared to placebo (40.1% vs. 16.8%); no serious adverse reactions were reported in either group. Of note, approximately 60% of patients received the drug (hydroxychloroquine or placebo) on days 3 or 4.

Study Strengths

Well conducted randomized controlled trial with a geographically diverse population.

Limitations

Given the median incubation time for SARS-CoV-2 is approximately 5 days, the optimal timing of prophylaxis administration is unknown. The study relied upon participant self-report of symptoms rather than laboratory-confirmed detection of SARS-CoV-2. Authors were also unable to capture asymptomatic infections. The study population was younger and healthier than populations at higher risk for severe COVID-19.

Value added

This is the first randomized controlled trial to evaluate the efficacy of hydroxychloroquine as a post-exposure prophylactic agent for COVID-19.

Our take —

Remdesivir (RDV) reduced time to symptom resolution and possibly reduced mortality. The finding of reduced duration of symptoms with RDV contrasts with a smaller trial of RDV which found no benefit (Wang et al. Lancet 2020). Differences between these trials include the smaller sample size and the use of other off-label agents in the Wang study. The preliminary results of this study support the use of RDV for COVID-19, and suggest that individuals requiring supplemental O2 (but not mechanical ventilation or ECMO) may yield the most benefit. Analysis of the final results of this study, when available, will be helpful. Further analysis of a larger sample size and additional studies are needed to test hypotheses on the ideal timing of RDV use in COVID-19 disease. These results formed the basis of the FDA emergency use authorization for RDV use.

Study design

Randomized Controlled Trial

Study population and setting

This was a randomized, double-blinded, placebo-controlled, multi-center clinical trial of a 10-day course of daily remdesivir (RDV) versus placebo among inpatients at 60 trial sites in North America, Europe, and Asia with a positive SARS-CoV-2 RT-PCR, and evidence of lower respiratory tract infection based on radiographic infiltrates, SpO2 ≤94% on room air, or requiring supplementation oxygen via nasal cannula, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). There was no limit to the duration of symptoms prior to enrollment. Inclusion required an alanine aminotransferase test and aspartate transaminase test <5x upper limit of normal, and an estimated glomerular filtration rate (eGFR)>30 mL/min/mm2 (liver function tests). The primary outcome was time to recovery during the 28 days after enrollment, with recovery defined as: 1) not hospitalized and no limitations of activities, 2) not hospitalized, limitation of activities, home oxygen requirement, or both, or 3) hospitalized but not requiring supplemental oxygen or inpatient medical care. A secondary outcome was mortality at 14 and 28 days after enrollment.

Summary of Main Findings

A total of 1063 patients were enrolled from 60 sites (79.8% from North America), 11.3% did not require supplemental O2, 88.7% had “severe” disease (required supplemental oxygen to maintain an oxygen saturation ≥94%), 25.6% were on mechanical ventilation or ECMO at the time of enrollment, the mean age was 58.9 years, and 64.3% were men. The median duration of symptoms prior to enrollment was 9 days (IQR 6 to 12). A total of 541 participants were assigned to RDV and 522 to placebo; 49 RDV and 53 placebo participants discontinued treatment before day 10 due to adverse events other than death or withdrawal of consent. At the time of analysis, 391 RDV and 340 placebo group participants had completed day 29 of follow-up, died, or recovered.

Participants in the RDV arm had a median of 11 days to recovery compared with 15 days in the placebo arm (rate ratio 1.32, 95% CI: 1.12 to 1.55, p<0.001). In subgroup analysis, the difference in recovery by 29 days was observed among the sub-group of participants receiving supplemental oxygen via nasal cannula but not those with either less or more severe disease: those not needing supplemental oxygen, receiving high-flow oxygen, noninvasive mechanical ventilation, mechanical ventilation, or ECHO; however, a test of interaction by baseline clinical status was not significant. In subgroup analysis among groups with either 10 or less days or more than 10 days of symptoms at the time of enrollment, there was no clear difference in the effect of RDV on time to clinical improvement (similar effect sizes and overlapping confidence intervals). The Kaplan-Meier estimates of mortality at 14 days were 7.1% and 11.9% for RDV and placebo, respectively (hazard ratio 0.7; 95% CI: 0.47 to 1.04).

The occurrence of serious adverse events was balanced between arms with 21.1% in the RDV arm and 27% in the placebo arm suffering a serious adverse event. Two events in each arm was adjudicated to be related to RDV or placebo. The frequency of serious adverse events was similar by arm except for respiratory failure and hypotension which occurred more frequently in the placebo arm. Non-serious adverse events were also similar by study arm including no difference in increase in transaminases or decrease in eGFR.

Study Strengths

This was a placebo-controlled RCT examining remdesivir efficacy and safety among people with SARS-CoV-2 infection. The study was powered for clinical efficacy and was completed with minimal drop-out and excellent ascertainment of study endpoints.

Limitations

The findings from this study should not be over-interpreted in terms of final outcomes. These results are preliminary, with follow-up incomplete at the time of analysis for some participants who had not had 28 days of observation from enrollment. In addition, the sample size for subgroups (oxygenation requirements and duration of symptoms at enrollment) are too small to draw strong conclusions regarding who may most benefit from RDV in terms of illness severity or duration of symptoms. Finally, RNA clearance is a commonly measured outcome in antiviral agent studies; it was missing from this report.

Value added

This well-conducted randomized controlled trial (RCT) demonstrated a clinical benefit of RDV use with the possibility of reduced mortality. It also suggests the safety of RDV, as there was no evidence of an increase in serious or non-serious adverse events among participants receiving the drug.

Our take —

In a small randomized controlled trial in China, patients with persistent mild and moderate COVID-19 who received hydroxychloroquine were no more likely to clear the virus or to improve clinically. Further work is needed to examine whether the drug might have a role in early treatment of COVID-19. However, this study adds to the growing evidence suggesting that hydroxychloroquine is not efficacious in treating the disease.

Study design

Randomized Controlled Trial

Study population and setting

The study included 150 patients with laboratory-confirmed SARS-CoV-2 infection admitted to treatment centers in three Chinese provinces between February 11, and February 29, 2020. Patients were randomly assigned to either standard of care (75 patients) or standard of care plus hydroxychloroquine (75 patients; hydroxychloroquine administered for 2-3 weeks). Treatment assignments were known to the patients and providers. Illness severity at admission was generally mild (15%) or moderate (84%), with few severe cases (1%). The primary outcome was the resolution of detectable viral RNA, with a principal secondary outcome of alleviation of clinical symptoms.

The study was terminated early due to declining infection rates and pharmaceutical futility. Patients still under follow-up were censored.

Summary of Main Findings

Among the 150 participants, the average duration of symptoms prior to admission was 16.6 days. Patients were followed for a median of 21 days in the standard of care group, and 20 days in the hydroxychloroquine group. 73% of participants cleared the virus before 28 days of follow-up. There were no differences by study arm in the probability of resolution of detectable virus or the time to resolution. Further, there was no difference by study arm in the probability of alleviation of clinical symptoms or time to alleviation. Participants receiving hydroxychloroquine were more likely to report adverse events (30% vs. 9%) with diarrhea being the most common (10% of patients receiving hydroxychloroquine). No participants died and only one participant, in the hydroxychloroquine group, progressed to severe disease.

Study Strengths

The study protocol and follow-up of participants was thorough.

Limitations

The study included a relatively small sample size, in particular of severe cases. This makes it impossible to assess the potential role of hydroxychloroquine in treating severe disease. Because patients were enrolled on average more than two weeks after disease onset, there is no ability to assess the impact of hydroxychloroqine early in the course of the infection. Further, patients who did not progress to severe disease within this time-period before admission may be a distinct group that would be less likely to benefit from the drug. Finally, the study arm assignment was not blinded which may have biased the reporting and assessment of clinical outcomes and adverse events.

Value added

This is one of the first published randomized clinical trials of hydroxychloroquine for COVID-19.

Our take —

In this trial of hospitalized patients with COVID-19 who had either an O2 saturation of ≤ 94% or PaO2:FiO2 ≤ 300mm Hg, no substantial clinical benefit was seen in patients receiving lopinavir compared to standard of care.

Study design

Randomized Controlled Trial

Study population and setting

This study was conducted among hospitalized adults in China with COVID-19 and “severe” disease, defined by O2 saturation of ≤ 94% or PaO2:FiO2 ≤ 300 mm Hg. An open-label, individually randomized, controlled trial conducted from January 18, 2020, through February 3, 2020. 199 patients were included– 99 were assigned to receive lopinavir-ritonavir, and 100 were assigned to the standard of care (comprised of any of the following as necessary: supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation (ECMO)). The primary outcomes were time to clinical improvement and mortality assessed by 28 days following enrollment.

Summary of Main Findings

The median interval time between symptom onset and randomization was 13 days (IQR:11 to 16 days).Treatment with lopinavir–ritonavir was not associated with a difference in the time to clinical improvement as compared to the standard of care (hazard ratio, 1.31; 95% CI: 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard ofcare group (19.2% vs. 25.0%; difference, −5.8%; 95% CI, −17.3 to 5.7). Detection of viral RNA at several time points did not differ between the groups. Lopinavir-ritonavir was stopped early in 14% of patients due to adverse events.

Study Strengths

A trial conducted under emergency conditions providing some of the first randomized data on treatment for COVID-19.

Limitations

Patients received therapy well into their disease course (average of 13 days), a larger trial targeting patients earlier may be justifiable. Among 99 patients assigned to lopinavir-ritonavir, 5 did not receive the therapy due to either death or refusal of administration by the attending physician. The study was neither blinded nor placebo-controlled. The study sample size was modest, and the study underpowered to detect more modest, yet still clinically relevant, effect sizes.

Value added

This is the first peer reviewed, published randomized trial of lopinavir-ritonavir for the treatment of SARS-Cov-2.

Our take —

This vaccine trial will test multiple versions of an RNA-based vaccine against SARS-CoV-2 across different age groups with different vaccination regimens. In addition to incidence of COVID-19 in study participants, antibody titer will be assessed over a period of two-years, allowing response and longevity of response to be analyzed. Though assessing multiple vaccine candidates and multiple vaccine regimens at one time may make interpretation of the data and therefore selection of a lead candidate difficult, a successful trial of this nature could greatly speed the time to identification of a viable candidate vaccine.

Study design

This is a multi-arm, placebo-controlled and observer-blinded phase 1/2 study of four different RNA-based vaccine candidates against SARS-CoV-2. The intention is to determine the correct dose for each of the vaccine candidates, and identify the best candidate based on safety, tolerability, immunogenicity, and potential efficacy. The four different RNA-based vaccine candidates will be tested at multiple doses (low, medium, and high) across multiple age ranges (18-55, 65-85, and 18-85 years) with either one or two dose regimens, for a total of 18 study groups with 3 placebo groups (age 18-55, age 65-85, and age 18-85 years) receiving a single injection. This study will be performed in three stages: Stage 1 will identify the preferred vaccine candidate, dose level and dosing regimen; Stage 2 will be an expanded cohort study presumably to examine immunogenicity, and Stage 3 will be a final large-scale study with the final candidate, dose, and regimen most likely to examine efficacy.

Study population and setting

7600 participants will be recruited consisting of  healthy males and females age 18-85 years with no previous clinical or microbiological diagnosis of COVID-19. Participants must be HIV, hepatitis C, and hepatitis B-negative, have no known medical or psychiatric condition, and have no known history of severe adverse reaction or severe allergies associated with a vaccine. Additionally, participants must not have received medications intended to treat COVID-19, must not be immunocompromised, have not received treatment with immunosuppressive therapy; have no history of autoimmune disorder; have no condition associated with prolonged bleeding; not be pregnant or breast-feeding; as well as others. Stage 1 participants must not work in occupations with high risk of exposure to SARS-CoV-2, must not test positive on serological tests for SARS-CoV-2, have no abnormal hematology and/or blood chemistry laboratory values, and must have a SARS-CoV-2 NAAT-negative nasal swab within 24 hours of the vaccine administration.

Recruitment centers are at the University of Maryland General Clinical Research Center, the University of Maryland Medical Center Investigational Drug Service Pharmacy, the University of Maryland, Center for Vaccine Development and Global Health, and NYU Langone Health.

Primary outcome measures will include injection site reactions, adverse and serious events, , and hematology and chemistry laboratory values and changes. Secondary outcomes include analysis of SARS-CoV-2 serum neutralizing antibodies, and serum antibodies specific to SARS-CoV-2 spike protein and the receptor binding domain of the spike protein. Analysis will occur at multiple time points over two years and will include antibody titer, change in titer over time, percent of participants who achieve greater than or equal to a four-fold increase in antibody titer. Confirmed COVID-19 incidence will also be monitored.

Summary of Main Findings

N/A, study is incomplete

Study Strengths

N/A, study is incomplete

Limitations

N/A, study is incomplete

Value added

Assessing multiple vaccine candidates and multiple vaccine regiment at one time could greatly speed the time to identification of a viable candidate vaccine. Testing antibody titers over two years will aid in understanding the longevity of the immune response to the vaccine. If successful, this has the potential to be the first licensed RNA-based vaccine.

Our take —

Remdesivir did not appear to change outcomes in this underpowered study when used later in the disease course (median of 10 days). In addition, remdesivir did not appear to affect viral replication. This study does not support the clinical use of remdesivir later in the course of COVID-19 disease. However, conclusions should be made cautiously given the lack of statistical power for examining the study hypotheses.

Study design

Randomized Controlled Trial

Study population and setting

This was a randomized, double-blinded, placebo-controlled, multi-center clinical trial of a 10-day course of daily remdesivir versus placebo among inpatient participants who mostly required supplemental oxygen and had laboratory-confirmed SARS-CoV-2 infection.

Summary of Main Findings

In this 2:1 placebo-controlled RCT, 237 patients were enrolled from 10 hospitals in China; 158 participants were assigned remdesivir, 78 were assigned to placebo. This was lower enrollment than planned due to a lack of further SARS-CoV-2 patients identified in the province. Eligible adults (18+ years) were SARS-CoV-2 positive, had <12 days of symptoms, and had pneumonia on imaging. Patients in the remdesivir arm received 10 days of IV-administered drug. Other antivirals were permitted, and their use was balanced between the remdesivir and placebo groups at baseline; while under study more placebo arm participants received inhaled interferon-alpha than remdesivir arm participants (38% vs. 29%). In addition, there was prevalent use of antibiotics (>90% in both arms) and corticosteroids (>65% in both arms). Upon enrollment, 96% of participants required supplemental oxygen. There was a higher proportion of men in the remdesivir arm, 65%, compared to placebo, 56%. Other characteristics of participants were roughly matched, with a median age in the remdesivir arm of 66 years, and in the placebo arm of 64 years. Comorbidities were found in approximately 70% of participants in both arms. The median interval between symptom onset and randomization was 10 days (11 for remdesivir and 10 for placebo).

The primary endpoint was time to clinical improvement, defined as a decrease in two stages on a 6-stage scale. There were no differences in the time to clinical improvement, which was on average 23 and 21 days in the remdesivir and placebo arms, respectively. There was also no difference in mortality between the arms, nor in the number of people requiring mechanical ventilation. Nucleic acid amplification data showed high-level replication in the upper and lower respiratory tracts at baseline. The kinetics of viral decline did not appear different by arm; both declined to low levels 28 days after enrollment. Adverse events were recorded in both remdesivir (66%) and placebo (64%) arms, and consisted of lab abnormalities (e.g., low albumin, low potassium, anemia, low platelets), rash, and gastrointestinal complaints. Serious adverse events were found less frequently in the remdesivir arm (18%) than in the placebo arm (26%). More people in the remdesivir arm (12%) discontinued the drug than in the placebo arm (5%). None of the deaths that occurred during the study were determined to be related to remdesivir or placebo.

Study Strengths

This is a placebo-controlled RCT examining remdesivir efficacy and safety in a clinical cohort of people with SARS-CoV-2 infection. The study was completed with minimal drop-out and excellent ascertainment of study endpoints.

Limitations

The study was terminated early because of failure to fully enroll. This affects the overall power of the study. In addition, the study protocol enrolled people within up to 12 days of symptom onset, with a median time since symptom onset of 10 days. There was an imbalance in duration of symptoms prior to study entry: 54% of the remdesivir arm and 40% of placebo arm had >10 days of symptoms. In acute viral infections such as influenza, treatment needs to be early to improve clinical outcomes; the late initiation of treatment in this trial may have affected the efficacy outcome. The lack of difference in viral nucleic acid clearance during serial RNA assays raises some questions as to the antiviral effect and the biological plausibility of antiviral activity. Use of these PCR assays rather than viral culture is an additional limitation as the correlation between PCR positivity and viral replication and infectious virion is unclear at this time. One non-significant finding was more rapid clinical improvement in those receiving remdesivir when compared to placebo among the subgroup enrolling within 10 days of symptoms. Given that this was a subgroup analysis of an already underpowered study, no conclusions should be drawn from this observation.

Value added

This was a well-conducted RCT that suggested the safety of remdesivir use in treating COVID-19 and found no benefit when remdesivir is used later in the disease course.

Our take —

This trial will provide insight into the safety and reactivity of an aAPC vaccine for COVID-19. Participants include both healthy and COVID-19+ subjects, and therefore this trial will be useful in testing the safety and reactivity of this vaccine in both populations as either a protective or therapeutic vaccine, respectively.

Study design

Randomized Controlled Trial

Study population and setting

This is a Phase I, interventional trial of a COVID-19/artificial antigen presenting cell (aAPC) vaccine,that is taking place at Shenzen Geno-Immune Medical Institute in collaboration with Shenzen Second and Third People’s Hospitals in Shenzen, China. It began on February 15th, 2020 and is currently recruiting. This trial has an estimated enrollment of 100 participants who meet the following criteria: healthy or COVID-19 positive, between 6 months and 80 years of age, white blood cells ≥ 3,500/μl, lymphocytes ≥ 750/μl, HIV, HBV, HCV, and TB negative, and the interval between onset of symptoms and randomization is within 7 days for participants who are COVID-19 positive. The COVID-19 positive patients are included to test if the vaccine could possibly be used as a therapeutic vaccine.

Study participants receive 5×10^6 aAPCs via subcutaneous injection at 0, 14, and 28 days post-randomization. Peripheral blood samples are collected for analysis at 0, 14, 21, 28, and 60 days post-randomization.

The vaccine is comprised of aAPCs that are inactivated so that they cannot proliferate. Primary outcomes include frequency of vaccine events (ex. Fever, rash, abnormal heart function), frequency of serious vaccine events, and the proportion of subjects with a positive T-cell response against SARS-CoV-2 antigens. Secondary endpoints also include tracking the need for mechanical ventilation, vaccine related deaths, clinical improvement, and lung injury in the COVID-19 patients who are vaccinated.

Summary of Main Findings

N/A, study is incomplete

Study Strengths

N/A, study is incomplete

Limitations

N/A, study is incomplete

Value added

Though this is a relatively small trial (n = ~100), it is one of the first test a vaccine using aAPCs to increase immunity to COVID-19.

Our take —

By utilizing a vaccine construct design that has previously been shown to be safe and generate a moderate immune response to MERS (another coronavirus), the researchers were able to combine a phase 1 and 2 trial together, which may speed up the process for identifying if this vaccine will be effective against COVID-19 infection.

Study design

Randomized Controlled Trial

Study population and setting

This is a phase I/II clinical trial examining the safety and ability to generate an immune response to SARS-CoV-2 of an attenuated adenovirus vaccine that produces the spike (S) protein of SARS-CoV-2. This same strategy has been used to generate a Middle Eastern Respiratory Syndrom (MERS) vaccine, which was found to be safe and generated moderate immune responses to MERS (another coronavirus). The trial aims to recruit 1112 volunteers (age 18-55 years) that will be randomly assigned to 4 study groups. One group will receive two doses of the Covid vaccine. The other groups will all receive either one dose of the Covid vaccine, or a dose of MenACWY (a vaccine against Meningococcal bacteria) as a control. The study is being done in the United Kingdom, and has started recruiting volunteers in April 2020. The study will last 6 months.

Summary of Main Findings

N/A, study incomplete

Study Strengths

The sample size will be large and is examining two dose strategies of a single dose, known as a “prime boost” strategy. The size of the study will allow for analysis of accurate immunogenicity for the single dose regimen, which has shown promise in MERS using a similar construct. By combining the phase 1 and 2 stages of the vaccine approval process, it may speed up the regulatory process to see if the vaccine is likely to be effective in preventing infection.

Limitations

Primary findings will not be for 6 months, however, safety analyses will be done at days 7 and 28, as well as 6 months.

Value added

There is currently no approved, effective vaccine available for SARS-CoV-2 infection.