Coronavirus Disease 2019 Trials Research Articles

A Bayesian multivariate hierarchical model for developing a treatment benefit index using mixed types of outcomes

BackgroundPrecision medicine has led to the development of targeted treatment strategies tailored to individual patients based on their characteristics and disease manifestations. Although precision medicine often focuses on a single health outcome for individualized treatment decision rules (ITRs), relying only on a single outcome rather than all available outcomes information leads to suboptimal data usage when developing optimal ITRs.MethodsTo address this limitation, we propose a Bayesian multivariate hierarchical model that leverages the wealth of correlated health outcomes collected in clinical trials. The approach jointly models mixed types of correlated outcomes, facilitating the “borrowing of information” across the multivariate outcomes, and results in a more accurate estimation of heterogeneous treatment effects compared to using single regression models for each outcome. We develop a treatment benefit index, which quantifies the relative benefit of the experimental treatment over the control treatment, based on the proposed multivariate outcome model.ResultsWe demonstrate the strengths of the proposed approach through extensive simulations and an application to an international Coronavirus Disease 2019 (COVID-19) treatment trial. Simulation results indicate that the proposed method reduces the occurrence of erroneous treatment decisions compared to a single regression model for a single health outcome. Additionally, the sensitivity analyses demonstrate the robustness of the model across various study scenarios. Application of the method to the COVID-19 trial exhibits improvements in estimating the individual-level treatment efficacy (indicated by narrower credible intervals for odds ratios) and optimal ITRs.ConclusionThe study jointly models mixed types of outcomes in the context of developing ITRs. By considering multiple health outcomes, the proposed approach can advance the development of more effective and reliable personalized treatment.

Lower or Higher Oxygenation Targets in Patients With COVID-19 in the ICU: A Secondary Bayesian Analysis of the Handling Oxygenation Targets in COVID-19 Trial

BackgroundIn the Handling Oxygenation Targets in COVID-19 (HOT-COVID) trial, a partial pressure of arterial oxygen (PaO2) target of 60 mmHg compared to 90 mmHg resulted in more days alive without life support at 90 days in adult ICU patients with coronavirus disease 2019 (COVID-19) and hypoxemia. The trial was stopped after enrolling 726 of 780 planned patients due to slow recruitment. Here, we present the preplanned Bayesian analysis of the HOT-COVID trial. Research QuestionWhat are the probabilities of any and of clinically relevant benefits from a PaO2 target of 60 mmHg versus 90 mmHg in adult ICU patients with COVID-19 and hypoxemia, and is there heterogeneity of treatment effects (HTE) according to selected baseline characteristics? Study Designand Methods We analyzed days alive without life support and 90-day mortality in the HOT-COVID intention-to-treat population (n=697) using Bayesian general linear models to assess probabilities for benefit or harm, including clinically relevant benefits defined as >1 day alive without life support and >2 percentage points lower 90-day mortality. HTE was evaluated based on baseline SOFA scores, PaO2:FiO2, norepinephrine doses, and lactate concentrations. ResultsThe mean difference in days alive without life support was 5.7 days (95% credible interval (CrI): 0.2 to 11.2), with a 95.2% probability of clinically relevant benefit and a 98.0% probability of any benefit from the lower PaO2 target. The risk difference in 90-day mortality was -4.6 percentage points (95% CrI: -11.8 to 2.6), with a 76.5% probability of a clinically relevant benefit from the lower target. HTE analyses revealed potential interaction with baseline norepinephrine dose and lactate concentrations for both outcomes. InterpretationIn ICU patients with COVID-19 and hypoxemia, we found high probability for a clinically relevant benefit of targeting a PaO2 of 60 mmHg vs. 90 mmHg on number of days alive without life support.

The relationship between trust in federal oversight of vaccine safety and willingness to participate in COVID-19 clinical trials: a repeated measures study of Philadelphia residents (September 2021 – March 2023)

BackgroundThe Coronavirus Disease 2019 (COVID-19) pandemic precipitated an urgent need for clinical trials to discover safe and efficacious treatments. We examined how COVID-19 experiences, clinical trial awareness, and trust in the vaccine safety process were associated with willingness to participate in COVID-19 clinical trials. The objective was to investigate the relationship between trust in federal oversight of vaccine safety and willingness to participate in clinical trials for COVID-19 treatment across four distinct time points over an 18-month period during the COVID-19 pandemic.MethodsWe used four waves of data collected from September 2021 to March 2023 among 582 Philadelphia residents (with a missing data rate of 0.9%). Generalized estimating equations estimated the association between willingness to participate in COVID-19 clinical trials and participants’ trust in the federal government’s oversight of COVID-19 vaccine safety, COVID-19-related variables (COVID-19 related health challenges, history of COVID-19 infection), awareness of clinical trials and how to enroll in them, and sociodemographic characteristics (age, race/ethnicity, sexual orientation, gender, parental status, education, and insurance).ResultsOn average, willingness to participate in a COVID-19 clinical trial was positively associated with greater trust in the federal government’s oversight of vaccine safety [β = 0.34, 95% confidence interval (CI): 0.15–0.53], having COVID-19 (β = 0.40, 95% CI: 0.08–0.73), awareness of clinical trials (β = 0.38, 95% CI: 0.04–0.73), and knowledge of how to enroll (β = 0.83, 95% CI: 0.44–1.23). Among sociodemographic characteristics, race/ethnicity (p = 0.001) and gender (p = 0.018) were identified as predictors for COVID-19 trial willingness.ConclusionWillingness to participate in clinical trials may be bolstered by strengthening the public’s trust in the federal government’s role within vaccine safety oversight, increasing the perceived relevance of clinical trials to individuals’ health and well-being, and offering tailored information to educate diverse communities about ongoing trials and how to enroll in them.

Effect of early administration of dexamethasone in patients with COVID-19 pneumonia without acute hypoxemic respiratory failure and risk of development of acute respiratory distress syndrome: EARLY-DEX COVID-19 trial.

Corticosteroids are among the drugs demonstrating a mortality benefit for coronavirus disease 2019 (COVID-19). The RECOVERY trial highlighted that dexamethasone reduced 28-day mortality for hospitalized COVID-19 patients requiring either supplemental oxygen or mechanical ventilation. It is noted that approximately 30% of COVID-19 patients, initially presenting with mild symptoms, will advance to acute respiratory distress syndrome (ARDS), especially those with detectable laboratory markers of inflammation indicative of disease progression. Our research aimed to explore the efficacy of dexamethasone in preventing the progression to ARDS in patients hospitalized with COVID-19 pneumonia who do not yet require additional oxygen but are at high risk of developing ARDS, potentially leading to a reduction in morbimortality. In this multicenter, randomized, controlled trial, we evaluated the impact of dexamethasone on adult patients diagnosed with COVID-19 pneumonia who did not need supplementary oxygen at admission but were identified as having risk factors for ARDS. The risk of ARDS was determined based on specific criteria: elevated lactate dehydrogenase levels over 245 U/L, C-reactive protein levels exceeding 100 mg/L, and a lymphocyte count below 0.80 × 109/L. Participants were randomly allocated to either receive dexamethasone or the standard care. The primary endpoints included the incidence of moderate or severe ARDS and all-cause mortality within 30 days post-enrollment. One hundred twenty-six patients were randomized. Among them, 41 were female (30.8%), with a mean age of 48.8 ± 14.4 years. Ten patients in the dexamethasone group (17.2%) and ten patients in the control group (14.7%) developed moderate ARDS with no significant differences. Mechanical ventilation was required in six patients (4.7%), with four in the treatment group and two in the control group. There were no deaths during hospitalization or during follow-up. An intermediate analysis for futility showed some differences between the control and treatment groups (Z = 0.0284). However, these findings were within the margins close to the region where the null hypothesis would not be rejected. In patients with COVID-19 pneumonia without oxygen needs but at risk of progressing to severe disease, early dexamethasone administration did not lead to a decrease in ARDS development. ClinicalTrials.gov, identifier NCT04836780.

COVID-19 Convalescent Plasma Therapy: Long-term Implications.

The long-term effect of coronavirus disease 2019 (COVID-19) acute treatments on postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) is unknown. The CONTAIN-Extend study explores the long-term impact of COVID-19 convalescent plasma (CCP) therapy on postacute sequelae of SARS-CoV-2 infection (PASC) symptoms and general health 18 months following hospitalization. The CONTAIN-Extend study examined 281 participants from the original CONTAIN COVID-19 trial (CONTAIN-RCT, NCT04364737) at 18 months post-hospitalization for acute COVID-19. Symptom surveys, global health assessments, and biospecimen collection were performed from November 2021 to October 2022. Multivariable logistic and linear regression estimated associations between the randomization arms and self-reported symptoms and Patient-Reported Outcomes Measurement Information System (PROMIS) scores and adjusted for covariables, including age, sex, race/ethnicity, disease severity, and CONTAIN enrollment quarter and sites. There were no differences in symptoms or PROMIS scores between CCP and placebo (adjusted odds ratio [aOR] of general symptoms, 0.95; 95% CI, 0.54-1.67). However, females (aOR, 3.01; 95% CI, 1.73-5.34), those 45-64 years (aOR, 2.55; 95% CI, 1.14-6.23), and April-June 2020 enrollees (aOR, 2.39; 95% CI, 1.10-5.19) were more likely to report general symptoms and have poorer PROMIS physical health scores than their respective reference groups. Hispanic participants (difference, -3.05; 95% CI, -5.82 to -0.27) and Black participants (-4.48; 95% CI, -7.94 to -1.02) had poorer PROMIS physical health than White participants. CCP demonstrated no lasting effect on PASC symptoms or overall health in comparison to the placebo. This study underscores the significance of demographic factors, including sex, age, and timing of acute infection, in influencing symptom reporting 18 months after acute hypoxic COVID-19 hospitalization.

Impact of Allocation Concealment and Blinding in Trials Addressing Treatments for COVID-19: A Methods Study.

We aimed to assess the impact of allocation concealment and blinding on the results of coronavirus disease 2019 (COVID-19) trials, using the World Health Organization COVID-19 database (to February 2022). We identified 488 randomized trials comparing drug therapeutics with placebo or standard care in patients with COVID-19. We performed random-effects meta-regressions comparing the results of trials with and without allocation concealment and blinding of health-care providers and patients. We found that, compared with trials with allocation concealment, trials without allocation concealment may estimate treatments to be more beneficial for mortality, mechanical ventilation, hospital admission, duration of hospitalization, and duration of mechanical ventilation, but results were imprecise. We did not find compelling evidence that, compared with trials with blinding, trials without blinding produce consistently different results for mortality, mechanical ventilation, and duration of hospitalization. We found that trials without blinding may estimate treatments to be more beneficial for hospitalizations and duration of mechanical ventilation. We did not find compelling evidence that COVID-19 trials in which health-care providers and patients are blinded produce different results from trials without blinding, but trials without allocation concealment estimate treatments to be more beneficial compared with trials with allocation concealment. Our study suggests that lack of blinding may not always bias results but that evidence users should remain skeptical of trials without allocation concealment.

NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis.

Immunothrombosis-immune-mediated activation of coagulation-is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as in severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines of the interleukin (IL)-1 family, IL-1β and IL-18, and induces pyroptotic cell death. Activation of the NLRP3 inflammasome pathway also promotes immunothrombotic programs including release of neutrophil extracellular traps and tissue factor by leukocytes, and prothrombotic responses by platelets and the vascular endothelium. NLRP3 inflammasome activation occurs in patients with COVID-19 pneumonia. In preclinical models, NLRP3 inflammasome pathway blockade restrains COVID-19-like hyperinflammation and pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety and efficacy and is approved for the treatment of hypoxaemic COVID-19 patients with early signs of hyperinflammation. The non-selective NLRP3 inhibitor colchicine reduced hospitalization and death in a subgroup of COVID-19 outpatients but is not approved for the treatment of COVID-19. Additional COVID-19 trials testing NLRP3 inflammasome pathway blockers are inconclusive or ongoing. We herein outline the contribution of immunothrombosis to COVID-19-associated coagulopathy, and review preclinical and clinical evidence suggesting an engagement of the NLRP3 inflammasome pathway in the immunothrombotic pathogenesis of COVID-19. We also summarize current efforts to target the NLRP3 inflammasome pathway in COVID-19, and discuss challenges, unmet gaps, and the therapeutic potential that inflammasome-targeted strategies may provide for inflammation-driven thrombotic disorders including COVID-19.

NLRP3, the inflammasome and COVID-19 infection.

Severe coronavirus disease 2019 (COVID-19) is characterized by respiratory failure, shock or multiorgan dysfunction, often accompanied by systemic hyperinflammation and dysregulated cytokine release. These features are linked to the intense and rapid stimulation of the innate immune response. The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a central player in inflammatory macrophage activation which via caspase-1 activation leads to the release of the mature forms of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and via cleavage of Gasdermin D pyroptosis, an inflammatory form of cell death. Here, we discuss the role of NLRP3 activation in COVID-19 and clinical trials currently underway to target NLRP3 to treat severe COVID-19.

COVID-19 site readiness initiative: Building clinical trial capacity for vaccine efficacy trials in Latin America in response to the pandemic

According to the World Health Organization, the American region has the highest coronavirus disease-2019 (COVID-19) cases and deaths since the start of the pandemic. This humanitarian tragedy presented the possibility of generating efficacy data from COVID-19 vaccine trials. The race to develop successful vaccines imposed a high demand for trained healthcare personnel and clinical sites where large scale randomized clinical trials could be conducted. This site readiness initiative, funded by the Bill and Melinda GatesFoundation (BMGF), was carried out to rapidly build site capacity for running COVID-19 vaccine trials in Latin America.Twenty-two sites across 7 countries were selected and received funding. Site selection was based on defined feasibility criteria which deemed these sites as suitable for running vaccine efficacy trials. Criteria for selection included investigator and core permanent staff experience, public health measures in place for COVID-19, import/export requirements for study drug and biological specimens, a clear and accelerated ethical and regulatory approval process for COVID-19 trials. Training was tailored and delivered according to the experience level of the investigator and site staff, and included GCP training, standard operating procedures (SOP) fundamentals, conducting vaccine trials, COVID-19 pathophysiology, and vaccine trials lessons learned. Most of the grant funds were utilized for space expansion and renovation (46 %) followed by purchase of equipment (36 %); the remaining 18 % was spent on human resources. By the end of this site readiness initiative project, which took approximately 4 months, 21 of 22 (95 %) sites had agreements in place or were in discussions with sponsors to conduct large scale COVID-19 vaccine trials.

Investigation of the effect of the angiotensin II type 2 receptor (AT2R) agonist C21 on plasma NT-proBNP, a diagnostic biomarker, in subjects hospitalised with COVID-19

Abstract The prohormone N-terminal pro-B-type natriuretic peptide (NT-proBNP) is released from stretched cardiac myocytes and is a diagnostic biomarker for heart failure and cardiac dysfunction as well as pulmonary embolism and pneumonia that are frequent complications to severe Coronavirus Disease 2019 (COVID-19). NT-proBNP is frequently elevated in COVID-19. In a recent publication, it was demonstrated that NT-proBNP was strongly associated with mortality in patients with COVID-19, and further investigation of its usefulness as a prognostic tool to predict disease outcomes in COVID-19 was suggested (1). In the recently completed phase 2 trial (angiotensin II type 2 receptor agonist COVID-19 trial [ATTRACT]; NCT04452435) in subjects hospitalised with COVID-19, it was investigated whether treatment with the AT2R agonist C21 for 7 days affected the release of the plasma biomarker NT-proBNP. ATTRACT was a randomised, double-blind, placebo-controlled, phase 2 trial that investigated the safety and efficacy of C21 treatment (100 mg twice daily) for 7 days in hospitalised subjects with COVID-19, not requiring mechanical ventilation. The results of the trial demonstrated that treatment with C21 on top of standard of care (vast majority of patients received glucocorticoids) significantly reduced the proportion of subjects requiring supplemental oxygen at Day 14, indicating faster recovery with C21 treatment compared to placebo. Blood samples for exploratory analysis were taken before and after 7 days of treatment with C21 or placebo. Plasma NT-proBNP was markedly elevated in both treatment groups before treatment, with average values of 357 and 438 pg/mL in the placebo and C21 groups, respectively, as compared to normal levels of approximately <100 pg/mL. After 7 days of treatment, the C21 group experienced a dramatic reduction in plasma NT-proBNP (by 259 pg/mL) as compared to the placebo group (63 pg/mL) (p=0.02). The results show that short-term C21 treatment decreased the release of NT-proBNP in subjects hospitalised with COVID-19. Further investigations are needed to elucidate whether this is related to effects on COVID-19-induced pulmonary damage or direct protective effects on the heart. We are currently conducting a global phase 3 trial (VP-C21–008) further investigating the effect of C21 in subjects hospitalised with COVID-19 including determination of NT-proBNP. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Vicore Pharma AB

Probiotics: A gut response to the COVID-19 pandemic but what does the evidence show?

Since the global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), research has focused on understanding the etiology of coronavirus disease 2019 (COVID-19). Identifying and developing prophylactic and therapeutics strategies to manage the pandemic is still of critical importance. Among potential targets, the role of the gut and lung microbiomes in COVID-19 has been questioned. Consequently, probiotics were touted as potential prophylactics and therapeutics for COVID-19. In this review we highlight the role of the gut and lung microbiome in COVID-19 and potential mechanisms of action of probiotics. We also discuss the progress of ongoing clinical trials for COVID-19 that aim to modulate the microbiome using probiotics in an effort to develop prophylactic and therapeutic strategies. To date, despite the large interest in this area of research, there is promising but limited evidence to suggest that probiotics are an effective prophylactic or treatment strategy for COVID-19. However, the role of the microbiome in pathogenesis and as a potential target for therapeutics of COVID-19 cannot be discounted.

Readmissions, Postdischarge Mortality, and Sustained Recovery Among Patients Admitted to Hospital With Coronavirus Disease 2019 (COVID-19).

BackgroundMany interventional in-patient COVID-19 trials assess primary outcomes through day 28 post-randomization. Since a proportion of patients experience protracted disease or relapse, such follow-up period may not fully capture the course of the disease, even when randomization occurs a few days after hospitalization.MethodsAmong adults hospitalized with COVID-19 in Eastern Denmark from March 18, 2020 - January 12, 2021 we assessed: all-cause mortality, recovery and sustained recovery 90 days after admission, and readmission and all-cause mortality 90 days after discharge. Recovery was defined as hospital discharge and sustained recovery as recovery and alive without readmissions for 14 consecutive days.ResultsAmong 3,386 patients included in the study 2,796 (82.6%) reached recovery and 2,600 (77.0%) achieved sustained recovery. Of those discharged from hospital, 556 (19.9%) were readmitted, and 289 (10.3%) died. Overall, the median time to recovery was 6 days (Interquartile range (IQR), 3-10), and 19 days (IQR, 11-33) among patients in intensive care in the first two days of admission.ConclusionsPost-discharge readmission and mortality rates were substantial. Therefore, sustained recovery should be favored to recovery outcomes in clinical COVID-19 trials. A 28-day follow-up period may be too short the critically ill.

Prescribing Nirmatrelvir/Ritonavir for COVID-19 in Advanced CKD.

Prescribing Nirmatrelvir/Ritonavir for COVID-19 in Advanced CKD.

Applying Lessons Learned From COVID-19 Therapeutic Trials to Improve Future ALI/ARDS Trials.

Host-directed therapeutics targeting immune dysregulation are considered the most promising approach to address the unmet clinical need for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19). To better understand the current clinical study landscape and gaps in treating hospitalized patients with severe or critical COVID-19, we identified COVID-19 trials developing host-directed therapies registered at ClinicalTrials.gov and discussed the factors contributing to the success vs failure of these studies. We have learned, instead of the one-size-fits-all approach, future clinical trials evaluating a targeted immunomodulatory agent in heterogeneous patients with ALI/ARDS due to COVID-19 or other infectious diseases can use immune-based biomarkers in addition to clinical and demographic characteristics to improve patient stratification and inform clinical decision-making. Identifying distinct patient subgroups based on immune profiles across the disease trajectory, regardless of the causative pathogen, may accelerate evaluating host-directed therapeutics in trials of ALI/ARDS and related conditions (eg, sepsis).

A new day for human challenge trials?

Two years into the coronavirus disease 2019 (COVID-19) pandemic and following several hot debates, the world’s first COVID-19 human challenge trial has recently been published by Killingley et al. We review its findings and explain why this particular juncture in time makes additional challenge trials for COVID-19 and for other diseases justified and important.

COVID-19 Trials: Who Participates and Who Benefits?

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately afflicted vulnerable populations. Older adults, particularly residents of nursing facilities, represent a small percentage of the population but account for 40% of mortality from COVID-19 in the United States. Racial and ethnic minority individuals, particularly Black, Hispanic, and Indigenous Americans have experienced higher rates of infection and death than the White population. Although there has been an unprecedented explosion of clinical trials to examine potential therapies, participation by members of these vulnerable communities is crucial to obtaining data generalizable to those communities. We undertook an open-label, factorial randomized clinical trial examining hydroxychloroquine and/or azithromycin for hospitalized patients. Of 53 screened patients, 11 (21%) were enrolled. Ten percent (3/31) of Black patients were enrolled, 33% (7/21) of White patients, and 50% (6/12) of Hispanic patients. Forty-seven percent (25/53) of patients declined participation despite eligibility; 58%(18/31) of Black patients declined participation. Forty percent (21/53) of screened patients were from a nursing facility and 10% (2/21) were enrolled. Enrolled patients had fewer comorbidities than nonenrolled patients: median modified Charlson comorbidity score 2.0 (interquartile range 0-2.5), versus 4.0 (interquartile range 2-6) for nonenrolled patients (P = 0.006). The limitations of the study were the low participation rate and the multiple treatment trials concurrently recruiting at our institution. The high rate of nonparticipation in our trial of nursing facility residents and Black people emphasizes the concern that clinical trials for therapeutics may not target key populations with high mortality rates.

Technical procedures and REDCap tools for internet-based clinical trials

In March of 2020 our team of researchers developed and opened three clinical trials to investigate hydroxychloroquine as prophylaxis or treatment for the coronavirus disease 2019 (COVID-19). We simultaneously built corresponding Research Electronic Data Capture (REDCap) projects for these low-touch, remote trials that relied on participant-reported data. REDCap has built-in features that support pragmatic, internet-based studies, and REDCap is flexible enough to allow creative solutions for specific trials. We describe challenges, choices, and suggestions based on our experience with REDCap for our COVID-19 trials.

Higher versus lower oxygenation targets in COVID-19 patients with severe hypoxaemia (HOT-COVID) trial: Protocol for a secondary Bayesian analysis.

Respiratory failure is the main cause of mortality and morbidity among ICU patients with coronavirus disease 2019 (COVID-19). In these patients, supplemental oxygen therapy is essential, but there is limited evidence the optimal target. To address this, the ongoing handling oxygenation targets in COVID-19 (HOT-COVID) trial was initiated to investigate the effect of a lower oxygenation target (partial pressure of arterial oxygen (PaO2 ) of 8 kPa) versus a higher oxygenation target (PaO2 of 12 kPa) in the ICU on clinical outcome in patients with COVID-19 and hypoxaemia. The HOT-COVID is planned to enrol 780 patients. This paper presents the protocol and statistical analysis plan for the conduct of a secondary Bayesian analysis of the primary outcome of HOT-COVID being days alive without life-support at 90 days and the secondary outcome 90-day all-cause mortality. Furthermore, both outcomes will be investigated for the presence heterogeneity of treatment effects based on four baseline parameters being sequential organ failure assessment score, PaO2 /fraction of inspired oxygen ratio, highest dose of norepinephrine during the 24 h before randomisation, and plasma concentration of lactate at randomisation. The results of this pre-planned secondary Bayesian analysis will complement the primary frequentist analysis of the HOT-COVID trial and may facilitate a more nuanced interpretation of the trial results.

A multi-center, adaptive, randomized, platform trial to evaluate the effect of repurposed medicines in outpatients with early coronavirus disease 2019 (COVID-19) and high-risk for complications: the TOGETHER master trial protocol

Background: There remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as treatments for early COVID-19 among outpatients at a high risk for severe complications. Methods: The TOGETHER Trial is a multi-center platform adaptive randomized, placebo-controlled, clinical trial. Patients are included if they are at least 18 years of age, have a positive antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and have an indication for high risk of disease severity, including co-morbidities, older age, or high body mass index. Eligible patients are randomized with equal chance to an investigational product (IP) or to placebo.The primary endpoint is hospitalization defined as either retention in a COVID-19 emergency setting for greater than 6 hours or transfer to tertiary hospital due to COVID-19. Secondary outcomes include mortality, adverse events, adherence, and viral clearance. Scheduled interim analyses are conducted and reviewed by the Data and Safety Monitoring Committee (DSMC), who make recommendations on continuing or stopping each IP. The platform adaptive design go-no-go decision rules are extended to dynamically incorporate external evidence on COVID-19 interventions from ongoing independent randomized clinical trials. Discussion: Results from this trial will assist in the identification of therapeutics for the treatment of early diagnosed COVID-19. The novel methodological extension of the platform adaptive design to dynamically incorporate external evidence is one of the first of its kind and may provide highly valuable information for all COVID-19 trials going forward. Clinicaltrials.gov registration: NCT04727424 (27/01/2021)

Vitamin C Intervention for Critical COVID-19: A Pragmatic Review of the Current Level of Evidence.

Severe respiratory infections are characterized by elevated inflammation and generation of reactive oxygen species (ROS) which may lead to a decrease in antioxidants such as vitamin C and a higher requirement for the vitamin. Administration of intravenous vitamin C to patients with pneumonia and sepsis appears to decrease the severity of the disease and potentially improve survival rate. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes pneumonia, sepsis and acute respiratory distress syndrome (ARDS) in severe cases, and is referred to as coronavirus disease 2019 (COVID-19). Patients with COVID-19 infection also appear to have depleted vitamin C status and require additional supplementation of vitamin C during the acute phase of the disease. To date there have been 12 vitamin C and COVID-19 trials published, including five randomised controlled trials (RCTs) and seven retrospective cohort studies. The current level of evidence from the RCTs suggests that intravenous vitamin C intervention may improve oxygenation parameters, reduce inflammatory markers, decrease days in hospital and reduce mortality, particularly in the more severely ill patients. High doses of oral vitamin C supplementation may also improve the rate of recovery in less severe cases. No adverse events have been reported in published vitamin C clinical trials in COVID-19 patients. Upcoming findings from larger RCTs will provide additional evidence on vitamin supplementation in COVID-19 patients.