Study protocol of a randomised, double-blind, placebo-controlled, two-arm parallel-group, multi-centre phase 3 pivotal trial to investigate the efficacy and safety of recombinant human alkaline phosphatase for treatment of patients with sepsis-associated acute kidney injury.

INTRODUCTION: Sepsis, the leading cause of acute kidney injury (AKI), is associated with a high morbidity and mortality. Alkaline phosphatase (ALP) is an endogenous detoxifying enzyme. A recombinant human ALP compound, ilofotase alfa, showed no safety or tolerability concerns in a phase 2 trial. Renal function improvement over 28 days was significantly greater in the ilofotase alfa group. Moreover, a significant relative reduction in 28-day all-cause mortality of >40% was observed. A follow-up trial has been designed to confirm these findings. METHODS AND ANALYSIS: This is a phase 3, global, multi-centre, randomised, double-blind, placebo-controlled, sequential design trial in which patients are randomly assigned to either placebo or 1.6 mg/kg ilofotase alfa. Randomisation is stratified by baseline modified Sequential Organ Failure Assessment (mSOFA) score and trial site. The primary objective is to confirm the survival benefit with ilofotase alfa by demonstrating a reduction in 28-day all-cause mortality in patients with sepsis-associated AKI requiring vasopressors. A maximum of 1400 patients will be enrolled at ∼120 sites in Europe, North America, Japan, Australia and New Zealand. Up to four interim analyses will take place. Based on predefined decision rules, the trial may be stopped early for futility or for effectiveness. In addition, patients with COVID-19 disease and patients with 'moderate to severe' chronic kidney disease are analysed as 2 separate cohorts of 100 patients each. An independent Data Monitoring Committee evaluates safety data at prespecified intervals throughout the trial. ETHICS AND DISSEMINATION: The trial is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will determine the potential of ilofotase alfa to reduce mortality in critically ill patients with sepsis-associated AKI and will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: EudraCT CT Number 2019-0046265-24. US IND Number 117 605 Pre-results. CLINICALTRIALS: gov number: NCT04411472.

Mixed-methods study protocol for exploring the perception of nurses' resilience in the COVID-19 pandemic: Designing, implementing and evaluation of intervention.

BACKGROUND: While the necessity for interventions to build resilient nurses in the COVID-19 pandemic is recognized, there is disagreement about the effective methods for achieving this. AIM: We present our research protocol that describes plans to design and test an interventional program for promoting nurses' resilience. DESIGN: This sequential exploratory interventional mixed-methods study is conducted in three phases (qualitative, intervention design, and quantitative). METHODS: It was funded from May 2021 for 24 months. In phase 1, we explored strategies for promoting resilience in the COVID-19 pandemic from nurses' perspectives (through semi-structured interviews). In phase 2, we will design an interventional program for promoting nurses' resilience (using the qualitative phase and literature review results). We will assess the program's effectiveness on nurses' resilience in a randomized controlled trial in phase 3. DISCUSSION: Given the different experiences of nurses of resilience in COVID-19, our innovative program can guide future research to enhance nurses' resilience based on specific situations.

STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: A structured protocol.

INTRODUCTION: Long COVID (LC), the persistent symptoms ≥12 weeks following acute COVID-19, presents major threats to individual and public health across countries, affecting over 1.5 million people in the UK alone. Evidence-based interventions are urgently required and an integrated care pathway approach in pragmatic trials, which include investigations, treatments and rehabilitation for LC, could provide scalable and generalisable solutions at pace. METHODS AND ANALYSIS: This is a pragmatic, multi-centre, cluster-randomised clinical trial of two components of an integrated care pathway (Coverscan™, a multi-organ MRI, and Living with COVID Recovery™, a digitally enabled rehabilitation platform) with a nested, Phase III, open label, platform randomised drug trial in individuals with LC. Cluster randomisation is at level of primary care networks so that integrated care pathway interventions are delivered as "standard of care" in that area. The drug trial randomisation is at individual level and initial arms are rivaroxaban, colchicine, famotidine/loratadine, compared with no drugs, with potential to add in further drug arms. The trial is being carried out in 6-10 LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes at 3 months. The trial also includes an economic evaluation which will be described separately. ETHICS AND DISSEMINATION: The protocol was reviewed by South Central-Berkshire Research Ethics Committee (reference: 21/SC/0416). All participating sites obtained local approvals prior to recruitment. Coverscan™ has UK certification (UKCA 752965). All participants will provide written consent to take part in the trial. The first participant was recruited in July 2022 and interim/final results will be disseminated in 2023, in a plan co-developed with public and patient representatives. The results will be presented at national and international conferences, published in peer reviewed medical journals, and shared via media (mainstream and social) and patient support organisations. TRIAL REGISTRATION NUMBER: ISRCTN10665760.

AZD1222-induced nasal antibody responses are shaped by prior SARS-CoV-2 infection and correlate with virologic outcomes in breakthrough infection.

The nasal mucosa is an important initial site of host defense against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, intramuscularly administered vaccines typically do not achieve high antibody titers in the nasal mucosa. We measure anti-SARS-CoV-2 spike immunoglobulin G (IgG) and IgA in nasal epithelial lining fluid (NELF) following intramuscular vaccination of 3,058 participants from the immunogenicity substudy of a phase 3, double-blind, placebo-controlled study of AZD1222 vaccination (ClinicalTrials.gov: NCT04516746). IgG is detected in NELF collected 14 days following the first AZD1222 vaccination. IgG levels increase with a second vaccination and exceed pre-existing levels in baseline-SARS-CoV-2-seropositive participants. Nasal IgG responses are durable and display strong correlations with serum IgG, suggesting serum-to-NELF transudation. AZD1222 induces short-lived increases to pre-existing nasal IgA levels in baseline-seropositive vaccinees. Vaccinees display a robust recall IgG response upon breakthrough infection, with overall magnitudes unaffected by time between vaccination and illness. Mucosal responses correlate with reduced viral loads and shorter durations of viral shedding in saliva.

Immune correlates analysis of the PREVENT-19 COVID-19 vaccine efficacy clinical trial.

In the PREVENT-19 phase 3 trial of the NVX-CoV2373 vaccine (NCT04611802), anti-spike binding IgG concentration (spike IgG), anti-RBD binding IgG concentration (RBD IgG), and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks post-dose two are assessed as correlates of risk and as correlates of protection against COVID-19. Analyses are conducted in the U.S. cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measures the markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases. All markers are inversely associated with COVID-19 risk and directly associated with vaccine efficacy. In vaccine recipients with nAb ID50 titers of 50, 100, and 7230 international units (IU50)/ml, vaccine efficacy estimates are 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), and 96.8% (88.3%, 99.3%). The results support potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use.

Lessons from a large-scale COVID-19 vaccine trial.

Global vaccination coverage remains indispensable in combatting the ongoing SARS-CoV-2 pandemic. Safety, efficacy, and durability of immune protection are the key parameters of randomized controlled trials (RCTs) and are essential for vaccine approvals, global distribution, and comprehensive population-vaccination programs. Immune protection from either vaccination or natural infection decreases over time, further challenged by rapid viral evolution. In this issue of the JCI, Sobieszczyk and colleagues report an update on the safety, efficacy, and durability of immune protection of AZD12222 in a large-scale, multinational, Phase III RCT. They report that protection lasted through 6 months, with immunity waning after 180 days. The study also highlights challenges facing vaccine trials, including the need for early unblinding for vulnerable participants, which may affect outcome measurements. Another challenge is to ensure fair representation of marginalized and minority ethnic groups in vaccine safety and efficacy studies worldwide.

Phase II/III trial of hyperimmune anti-COVID-19 intravenous immunoglobulin (C-IVIG) therapy in severe COVID-19 patients: study protocol for a randomized controlled trial.

BACKGROUND: COVID-19 poses a global health challenge with more than 325 million cumulative cases and above 5 million cumulative deaths reported till January 17, 2022, by the World Health Organization. Several potential treatments to treat COVID-19 are under clinical trials including antivirals, steroids, immunomodulators, non-specific IVIG, monoclonal antibodies, and passive immunization through convalescent plasma. The need to produce anti-COVID-19 IVIG therapy must be continued, alongside the current treatment modalities, considering the virus is still mutating into variants of concern. In this context, as the present study will exploit pooled diversified convalescent plasma collected from recovered COVID-19 patients, the proposed hyperimmune Anti-COVID-19 intravenous immunoglobulin (C-IVIG) therapy would be able to counter new infectious COVID-19 variants by neutralizing the virus particles. After the successful outcome of the phase I/II clinical trial of C-IVIG, the current study aims to further evaluate the safety and efficacy of single low dose C-IVIG in severe COVID-19 patients for its phase II/III clinical trial. METHODS: This is a phase II/III, adaptive, multi-center, single-blinded, randomized controlled superiority trial of SARS-CoV-2 specific polyclonal IVIG (C-IVIG). Patients fulfilling the eligibility criteria will be block-randomized using a sealed envelope system to receive either 0.15 g/Kg C-IVIG with standard of care (SOC) or standard of care alone in 2:1 ratio. The patients will be followed-up for 28 days to assess the primary and secondary outcomes. DISCUSSION: This is a phase II/III clinical trial evaluating safety and efficacy of hyperimmune anti-COVID-19 intravenous immunoglobulin (C-IVIG) in severe COVID-19 patients. This study will provide clinical evidence to use C-IVIG as one of the first-line therapeutic options for severe COVID-19 patients. TRIAL REGISTRATION: Registered at clinicaltrial.gov with NCT number NCT04891172 on May 18, 2021.

In vitro and in vivo evaluation of the main protease inhibitor FB2001 against SARS-CoV-2.

FB2001 is a drug candidate that targets the main protease of SARS-CoV-2 via covalently binding to cysteine 145. In this study, we evaluated the inhibitory activities of FB2001 against several SARS-CoV-2 variants in vitro and in vivo (in mice), and we also evaluated the histopathological analysis and immunostaining of FB2001 on lung and brain which have been rarely reported. The results showed that FB2001 exhibited potent antiviral efficacy against several current SARS-CoV-2 variants in Vero E6 cells, namely, B.1.1.7 (Alpha): EC50 = 0.39 ± 0.01 µM, EC90 = 0.75 ± 0.01 µM; B.1.351 (Beta): EC50 = 0.28 ± 0.11 µM, EC90 = 0.57 ± 0.21 µM; B.1.617.2 (Delta): EC50 = 0.27 ± 0.05 µM, EC90 = 0.81 ± 0.20 µM; B.1.1.529 (Omicron): EC50 = 0.26 ± 0.06 µM and EC50 = 0.042 ± 0.007 µM (in the presence of a P-glycoprotein inhibitor). FB2001 remained potent against SARS-CoV-2 replication in the presence of high concentrations of human serum, which indicating that human serum had no significant effect on the in vitro inhibitory activity. Additionally, this inhibitor exhibited an additive effect against SARS-CoV-2 when combined with Remdesivir. Furthermore, FB2001 significantly reduced the SARS-CoV-2 copy numbers and titers in the lungs and brains in vivo, and alleviated the pathological symptoms. In addition, FB2001 could alleviated local bleeding, erythrocyte overflow, edema, and inflammatory cell infiltration in brain tissue, and inhibitors reducing viral titers and improving inflammation in the brain have been rarely reported. A physiologically based pharmacokinetic model was established and verified to predict the FB2001 concentration in human lungs. When FB2001 was administered at 200 mg twice a day for 5 days, the observed Ctrough ss in plasma and predicted Ctrough ss of lung total concentration were 0.163 and 2.5 µg/mL, which were approximately 9 and 132-fold higher than the EC50 of 0.019 µg/mL (0.042 µM) against Omicron variant. Taken together, our study suggests that FB2001 is a promising therapeutic agent in COVID-19 treatment and can be combined with remdesivir to achieve improved clinical outcomes. Owing to its good safety and tolerability in healthy human (NCT05197179 and NCT04766931), FB2001 has been approved for Phase II/III clinical trial (NCT05445934).

COVID-19 Vaccines against Omicron Variant: Real-World Data on Effectiveness.

The efficacy of vaccines against coronavirus disease 2019 (COVID-19) has now been well established in phase III clinical trials. However, clinical studies based on real-world data remain critical to assess vaccines effectiveness (VE), especially in specific populations and against variants of concern (VOC). This review presents the principles and methods of VE studies and the main available results on VE of COVID-19 vaccines at the time of Omicron circulation. References for this narrative review were identified through searches of PubMed database up to 13 September 2022. The results of phase III clinical trials have been globally confirmed by VE in real-life studies, including in the elderly. Emergence of VOC Omicron emphasized the importance of booster doses to maintain a high level of protection against severe forms. There are still numerous challenges regarding booster(s) and duration of immunity, particularly in specific subpopulations, and regarding the need for adapted vaccines.

Building Emotional Awareness and Mental Health (BEAM): study protocol for a phase III randomized controlled trial of the BEAM app-based program for mothers of children 18-36 months.

BACKGROUND: The prevalence of maternal depression and anxiety has increased during the COVID-19 pandemic, and pregnant individuals are experiencing concerningly elevated levels of mental health symptoms worldwide. Many individuals may now be at heightened risk of postpartum mental health disorders. There are significant concerns that a cohort of children may be at-risk for impaired self-regulation and mental illness due to elevated exposure to perinatal mental illness. With both an increased prevalence of depression and limited availability of services due to the pandemic, there is an urgent need for accessible eHealth interventions for mothers of young children. The aims of this trial are to evaluate the efficacy of the Building Emotion Awareness and Mental Health (BEAM) app-based program for reducing maternal depression symptoms (primary outcome) and improve anxiety symptoms, parenting stress, family relationships, and mother and child functioning (secondary outcomes) compared to treatment as usual (TAU). METHODS: A two-arm randomized controlled trial (RCT) with repeated measures will be used to evaluate the efficacy of the BEAM intervention compared to TAU among a sample of 140 mothers with children aged 18 to 36 months, who self-report moderate-to-severe symptoms of depression and/or anxiety. Individuals will be recruited online, and those randomized to the treatment group will participate in 10 weeks of psychoeducation modules, an online social support forum, and weekly group teletherapy sessions. Assessments will occur at 18-36 months postpartum (pre-test, T1), immediately after the last week of the BEAM intervention (post-test, T2), and at 3 months after the intervention (follow-up, T3). DISCUSSION: eHealth interventions have the potential to address elevated maternal mental health symptoms, parenting stress, and child functioning concerns during and after the COVID-19 pandemic and to provide accessible programming to mothers who are in need of support. This RCT will build on an open pilot trial of the BEAM program and provide further evaluation of this evidence-based intervention. Findings will increase our understanding of depression in mothers with young children and reveal the potential for long-term improvements in maternal and child health and family well-being. TRIAL REGISTRATION: ClinicalTrials.gov NCT05306626 . Registered on April 1, 2022.

Antivirals for adult patients hospitalized with SARS-CoV-2 infection: A randomized, Phase II/III, multicenter, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocol and statistical analysis plan. / Antivirais para pacientes adultos hospitalizados com infecção por SARS-CoV-2: Um estudo de Fase II/III, randomizado, multicêntrico, controlado por placebo, adaptativo, com múltiplos braços e estágios. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocolo e plano de análise estatística.

Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier: NCT04468087.

Os medicamentos reaproveitados são importantes em contextos de recursos limitados porque as intervenções estão mais rapidamente disponíveis, já foram testadas com segurança em outras populações e são, em geral, mais baratas. Os medicamentos reaproveitados são uma solução eficaz, especialmente para doenças emergentes, como a COVID-19. O estudo REVOLUTIOn visa avaliar três medicamentos antivirais reaproveitados: atazanavir, daclatasvir e sofosbuvir, já utilizados em pacientes infectados pelo HIV ou pelo vírus da hepatite C, em um estudo randomizado, controlado por placebo, adaptativo, multibraço e em múltiplos estágios. Os medicamentos serão testados simultaneamente em um ensaio de Fase II para primeiro identificar se algum deles, isoladamente ou em combinação, reduz a carga viral. Se reduzirem, será iniciado um estudo de Fase III para investigar se tais medicamentos são capazes de aumentar o número de dias sem suporte respiratório. Os participantes devem ser adultos hospitalizados com idade ≥ 18 anos com início dos sintomas ≤ 9 dias e saturação de oxigênio ≤ 94% em ar ambiente ou necessidade de oxigênio suplementar para manter saturação de oxigênio > 94%. O tamanho total esperado da amostra varia entre 252 e 1.005 participantes, dependendo do número de estágios que serão concluídos no estudo. Assim, o protocolo é aqui descrito em detalhes, juntamente do plano de análise estatística. Em conclusão, o estudo REVOLUTIOn foi concebido para fornecer evidências se o atazanavir, o daclatasvir ou o sofosbuvir reduzem a carga viral de SARS-CoV-2 em pacientes com COVID-19 e aumentam o número de dias em que os pacientes ficam sem suporte respiratório. Neste artigo de protocolo, descrevem-se a fundamentação, o desenho e a situação do ensaio. Identificador do ClinicalTrials.gov: NCT04468087.

Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery in colorectal carcinoma at high risk of peritoneal carcinomatosis: short-term and long-term outcomes from the CHECK study - protocol for a randomised, multicentre, phase 3 trial.

INTRODUCTION: Up to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts' involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking. METHODS AND ANALYSIS: This is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method. ETHICS AND DISSEMINATION: This trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings. TRIAL REGISTRATION NUMBER: NCT03914820.

Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer's Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments.

BACKGROUND: Guanfacine is a α2A adrenergic receptor agonist approved for treating attention deficit hyperactivity disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer's disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect on symptomatic AD. The primary objective of the NorAD trial is to evaluate the change in cognition with 12 weeks of treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer's disease. METHODS/DESIGN: NorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer's disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is the change in cognition, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include the change in additional cognitive measures of attention (Tests of Attention: Trails A and B, digit-symbol substitution, Test of Everyday Attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory). From July 2020, observation of change following cessation of treatment is also being assessed. DISCUSSION: There is strong evidence for early noradrenergic dysfunction in Alzheimer's disease. The NorAD trial aims to determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03116126 . Registered on 14 April 2017 EudraCT: 2016-002598-36.

Evaluation of the safety and immunogenicity of different COVID-19 vaccine combinations in healthy individuals: study protocol for a randomized, subject-blinded, controlled phase 3 trial [PRIBIVAC].

BACKGROUND: Over 2021, COVID-19 vaccination programs worldwide focused on raising population immunity through the primary COVID-19 vaccine series. In Singapore, two mRNA vaccines (BNT162b2 and mRNA-1273) and the inactivated vaccine CoronaVac are currently authorized under the National Vaccination Programme for use as the primary vaccination series. More than 90% of the Singapore population has received at least one dose of a COVID-19 vaccine as of December 2021. With the demonstration that vaccine effectiveness wanes in the months after vaccination, and the emergence of Omicron which evades host immunity from prior infection and/or vaccination, attention in many countries has shifted to how best to maintain immunity through booster vaccinations. METHODS: The objectives of this phase 3, randomized, subject-blinded, controlled clinical trial are to assess the safety and immunogenicity of heterologous boost COVID-19 vaccine regimens (intervention groups 1-4) compared with a homologous boost regimen (control arm) in up to 600 adult volunteers. As non-mRNA vaccine candidates may enter the study at different time points depending on vaccine availability and local regulatory approval, participants will be randomized at equal probability to the available intervention arms at the time of randomization. Eligible participants will have received two doses of a homologous mRNA vaccine series with BNT162b2 or mRNA-1273 at least 6 months prior to enrolment. Participants will be excluded if they have a history of confirmed SARS or SARS-CoV-2 infection, are immunocompromised, or are pregnant. Participants will be monitored for adverse events and serious adverse events by physical examinations, laboratory tests and self-reporting. Blood samples will be collected at serial time points [pre-vaccination/screening (day - 14 to day 0), day 7, day 28, day 180, day 360 post-vaccination] for assessment of antibody and cellular immune parameters. Primary endpoint is the level of anti-SARS-CoV-2 spike immunoglobulins at day 28 post-booster and will be measured against wildtype SARS-CoV-2 and variants of concern. Comprehensive immune profiling of the humoral and cellular immune response to vaccination will be performed. DISCUSSION: This study will provide necessary data to understand the quantity, quality, and persistence of the immune response to a homologous and heterologous third booster dose of COVID-19 vaccines. This is an important step in developing COVID-19 vaccination programs beyond the primary series. TRIAL REGISTRATION: ClinicalTrials.gov NCT05142319 . Registered on 2 Dec 2021.

A group resilience training program for people with multiple sclerosis: Study protocol of a multi-centre cluster-randomized controlled trial (multi-READY for MS).

INTRODUCTION: REsilience and Activities for every DaY (READY) is an Acceptance and Commitment Therapy-based group resilience-training program that has preliminary empirical support in promoting quality of life and other psychosocial outcomes in people with multiple sclerosis (PwMS). Consistent with the Medical Research Council framework for developing and evaluating complex interventions, we conducted a pilot randomized controlled trial (RCT), followed by a phase III RCT. The present paper describes the phase III RCT protocol. METHODS AND ANALYSIS: This is a multi-centre cluster RCT comparing READY with a group relaxation program (1:1 ratio) in 240 PwMS from eight centres in Italy (trial registration: isrctn.org Identifier: ISRCTN67194859). Both interventions are composed of 7 weekly sessions plus a booster session five weeks later. Resilience (primary outcome), mood, health-related quality of life, well-being and psychological flexibility will be assessed at baseline, after the booster session, and at three and six month follow-ups. If face-to-face group meetings are interrupted because of COVID-19 related-issues, participants will be invited to complete their intervention via teleconferencing. Relevant COVID-19 information will be collected and the COVID-19 Peritraumatic Distress scale will be administered (ancillary study) at baseline and 3-month follow-up. Analysis will be by intention-to-treat to show superiority of READY over relaxation. Longitudinal changes will be compared between the two arms using repeated-measures, hierarchical generalized linear mixed models. CONCLUSION: It is expected that his study will contribute to the body of evidence on the efficacy and effectiveness of READY by comparing it with an active group intervention in frontline MS rehabilitation and clinical settings. Results will be disseminated in peer-reviewed journals and at other relevant conferences.

The incidence of COVID-19 infection following emergency use authorization of BBIBP-CORV inactivated vaccine in frontline workers in the United Arab Emirates.

Based on the findings from the Phase III clinical trials of inactivated SARS COV-2 Vaccine, (BBIBP-CORV) emergency use authorization (EUA) was granted for the vaccine to frontline workers in the UAE. A prospective cohort study was conducted among frontline workers to estimate the incidence rate and risk of symptomatic COVID-19 infection 14 days after the second dose of inoculation with BBIBP-CORV inactivated vaccine. Those who received two doses of the BBIBP-CORV vaccine in the period from 14th of September 2020 (first dose) to 21st of December 2020 (second dose) were followed up for COVID-19 infections. 11,322 individuals who received the two-dose BBIBP-CORV vaccine were included and were followed up post the second dose plus fourteen days. The incidence rate of symptomatic infection was 0.08 per 1000-person days (95% CI 0.07, 0.10). The estimated absolute risk of developing symptomatic infection was 0.97% (95% CI 0.77%, 1.17%). The confirmed seroconversion rate was 92.8%. There were no serious adverse events reported and no individuals suffered from severe disease. Our findings show that vaccinated individuals are likely to remain protected against symptomatic infection or becoming PCR positive for SARS COV 2 following the second dose of the vaccination.

COVID-19 Vaccination for Frail Older Adults in Singapore - Rapid Evidence Summary and Delphi Consensus Statements.

OBJECTIVE: This study aimed to synthesize available evidence on the effectiveness and safety of COVID-19 vaccines for frail older adults through a rapid review, supplemented with geriatricians' consensus statements. METHODS: References were identified through MEDLINE and Web of Science on 1st February 2021 using relevant terms related to COVID-19, vaccine, and older adults. Searches were also conducted on reference lists of review articles and Google Scholar. The content was updated on 8th April via hand searching. We included studies on Phase III randomized controlled trials, and data from real world administration of vaccines. A two-round Delphi study was conducted with 15 geriatricians to elicit their thoughts and recommendations regarding COVID-19 vaccination for frail older adults. RESULTS: Five Phase III randomized controlled efficacy trials reported vaccine efficacy ranging from 66.7% to 95% among participants aged 16 to 95. The vaccine efficacy for participants aged 65 and above is 94.7% and 86.4% for Pfizer-BioNTech and Moderna respectively. Sputnik V reported a vaccine efficacy of 91.8% for participants 60 and above. Serious adverse events were reported by 0.27% to 1% of participants who received at least one dose of the four vaccines. For the Delphi study, 16 out of 24 statements achieved consensus. The Delphi panel opined that frail or very old adults, except those with limited life expectancy, should be vaccinated due to their vulnerability. They also agree that vaccination decisions should be made by patients when possible, with the involvement of next-of-kin should the frail older adult be unable to do so. Lastly, the panel thought that frail older adults should be included in future clinical trials. CONCLUSION: In early clinical trials, there is paucity of evidence on efficacy and safety of current COVID-19 vaccines among frail older adults. Geriatricians' consensus indicate that frail older adults should be vaccinated except where life expectancy is limited. Future trials assessing efficacy and safety should include frail older adults.

A real-life experience as a proof of Guselkumab effectiveness and safety in patients with moderate to severe psoriasis.

Psoriasis is a skin disorder characterized by chronic inflammation driven by different immunologic pathways, among which the IL-23/Th17 axis plays a pivotal role. For this reason, the use of IL23p19 inhibitors in psoriasis treatment has been evaluated over the years. Guselkumab, a totally human IgG1 lambda monoclonal antibody, that selectively blocks the p 19 subunit of IL- 23 has demonstrated high efficacy and safety throughout several, randomized, double-blind phase III trials (VOYAGE 1 and 2, NAVIGATE and ECLIPSE). We designed a single-center retrospective cohort study in a population consisting of 46 patients followed from December 2018 to April 2021. After a diagnosis of moderate to severe psoriasis, all the patients were considered suitable to receive treatment with Guselkumab. In our population, among those who achieved clinical improvement in terms of Psoriasis Area Severity Index (PASI), PASI 75, 90, and 100 were achieved on average on weeks 14, 19, 21 respectively. We then analyzed a subgroup of our population, consisting of 35 patients, who had an identical follow-up time of 28 weeks, thus observing the trend in mean PASI at subsequent assessments and the number of patients who had reached PASI 75, PASI 90, and PASI 100 at week 4 (10; 3; 1), week 12 (12; 13; 11), week 20 (7; 6; 2), and week 28 (1; 4; 6), respectively. The results obtained are in line with those obtained from previous studies, thus confirming that Guselkumab is an excellent choice in terms of security, long-term efficacy, and overall tolerance.

Protocol for a phase 3 trial to evaluate the effectiveness and safety of a heterologous, two-dose vaccine for Ebola virus disease in the Democratic Republic of the Congo.

INTRODUCTION: Ebola virus disease (EVD) continues to be a significant public health problem in sub-Saharan Africa, especially in the Democratic Republic of the Congo (DRC). Large-scale vaccination during outbreaks may reduce virus transmission. We established a large population-based clinical trial of a heterologous, two-dose prophylactic vaccine during an outbreak in eastern DRC to determine vaccine effectiveness. METHODS AND ANALYSIS: This open-label, non-randomised, population-based trial enrolled eligible adults and children aged 1 year and above. Participants were offered the two-dose candidate EVD vaccine regimen VAC52150 (Ad26.ZEBOV, Modified Vaccinia Ankara (MVA)-BN-Filo), with the doses being given 56 days apart. After vaccination, serious adverse events (SAEs) were passively recorded until 1 month post dose 2. 1000 safety subset participants were telephoned at 1 month post dose 2 to collect SAEs. 500 pregnancy subset participants were contacted to collect SAEs at D7 and D21 post dose 1 and at D7, 1 month, 3 months and 6 months post dose 2, unless delivery was before these time points. The first 100 infants born to these women were given a clinical examination 3 months post delivery. Due to COVID-19 and temporary suspension of dose 2 vaccinations, at least 50 paediatric and 50 adult participants were enrolled into an immunogenicity subset to examine immune responses following a delayed second dose. Samples collected predose 2 and at 21 days post dose 2 will be tested using the Ebola viruses glycoprotein Filovirus Animal Non-Clinical Group ELISA. For qualitative research, in-depth interviews and focus group discussions were being conducted with participants or parents/care providers of paediatric participants. ETHICS AND DISSEMINATION: Approved by Comité National d'Ethique et de la Santé du Ministère de la santé de RDC, Comité d'Ethique de l'Ecole de Santé Publique de l'Université de Kinshasa, the LSHTM Ethics Committee and the MSF Ethics Review Board. Findings will be presented to stakeholders and conferences. Study data will be made available for open access. TRIAL REGISTRATION NUMBER: NCT04152486.

Humoral and cellular immunity in convalescent COVID-19 people with multiple sclerosis treated with ofatumumab.

OBJECTIVES: To report clinical outcome, development of humoral and T-cell mediated immunity in convalescent COVID-19 people with multiple sclerosis (pwMS) treated with ofatumumab in the ALITHIOS study from a single center. METHODS: Testing for SARS-Cov2 IgG antibodies was performed on two occasions with at least three months apart between the two testing. During the second antibody testing, interferon-γ ELISpot was used to assess cellular immunity. RESULTS: All four subjects had mild COVID-19 infection without any sequelae. In all subjects except subject 2, COVID-19 was confirmed with PCR. Subjects 1, 2 and 4 had normal levels of IgM and IgG without measurable counts of CD19 cells prior to COVID-19. Subject 3 administered the last dose of ofatumumab 24 days prior to COVID-19 symptoms, but had a gap of 28 weeks of ofatumumab application beforehand due to low IgM levels. Subject 4 received COVID-19 vaccinations before second testing, so second testing and T-cell immunity testing were not performed. Subjects who were CD19 depleted did not had measurable levels of SARS-Cov2 IgG antibodies. Subject 3 had first and second SARS-COV2 titer of 118 U/ml and > 250 U/ml, respectively. All three pwMS showed T cell immunity against SARS-CoV-2. Quotient of basal spots divided by interferon-γ secreting spot forming units were 4, 8 and 14.7 SI in subjects 1, 2 and 3, respectively (>3 considered reactive). CONCLUSION: While no antibody response was observed in pwMS who were CD19+ lymphocyte depleted, T cell immunity against SARS-CoV-2 was observed in all three pwMS treated with ofatumumab.