Skip to main content

Our take —

This randomized, placebo-controlled, phase 3 clinical trial tested the safety, immunogenicity, and efficacy of the ChAdOx1 n-CoV-19 vaccine (Oxford/AstraZeneca) in adults ages 18 and older in the United States, Chile, and Peru from August 28, 2020 to January 15, 2021. The vaccine was found to be safe and effective, with an overall vaccine efficacy of 74%. The vaccine proved to be effective across all age groups studied.

Study design

Randomized Controlled Trial

Study population and setting

This paper describes a randomized, placebo-controlled, phase 3 clinical trial that took place across 88 sites in the United States, Chile, and Peru between August 28, 2020 and January 15, 2021. The trial aimed to study safety, efficacy, and immunogenicity of the ChAdOx1 n-CoV-19 vaccine (Oxford/AstraZeneca) in these countries. There were 32,451 participants, who were randomized in a 2:1 ratio to either receive two doses of vaccine (5^10 viral particles) administered four weeks apart (21,635 participants) or two doses of a saline placebo four weeks apart (10,816 participants). Participants were aged 18 or older, and the group randomization was stratified by age group (18-64 or 64 years+). Safety analysis was performed on all participants who received at least one dose of vaccine or placebo. Unsolicited adverse events were recorded for 28 days following each dose, while serious adverse events were recorded throughout the duration of the study. A sub-study to assess reactogenicity and immunogenicity was conducted, with reactogenicity being studied for 7 days following each dose. Immunogenicity was analyzed by measuring antibodies against the SARS-CoV-2 spike protein and neutralizing antibodies found in serum samples from sub-study participants. The primary efficacy endpoint was to see how well the vaccine could prevent the onset of symptomatic and severe RT-PCR confirmed COVID-19 infection 15 or more days following the second dose compared to second dose of placebo. Patients in efficacy analysis were seronegative at baseline.

Summary of Main Findings

The safety analysis found that the most common adverse events were generalized pain, headache, injection-site pain, and fatigue, at a rate of at least 5% in either vaccine and/or placebo groups. A similar and very small percentage (around 0.5%) of participants in both groups had a serious adverse event within 28 days after any dose. Zero vaccine or placebo related deaths occurred during the trial, and no COVID-19 related deaths were noted, either. Importantly, incidences of deep-vein thrombosis, pulmonary embolism, thrombocytopenia, and immune thrombocytopenia was very low and similar in both groups (generally < 0.1%). The sub-study on reactogenicity found that more participants in the vaccine group experienced local and systemic adverse events compared to the placebo group. Most (about 92%) of these adverse events were mild or moderate in degree and resolved 1-2 days after onset. There were fewer adverse events following the second dose in both the vaccine and placebo group. Overall vaccine efficacy (VE) was estimated to be 74% (95% CI, 65.3-80.5; P < 0.0001). Due to the clinical trial being put on hold, some patients received their second dose outside of the normal 28-day window, but VE was calculated to be similar in this group 78.1%, 95% CI, 49.2-90.6). When using the CDC’s definition of COVID-19, which can include mild disease, overall VE was estimated to be 70%. VE in participants ages 65 and older was estimated to be 83.5% (95% CI, 54.2-94.1). No severe or critical symptomatic cases of COVID-19 were observed in fully vaccinated participants, while 8 cases were noted in the placebo group. Then efficacy of the vaccine in preventing infection, assessed by measuring antibodies in patient serum, was 64.3% (95% CI, 56.1-71.0; P < 0.001). As for the exploratory endpoint measuring the vaccine’s efficacy in prevention against COVID-19 hospitalizations, VE was estimated to be 94.2% (95% CI, 53.2-99.3). Neutralizing antibodies against the COVID-19 spike protein were observed to increase after the first dose of vaccine and even more so when measured 28 days after second dose of vaccine, while levels remained low throughout the trial in the placebo group.

Study Strengths

This trial aimed to include a diverse population, studying the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine in three new countries across a wide age range. Participants also included those with coexisting conditions, as well as some participants with well-controlled HIV.

Limitations

While trying to include a diverse population, 79% of participants were still white. Due to small COVID-19 case numbers in Chile and Peru sites, vaccine efficacy could not be estimated for those locations. The level of neutralizing antibodies that correlates with protection is still unknown. Early unblinding of group assignment for more than one third of participants occurred in order to allow patients a choice in deciding whether they would like to become vaccinated after other vaccines received emergency use approval. Finally, the results included in this report encompass only a short duration of follow up.

Value added

This report describes the safety and efficacy of the Oxford/AstraZeneca vaccine in United States, Chile, and Peru.

Our take —

This randomized controlled trial of daily testing of contacts of SARS-CoV-2 cases (“test-to-stay”) vs. 10-day quarantine in secondary schools and colleges in England found that the test-to-stay approach did not increase virus transmission within schools and may have reduced COVID-19 related school absences by 20%. However, compliance with the test-to-stay intervention varied substantially across schools, suggesting that the feasibility of this intervention is setting-dependent. Overall, transmission from index cases to close contacts within schools was low (~2%).  

Study design

Randomized Controlled Trial

Study population and setting

This open-label cluster randomized controlled trial of daily testing of close contacts of SARS-CoV-2 cases was conducted in 201 secondary schools and further education colleges (students aged 11 years and older) in England between April and June 2021, during which time the Delta (B.1.617.2) variant was the predominant circulating strain, but community transmission rates were low to moderate. SARS-CoV-2 cases in intervention and control arms were routinely identified through twice weekly asymptomatic testing using lateral flow devices (LFD; i.e., rapid tests) and symptom screening. Schools were randomized such that asymptomatic close contacts of cases in schools were given either 10-day quarantine (control arm) or daily testing with LFD for seven days, excluding weekends (intervention arm). Contacts in the intervention arm could remain in school if they tested negative on the LFD that day (i.e., test-to-stay). LFD testing was done using Orient Gene (Huzhou, China) by school staff on anterior nasal swabs. All individuals with a positive LFD test or with symptoms indicative of SARS-CoV-2 infection were required to isolate and obtain a PCR confirmatory test. Randomization was done at the school level, and stratified based on school type (secondary vs. college), presence of residential students, presence of a 6th form, and the proportion of students eligible for school meals (>17% or ≤17%). Co-primary outcomes were assessed in students and staff at the school-level and included (1) rates of COVID-19 school-related absences and (2) PCR-confirmed COVID-19, adjusted for community case rates. Data on school-related absences were either directly reported by the schools or obtained through government databases, whereas data on PCR-confirmed COVID-19 were obtained solely through the National Health Services (NHS) Test and Trace Program database. The trial was designed as a non-inferiority trial, meaning that it was powered to identify whether the intervention and control arms had similar outcomes rather than, as is more typical, powered to find a difference in the outcomes across arms.  Primary analyses were intent-to-treat and done using quasi-Poisson regression. In secondary analyses, efficacy was assessed after adjustment for compliance with the LFD testing intervention, where compliance was defined for individuals as 3 or more LFD tests or an LFD positive test.  

Summary of Main Findings

2000 schools were notified of the study, and 201 schools were enrolled and assigned to either the intervention (n=102) or control (n=99) arm. Among these schools, 77% (n=76) in the control arm and 84% (n=86) in the intervention arm directly reported student and staff lists and attendance data. Overall, SARS-CoV-2 transmission from index cases to close contacts was low in intervention and control arms (~2%). Mean compliance with the intervention (i.e., daily LFD testing) was 42% (n=2432/5763 contacts), but compliance varied substantially across schools (median 63%: IQR=40-79%). In primary, intent-to-treat-analyses, COVID-19 school-related absences were non-significantly reduced by 20% in the intervention arm (adjusted incidence rate ratio [IRR] 0.80; 95%CI 0.54-1.19). After adjustment for compliance, there was a greater relative reduction in COVID-19 related school absences observed in the intervention arm (IRR 0.61; 0.30-1.23), but this difference was also not statistically significantly different. In a separate analysis of impact on all-cause school absence rates, there were no differences observed between study arms (0.97; 95%CI: 0.82-1.16). There were also no differences in rates of PCR-confirmed symptomatic infection between study arms (IRR 0.96; 95%CI:0.75-1.22). While cases were more commonly found among students in both arms, intervention efficacy for either of the two primary outcomes did not significantly differ between students and staff. Using data on a subset of PCR-confirmed infections, the LFD rapid was estimated to have 99.93% specificity and 53% sensitivity.

Study Strengths

The major strength of this study is that it was a randomized controlled trial. Multiple, independent databases were used to obtain information on the primary outcomes. Infection rates in schools were adjusted for background community transmission rates. Multiple policy relevant outcomes were assessed, and sensitivity analyses conducted. The non-inferiority design was appropriate given the study hypotheses, which were that there would be a reduction in COVID-19 related absences but that there would not be a difference in SARS-CoV-2 transmission across arms.

Limitations

Compliance with routine asymptomatic testing and symptom screening to identify index cases was reportedly poor, but not quantified in either study arm. Not all schools directly reported data to the study teams, and so intervention compliance could only be assessed from a subset of schools, which likely had higher compliance rates. This study was conducted over a relatively short time frame (~10 weeks), during periods of low/moderate SARS-CoV-2 transmission, and was underpowered to detect modest differences in outcomes between arms. Variability in other transmission control measures (e.g., masking protocols, air circulation protocols, spacing of students in classrooms) across schools was not reported, and so it is possible that there was unmeasured confounding by these measures due to chance imbalances. Given that this study only included secondary schools or higher, the findings may not be applicable to children in primary schools, pre-school, or day care.

Value added

This is the first randomized controlled trial to study an intervention to reduce SARS-CoV-2 transmission in an educational setting. Detailed, high quality information on the epidemiology of virus transmission within schools is also provided.

Our take —

COVID-19 convalescent plasma has been widely employed in the US through an Extended Access Program. However, the results of this randomized clinical trial of 938 hospitalized patients needing oxygen support, which took place between May 2020 and January 2021, show that convalescent plasma does not reduce mortality or the need for intubation at 30 days post enrollment. Furthermore, the risk of serious adverse effects (worsening hypoxemia, respiratory failure) was significantly increased in patients who received convalescent plasma treatment (33.4% vs 26.4%, RR 1.27). The results of this study provide further evidence against the use of convalescent plasma for patients hospitalized with COVID-19.

Study design

Randomized Controlled Trial

Study population and setting

The study described in this article is a multi-center, open-label randomized controlled trial of 938 patients hospitalized within 12 days of onset with COVID-19 needing oxygen support. The study was conducted between May 14, 2020 and January 29, 2021, across 72 hospitals in the US, Canada, and Brazil. The study compared the proportion of patients who died or who required intubation within 30 days of enrollment between those receiving standard of care (n = 307) and those receiving COVID-19 convalescent plasma (n = 614). Secondary analyses of note include that of safety of convalescent plasma, as well as the role of antibodies in modifying the effect of convalescent plasma.

Summary of Main Findings

The trial was stopped at 78% of planned enrollment after an interim analysis suggested no benefit to the intervention group. In an intention-to-treat analysis, 199/614 (32.4%) of patients in the convalescent plasma group died or were intubated within 30 days, versus 86/307 (28.0%) in the standard of care group, a nonsignificant difference (RR 1.16, 95% CI: 0.94 – 1.43, p 0.18). Subgroup analysis found that patients receiving plasma from supplier 3, as well as patients not on corticosteroids, had worse outcomes when receiving convalescent plasma compared to standard of care. However, there were no significant differences in outcomes of any other subgroup analyses, including age, sex, ethnicity, blood type, smoking history, comorbidities, disease timeline, or level of oxygen dependency. Serious adverse events, typically worsening hypoxemia and respiratory failure, were significantly more likely in the convalescent plasma group (33.4%) compared to the standard of care group (26.4%; RR 1.27, 95% CI: 1.02 – 1.57, p 0.034).

Study Strengths

A major strength of this study was the additional serological testing of the plasma, which identifies factors that change and may explain variations in the treatment effect. Specifically, the study found plasma with higher capability for antibody-dependent cell cytotoxicity reduced the odds ratio by 24% per unit (95% CI 0.62 – 0.92). Similarly, plasma with higher capability for neutralization reduced the odds ratio by 23% per unit (95% C1 0.63 – 0.94). Another strength of the study was the accompanying meta-analysis, which summarized evidence both from studies that evaluated exclusively high-titer convalescent plasma therapy and those that evaluated  convalescent plasma of indiscriminate titer but found no evidence of benefit from either approach.

Limitations

This is an open-label study, which can introduce bias into the observation and reporting of adverse effects, as well as the planning of treatment strategies and potentially skew the data.

Value added

This study corroborates previous randomized controlled trials in finding that treatment with COVID-19 convalescent plasma does not reduce mortality or need for intubation at 30 days. In addition, this study found that convalescent plasma treatment was significantly more likely to lead to serious adverse effects, including worsening hypoxemia and respiratory failure, compared to usual standard of care.

Our take —

This was a very large and well-designed cluster-randomized controlled trial of a multi-pronged intervention program to encourage mask-wearing in rural and peri-urban Bangladesh from November 2020 to April 2021; it was available as a preprint and is thus not yet peer reviewed. The study found that the intervention package (which included mask distribution, public role-modeling, and encouragement to non-mask-wearers in public settings) more than tripled public mask usage behaviors (from 13% to 42%) without diminishing observed physical distancing. Most importantly, villages with the intervention had a 10% relative reduction in symptomatic seroprevalence (reported COVID-19 symptoms with presence of SARS-CoV-2 antibodies) compared to control villages. Surgical masks were apparently more effective than cloth masks. This study did not measure whether mask wearing was associated with COVID-19 at an individual level, and there are potential problems with the outcome measure of symptomatic seroprevalence. However, the study provides evidence that interventions promoting mask use can reduce community SARS-CoV-2 transmission even when fewer than half of community members wear masks. If the results are valid, they imply that near-universal mask wearing would be associated with much larger reductions in transmission.

Study design

Randomized Controlled Trial

Study population and setting

This was a cluster-randomized trial of community-level promotion of mask-wearing, designed to estimate the impact of interventions on SARS-CoV-2 symptomatic seroprevalence in Bangladesh from November 2020 to April 2021. Secondary outcomes included mask-wearing behavior, physical distancing behavior, and COVID-19 symptom prevalence. The study was conducted in 600 rural and peri-urban villages containing 341,830 adults throughout Bangladesh. From an initial sampling frame of 1,000 rural and peri-urban unions (a union is a rural administrative unit in Bangladesh, consisting of ~80,000 people), the authors used pairwise randomization to select 300 intervention and 300 control unions, and selected one village (containing the largest regional market) in each union. The intervention was rolled out in waves from November 2020 to January 2021, and lasted for 8 weeks. Control group villages received no intervention. Intervention group villages received a multi-pronged mask promotion strategy, designed in conjunction with local leaders. The intervention had five elements: 1) one-time mask distribution and promotion to households, 2) mask distribution in markets 3-6 days per week, 3) mask distribution at mosques on three Fridays, 4) mask promotion in public spaces and markets, during which non-mask-wearers were encouraged to wear masks, and 5) role-modeling and active promotion of masks by religious and other community leaders. In addition, intervention villages were cross-randomized to four additional interventions: 1) cloth vs. surgical masks, 2) village-level incentives if a given level of mask-wearing was achieved vs. no incentives, 3) public commitments via provision of signs to households vs. no public commitments, and 4) additional text message reminders vs. no reminders. There were also three additional household-level cross randomizations: 1) messages focused on community protection vs. self-protection, 2) twice-weekly text message reminders, and 3) asking households to make a verbal commitment to mask-wearing. The households received differently colored masks depending on the sub-arm to which they were randomized, and the color schemes themselves were randomized village-by-village. The behavioral outcomes for this study were measured by an enumerator who recorded behaviors in a public space in each village. The enumerator noted whether people were wearing masks, the colors of those masks, whether both mouth and nose were covered, and whether people were keeping physical distance from each other. Behavioral data was measured up to 10 weeks following the start of the intervention, and additionally 20-27 weeks after baseline. One member per household completed phone surveys at weeks 5 and 9 to assess SARS-CoV-2 symptom prevalence (consistent with the WHO COVID-19 case definition for suspected or probable cases with an epidemiologic link) in the previous month. Participants who reported symptoms were tested for IgG antibodies against SARS-COV-2 during weeks 10-12.

Summary of Main Findings

Symptomatic seroprevalence: Symptom data was collected from 98% of the study population; 8.6% of participants in control villages reported having COVID-19 symptoms, while the figure for intervention villages was 7.6%. Of all 13,893 symptomatic participants, 40% consented to providing blood, and 37% were tested for SARS-CoV-2 antibodies. The adjusted prevalence ratio for symptomatic seroprevalence was 0.907 (95% CI: 0.817 to 0.997), implying a 9% relative reduction in symptomatic seroprevalence comparing intervention villages to control villages. When considering only symptoms, the adjusted prevalence ratio was 0.88 (0.83 to 0.93), implying a 12% reduction in self-reported COVID-19 symptoms during the study period for intervention villages relative to control villages. Subgroup analyses suggested greater reductions in symptomatic seroprevalence for surgical masks compared to cloth masks, and for older participants relative to younger participants. Among participants aged 60 years and older, the adjusted prevalence ratio was 0.65 (0.46 to 0.85), implying a 35% reduction in symptomatic seroprevalence in intervention villages.

Mask-wearing behavior: The estimated prevalence of mask-wearing behavior was 13% in the control group and 42% in the intervention villages, implying that the intervention increased mask-wearing behavior by 29 percentage points. Models controlling for baseline characteristics of villages (baseline mask-wearing, baseline SARS-CoV-2 symptom prevalence) produced the same result. Physical distancing behavior also increased from 24% in the control arms to 29% in the intervention arms, suggesting that increased mask wearing did not cause net risk-compensating behaviors. Mask wearing behavior effects persisted for the full 10-week period of the study; however, by weeks 20-27, mask-wearing in intervention villages declined to 22% while mask-wearing in control villages declined to 14%. None of the cross-randomized interventions (e.g. changes in messaging, monetary incentives, etc.) had any substantial effects on mask-wearing behavior. Evidence from pilot studies indicated that the primary mechanism of the intervention’s effectiveness was promotion of mask-wearing in public spaces.

Study Strengths

This study was a very large and well-designed cluster randomized controlled trial of a realistic intervention. Outcome measures included directly observed behavior, rather than self-reported behavior. Symptom data was measured in a very high proportion of participating households. Analyses were pre-specified.

Limitations

The outcome measure– the proportion of individuals who reported symptoms and who tested positive for antibodies– is a poor proxy for actual SARS-CoV-2 infections during the study period. Moreover, only 40% of those reporting SARS-CoV-2 symptoms consented to providing a blood sample for antibody testing. If there were systematic differences between intervention and control villages in the proportion of antibody-positive individuals among the >60% of symptomatic individuals who were not tested, the results would be biased. As this was a cluster randomized trial, the study could not link individual mask-wearing behavior with incident SARS-CoV-2 infection, and could only measure putative effects on community-level transmission. It is unclear whether the serological assay used to assess the primary outcome was validated in the population under study, or when serological measurements were taken relative to symptom onset. Furthermore, using symptomatic seroprevalence as an outcome means that authors could not distinguish between effects on infections and on symptom severity. Another key limitation is that the persons recording the behavior data could not be blinded to whether the village was a control or intervention arm, leaving open the possibility that data recorders could have been influenced by knowledge of the study arm. People from control villages may have acquired masks or encountered mask promotion in nearby intervention villages, which would dilute the apparent effectiveness of the intervention on behavior. Finally, it is unclear whether or how the intervention would need to be modified to obtain similar results outside the setting of Bangladesh.

Value added

This study is the largest and best-designed randomized controlled trial to date of a realistic non-pharmaceutical intervention on SARS-CoV-2 transmission.

Our take —

Although awake prone positioning has gained favor in clinical practice for treatment of COVID-19 patients requiring high-flow oxygen supplementation, no clinical trials to date had assessed its efficacy. This large meta-trial of 1,121 patients (including six individual randomized trials from Canada, France, Ireland, Mexico, Spain, and the USA) evaluated the efficacy of awake prone positioning, in addition to standard high-flow nasal cannula, for preventing intubation or death among COVID-19 patients with acute hypoxemic respiratory failure. Patients in the intervention arm were 14% less likely to have treatment failure (intubation or death by 28 days after enrollment) and more likely to be weaned off high-flow nasal cannula compared to the standard of care. On the other hand, among those who survived, the two groups spent a similar amount of time in the hospital (16.4 vs. 16.5 days in intervention vs. control groups, respectively) and, among those intubated, on invasive mechanical ventilation (12.4 vs. 12.4 days). Despite some possible sources of bias, this study provides strong evidence of the benefits for awake prone positioning among patients with severe COVID-19 pneumonia in six upper-middle and high-income settings.

Study design

Randomized Controlled Trial

Study population and setting

This collaborative, prospective meta-trial combined individual-level data from six randomized clinical trials in hospitals from six countries (Ireland, USA, Mexico, Spain, Canada and France) to evaluate the efficacy of awake prone positioning for COVID-19 patients between April 2, 2020 and January 26, 2021. The study included patients with acute hypoxemic respiratory failure (requiring respiratory support with high-flow nasal cannula and with a ratio of peripheral arterial oxygen saturation to the fraction of expired oxygen (SpO2: FiO2) of 315 or lower) due to clinically confirmed or suspected COVID-19 pneumonia. The study excluded those with body mass index above 40 kg/m2, pregnant women, hemodynamically unstable patients, those unable to provide consent, and those with a contraindication to awake prone positioning. The primary outcome was treatment failure, defined as intubation or death. Secondary outcomes included intubation, death, use of noninvasive mechanical ventilation, time to weaning off high-flow nasal cannula, time to treatment failure, time to intubation, and time to death. The relative risk for the primary outcome was estimated with a mixed effect log-binomial model. Proportional hazards models were used to estimate differences in times to events. For intubation, mortality was considered as a competing risk. Analyses were pre-specified, including a subgroup analysis among patients who had SpO2/FiO2 less than 190.

Summary of Main Findings

Among the 1,126 patients in the study, 564 were randomized to the awake prone positioning arm and 557 to the standard of care arm. The median duration of awake prone positioning was 5 hours. In intention-to-treat analysis, 40% of the patients assigned to the intervention arm had been intubated or died by day 28 of enrollment compared to 46% in the standard of care arm (RR=0.86, 95% CI: 0.75 to 0.98). The estimated number of patients who need to be treated with awake prone positioning to prevent one intubation or death was 15 (95%CI: 8 to 156).  Regarding secondary outcomes, patients in the intervention arm were less likely to be intubated (33% vs. 40%) and were more likely to be weaned off high-flow nasal cannula. There were no differences in 28-day mortality, time to death, length of hospital stay, or time for weaning off mechanical ventilation. In the intervention arm, those who were able to maintain prone positioning daily for at least 8 hours were less likely to be intubated or die compared to those who had less than 8 hours of daily prone position (17% vs. 48%).  There was no difference in the incidence of central or arterial line dislodgement between the two groups, and none of the patients had cardiac arrest due to prone positioning.

Study Strengths

This was a large meta-trial including six randomized clinical trials, with a large sample size, coordination across study protocols, and pre-specified analytical plans. The study included trials from six different countries with wide variation in their health care systems, allowing greater confidence in the generalizability of the findings.

Limitations

There was significant variability in the median duration of awake prone positioning across trials, with a total median duration of only 5 hours. It is possible that longer durations could have led to better outcomes. Also, one in ten patients in the control group were treated with awake prone positioning. This, combined with the intention-to-treat analysis, could have resulted in underestimating the true effect of prone positioning in preventing intubation or death. Also, no stratification for the duration of prone positioning was done at study enrollment, which limits the interpretation of lower rates of intubation and death among patients who had eight hours or more of awake prone positioning. The trial could not be blinded, and treatment assignment may have affected clinical decision-making. For example, mechanical ventilation may have been delayed in the intervention arm due to temporary improvement of respiratory parameters during prone positioning. Finally, despite coordination, there were variations across trials in inclusion criteria that may have had unpredictable effects on results.

Value added

This is the first prospective randomized study to evaluate the efficacy of awake prone positioning for COVID-19 patients requiring high flow oxygen supplementation.

Our take —

Moderna’s mRNA-1273 vaccine against COVID-19 was determined to be safe in adolescents ages 12-17. The immune response generated by the vaccine was similar to those in young adults ages 18-25 years that were included in the larger phase 3 trial of adults. The vaccine was estimated to be over 90% effective at preventing COVID-19 in this age group, and therefore there was an overall favorable benefit-risk ratio. The success of this vaccine is important since there are few vaccine options for people in the adolescent age group.

Study design

Randomized Controlled Trial

Study population and setting

This phase 2-3, randomized, placebo-controlled trial tested Moderna’s mRNA-1273 vaccine in healthy male and female adolescents ages 12-17 years old. The trial took place between December 9, 2020 and February 28, 2021 at 26 sites in the United States and included 3,732 participants. Participants were randomized 2:1 to either receive two doses of 100ug of mRNA-1273 or two doses of placebo 28 days apart. Primary objectives were safety of the vaccine, which was tracked through adverse events and data on multi-inflammatory syndrome in children (MIS-C) throughout the trial, and noninferiority of the immune response in the adolescent age group compared to the young adult (18-25) age group. Noninferiority was assessed by measuring neutralizing antibody titers 28 days after the second dose and comparing these values to those of the young adult group. A secondary aim of the study was to gain a preliminary assessment of vaccine efficacy against preventing COVID-19 or asymptomatic SARS-CoV-2, evaluated by PCR testing and clinical symptoms.

Summary of Main Findings

In the safety assessment, the most common solicited reaction was injection site pain after first dose. Other common systemic reactions included fatigue, headache, muscle pain, and chills. There was a higher incidence of adverse events in the vaccine group compared to the placebo group. Additionally, incidence of erythema, or skin redness, was higher in the adolescent group compared to young adults. No deaths, MIS-C or adverse events occurred in either group. The criteria for noninferiority of the immunogenicity were met for both objectives, and it was determined that the vaccine worked as well in adolescents as it does in young adults. Vaccine efficacy was estimated to be 93.3% using the CDC’s definition of COVID-19 with onset at least 14 days after the 2nd dose. For asymptomatic infection, vaccine efficacy was estimated to be 39.2% for the per protocol population, but this is consistent with other age groups in that efficacy against asymptomatic infection is lower than efficacy against symptomatic COVID-19.

Study Strengths

This trial included a modest number of participants in an age group that has been sparsely studied in the realm of COVID-19 vaccines. The data from the adolescents in this study was compared to results from young adults in the phase 3 trial. Also, the young adults had similar demographic characteristics to the adolescents in this trial.

Limitations

The trial population was less diverse, and therefore less representative of the US population, compared to the participants in the phase 3 trial. Over 80% of participants were white. Next, efficacy was difficult to assess here due to a very low incidence of COVID-19 in the participants, with only 4 cases in the placebo group and 0 cases in the vaccine group, therefore the authors used the CDC’s less stringent definition of COVID-19. There was also a relatively low number of asymptomatic cases, resulting in a negative lower boundary of the 95% confidence interval. Finally, safety data was based on assessments for a median of 83 days of follow-up, and therefore any longer-term effects cannot be determined from this study. Although it should be noted that there have been no long-term effects of the vaccine reported in previous trials suggesting this is not a concern.

Value added

First report of safety, immunogenicity, and efficacy results for Moderna’s mRNA-1273 vaccine in adolescents.

Our take —

Given evidence of COVID-related thrombosis (blood clots), these two randomized controlled trials (first, second) assessed whether heparin was better than usual-care blood clot prevention (i.e., thromboprophylaxis) for patients hospitalized with COVID-19. For patients with noncritical COVID-19, therapeutic-dose heparin reduced the need for organ support significantly (19.8% vs. 23.6%) and reduced death (7.3% v 8.2%), albeit non-significantly. In contrast, patients with critical COVID-19 received no benefit from therapeutic-heparin; in fact, patients with critical COVID-19 likely had an increased risk of in-hospital mortality (37.3% vs. 35.5%) and the need for organ support (1 vs. 4 organ support-free days) as compared to standard thromboprophylaxis. Additionally, critically and non-critically ill patients receiving therapeutic heparin were both slightly more likely to have major bleeds. Overall, these studies can inform clinical decision-making regarding blood clot prevention and provide evidence that therapeutic-dose heparin may be beneficial, but only for patients with mild to moderate COVID-19 symptoms.

Study design

Randomized Controlled Trial

Study population and setting

These were two international open-label, multiplatform, randomized controlled trials published concurrently comparing therapeutic dosing of heparin to usual standard thromboprophylaxis in patients hospitalized with Covid-19. The patients were determined to be critically ill based on the need for critical-care organ support (high-flow nasal cannula, mechanical ventilation, extracorporeal life support, vasopressors, or inotropes) at time of enrollment, or noncritically ill otherwise. The primary outcome was number of days free of organ support in the first 21 days, with patients who did not survive to discharge being automatically scored -1.

Summary of Main Findings

Enrollment began in April 2020 for both studies. For critically ill patients, the study enrolled 1207 patients through December 2020, when an interim analysis showed futility. Patients who received therapeutic dose heparin had a median of 1 organ support-free day (IQR -1 to 16) versus 4 (IQR -1 to 16) in the usual standard of care group (OR = 0.93; 95%CI 0.67 – 1.03; posterior probability of futility = 99.9%; posterior probability of inferiority = 95%). 62.7% of patients in the heparin group survived to hospital discharge, versus 64.5% in the usual standard of care group (OR = 0.85; 95%CI = 0.64 – 1.11; posterior probability of inferiority = 89.2%).

For noncritically ill patients, the study enrolled 2244 patients through January 2021, when an interim analysis showed superiority. The median number of organ support-free days was 22 in both groups; 80.2% of noncritically ill patients who received therapeutic dose heparin survived until hospital discharge without needing organ support, versus 76.4% in the standard of care group (absolute difference 4.0%, 95%CI = 0.5 – 7.2). The odds ratio of organ-support free days was 1.27 (95%CI 1.03 – 1.58; posterior probability of superiority 98.6%) and was similarly high after stratification by D-dimer level. Major bleeding occurred in 1.9% of patients in the treatment group, versus 0.9% in the standard of care group, with 3 cases of fatal bleeding in the treatment group, versus 1 in the standard of care group.

Study Strengths

As the studies were paired, the results between the two can be readily controlled and compared. The sample size of both studies was large, allowing for stratified analyses. By using Bayesian analyses, the authors were able to set and use cutoffs to determine when the study was sufficiently powered. The multiplatform nature of the studies also suggests that these findings are generally reproducible in broad clinical contexts.

Limitations

This was a pair of open-label studies, so participants were not blinded to treatment group. This introduced the risk of ascertainment bias, in which a patient on a higher dose of heparin may have been more aggressively monitored for bleeds. The study excluded patients with an increased risk of bleeding, which was important for study balance but excluded a nontrivial amount of people at risk for moderate to severe COVID-19. Standard-of-care thromboprophylaxis varied between sites; most critically ill participants were enrolled in the UK, where standard treatment guidelines included intermediate-level heparin treatment for all COVID-19 patients, which may have impacted between-group comparisons and study generalizability. Early trial conclusion prevented researchers from identifying long-term secondary benefits of treatment.

Value added

These paired studies provide strong evidence that treatment with therapeutic dose heparin (as if the patient had a known venous thromboembolism) is beneficial for reducing in-hospital mortality and the need for organ support among patients with noncritical COVID-19. However, this approach provides no benefit to patients with critical illness (patients needing ICU-level care at time of enrollment), and is likely inferior to standard thromboprophylaxis treatment.

Our take —

This randomized controlled trial conducted in the UK provides strong evidence that doxycycline use did not affect time-to-recovery, risk of hospitalization or death within 28 days compared to usual care in patients with COVID-19 who were older than 65 years, or older than 50 years with a comorbidity that put them at higher risk of severe COVID-19. These findings suggest that routine use of doxycycline in the treatment of COVID-19 is unlikely to be of benefit, except plausibly in cases of known bacterial super-infection.

Study design

Randomized Controlled Trial

Study population and setting

Data for this study come from a subset of participants in the randomized trial of interventions against COVID-19 in older people (PRINCIPLE) trial, which compares therapies for the treatment of COVID-19 patients in the community who are a high-risk for severe disease. The study recruited 2689 patients in the United Kingdom between April 2 and December 14, 2020. Patients were aged 65+ years or 50+ years with comorbidities that increase the risk for severe COVID-19 disease, including being immunocompromised, heart disease, hypertension, lung disease, diabetes, hepatic impairment, neurological problem/stroke, or self-reported BMI >35 kg/m2, and were within 14 days of onset of symptoms with either suspected or PCR-confirmed COVID-19 at the time of enrollment. The study compared the 28-day hospitalization or mortality rates of patients receiving usual care (n = 1013) to patients receiving oral doxycycline in addition to usual care (n = 827). Due to a lower rate of hospitalization and death than anticipated, a Bayesian analysis of self-reported time to recovery was added as a study outcome before any interim analyses were done.

Summary of Main Findings

A Bayesian analysis method was employed in this study to allow for adaptive design of this multi-arm trial. 76.4% of patients who received doxycycline reported recovery within 28 days of randomization, compared to 75.6% in the usual care group. The median time to recovery was 9.6 days in the doxycycline group, vs. 10.1 days in the usual care group (HR 1.04, 95% credible interval 0.93 – 1.17). Probability that time to recovery was shorter in the doxycycline group was 0.74, and the probability of a clinically meaningful benefit (recovery hastened by >1.5 days) was 0.10, failing to meet the 0.99 threshold of superiority via the Bayesian analysis. Rate of hospitalization or death within 28 days was 5.3% in the doxycycline group, vs. 4.5% in the usual care group (absolute % difference = -0.5%, 95% credible interval -2.6 – 1.4), which gives a probability of superiority of 0.30.

Study Strengths

This study targets a population for which early outpatient treatment of COVID-19 may greatly reduce the morbidity associated with severe COVID-19 and a possible extended hospital or intensive care stay. The study was large, and part of a larger multiplatform, multi-center study, which has previously published findings about other pharmaceutical interventions for COVID-19, including hydroxychloroquine, azithromycin, and budesonide, which suggests that the results are reliable.

Limitations

Only 51.2% of the participants had a PCR-confirmed SARS-CoV-2 infection, which means that almost half the patients were enrolled based on clinical judgment, which means that many patients may not have had COVID-19. The overall rate of hospitalization and mortality was low overall, and so one of the co-primary endpoints was self-reported time to initial recovery. COVID-19 can occasionally continue to cause chronic symptoms after the initial recovery phase, and this was not closely monitored in this study, especially beyond 28 days.

Value added

This is the first major published randomized clinical trial regarding the use of doxycycline in an outpatient setting for mild cases of COVID-19 among persons at high risk for COVID-19 hospitalization and death and fails to show any benefit of doxycycline treatment in the community.

Our take —

Global vaccination against COVID-19 will continue for the remainder of 2021, overlapping with seasonal influenza vaccine administration. Provision of both vaccines in a single visit would help maximize vaccine compliance, but there have been concerns regarding the safety and efficacy of co-administered vaccines. This study, available as a preprint and thus not yet peer-reviewed, demonstrates that co-administration of vaccines for SARS-CoV-2 and influenza is both safe and effective. While further research is needed, particularly among those over 65 years of age, these data could be used to guide national vaccine policy decision making, since vaccine co-administration appears to be a viable and safe option.

Study design

Randomized Controlled Trial, Non-Randomized Trial

Study population and setting

Conducted as a substudy of the phase 3 trial for NVX-CoV2373 (Novavax; September-November 2020), this study assessed the safety and efficacy of open label influenza vaccine coadministration with the first dose of NVXCoV2373 (n= 217) vs. placebo (n=214). Rates of minor vaccine reactions (collected via electronic diary) and adverse events were compared to a reactogenicity cohort from the main study (n=2000). Immunogenicity against influenza was assessed using a hemagglutination inhibitor assay, while that against SARS-CoV-2 was assessed by quantifying anti-spike IgG with ELISA; results were compared to an immunogenicity cohort from the main study (n=900). The primary vaccine efficacy endpoint was based on PCR detection of symptomatic SARS-CoV-2 infection at least seven days after administration of the second vaccine dose in participants aged 18 to 64 years who had not been previously infected with SARS-CoV-2 (n=360). Results were compared to vaccine efficacy for the per-protocol population of the main study age 18 to 64 years (n= 10,129), as well as vaccine efficacy against the Alpha variant for the per-protocol population of the main study (n=14,040).

Summary of Main Findings

Participants who received both vaccines had an increased frequency of minor reactions, including pain at the injection site, muscle aches, and fatigue. True adverse events were infrequent and not associated with vaccine co-administration. There was no significant change in the immune response to the influenza vaccine as a function of co-administration. However, antibody responses generated to NVX-CoV2373 were reduced among participants who had received both vaccines, as compared to those who had received only NVX-CoV2373. Vaccine efficacy in the co-administration substudy was 87.5% (CI: -0.2 – 98.4%), as compared to 89.8% (95% CI: 79.7 – 95.5%) for the main study. All substudy breakthrough infections were due to the Alpha variant; vaccine efficacy in the main study against the Alpha variant was 86.3% (95% CI: 71.3 – 93.5%).

Study Strengths

This study employed a placebo-controlled design to assess the safety and efficacy of coadministration of vaccines for SARS-CoV-2 and influenza. Influenza vaccines were assigned based on the public health guidelines for each age group. The study included laboratory measures of immunogenicity, as well as vaccine efficacy based on breakthrough infection events.

Limitations

Participation in the co-administration substudy, the reactogenicity cohort, and the immunogenicity cohort was not randomized. Substudy participants were younger, more diverse, and had fewer comorbidities than those in the main study. Influenza vaccine was administered open label to allow participants to discriminate between vaccine sites for reaction documentation. NVX-CoV2373 immunogenicity was assessed based on total antibody titer to spike protein, not neutralizing antibody titer. Due to the small number of substudy endpoint cases, 95% confidence intervals for NVX-CoV2373 efficacy were quite broad and the lower bound contained zero. The small number of breakthrough infection events also prevented the assessment of co-administered vaccine efficacy in individuals age 65 or older.

Value added

This is the first study demonstrating the safety and efficacy of coadministration of vaccines for SARS-CoV-2 and influenza.

Our take —

This double-blind, multicenter, 1:1 randomized controlled trial was conducted between March and December 2020 among 4,488 non-hospitalized patients diagnosed with COVID-19 who were either aged 70+ years or aged >40 years with at least one risk factor for severe disease (i.e., common comorbidities, shortness of breath, fever > 38.4 degrees C, or lab abnormalities). Patients were enrolled within 24 hours of their diagnosis. Then, within 4 hours of their enrollment, patients received their treatment (colchicine or placebo) via home-delivery. The results suggest that treatment with oral colchicine (0.5 mg twice daily for 3 days and then once daily for 27 days) reduced the risk of hospitalization or death from COVID-19. While this result did not reach statistical significance because the trial was stopped early, additional trials showing similar effects would strengthen the case for considering colchicine to prevent adverse short-term outcomes from COVID-19.

Study design

Randomized Controlled Trial

Study population and setting

The COLCORONA trial was a phase 3, double-blind, multicenter randomized controlled trial that compared treatment with oral colchicine (0.5 mg twice a day for 3 days and subsequently once a day for 27 more days) against placebo. It enrolled 4488 participants (n=2235 colchicine arm, n=2253 placebo arm) between March 23 and December 22, 2020 in Brazil, Canada, Greece, South Africa, Spain, and the United States. Participants were eligible if they had been diagnosed with COVID-19 within 24 hours of enrollment but were not being considered for immediate hospitalization, and were either >70 years old or >40 years old with at least one of: BMI > 30 kg/m2, diabetes, systolic blood pressure > 150 mmHg, known respiratory or heart disease, fever > 38.4 deg C, dyspnea, had more than one low cell count, or a high neutrophil count with lymphocytopenia. Eligible participants were 1:1 randomized in block sizes of six to 0.5 mg of colchicine twice daily for three days and then daily for 27 days or a matching placebo. The primary endpoint was a composite of death or need for hospitalization due to COVID-19 within 30 days after randomization, and the one planned subgroup analysis included the participants (n=2075 colchicine, n=2084 placebo) who enrolled after a positive PCR test.

Summary of Main Findings

In an intention-to-treat analysis, 104/2235 (4.7%) patients treated with colchicine had a primary endpoint event (death and/or hospitalization due to COVID-19), compared to 131/2253 (5.8%) patients in the placebo group (OR 0.79; 95%CI 0.61,1.03). Subgroup analysis of only patients with PCR-confirmed COVID-19 (n=2075 colchicine arm, n=2084 placebo arm) revealed a reduction in primary endpoint event among patients treated with colchicine (4.6% vs. 6.0% placebo; OR 0.75; 95%CI 0.57,0.99). Post-hoc analyses reveal a significant reduction in the rate of hospitalization (OR 0.75; 95%CI 0.57,0.99) but not in the mortality rate (OR 0.56; 95%CI 0.19,1.66). Stratification of the patients by any of the aforementioned risk factors showed nonsignificant decreases in the primary endpoint rate. Participants in the colchicine arm were more likely to have gastrointestinal adverse effects than those in the placebo arm (23.9% vs 13.8%).

Study Strengths

The study population consisted of patients with above-average risk for severe COVID-19 but who were not immediately considered for hospitalization, which describes a sizeable proportion of COVID-19 cases. The double-blinded, randomized participant allocation reduced the risk of unmeasured confounding, selection bias, and analytical bias. Lastly, the enrolled patients were 53.9% women, which is more representative of the population at large, compared to trials with a heavy male-predominant population.

Limitations

The study only recruited 75% of the anticipated number of patients, which left the study slightly underpowered for the composite primary endpoint of death or hospitalization due to COVID-19. Furthermore, they did not utilize a stratified randomization scheme or condition on covariates associated with the outcome, both of which could have increased power and mitigated the fact that they ended the study early. Also, colchicine treatment was only assessed with a 30-day course, and endpoints were measured only up to 30 days from randomization, which limits the ability to make conclusions about shorter courses of treatment, longer-term outcomes of colchicine treatment, or the potential impact of colchicine on COVID-19 symptoms that linger beyond the initial infection. Finally, the majority of participants lived in Canada or the United States, potentially limiting generalizability to regions outside of North America.

Value added

This study suggests that oral colchicine can be used as an effective treatment in preventing death or hospitalization among individuals with an elevated risk profile for severe COVID-19 shortly after a diagnosis.