Patiromer utility as an adjunct treatment in patients needing urgent hyperkalaemia management (PLATINUM): design of a multicentre, randomised, double-blind, placebo-controlled, parallel-group study.

INTRODUCTION: Hyperkalaemia is common, life-threatening and often requires emergency department (ED) management; however, no standardised ED treatment protocol exists. Common treatments transiently reducing serum potassium (K+) (including albuterol, glucose and insulin) may cause hypoglycaemia. We outline the design and rationale of the Patiromer Utility as an Adjunct Treatment in Patients Needing Urgent Hyperkalaemia Management (PLATINUM) study, which will be the largest ED randomised controlled hyperkalaemia trial ever performed, enabling assessment of a standardised approach to hyperkalaemia management, as well as establishing a new evaluation parameter (net clinical benefit) for acute hyperkalaemia treatment investigations. METHODS AND ANALYSIS: PLATINUM is a Phase 4, multicentre, randomised, double-blind, placebo-controlled study in participants who present to the ED at approximately 30 US sites. Approximately 300 adult participants with hyperkalaemia (K+ ≥5.8 mEq/L) will be enrolled. Participants will be randomised 1:1 to receive glucose (25 g intravenously <15 min before insulin), insulin (5 units intravenous bolus) and aerosolised albuterol (10 mg over 30 min), followed by a single oral dose of either 25.2 g patiromer or placebo, with a second dose of patiromer (8.4 g) or placebo after 24 hours. The primary endpoint is net clinical benefit, defined as the mean change in the number of additional interventions less the mean change in serum K+, at hour 6. Secondary endpoints are net clinical benefit at hour 4, proportion of participants without additional K+-related medical interventions, number of additional K+-related interventions and proportion of participants with sustained K+ reduction (K+ ≤5.5 mEq/L). Safety endpoints are the incidence of adverse events, and severity of changes in serum K+ and magnesium. ETHICS AND DISSEMINATION: A central Institutional Review Board (IRB) and Ethics Committee provided protocol approval (#20201569), with subsequent approval by local IRBs at each site, and participants will provide written consent. Primary results will be published in peer-reviewed manuscripts promptly following study completion. TRIAL REGISTRATION NUMBER: NCT04443608.

A Review on Immunological Responses to SARS-CoV-2 and Various COVID-19 Vaccine Regimens.

The transmission of SARS-CoV-2 has caused serious health crises globally. So far, 7 vaccines that are already being assessed in Phase IV clinical trials are, Comirnaty/ Pfizer; Spikevax/Moderna (m RNA vaccine); Vaxzevria or Covishield; Ad26.COV2.S; Ad5-nCoV (adenoviral vector-based vaccine); CoronaVac and BBIBP-CorV (inactivated virus vaccine). Besides, there are about 280 vaccines that are undergoing preclinical and clinical trials including Sputnik-V, Covaxin or BBV152, and NVX-CoV2373. These vaccines are being studied for their immunological responses and efficiency against COVID-19, and have been reported to demonstrate effective T and B cell responses. However, the long-lasting immunity of these vaccine regimens still needs to be investigated. An in-depth understanding of the vaccine efficacy and immune control mechanism is imperative for the rational purposing and implementation of the vaccines. Hence, in this review, we have comprehensively discussed the immune response induced in COVID-19 patients, as well as in the convalescent individuals to avoid reinfection. Moreover, we have also summarized the immunological responses and prophylactic efficacy of various COVID-19 vaccine regimens. In this context, this review can give insights into the development of effective vaccines against SARS-CoV-2 and its variants in the future.

Nature-Derived Hit, Lead, and Drug-Like Small Molecules: Current Status and Future Aspects Against Key Target Proteins of Coronaviruses.

BACKGROUND: COVID-19 pandemic, the most unprecedented event of the year 2020, has brought millions of scientists worldwide in a single platform to fight against it. Though several drugs are now in the clinical trial, few vaccines are available on the market already, but the lack of an effect of those is making the situation worse. AIM OF THE STUDY: In this review, we demonstrated comprehensive data of natural antiviral products showing activities against different proteins of Human Coronaviruses (HCoV) that are responsible for its pathogenesis. Furthermore, we categorized the compounds into the hit, lead, and drug based on the IC50/EC50 value, drug-likeness, and lead-likeness test to portray their potentiality to be a drug. We also demonstrated the present status of our screened antiviral compounds with respect to clinical trials and reported the lead compounds that can be promoted to clinical trial against COVID-19. METHODS: A systematic search strategy was employed focusing on Natural Products (NPs) with proven activity (in vitro, in vivo, or in silico) against human coronaviruses, in general, and data were gathered from databases like PubMed, Web of Science, Google Scholar, SciVerse, and Scopus. Information regarding clinical trials retrieved from the Clinical Trial Database. RESULTS: Total "245" natural compounds were identified initially from the literature study. Among them, Glycyrrhizin, Caffeic acid, Curcumin is in phase 3, and Tetrandrine, Cyclosporine, Tacrolimus, Everolimus are in phase 4 clinical trial. Except for Glycyrrhizin, all compounds showed activity against COVID-19. CONCLUSION: In summary, our demonstrated specific small molecules with lead and drug-like capabilities clarified their position in the drug discovery pipeline and proposed future research against COVID-19.

Impact of comprehensive molecular testing to reduce antibiotic use in community-acquired pneumonia (RADICAP): a randomised, controlled, phase IV clinical trial protocol.

INTRODUCTION: Community-acquired pneumonia (CAP) continues to be a major health problem worldwide and is one of the main reasons for prescribing antibiotics. However, the causative agent is often not identified, resulting in antibiotic overtreatment, which is a key driver of antimicrobial resistance and adverse events. We aim to test the hypothesis that comprehensive molecular testing, compared with routine microbiological testing, would be effective in reducing antibiotic use in patients with CAP. METHODS AND ANALYSIS: We will perform a randomised, controlled, open-label clinical trial with two parallel groups (1:1) at two tertiary hospitals between 2020 and 2022. Non-severely immunosuppressed adults hospitalised for CAP will be considered eligible. Patients will be randomly assigned to receive either the experimental diagnosis (comprehensive molecular testing plus routine microbiological testing) or standard diagnosis (only microbiological routine testing). The primary endpoint will be antibiotic consumption measured as days of antibiotic therapy per 1000 patient-days. Secondary endpoints will be de-escalation to narrower antibiotic treatment, time to switch from intravenous to oral antibiotics, days to reaching an aetiological diagnosis, antibiotic-related side effects, length of stay, days to clinical stability, intensive care unit admission, days of mechanical ventilation, hospital readmission up to 30 days after randomisation and death from any cause by 48 hours and 30 days after randomisation. We will need to include 440 subjects to be able to reject the null hypothesis that both groups have equal days of antibiotic therapy per 1000 patient-days with a probability >0.8. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Bellvitge Hospital (AC028/19) and from the Spanish Medicines and Medical Devices Agency, and it is valid for all participating centres under existing Spanish legislation. Results will be presented at international meetings and will be made available to patients, their caregivers and funders. TRIAL REGISTRATION NUMBER: ClinicalTrials: NCT04158492. EudraCT: 2018-004880-29.

A SMARTTT approach to Treating Tobacco use disorder in persons with HIV (SMARTTT): Rationale and design for a hybrid type 1 effectiveness-implementation study.

BACKGROUND: Tobacco use disorder is a leading threat to the health of persons with HIV (PWH) on antiretroviral treatment and identifying optimal treatment approaches to promote abstinence is critical. We describe the rationale, aims, and design for a new study, "A SMART Approach to Treating Tobacco Use Disorder in Persons with HIV (SMARTTT)," a sequential multiple assignment randomized trial. METHODS: In HIV clinics within three health systems in the northeastern United States, PWH with tobacco use disorder are randomized to nicotine replacement therapy (NRT) with or without contingency management (NRT vs. NRT + CM). Participants with response (defined as exhaled carbon monoxide (eCO)-confirmed smoking abstinence at week 12), continue the same treatment for another 12 weeks. Participants with non-response, are re-randomized to either switch medications from NRT to varenicline or intensify treatment to a higher CM reward schedule. Interventions are delivered by clinical pharmacists embedded in HIV clinics. The primary outcome is eCO-confirmed smoking abstinence; secondary outcomes include CD4 cell count, HIV viral load suppression, and the Veterans Aging Cohort Study (VACS) Index 2.0 score (a validated measure of morbidity and mortality based on laboratory data). Consistent with a hybrid type 1 effectiveness-implementation design and grounded in implementation science frameworks, we will conduct an implementation-focused process evaluation in parallel. Study protocol adaptations related to the COVID-19 pandemic have been made. CONCLUSIONS: SMARTTT is expected to generate novel findings regarding the impact, cost, and implementation of an adaptive clinical pharmacist-delivered intervention involving medications and CM to promote smoking abstinence among PWH. ClinicalTrials.govidentifier:NCT04490057.

Assessing the Safety of COVID-19 Vaccines: A Primer.

Vaccines against COVID-19 are being developed at speeds not previously achieved. With this unprecedented effort comes challenges for post-marketing safety monitoring and challenges for vaccine safety communication. To deploy these new vaccines fast across diverse populations, it is vital that robust pharmacovigilance and active surveillance systems are in place. Not all countries have the capability or resources to undertake adequate surveillance and will rely on data from those who can. The tools exist to assess COVID-19 vaccines as they are deployed such as surveillance systems, administrative data and case definitions for adverse events of special interest. However, stitching these all together and using them effectively requires investment and collaboration. This paper provides a high-level overview of some of the facets of modern vaccine safety assessment and how they are, or can be, applied to COVID-19 vaccines.

Implementation of the Randomized Embedded Multifactorial Adaptive Platform for COVID-19 (REMAP-COVID) trial in a US health system-lessons learned and recommendations.

BACKGROUND: The Randomized Embedded Multifactorial Adaptive Platform for COVID-19 (REMAP-COVID) trial is a global adaptive platform trial of hospitalized patients with COVID-19. We describe implementation at the first US site, the UPMC health system, and offer recommendations for implementation at other sites. METHODS: To implement REMAP-COVID, we focused on six major areas: engaging leadership, trial embedment, remote consent and enrollment, regulatory compliance, modification of traditional trial management procedures, and alignment with other COVID-19 studies. RESULTS: We recommend aligning institutional and trial goals and sharing a vision of REMAP-COVID implementation as groundwork for learning health system development. Embedment of trial procedures into routine care processes, existing institutional structures, and the electronic health record promotes efficiency and integration of clinical care and clinical research. Remote consent and enrollment can be facilitated by engaging bedside providers and leveraging institutional videoconferencing tools. Coordination with the central institutional review board will expedite the approval process. Protocol adherence, adverse event monitoring, and data collection and export can be facilitated by building electronic health record processes, though implementation can start using traditional clinical trial tools. Lastly, establishment of a centralized institutional process optimizes coordination of COVID-19 studies. CONCLUSIONS: Implementation of the REMAP-COVID trial within a large US healthcare system is feasible and facilitated by multidisciplinary collaboration. This investment establishes important groundwork for future learning health system endeavors. TRIAL REGISTRATION: NCT02735707 . Registered on 13 April 2016.

Clinical approval of nanotechnology-based SARS-CoV-2 mRNA vaccines: impact on translational nanomedicine.

One year after the first human case of SARS-CoV-2, two nanomedicine-based mRNA vaccines have been fast-tracked, developed, and have received emergency use authorization throughout the globe with more vaccine approvals on the heels of these first two. Several SARS-CoV-2 vaccine compositions use nanotechnology-enabled formulations. A silver lining of the COVID-19 pandemic is that the fast-tracked vaccine development for SARS-CoV-2 has advanced the clinical translation pathway for nanomedicine drug delivery systems. The laboratory science of lipid-based nanoparticles was ready and rose to the clinical challenge of rapid vaccine development. The successful development and fast tracking of SARS-CoV-2 nanomedicine vaccines has exciting implications for the future of nanotechnology-enabled drug and gene delivery; it demonstrates that nanomedicine is necessary and critical to the successful delivery of advanced molecular therapeutics such as nucleic acids, it is establishing the precedent of safety and the population effect of phase four clinical trials, and it is laying the foundation for the clinical translation of more complex, non-lipid nanomedicines. The development, fast-tracking, and approval of SARS-CoV-2 nanotechnology-based vaccines has transformed the seemingly daunting challenges for clinically translating nanomedicines into measurable hurdles that can be overcome. Due to the tremendous scientific achievements that have occurred in response to the COVID-19 pandemic, years, perhaps even decades, have been streamlined for certain translational nanomedicines.

Lead SARS-CoV-2 Candidate Vaccines: Expectations from Phase III Trials and Recommendations Post-Vaccine Approval.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted primarily through respiratory droplets/aerosols and it causes COVID-19. The virus infects epithelial cells by using the spike protein on its surface to bind to angiotensin-converting enzyme 2 receptor on the cells. Thus, candidate vaccines targeting the spike protein are currently being developed to prevent against infections. Approximately 44 SARS-CoV-2 candidate vaccines are in clinical trials (phase I-III) and an additional 164 candidates are in preclinical stages. The efficacy data from phase I/II trials of lead candidate vaccines look very promising with virus-neutralizing geometric mean antibody titers in the range of 16.6-3906. Most recently, two SARS-CoV-2 candidate vaccines, BNT162b2 and mRNA-1273, have been granted the first emergency use authorization (EUA) in the U.S.; BNT162b2 has also been granted an EUA in the United Kingdom, Canada, and in the European Union. This review assesses whether SARS-CoV-2 candidate vaccines (with approved EUA or in phase III trials) meet the criteria for an ideal SARS-CoV-2 vaccine. The review concludes with expectations from phase III trials and recommendations for phase IV studies (post-vaccine approval).

Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)--The BRACE CORONA Trial.

Angiotensin-converting enzyme-2 (ACE2) expression may increase due to upregulation in patients using angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs). Because renin-angiotensin system blockers increase levels of ACE2, a protein that facilitates coronavirus entry into cells, there is concern that these drugs could increase the risk of developing a severe and fatal form of COVID-19. The impact of discontinuing ACEI and ARBs in patients with COVID-19 remains uncertain. DESIGN: BRACE CORONA is a pragmatic, multicenter, randomized, phase IV, clinical trial that aims to enroll around 500 participants at 34 sites in Brazil. Participants will be identified from an ongoing national registry of suspected and confirmed cases of COVID-19. Eligible patients using renin-angiotensin system blockers (ACEI/ARBs) with a confirmed diagnosis of COVID-19 will be randomized to a strategy of continued ACEI/ARB treatment versus temporary discontinuation for 30 days. The primary outcome is the median days alive and out of the hospital at 30 days. Secondary outcomes include progression of COVID-19 disease, all-cause mortality, death from cardiovascular causes, myocardial infarction, stroke, transient ischemic attack, new or worsening heart failure, myocarditis, pericarditis, arrhythmias, thromboembolic events, hypertensive crisis, respiratory failure, hemodynamic decompensation, sepsis, renal failure, and troponin, B-type natriuretic peptide (BNP), N-terminal-proBNP, and D-dimer levels. SUMMARY: BRACE CORONA will evaluate whether the strategy of continued ACEI/ARB therapy compared with temporary discontinuation of these drugs impacts clinical outcomes among patients with COVID-19.

Sargramostim to treat patients with acute hypoxic respiratory failure due to COVID-19 (SARPAC): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The hypothesis of the proposed intervention is that Granulocyte-macrophage colony-stimulating factor (GM-CSF) has profound effects on antiviral immunity, and can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. Sargramostim is a man-made form of the naturally-occurring protein GM-CSF. TRIAL DESIGN: A phase 4 academic, prospective, 2 arm (1:1 ratio), randomized, open-label, controlled trial. PARTICIPANTS: Patients aged 18-80 years admitted to specialized COVID-19 wards in 5 Belgian hospitals with recent (< 2 weeks prior to randomization) confirmed COVID-19 infection and acute respiratory failure defined as a PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen. Patients were excluded from the trial in case of (1) known serious allergic reactions to yeast-derived products, (2) lithium carbonate therapy, (3) mechanical ventilation prior to randomization, (4) peripheral white blood cell count above 25.000/µL and/or active myeloid malignancy, (5) high dose systemic steroid therapy (> 20 mg methylprednisolone or equivalent), (6) enrolment in another investigational study, (7) pregnant or breastfeeding or (8) ferritin levels > 2000 µg/mL. INTERVENTION AND COMPARATOR: Inhaled sargramostim 125 µg twice daily for 5 days in addition to standard care. Upon progression of disease requiring mechanical ventilation or to acute respiratory distress syndrome (ARDS) and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125 µg/m2 body surface area once daily until the 5 day period is reached. From day 6 onwards, progressive patients in the active group will have the option to receive an additional 5 days of IV sargramostim, based on the treating physician's assessment. Intervention will be compared to standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards in the standard of care group will have the option (clinician's decision) to initiate IV sargramostim 125m µg/m2 body surface area once daily for 5 days. MAIN OUTCOMES: The primary endpoint of this intervention is measuring oxygenation after 5 days of inhaled (and intravenous) treatment through assessment of a change in pretreatment and post-treatment ratio of PaO2/FiO2 and through measurement of the P(A-a)O2 gradient (PAO2= Partial alveolar pressure of oxygen, PaO2=Partial arterial pressure of oxygen; FiO2= Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 1:1 ratio. Randomization will be done using REDCap (electronic IWRS system). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 80 patients with confirmed COVID-19 and acute hypoxic respiratory failure will be enrolled, 40 in the active and 40 in the control group. TRIAL STATUS: SARPAC protocol Version 2.0 (April 15 2020). Participant recruitment is ongoing in 5 Belgian Hospitals (i.e. University Hospital Ghent, AZ Sint-Jan Bruges, AZ Delta Roeselare, University Hospital Brussels and ZNA Middelheim Antwerp). Participant recruitment started on March 26th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on March 30th, 2020 (ClinicalTrials.gov Identifier: NCT04326920) - retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT04326920?term=sarpac&recrs=ab&draw=2&rank=1 and on EudraCT on March 24th, 2020 (Identifier: 2020-001254-22). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.