COVID-19 Clinical Trials Research Articles

627. CURE ID as a Tool for Curating and Analyzing Drugs Used in COVID-19 Clinical Trials

BackgroundCURE ID is an internet-based data repository (https://cure.ncats.io/explore) developed collaboratively by FDA and NCATS/NIH. It is designed to capture real-world clinical outcome data to advance drug repurposing and to inform future clinical trials for infectious diseases with high unmet medical need. It also serves as a repository of clinical trials automatically pulled from https://www.clinicaltrials.gov into the CURE ID platform, where they were then manually curated, with the intention of keeping the infectious diseases community updated on the various clinical trials underway. The current study is a descriptive analysis of various therapeutics in clinical trials against COVID-19 on the CURE ID platform. MethodsUsing clinicaltrials.gov we selected those trials addressing therapeutics for COVID-19 and reviewed the drugs used, the current status of the trials, and the phases of development.ResultsAs of May 2021, we identified 2,154 clinical trials and 933 drugs from clinicaltrials.gov that met the inclusion criteria. Hydroxychloroquine (n=251) was the most commonly investigated agent, followed by convalescent plasma (n=147), azithromycin (n=98), ivermectin (n=68), mesenchymal Stem Cells (n=63), tocilizumab (n=58), remdesivir (n=53) and favipiravir (n=51). At the time of our analysis, the majority (45%) of the clinical trials were in the recruiting phase, 12% were in the active phase, and 13% of the studies were completed. The majority (31%) of trials were in phase two, followed by phase three (21%) and phase one (10%). The vast majority of the agents were repurposed (92%), while only 8% of the agents were new molecular entities. Remdesivir was the only drug approved for marketing for treatment of certain patients with COVID-19 at the time of our analysis.ConclusionSeveral repurposed and novel drugs are being investigated to treat COVID-19 in clinical trials. CURE ID provides a broad view of the various drugs being researched and serves to keep the scientific community informed. Such a platform may help prevent duplication of efforts and help the scientific community with more coordinated research efforts and larger platform trials that can robustly answer scientific questions during a pandemic.Disclosures All Authors: No reported disclosures

The Drug Repurposing for COVID-19 Clinical Trials Provide Very Effective Therapeutic Combinations: Lessons Learned From Major Clinical Studies.

SARS-CoV-2 has spread across the globe in no time. In the beginning, people suffered due to the absence of efficacious drugs required to treat severely ill patients. Nevertheless, still, there are no established therapeutic molecules against the SARS-CoV-2. Therefore, repurposing of the drugs started against SARS-CoV-2, due to which several drugs were approved for the treatment of COVID-19 patients. This paper reviewed the treatment regime for COVID-19 through drug repurposing from December 8, 2019 (the day when WHO recognized COVID-19 as a pandemic) until today. We have reviewed all the clinical trials from RECOVERY trials, ACTT-1 and ACTT-2 study group, and other major clinical trial platforms published in highly reputed journals such as NEJM, Lancet, etc. In addition to single-molecule therapy, several combination therapies were also evaluated to understand the treatment of COVID-19 from these significant clinical trials. To date, several lessons have been learned on the therapeutic outcomes for COVID-19. The paper also outlines the experiences gained during the repurposing of therapeutic molecules (hydroxychloroquine, ritonavir/ lopinavir, favipiravir, remdesivir, ivermectin, dexamethasone, camostatmesylate, and heparin), immunotherapeutic molecules (tocilizumab, mavrilimumab, baricitinib, and interferons), combination therapy, and convalescent plasma therapy to treat COVID-19 patients. We summarized that anti-viral therapeutic (remdesivir) and immunotherapeutic (tocilizumab, dexamethasone, and baricitinib) therapy showed some beneficial outcomes. Until March 2021, 4952 clinical trials have been registered in ClinicalTrials.gov toward the drug and vaccine development for COVID-19. More than 100 countries have participated in contributing to these clinical trials. Other than the registered clinical trials (medium to large-size), several small-size clinical trials have also been conducted from time to time to evaluate the treatment of COVID-19. Four molecules showed beneficial therapeutic to treat COVID-19 patients. The short-term repurposing of the existing drug may provide a successful outcome for COVID-19 patients. Therefore, more clinical trials can be initiated using potential anti-viral molecules by evaluating in different phases of clinical trials.

A Systematic Review of the Sex and Gender Reporting in COVID-19 Clinical Trials

Sex and gender have implications for COVID-19 vaccine efficacy and adverse effects from the vaccine. As vaccination is one of the key responses to the COVID-19 pandemic, it is vital that sex and gender differences be acknowledged, measured, and analysed in clinical research. Here, we systematically review published COVID-19 vaccine trials, both interventional and observational, to assess the quality of reporting of sex and gender. Of the 75 clinical trials on COVID-19 vaccines included in this review, only 24% presented their main outcome data disaggregated by sex, and only 13% included any discussion of the implications of their study for women and men. Considering the sex differences in adverse events after vaccination, and the gendered aspects of vaccine hesitancy, these oversights in clinical research on vaccines have implications for recovery from the COVID-19 pandemic and for wider public health.

Implementation of platform trials in the COVID-19 pandemic: A rapid review

MotivationPlatform designs - master protocols that allow for new treatment arms to be added over time - have gained considerable attention in recent years. Between 2001 and 2019, 16 platform trials were initiated globally. The COVID-19 pandemic seems to have provided a new motivation for these designs. We conducted a rapid review to quantify and describe platform trials used in COVID-19. MethodsWe cross-referenced PubMed, ClinicalTrials.gov, and the Cytel COVID-19 Clinical Trials Tracker to identify platform trials, defined by their stated ability to add future arms. ResultsWe identified 58 COVID-19 platform trials globally registered between January 2020 and May 2021. According to trial registries, 16 trials have added new therapies (median 3, IQR 4) and 11 have dropped arms (median 3, IQR 2.5). About 50% of trials publicly share their protocol, and 31 trials (53%) intend to share trial data. Forty-nine trials (84%) explicitly report adaptive features, and 21 trials (36%) state Bayesian methods. ConclusionsDuring the pandemic, there has been a surge in the number of platform trials compared to historical use. While transparency in statistical methods and clarity of data sharing policies needs improvement, platform trials appear particularly well-suited for rapid evidence generation. Trials secured funding quickly and many succeeded in adding new therapies in a short time period, thus demonstrating the potential for these trial designs to be implemented beyond the pandemic. The evidence gathered here may provide ample insight to further inform operational, statistical, and regulatory aspects of future platform trial conduct.

Characteristics of published/registered clinical trials on COVID-19 treatment: A systematic review.

ObjectivesDue to the rapid spread of COVID-19 worldwide, many countries have designed clinical trials to find efficient treatments. We aimed to critically report the characteristics of all the registered and published randomized clinical trials (RCTs) conducted on COVID-19, and summarize the evaluation of potential therapies developed in various regions.Evidence acquisitionWe comprehensively searched PubMed, Cochrane Library, Web of Science, Scopus, and Clinicaltrial.gov databases to retrieve all the relevant studies up to July 19, 2021, in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. We included all English-language published/registered RCTs on COVID-19, and excluded non-RCT, in-vitro/in-vivo, editorials, and review studies. Two reviewers independently evaluated all the records, and then analyzed by using SPSS 17.ResultsWithin 3018 included studies, 2801 (92.8%) and 217 (7.2%) were registered or published RCTs consisting of about 600 synthetic drugs. Herbal medicines have been studied in 23 trials (10.6%) among the published RCTs and in 357 registered RCTs (12.7%). Hydroxychloroquine 23 (10.6%) and convalescent plasma 194 (6.9%) alone or in combination with other agents were the most frequently used interventions in published and registered RCTs, respectively. Most published RCTs have been conducted in Western Pacific Region (WPRO) (50 trials, 23.0%) including 45 trials from China. Also, a greater proportion of registered RCTs have been conducted in the Region of the Americas (PAHO) (885 trials, 31.6%) including 596 RCTs from the United States (U.S). Globally, 283 registered trials have been conducted to assess new developed vaccines for COVID or previously established for other disorders.ConclusionThe present study highlighted the wide range of potential therapeutic agents in published and registered COVID-19 clinical trials across a wide range of regions. However, it is urgently required to global coordination in order to conduct more well-designed trials and progress in discovering safe and effective treatments.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s40199-021-00422-8.

Results availability and timeliness of registered COVID-19 clinical trials: interim cross-sectional results from the DIRECCT study

ObjectiveTo examine how and when the results of COVID-19 clinical trials are disseminated.DesignCross-sectional study.SettingThe COVID-19 clinical trial landscape.Participants285 registered interventional clinical trials for the treatment and prevention of COVID-19 completed...

Physician Perspectives on Including Pregnant Women in Covid-19 Clinical Trials: Time for a Paradigm Change.

Excluding pregnant people from Covid‐19 clinical trials may lead to unintended harmful consequences. For this study, an online questionnaire was sent to physicians belonging to Canadian professional medical associations in order to evaluate their perspectives on the participation of pregnant women in Covid‐19 clinical trials. The majority of respondents expressed support for including pregnant women in Covid‐19 trials (119/165; 72%), especially those investigating therapies with a prior safety record in pregnancy (139/164; 85%). The main perceived barriers to inclusion identified were unwillingness of pregnant patients to participate and of treating teams to offer participation, the burden of regulatory approval, and a general “culture of exclusion” of pregnant women from trials. We describe why some physicians may be reluctant to include pregnant individuals in trials, and we identify barriers to the appropriate participation of pregnant people in clinical research.

Colchicine treatment in COVID-19: the remaining unsolved question

Colchicine treatment in COVID-19: the remaining unsolved question

Characterisation of current pharmacotherapeutic COVID-19 clinical trials in India: A registry-based descriptive analysis

COVID-19 has emerged as a global pandemic. There is currently a spurt of clinical research to generate evidence to treat this novel disease. The aim of the current study is to characterise the pharmacotherapeutic intervention-related clinical trials registered in India. COVID-19 clinical trials registered in India were analysed from data retrieved from Clinical Trial Registry-India, ClinicalTrials.gov and International Clinical Trial Registry Platform. Parameters such as study design, sample size, pharmacotherapeutic interventions and primary outcomes were evaluated. A total of 267 studies were screened among which 103 clinical trials were assessed for descriptive analysis. Majority of registered trials (55.3%) were in Indian System of Medicine followed by antimalarials such as hydroxychloroquine/chloroquine (10.5%) and plasma therapy (7.1%). Most commonly used study design was randomised parallel group in 63%. Open-label study was seen in 47.5%. Primary outcome was improvement of clinical symptoms in 46.6% followed by rate and time of viral load reduction in 18.2%. Maharashtra (n = 35) followed by Delhi (n = 29) had the maximum number of registered trial sites. The study gives broad perspective on the current trend of clinical trials on COVID-19 being conducted in India. The outcomes of these trials will lead to generation of valuable data for evidence-based treatment of COVID-19.

Peptides in COVID-19 Clinical Trials—A Snapshot

Since the beginning of the COVID-19 pandemic, there has been a strong drive and desire to find effective treatments for and protection against the disease. On the webpage ClinicalTrials.gov, a total of 6505 clinical trials currently (September 2021) investigating various aspects of COVID-19 are registered. Of these, 124 studies involving peptides were identified. These 124 were further evaluated, and 88 trials that used peptides only for routine diagnostics were excluded. The remaining 36 trials were classified into 5 different classes according to their function: immunomodulatory (5 trials), regain homeostasis (10 trials), diagnostics/biomarkers (8 trials), vaccination (9 trials), and antiviral activity (4 trials, all overlap with immunomodulatory activities). In the current review, these 36 trials are briefly described and tabularly summarised. According to the estimated finish date, 14 trials have not yet finished. All of the finished trials are yet to report their results. Seven trials were based in the USA, and Egypt, France, the UK, Turkey, and the Russian Federation conducted three trials each. This review aims to present a snapshot of the current situation of peptides in COVID-19 clinical trials and provides a template to follow up on trials of interest; it does not claim to be a complete overview.

Acceptability of Clinical Trials on COVID-19 during Pregnancy among Pregnant Women and Healthcare Providers: A Qualitative Study.

Participation of pregnant women in clinical trials entails challenges mainly related to concerns about the risks for fetuses. We undertook a qualitative study from June to October 2020 to assess the acceptability of participating in COVID-19 clinical trials among pregnant women in Spain. Phenomenology and grounded theory were used as methodological approaches. Semi-structured interviews were conducted with 24 pregnant women and six healthcare providers. Women were unsure if pregnancy was a risk factor to acquire the infection or to develop severe disease and expressed the limited information they had received, which led to uncertainties and emotional suffering. They had concerns regarding participation in clinical trials on COVID-19, regardless of the drug under study. Healthcare providers alluded to the importance of involving pregnant women’s relatives at the recruitment visit of the clinical trial. These findings may be useful to facilitate pregnant women’s participation in clinical trials.

Drug repositioning by merging active subnetworks validated in cancer and COVID-19

Computational drug repositioning aims at ranking and selecting existing drugs for novel diseases or novel use in old diseases. In silico drug screening has the potential for speeding up considerably the shortlisting of promising candidates in response to outbreaks of diseases such as COVID-19 for which no satisfactory cure has yet been found. We describe DrugMerge as a methodology for preclinical computational drug repositioning based on merging multiple drug rankings obtained with an ensemble of disease active subnetworks. DrugMerge uses differential transcriptomic data on drugs and diseases in the context of a large gene co-expression network. Experiments with four benchmark diseases demonstrate that our method detects in first position drugs in clinical use for the specified disease, in all four cases. Application of DrugMerge to COVID-19 found rankings with many drugs currently in clinical trials for COVID-19 in top positions, thus showing that DrugMerge can mimic human expert judgment.

Drug repurposing for COVID-19 based on an integrative meta-analysis of SARS-CoV-2 induced gene signature in human airway epithelium.

Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic—COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature’-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.

Molecular Docking, DFT Studies and ADMET Simulations for Evaluating Already Approved FDA Drugs as Inhibitors for SARS-Cov-2 RNADependent Polymerase

Background: Remdesivir, a drug in use for Ebola it is already tested in clinical trials phase III. Objective: To evaluate any other possible related structures with similar properties that could be used in clinical trials for COVID-19. Methods: Molecular docking studies, DFT studies, ADMET studies Result: Saquinavir is a chemical structure with similar and even a better chemical activity that drugs that entered clinical trials for Covid-19 Conclusion: Saquinavir should be entered the clinical trials for the treatment of the COVID-19 disease, as it has shown excellent binding affinities to SARS Cov-2 RNA depended polymerase and forms stable complexes with the protein and could possible inhibited its action.

Comparison of COVID-19 studies registered in the clinical trial platforms: A research ethics analysis perspective.

BackgroundThe coronavirus disease (COVID‐19) treatment must be based on scientific methods such as clinical trials. Trials involving human subjects and those requiring a risk‐benefit analysis may occasionally face challenges owing to the time limitations in the pandemic.MethodologyThis study analyses the WHO's International Clinical Trials Registry Platform and clinicaltrials.gov, where most COVID‐19 clinical trials are registered, according to ethical criteria including study design, conflicts of interest, enrollment of healthcare workers, study locations, site‐, design‐, and participant‐related issues. The discussion is based on three aspects: the quality of the information to be produced, the relevance to significant health problems, and the creation or evaluation of interventions, policies, or practices that promote individual or public health.ResultsThere were significant differences between the two platforms regarding the investigational medicinal product (IMP), the comparator, ethics committee/institutional review board approval, plan to share individual participant data, study phase, site, IMP, and design‐related issues. Conflict of interest, sponsor information, and management of vulnerable groups were the main areas wherein both platforms lacked sufficient information.ConclusionWith this analysis, we aimed to define a minimum set of ethical criteria for clinical trial platforms to obtain standardization between these two platforms.

Power and sample size calculation for the win odds test: application to an ordinal endpoint in COVID-19 trials

ABSTRACT The win odds is a distribution-free method of comparing locations of distributions of two independent random variables. Introduced as a method for analyzing hierarchical composite endpoints, it is well suited to be used in the analysis of ordinal scale endpoints in COVID-19 clinical trials. For a single outcome, we provide power and sample size calculation formulas for the win odds test. We also provide an implementation of the win odds analysis method for a single ordinal outcome in a commonly used statistical software to make the win odds analysis fully reproducible.

Clinical trial research on COVID-19 in Germany - a systematic analysis.

Background: In 2020, the COVID-19 pandemic led to an unprecedented volume of almost 3,000 clinical trials registered worldwide. We aimed to describe the COVID-19 clinical trial research agenda in Germany during the first year of the pandemic. Methods: We identified randomized clinical trials assessing interventions to treat or prevent COVID-19 that were registered in 2020 and recruited or planned to recruit participants in Germany. We requested recruitment information from trial investigators as of April 2021. Results: In 2020, 65 trials were completely (n=27) or partially (n=38) conducted in Germany. Most trials investigated interventions to treat COVID-19 (86.2%; 56/65), in hospitalized patients (67.7%; 44/65), with industry funding (53.8%; 35/65). Few trials were completed (21.5%; 14/65). Overall, 187,179 participants were planned to be recruited (20,696 in Germany), with a median number of 106 German participants per trial (IQR 40 to 345). From the planned German participants, 13.4% were recruited (median 15 per trial (IQR 0 to 44). Conclusions: The overall German contribution to the worldwide COVID-19 clinical trial research agenda was modest. Few trials delivered urgently needed evidence. Most trials did not meet recruitment goals. Evaluation and international comparison of the challenges for conducting clinical trials in Germany is needed.

Volumetric absorptive microsampling: its use in COVID-19 research and testing.

COVID-19 led to changes in the way blood samples are collected. As societies were isolated to control viral spread, access to facilities became limited. Remote sample collection with a volumetric microsampling approach, using Mitra® devices based on VAMS® technology, proved to be highly effective. It allowed people to collect high-quality samples at home and post them to a laboratory. This enabled scientists to conduct large serosurveillance studies, with results showing that seroprevalence of COVID-19 was higher than initially expected. Furthermore, remote microsampling studies by several institutions were conducted to measure the relationship between antigen levels and antibody response and duration. VAMS technology was also used in COVID-19 clinical trials. In summary, the independent research reviewed in this paper proved that VAMS is an effective sample collection alternative.

Festina lente

The provisions adopted in Italy for clinical trials on medicinal products and medical devices for the epidemiological emergency caused by COVID-19 had an impact also on the functioning of Ethics Committees (ECs). All COVID-19 clinical trials are evaluated preliminarily by the Technical Scientific Committee of the Italian Medicines Agency (AIFA). They are then evaluated by the Clinical Trial Office of the Competent Authority (AIFA) and by the EC of the Lazzaro Spallanzani National Institute for Infectious Diseases. On the basis of this experience, several parties have recommended the adoption of a new structure that envisages the involvement of a single EC for the activation of new studies, similar to the system put in place for studies on COVID-19.Rather than a single EC with jurisdiction over the entire country, we could envisage the accreditation of a certain number of ECs, possibly subdivided by therapeutic fields, with the trials to be evaluated distributed among them, so that each is authorised to issue an opinion that is valid nationally.

34 Polk COVID-19 and Flu Response Clinical Trial

Study Objective: To report on the preliminary results of the Polk COVID-19 and Flu Response clinical trial (NCT04682132). Methods: This clinical trial was conducted at Polk County Fire Rescue (PCFR), one of the largest EMS systems in the state of Florida. PCFR responds to over 115,000 calls per year and covers a geographic area of over 2000 square miles. The study assessed COVID-19 antibody status in PCFR medics and correlated antibody status to 1) symptomatology, 2) amount of patient contact and 3) individual co-morbidities. For symptoms survey, medics were given a QR code to a survey prior to antibody testing. Results: The median age was 43 years (IQR 33-52). 41% were female. 83% were White, 9% were Black, 1% were Asian, and 6% were other. 12% were Hispanic. 33% had the following co-morbidities: 5% diabetes, 6% asthma or chronic obstructive pulmonary disease. 17% had hypertension. Forty five percent had received their influenza vaccine. The median BMI was 19.8 (IQR 25.9-34.8 ). 19% were symptomatic. The most common symptoms were cough, fatigue and headache. Almost 40% had direct patient contact. 15% had less than 5 hours per week;27% had 5-20 hours per week, and 57% had more than 20 hours per week of direct patient contact. A total of 7% had a positive COVID-19 antibody test. The only univariate analysis that was statistically significant for antibody status was race. Blacks had 3.94 times the odds of having a positive COVID-19 antibody compared to Whites. (P=0.0012 Pearson correlation, 95% CI 0.0560 – 0.2248). Black race remained a statistically significant predictor in a multivariate model that included the age, sex, BMI, number of hours of direct patient contact, whether the medic was symptomatic, presence of co-morbidities and whether or not the medic had received a flu shot prior was symptomatic (P=0.0008, 95% CI 0.0621-0.2354). Conclusion: In a cohort of paramedics actively managing patients, the COVID-19 positivity rate was significantly higher in Blacks compared to Whites. Symptomatology did not correlate with the presence of antibodies. [Formula presented]