The role of dorsolateral prefrontal cortex on placebo effect of regulating social pain: A TMS study

Under the influence of the novel coronavirus epidemic, some negative social events, such as separation of family or friends and home isolation have increased. These events can cause negative emotion experiences similar to physical pain, thus they are called social pain. Placebo effect refers to the positive response to the inert treatment with no specific therapeutic properties, which has been shown to be one of the effective ways to alleviate social pain. Studies have shown that the dorsolateral prefrontal cortex (DLPFC) plays a key role in placebo effect. Therefore, this study aimed to explore whether activating DLPFC by using transcranial magnetic stimulation (TMS) could improve the ability of placebo effects to regulate social pain. Besides, we also combined neuroimaging and neuromodulation techniques to provide bidirectional evidence for the role of the DLPFC on placebo effects. We recruited a total of 100 participants to finish the task of negative emotional rating of the social exclusion images. Among them, 50 participants were stimulated by TMS at the right DLPFC (rDLPFC), while the others were assigned to the sham group. This study contained two independent variables. The between-subject variable was TMS group (rDLPFC-activated group or sham group) and the within-subject variable was placebo type (no-placebo and placebo). All participants received nasal spray in two blocks. In the no-placebo condition, participants were instructed that they would receive a saline nasal spray which helped to improve physiological readings;in placebo block, participants were told to administrate an intranasal fluoxetine spray (saline nasal spray in fact) that could reduce unpleasantness within 10 minutes. To strengthen the expectation of intranasal fluoxetine, participants viewed a professional introduction to fluoxetine's clinical and academic usage including downregulating negative emotion, such as fear, anxiety, and disgust. Participants who received the placebo block first would be reminded that fluoxetine's effect was over before the next block to reduce the carry-over for the following block. Self-reported negative emotional and electroencephalogram data were recorded. There was a significant two-way interaction of TMS group and placebo type. Results showed that compared with the sham group, participants in the rDLPFC-activated group reported less negative emotional feeling and had a lower amplitude of the late positive potential (LPP) in placebo condition, a component that reflects the emotional intensity, suggesting that activating rDLPFC can improve the ability of placebo effect to regulate social pain. The above finding suggested that activating DLPFC can improve the placebo effect of regulating negative emotion. Moreover, this study is the first attempt to investigate the enhancement of placebo effects by using TMS on emotion regulation. The findings not only support the critical role of DLPFC on placebo effect using neuroimaging and neuromodulation techniques, but also provide a potential brain target for treating emotional regulation deficits in patients with psychiatric disorders. © 2023 WANG Mei.

Reproduction of the Control Group in REMDACTA Trial Using the Millennial Medical Record, an Electric Health Record Database, in Japan

Objectives: Developing a control group of a clinical trial using real world data is desirable and ethically sound despite challenges pertaining to internal validity. To examine the internal validity, we reproduced the control group in a Randomized Controlled Trial (RCT) using Electric Health Record (EHR) data and evaluated the difference between the outcome of the original trial and that of the reproduced analysis. Method(s): We selected an RCT, REMDACTA trial, that was performed to evaluate the efficacy of tocilizumab plus remdesivir against placebo plus remdesivir in patients with severe COVID-19 pneumonia. We reproduced its control group (patients with severe COVID-19 pneumonia taking only remdesivir), using Japanese EHR data, Millennial Medical Record provided by Life Data Initiative. Target patients for the main analysis were those prescribed remdesivir within 2 days after admission and diagnosed with COVID-19 (defined by ICD-10 code, U07.1) and/or with COVID-19 pneumonia (defined by diagnosis name). Patients in the sub analysis included only those with COVID-19 pneumonia diagnosis. Among the target patients, those undergoing image inspection, oxygen administration, and not taking any medicines for pneumonia before the first remdesivir prescription were eligible for the analyses. Median length of stay was compared in the reproduced group and in REMDACTA trial. Result(s): The database included 676 and 110 target patients for the main and sub analyses, respectively. However, only 57 and 14 patients met the eligibility criteria for the main and sub analyses, respectively. The reduction in the number of patients is attributed to the criteria of image inspection and oxygen administration. Median length of stay in the reproduced group were 13 and 11 days in the main and sub analyses, respectively. In REMDACTA trial, 95% CI of median time was 11.0-16.0. Conclusion(s): We successfully reproduced the median time of the control group by EHR data.Copyright © 2023

Mesenchymal Stem/Stromal Cells: HUMAN MESENCHYMAL STEM CELL THERAPY IN SEVERE COVID-19 PATIENTS: 2-YEAR FOLLOW-UP RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

Background & Aim: The long-term effects of human mesenchymal stem cell (MSC) treatment on COVID-19 patients have not been fully characterized. The aim of this study was to evaluate the safety and efficacy of a MSC treatment administered to severe COVID-19 patients enrolled in a randomized, double-blind, placebo-controlled clinical trial (NCT 04288102). Methods, Results & Conclusion(s): A total of 100 patients experiencing severe COVID-19 received either MSC treatment (n = 65, 4x107 cells per infusion) or a placebo (n = 35) combined with standard of care on days 0, 3, and 6. Patients were subsequently evaluated 18 and 24 months after treatment to evaluate the long-term safety and efficacy of the MSC treatment. The outcomes measured included: 6-minute walking distance (6-MWD), lung imaging, quality of life according to the Short Form 36 questionnaire, COVID-19-related symptoms, titers of SARS-CoV-2 neutralizing antibodies, MSC-related adverse events (AEs), and tumor markers. Two years after treatment, a marginally smaller proportion of patients had a 6-MWD below the lower limit of the normal range in the MSC group than in the placebo group (OR = 0.19, 95% CI: 0.04-0.80, Fisher's exact test, p = 0.015). On the SF-36 questionnaire, a marginally higher general health score was received by the MSC group at month 18 compared with the placebo group (50.00 vs. 35.00;95% CI: 0.00-20.00, Wilcoxon rank sum test, p = 0.016). In contrast, there were no differences in the total severity score of lung imaging or the titer of neutralizing antibodies between the two groups. Meanwhile, there were no MSC-related AEs reported at the 18- or 24-month follow-ups. The serum levels of most of the tumor markers examined remained within normal ranges and were similar between the MSC and placebo groups. Long-term safety was observed for the COVID-19 patients who received MSC treatment. Yet few sustained efficacy of MSC treatment was observed at the end of the 2-year follow-up period. Funding(s): The National Key Research and Development Program of China (2022YFA1105604, 2020YFC0860900), the specific research fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202216) and the Fund of National Clinical Center for Infectious Diseases, PLA General Hospital (NCRCID202105,413FZT6). [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

The Importance of the Treatment Rationale for Pain in Animal-Assisted Interventions: A Randomized Controlled Trial in Healthy Participants.

Animal-assisted interventions (AAIs) is a promising treatment approach for pain, but possible mechanisms still need to be elucidated. This study set out to investigate the analgesic effects of an animal provided with a treatment rationale in a randomized controlled trial employing a standardized experimental heat-pain paradigm. We randomly assigned 128 healthy participants to: dog treatment (DT), placebo treatment (PT), dog and placebo treatment (DPT), and no treatment (NT). Primary outcomes were heat-pain tolerance and the corresponding self-reported ratings of pain unpleasantness and intensity. Results revealed no differences in heat-pain tolerance between the conditions. However, participants in the DT condition experienced heat-pain as significantly less unpleasant at the limit of their tolerance compared to participants in the NT condition (estimate = -0.96, CI = -1.58 to 0.34, P = .010). Participants in the DT condition also showed lower ratings of pain intensity at the limit of their tolerance compared to participants in the NT condition (estimate = -0.44, CI = -0.89 to 0.02, P = .060). This study indicates that a dog has analgesic effects on pain perception when integrated into the treatment rationale. We assume that providing a treatment rationale regarding the animal is important in AAIs for pain. PERSPECTIVE: This study shows that the presence of an animal is not sufficient for animal-assisted interventions (AAIs) to have an analgesic effect on pain unless they are provided with a treatment rationale. This could imply that not only the animal but also contextual factors are important in AAIs. TRIAL REGISTRATION: Clinical Trials NCT04361968.

Long-Term Efficacy and Safety of Upadacitinib in Patients with Psoriatic Arthritis Refractory to Biologic Therapies: 2-Year Results from the Phase 3 Select-Psa 2 Study

Background/Aims Upadacitinib (UPA), an oral Janus kinase (JAK) inhibitor, demonstrated efficacy and safety in patients (pts) with psoriatic arthritis (PsA) and prior inadequate response or intolerance to >=1 biologic disease modifying antirheumatic drug (bDMARD) at week (wk) 56 in the phase 3 SELECT-PsA 2 study. We aimed to evaluate the efficacy and safety of UPA at wk 104 from the ongoing long-term extension of SELECTPsA 2. Methods Pts were randomized to UPA 15mg (UPA15), UPA 30mg (UPA30), or placebo (PBO) for 24 wks;PBO pts were then switched to UPA15 or UPA30. For continuous UPA treatment groups, efficacy endpoints at wk 104 were analyzed using non-responder imputation (NRI) and as observed (AO) (binary endpoints) or mixed-effect model repeated measures (MMRM) and AO (continuous endpoints). Treatmentemergent adverse events (TEAEs) were summarized for pts who received >=1 dose of study drug using visit-based cut-off at wk 104. Results A total of 641 pts received >=1 dose of study drug. At wk 104, 38.4% of all patients had discontinued study drug, with the highest discontinuation observed in patients randomized to PBO at baseline (all PBO: 46.7%). The most common reasons for discontinuation were lack of efficacy (UPA15: 12.3%, UPA30: 8.7%, all PBO: 21.7%) and adverse event (UPA15: 10.9%, UPA30: 13.3%, all PBO: 12.7%). The proportion of UPA pts that achieved ACR20/50/70, MDA, PASI75/90/100, and resolution of dactylitis and enthesitis were generally similar, or further improved, with 104 wks of treatment vs 56 wks. Similarly, mean change from baseline in HAQ-DI, patient's assessment of pain, BASDAI, and ASDAS was improved with UPA treatment. At 104 wks of therapy, clinical responses were largely similar with UPA15 and UPA30. Generally, safety data at wk 104 were consistent with that reported at wk 56. Rates of serious infection, herpes zoster, hepatic disorder, anemia, neutropenia, lymphopenia, and CPK elevation remained numerically higher with UPA30 vs UPA15, while rates of malignancies, MACE, and VTE were similar for both UPA groups. One death was reported with UPA15 (unexplained due to lack of information;however, the patient had recently been diagnosed with ovarian cancer) and two with UPA30 (pancytopenia and COVID-19 pneumonia). Conclusion In PsA pts with prior inadequate response or intolerance to>=1 bDMARD, clinical responses were maintained with UPA15 and UPA30 up to two years of treatment. No new safety signals were identified in this long-term extension.

Effect of the capsid assembly modulator (CAM) ALG-000184 on HBsAg Levels in subjects with HBeAg positive chronic hepatitis B (CHB)

Background: ALG-000184 is a prodrug of ALG-001075, a novel, potent, pan-genotypic Class II CAM. CAMs are thought to have two mechanisms of action (MoA). The primary MoA affects pgRNA encapsidation resulting in inhibition of HBV DNA/RNA replication, as confirmed in CHB subjects receiving ALG-000184. The secondary MoA, which occurs at higher concentrations, regulates the establishment and replenishment of cccDNA, resulting in lowering of HBsAg, an effect that has not been reported to date with ALG- 000184. Method(s): ALG-000184-201 is a multi-part, multicenter, doubleblind, randomized, placebo-controlled study. In healthy volunteers (HVs), single doses up to 500 mg and multiple doses up to 250 mg were well tolerated with linear PK (Gane E., HBV TAG and APASL 2021). In treatment naive (TN) subjects with CHB, daily oral doses of 10-100 mg ALG-000184 for 28 days were well tolerated with linear PK and were associated with profound reductions of DNA/RNA regardless of HBeAg status or dose (Yuen MF, EASL 2022). Plasma exposures required to engage the secondary MoA are expected to be achieved at the 300 mg dose level. Data from a 300 mg cohort treated for 28 days are described here. Data from another ongoing cohort treated with 300 mg for 12 weeks will be presented at the conference. Result(s): Ten subjects were randomized to 300 mg ALG-000184 for 28 days and two to placebo. Two subjects randomized to ALG- 000184 were replaced due to missing data due to Covid-19 lockdown. Subjects were Asian, HBeAg positive, and genotype B or C. Mean baseline HBV DNA and RNA levels were 8.4 log10 IU/mL and 7.3 log10 copies/mL, respectively. One subject experienced a serious adverse event (AE) of pneumothorax>8 weeks after last dose which was considered unlikely related to study drug. No subjects prematurely discontinued study drug. All treatment emergent AEs were Grade <= 2 except for 4 Grade >= 3 alanine aminotransferase (ALT) elevations, which an independent ALT Flare Committee assessed as not related to study drug toxicity. PK was similar to HBeAg negative and HV cohorts following body weight adjustment. Subjects dosed with 300 mg ALG-000184 experienced mean declines of 4.0 log10 IU/mL and 2.6 log10 copies/mL in HBV DNA and RNA levels, respectively, at Day 28. Three of 7 evaluable subjects who received ALG-000184 had HBsAg declines>0.2 log10 IU/mL (0.23-0.78 log10 IU/mL). One subject receiving ALG-000184 had unquantifiable HBsAg throughout the study. Additionally, one HBeAg positive subject in a prior 100 mg cohort had plasma exposures equivalent to the 300 mg dose level and experienced a 0.5 log10 IU/mL HBsAg decline. Conclusion(s): In TN HBeAg positive CHB subjects, 300 mg ALG- 000184 for 28 days was well tolerated, exhibited predictable PK and resulted in rapid and substantial declines in HBV DNA and RNA. Notably, 3 of 7 evaluable subjects from this cohort experienced HBsAg declines of up to 0.78 log10 IU/mL. These data suggest that ALG-000184 can engage the secondary MoA of CAM II. Cohorts evaluating 300 mg over longer durations are planned or ongoing.

Cuban Vaccines Abdala and Mambisa against Covid-19

Intro: With the first case of COVID-19 in Cuba on March 11, 2020, the Center for Genetic Engineering and Biotechnology in Havana began an extensive vaccine program. Two vaccines based on RBD recombinant protein were developed, one for systemic administration "Abdala" and one mucosal vaccine "Mambisa". Abdala received the EUA in July 2021 and "Mambisa" completed its clinical development as a booster dose for convalescent subjects. Method(s): Two doses (25 and 50 microg) and two schedules (0-14-28 and 1-28-56 days) were evaluated in phase I clinical trials with volunteers 19 to 54 years old. The phase II and III clinical trials were also double-blind, randomized, and placebo-controlled, and included respectively 660 and 48,000 volunteers from 19 to 80 years. The anti-RBD titers were evaluated using a quantitative ELISA system developed at the Center for Immunoassay, Havana Cuba, and ELECSYS system from Roche. The RBD to ACE2 plate-based binding competitive ELISA was performed to determine the inhibitory activity of the anti-RBD polyclonal sera on the binding of the hFc-ACE2 coated plates. The neutralization antibody titers were detected by a traditional virus microneutralization assay (MN50). Finding(s): The Abdala vaccine reached 92.28% efficacy. The epidemic was frankly under control in Cuba after the vaccine introduction having reached the highest levels of cases and mortality in July 2021 with the dominance of the Delta strain. The peak of the Omicron wave, unlike other countries, did not reach half of the cases of the Delta wave with a significant reduction in mortality. The mucosal vaccine candidate "Mambisa" completed its clinical development as a booster dose for convalescent subjects reaching the trial end-point. Conclusion(s): Vaccine composition based on RBD recombinant antigen alone is sufficient to achieve high vaccine efficacy comparable to mRNA and live vaccine platforms. The vaccine also protects against different viral variants including Delta and Omicron strains.Copyright © 2023

Relationship between Sars-Cov-2 Viral Load, Antigen Positivity and Infectious Titer

Intro: Performance of SARS-CoV-2 antigen tests is described relative to RT-PCR cycle threshold (Ct) values. However, Ct values may not be consistent between tests from different manufacturers, or even between runs. Here we correlate the Roche Elecsys SARS-CoV-2 Antigen assay results to a quantitative RT-PCR readout as a more reproducible measure of viral load. Additionally, we look at the relationship between the antigen test results, viral load and infectious titer. Method(s): Longitudinal nasopharyngeal swab samples from patients (N=452) with severe Covid-19 pneumonia collected between 03 April and 28 May 2020 in a randomized, double-blind, placebo controlled, multicenter study to evaluate the safety and efficacy of Tocilizumab (COVACTA), were assessed for SARS-CoV-2 viral load (RNA copies/ mL) and a qualitative and semi-quantitative readout of Elecsys SARS-CoV-2 Antigen assay. Viral culture experiments were performed to determine the infectious titer (TCID50/ mL) in a subset of samples. Agreement analysis was performed to compare the results of the assays. Please note that the current intended use of Elecsys SARS-CoV-2 Antigen assay is the qualitative detection of SARS-CoV-2 antigen. Finding(s): We observed high negative percent agreement between the Elecsys SARS-CoV-2 Antigen assay results and the RT-PCR results, while the positive percent agreement was only high in samples exceeding a certain viral load and at earlier time points from symptom onset. Infectious titer values and both the antigen assay semi-quantitative readout and the quantitative RT-PCR results correlated well. Positive percent agreement of RT-PCR and antigen results in relation to infectious titer was very high in both cases, while negative percent agreement was moderate to low. Conclusion(s): These data show that in patients with high viral load the Elecsys SARS-CoV-2 Antigen assay correlates well qualitatively and quantitatively with the presence of SARS-CoV-2 RNA and infectious virus as determined by RT-PCR and viral culture, respectively.Copyright © 2023

Week 48 results of a phase 3 randomized controlled trial of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) vs dolutegravir 1 emtricitabine/tenofovir disoproxil fumarate (DTG 1 F/TDF) as initial treatment in HIV-1/HBV-coinfected adults (ALLIANCE)

Background/Aims: The clinical course of hepatitis B virus (HBV) infection in individuals with HIV-1 coinfection is marked by accelerated disease progression. A tenofovir-containing antiretroviral regimen is recommended in most people with HIV-1/HBV-coinfection, but there have not been randomized studies of tenofovir disoproxil fumarate (TDF) vs tenofovir alafenamide (TAF) in treatment- naive HIV-1/HBV-coinfected individuals. We report primary endpoint results from a Phase 3 study comparing bictegravir/emtricitabine/ TAF (B/F/TAF) vs dolutegravir + emtricitabine/TDF (DTG + F/TDF) at Week (W)48 in participants initiating treatment for both viruses. Method(s): Adults with HIV-1/HBV coinfection were randomized 1:1 to initiate blinded treatment with B/F/TAF or DTG + F/TDF (with placebo). Primary endpoints were the proportion of participants with HIV-1 RNA<50 copies/mL (FDA Snapshot) and plasma HBV DNA<29 IU/mL (missing = failure) at W48. Noninferiority was assessed with 95% CI (12% margin). Secondary and other endpoints included change from baseline cluster of differentiation 4 (CD4) count, proportion with hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) loss/seroconversion, and alanine transaminase (ALT) normalization (AASLD criteria). Result(s): Participants (N = 243) were randomized and treated (B/F/ TAF [n = 121], DTG + F/TDF [n = 122]) from 11 countries in Asia, Europe, North, and Latin America. Baseline characteristics were median age of 32 years, 4.5% female, 88% Asian, 30% HIV-1 RNA>100,000 c/mL, 40% CD4<200 cells/lL, median HBV DNA 8.1 log10 IU/mL, 78% HBeAg+. At W48, B/F/TAF was noninferior to DTG + F/TDF at achieving HIV-1 RNA<50 copies/mL (95% vs 91%, difference 4.1%;95% CI -2.5%-10.8%;P = 0.21), with mean CD4 gains of + 200 and + 175 cells/lL, respectively. B/F/TAF was superior to DTG + F/TDF at achieving HBV DNA<29 IU/mL (63% vs 43%, difference 16.6%;95% CI 5.9%-27.3%;P = 0.0023). Participants treated with B/F/TAF vs DTG + F/TDF had numerically higher HBsAg loss (13% vs 6%;P = 0.059), HBeAg loss (26% vs 14%;P = 0.055), HBeAg seroconversion (23% vs 11%;P = 0.031), and ALT normalization (73% vs 55%;P = 0.066). The most frequent adverse events among participants treated with B/F/TAF vs DTG + F/TDF were upper respiratory tract infection (17% vs 11%), COVID- 19 (13% vs 11%), pyrexia (9% vs 12%), ALT increase (7% vs 11%), and nasopharyngitis (11% vs 4%). ALT flares (elevations at >= 2 consecutive postbaseline visits) occurred in 11 participants (7 B/F/ TAF, 4 DTG + F/TDF), and all resolved. Conclusion(s): Among adults with HIV-1/HBV-coinfection starting antiviral therapy, both B/F/TAF and DTG + F/TDF had high HIV-1 suppression at year 1, with B/F/TAF resulting in superior HBV DNA suppression and significantly more HBeAg seroconversion. Safety findings were similar between groups.

QUASAR Induction Study 1 Cumulative Response to Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis

Introduction: Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission atWeek (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1. Method(s): Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore >=2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IV->GUS 200mg IV;GUS 200mg IV->GUS 200mg SC;GUS 400mg IV->GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure). Matching IV or SC PBO was administered to maintain the blind. Result(s): Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. AtWk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6 % (29/105) of patients randomized to PBO IV (both p< 0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV->200mg SC group and 50.0% (19/38) in the GUS 400mg IV->200mg SC group achieved clinical response at Wk 24. Clinical response atWk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV->GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar toWk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results. Conclusion(s): Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified. (Figure Presented).

Immunogenicity of Sars-Cov-2 Vaccines by Vaccine Type in Randomised Clinical Trials

Background: Currently five SARS-CoV-2 vaccines are approved in North America (FDA) and Europe (EMA). Across the world other vaccines have been developed but not approved in high-income countries. Of the approved vaccines, 2 are mRNA vaccines, 2 are viral vectored vaccines, and 1 is a protein subunit vaccine. As immunogenicity markers are increasingly being used by regulatory agencies as surrogate markers for vaccine efficacy to inform authorization decisions, this meta-analysis compared the size of immunogenicity responses response elicited by the different COVID-19 vaccine types (mRNA, protein subunit, inactivated virus, viral vectors) and approved and unapproved COVID-19 vaccines. Method(s): Systematic review of trial registers and databases identified RCTs for SARS-CoV-2 vaccines. Risk of bias analysis was conducted using the Cochrane Risk of Bias tool. High risk of bias studies were excluded from analysis. Meta-analysis of seroconversion rates and geometric antibody titers (GMT) for neutralising (NAb) and anti-spike antibodies was conducted, each compared with a placebo using random effects model Cochrane-Mantel Haenszel Tests. Result(s): All studies assessed immunogenicity of COVID-19 vaccines on healthy non-immunocompromised adults between the age of 18 and 59. Statistically significant difference was identified between the different vaccine types for NAb GMT, anti-spike GMT, NAb seroconversion, and anti-spike seroconversion (P< 0.00001 for all). Conversely, no statistical significant difference was identified between approved and unapproved vaccines for NAb seroconversion (P=0.39), Nab GMT (P=0.36), anti-spike seroconversion (P=0.07), and antispike GMT (P=0.54). mRNA vaccines had the best immunogenicity results for NAb seroconversion, GMT, and anti-spike seroconversion. Viral vector vaccines had the lowest results for NAb seroconversion and GMT, while inactivated viruses had the lowest result for anti-spike seroconversion and mRNA vaccines for anti-spike GMT. High heterogeneity was observed across the different studies. Conclusion(s): This metanalysis of 35 randomised trials in 33,813 participants showed approved and unapproved vaccines to be comparable in postvaccination GMT values and seroconversion for both NAb and anti-spike. However, while comparing COVID-19 vaccines by vaccine types, statistically significant differences are observed. Variations in study designs, populations enrolled, and infection prevalence during trial duration could have influenced results.

Tolerance of ETD001, a long-acting inhaled epithelial sodium channel blocker, in humans

Background: To assess the safety, tolerability, and pharmacokinetic (PK) profile in humans of the novel inhaled epithelial sodium channel blocker ETD001. Method(s): Inhaled ETD001 or placebo, delivered via nebulizer, have been administered in a 3:1 ratio to 96 healthy subjects in a blinded, first-inhuman clinical trial (ClinicalTrials.gov Identifier: NCT04926701). The study consisted of two parts. Part A evaluated single ascending doses (SADs) up to 10.8 mg, and Part B evaluated multiple ascending doses (MADs) up to 3.1 mg once daily (QD) for 7 days and 4.65 mg twice daily (BID) for 14 days. Safety was assessed by monitoring for adverse events (AEs), laboratory safety tests (including blood potassium monitoring), vital signs, 12-lead electrocardiogram (ECG), and spirometry. Systemic exposurewas assessed using serial pharmacokinetic blood draws. Result(s): Therewere no serious AEs. Twenty-four subjects reported 38 AEs, all of mild to moderate intensity and all resolved. There were no clinically relevant changes in laboratory safety tests, vital signs, ECGs, or spirometry measurements. All blood potassium assessments were within normal range at all doses. Three subjects withdrew in Part B;all withdrawals were considered unrelated to study drug: one on day 6 from the 3.1-mg QD cohort for personal reasons, one after the first dose of the 3.1-mg BID cohort because of vasovagal syncope at time of venipuncture triggering atrial fibrillation that spontaneously resolved, and one on Day 4 of the 3.1- mg BID cohort because of a positive COVID-19 test. Pharmacokinetic parameters were approximately dose proportional in Part A, with peak concentrations 1 to 2 hours after dose and exposure out to 12 to 24 hours at all doses, indicating good lung retention. Part B plasma concentrations displayed dose-independent kinetics and showed minimal accumulation, with a mean of 1.11-fold observed over 14 days. Conclusion(s): ETD001 was well tolerated at single doses up to 10.8 mg and multiple doses of 3.1 mg QD for 7 days and 4.65 mg BID for 14 days. The wide safety margin is predicted to enable doses capable of durable target engagement in the lung, which are expected to enhance mucociliary clearance in people with cystic fibrosis.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Remdesivir Resistance Analyses from the Pinetree Study in Outpatients with Covid-19

Background: Remdesivir (RDV) is a broad-spectrum nucleotide analog antiviral approved for the treatment of COVID-19 in patients who are hospitalized or non-hospitalized and at risk of progressing to severe disease. Here we present SARS-CoV-2 resistance analyses from the Phase 3 PINETREE trial. Method(s): PINETREE was a double-blind, placebo-controlled trial of nonhospitalized participants (N=562) with COVID-19 and >=1 risk factor for disease progression, randomized to receive RDV or placebo once-daily for 3 days. The whole genome of SARS-CoV-2 was sequenced from nasopharyngeal swabs collected at days 1 (baseline), 2, 3, 7, and 14 using next-generation sequencing. Emergent amino acid substitutions in SARS-CoV-2 from participants treated with RDV were tested in a replicon system to determine if they alter sensitivity to RDV. Result(s): Resistance analysis criteria included all participants in the RDV group and 50% in the placebo group with viral load above the lower limit of detection for the viral load assay. Of 281 participants who met these criteria, baseline and postbaseline sequencing data were available for 115/130 (88.5%) participants in the RDV group and 129/151 (85.4%) participants in the placebo group (Table 1). Among these, emergent substitutions in Nsp12 were observed in 8/115 (7.0%) in the RDV group and 7/129 (5.4%) in the placebo group. A total of 7 emergent amino acid substitutions in Nsp12 were observed in the RDV group, but not in the placebo group. Among these, only one substitution from one participant (A376V;first detected at day 14), showed reduced in vitro susceptibility to RDV, with a half-maximal effective concentration (EC50) fold-change of 12.6 compared with a wildtype reference. The participant achieved clinical recovery by day 14. None of the other substitutions impacted RDV susceptibility (EC50 fold-change <=1.4). Emergent substitutions in Nsp8, Nsp10, Nsp13, or Nsp14 were detected in 10/115 (8.7%) of participants in the RDV group and 10/129 (7.8%) in the placebo group, with substitutions in the RDV group showing similar susceptibility to RDV as the wildtype reference (EC50 fold-change <=2.3). Conclusion(s): Overall, emergent substitutions in the SARS-CoV-2 replication complex including Nsp12 were observed with similar frequency in the RDV and placebo groups, with only one participant developing a substitution associated with reduced in vitro RDV susceptibility, indicating a high barrier to the development of RDV resistance in COVID-19 patients.

Effect of Early Treatment with Pegylated Interferon Lambda for Covid-19

Background: We assessed the efficacy of a single dose of peginterferon lambda in preventing clinical events among acutely symptomatic COVID-19 outpatients. Method(s): We conducted a placebo-controlled, randomized, adaptive platform trial among predominantly vaccinated SARS-CoV-2-positive adults in Brazil and Canada receiving either one subcutaneous injection of peginterferon lambda or placebo. The primary composite endpoint was medical admission to hospital, defined as either observation in a COVID-19 emergency setting for > 6 hours, or transfer to a tertiary hospital due to symptomatic COVID-19 within 28 days post-randomization. Result(s): For this evaluation, 931 patients received peginterferon lambda and 1018 received placebo. 84% of the population were vaccinated and the trial occurred across multiple COVID-19 variants. In the primary analysis of patients, the primary outcome was reduced by 51% in the peginterferon lambda vs. placebo groups (relative risk 0.49 [25/916 vs 57/1003], 95% Bayesian credible interval 0.30-0.76, posterior probability >99.9%). This effect was maintained in subgroup analyses including COVID-19-related hospitalization alone (relative risk 0.57, 95% Bayesian credible intervals 0.33-0.95, ) and COVID-19-related hospitalization or death (Hazard ratio 0.59, 95% Bayesian credible interval 0.35- 0.97). The effects were consistent across dominant variants and vaccination status. Among individuals with a high viral level at baseline, peginterferon lambda resulted in lower viral loads by Day 7, compared to placebo. The incidence of adverse events was similar in the two groups. Conclusion(s): Among predominantly vaccinated outpatients with COVID-19, single-dose of peginterferon lambda resulted in significantly decreased clinical events.

Safety and Pharmacokinetics of a Novel Double Prodrug Asc10 in Healthy Subjects

Background: ASC10 is an oral double prodrug of the active antiviral ribonucleoside analog, ASC10-A (also known as beta-d-N4-hydroxycytidine), which is a potent inhibitor of SARS-CoV-2. ASC10 is rapidly metabolized into ASC10-A in vivo after oral dosing. Here, we report the results of the first-in-human, phase 1 study to determine the safety, tolerability, and pharmacokinetics (PK) of ASC10 in healthy subjects, and to assess the food effect on the pharmacokinetics. Method(s): This study included 2 parts. Part 1 (multiple-ascending-dose) consisted of 6 cohorts (8 or 12 subjects per cohort). Eligible subjects were randomized in a 3:1 ratio to receive either twice-daily (BID) doses of 50 to 800 mg ASC10 or placebo for 5.5 days, and were then followed for 7 days for safety. In Part 2 (food effect), 12 subjects were randomized in a 1:1 ratio to either 800 mg ASC10 in the fed state followed by 800 mg in the fasted state, or vice versa, with a 7-day washout period between doses. PK blood samples were collected and measured for ASC10-A along with ASC10 and molnupiravir. Safety assessments included monitoring of adverse events (AEs), measurement of vital signs, clinical laboratory tests, and physical examinations. Result(s): ASC10-A was the major circulating metabolite ( >99.94%) in subjects after oral dosing of ASC10. ASC10-A appeared rapidly in plasma, with a median Tmax of 1.00 to 2.00 h, and declined with a geometric t1/2 of approximately 1.10 to 3.04 h. After multiple dosing for 5.5 days, both Cmax and AUC of ASC10-A increased in a dose-proportional manner from doses of 50 to 800 mg BID without accumulation. of ASC10-A in the fed state occurred slightly later, with a median of 3.99 h postdose versus 2.00 h (fasted state). However, Cmax and AUC were very similar or the same between fed and fasted states. Thus, administration of ASC10 with food is unlikely to have an effect on exposure. The incidence of AEs was similar between subjects receiving ASC10 or placebo (both 66.7%) and 95.0% of AEs were mild. There were no serious adverse events as well as no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Conclusion(s): Results of this study showed that ASC10 was well tolerated, and the increase in plasma exposure of ASC10-A was dose proportional across the range of doses tested with no accumulation and no food effect. 800 mg ASC10 BID is selected for further studies in patients infected with SARS-CoV-2.

A Randomized Trial of Ivermectin 600 Mcg/Kg Vs Placebo in Mild/ Moderate Covid-19

Background: Whether ivermectin, with a maximum targeted dose of 600 mug/ kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) remains unknown. Our objective was to evaluate the effectiveness of ivermectin, maximum targeted dose of 600 mug/kg, daily for 6 days compared with placebo for the treatment of early mild to moderate COVID-19. Method(s): ACTIV-6, an ongoing, decentralized, randomized, double-blind, placebo-controlled, platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1206 participants age >=30 years with confirmed COVID-19, experiencing >=2 symptoms of acute infection for <=7 days, were enrolled from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022, at 93 sites in the US. Participants were randomized to receive ivermectin, with a maximum targeted dose of 600 mug/kg (n=602), daily vs placebo daily (n=604) for 6 days. The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28. Result(s): Among 1206 randomized participants who received study medication or placebo, median (interquartile range) age was 48 (38-58) years;713 (59%) were women;and 1008 (84%) reported >=2 SARS-CoV-2 vaccine doses. Median time to recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (HR) (95% credible interval [CrI], posterior probability of benefit) for improvement in time to recovery was 1.02 (0.92-1.13;P[HR >1]=0.68). In those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (HR 1.0, 0.6-1.5;P[HR< 1]=0.53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%);2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups. Conclusion(s): Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 mug/kg daily for 6 days, compared with placebo did not improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Primary and secondary outcomes.

PHASE 1 CLINICAL TRIALS OF A Q-GRIFFITHSIN NASAL SPRAY FOR SARS-CoV-2 PROPHYLAXIS

Background: The currently approved vaccines do not induce sterilizing immunity against SAR-CoV-2 infection, and immunity wanes over time. A robust broad spectrum topical prophylaxis strategy could protect vulnerable populations in the face of continuous evolution of SARS-CoV-2. The algal antiviral lectin Griffithsin (GRFT), and an engineered oxidation-resistant variant Q-GRFT have robust entry inhibitory activity against SARS-CoV variants of concern, in addition to other respiratory viruses with pandemic potential. We designed a nasal spray to deliver Q-GRFT to the upper respiratory tract mucosa for on-demand use as a broad-spectrum prophylactic. Two clinical trials (Phase 1a and 1b) were conducted to assess safety, tolerability, and pharmacokinetics of Q-GRFT nasal spray in healthy adults. Method(s): Healthy adult volunteers were enrolled in a Phase 1a double blinded, randomized study to receive a single dose of either intranasal Q-GRFT (3.0 mg, 2 sprays per nostril) or placebo at 2:1 ratio. Following a safety review, the Phase 1b study was initiated. Eleven volunteers in Group 1 received 3.0 mg dose once daily, for 7 days. After a safety review, 11 volunteers in Group 2 received a total of 6.0 mg Q-GRFT (3.0 mg twice daily for 7 days). Topical Q-GRFT concentrations were measured by ELISA in collected nasal and nasopharyngeal fluids. Drug levels in plasma were assayed to determine systemic exposure. Viral microneutralization cytopathic effect (CPE) assays were performed against SARS-CoV-2 Omicron BA-5 and MERS-CoV. Result(s): Eighteen adults (24-54 years;Males 58.3%, Females 41.7%;12 Q-GRFT, 6 Placebo), and 22 adults (aged 23-59 years;Males 52.4%, Females 47.6%) were enrolled in Phase 1a and 1b, respectively. In Phase 1a, a single dose of Q-GRFT maintained quantifiable levels in nasal passages and nasopharynx for up to 24 hours. Similarly, Q-GRFT was quantifiable in nasal and nasopharyngeal regions in the Phase 1b study. No dose accumulation effect or systemic exposure was observed. Nasal and nasopharyngeal swab eluates inhibited SARS-CoV-2 Omicron BA.5 and MERS-CoV in CPE assays. Q-GRFT did not modify olfactory sensation. No severe adverse events were reported. Thus, the nasal spray was deemed safe. Conclusion(s): Intranasal Q-GRFT was safe and enhanced mucosal SARSCoV-2 inhibitory activity in human volunteers. The results support further development of Q-GRFT as a broad-spectrum prophylactic against coronaviruses to curb ongoing infections, and for future pandemic preparedness.

Outcomes of a community-based bamlanivimab infusion program for COVID-19

Introduction: The U.S. FDA issued an Emergency Use Authorization in 11/2020 for Bamlanivimab (Bam), a monoclonal antibody infusion, in high-risk outpatients with COVID-19. We examined the effectiveness of Bam given in a coordinated community wide initiative in reducing ED visits, hospitalizations, and deaths during the first 30 days post-treatment. Method(s): Bam treated adults at a community-based (CB) infusion center in the SW USA were identified in a regional EMR database covering all local hospitals. Individual patients were de-identified but tracked for 30 days for ED visits, hospital admissions, ICU admissions, and deaths. Patient demographics including age, sex and ethnicity were recorded. Our local IRB approved the project as exempt. Result(s): A total of 2242 patients received Bam between 11/2020 and 3/2021, while the Wuhan variant was predominant. The mean age was 52, 54% were female and 64% identified as Hispanic or Latino. During the 30 days post infusion 13% of patients visited the ED, but only 2% of the total patients were admitted, 0.6% were admitted to the ICU and 14 died (0.6%). For comparison, a historical placebo control group of COVID patients in Chen et al. [1] is shown in Table 1. Hospitalizations among patients over 60 occurred at the same rate as the total cohort versus more than double the rate in older patients in the control group. Conclusion(s): A CB Bam infusion program reduced ED visits, and hospitalizations, particularly among older patients, with a smaller reduction in ICU admissions and death. Our population is older and including a higher percentage of Hispanic patients who tend to have worse outcomes from COVID-19 [2]. While Bam has now been replaced by newer monoclonal antibodies, our results support the potential community benefit of coordinated monoclonal antibody treatment of patients with COVID-19, with a need for more research to identify patient subgroups who may receive the greatest benefit.

A PHASE 1B STUDY OF ZOTATIFIN FOR THE TREATMENT OF MILD TO MODERATE COVID (PROpel)

Background: Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic initiation factor 4A (eIF4A), a host RNA helicase required for SARS-CoV-2 replication. In vitro, zotatifin demonstrates broad spectrum antiviral activity against all human coronaviruses tested. Zotatifin has physicochemical and pharmacokinetic (PK) properties suitable for convenient, single subcutaneous (sc) injection. This study assessed the safety, antiviral activity, and PK of zotatifin in non-hospitalized patients (pts) with mild/moderate COVID. Method(s): PROPEL is a randomized, placebo-controlled, double-blind study in non-hospitalized pts with mild/moderate COVID. At randomization, pts must have had a SARS-CoV-2 positive test within 7 days and at least 1 COVID symptom. Pts were randomized (3:1) to zotatifin or placebo sc in 3 cohorts of 12 pts each. Cohort 1, 2 and 3 received a single dose (SD) of zotatifin of 0.01. 0.02 and 0.035 mg/kg or matching placebo. Safety (adverse event (AE) and laboratory tests), antiviral activity (mid-turbinate nasal swabs and saliva), and plasma PK were collected over 30 days. The primary endpoint was safety;key secondary endpoints included SARS-CoV-2 viral load (VL) and PK. The study was not powered for statistical inferential testing. Result(s): 36 pts were enrolled across all three cohorts and completed a 30-day follow up. Data is currently available for pts in cohorts 1 and 2, 18 and 6 of whom received zotatifin and placebo, respectively. Baseline characteristics were comparable between groups. The most common AE was erythema at injection site in cohort 1 (44%) and cohort 2 (89%), vs. 0% in the zotatifin and pooled placebo groups, respectively. Other AE frequencies were comparable between zotatifin and placebo and no serious AEs were reported. The concentrationtime profile of zotatifin from cohorts 1 and 2 following sc administration was similar to that reported previously following IV administration, demonstrated a terminal elimination half-life (t1/2) of ~ 4 days, high steady-state volume of distribution (Vss) of 31 L/kg, and low plasma clearance (Cl) of 3.9 mL/min/kg. A faster time to viral RNA undetectability was observed with zotatifin vs. placebo (see Fig 1. Not statistically significant). Conclusion(s): Zotatifin was safe, well tolerated and demonstrated a trend in clinical antiviral activity in patients with mild to moderate COVID which supports further clinical development. Zotatifin sc route of administration supports a point of care treatment for COVID.

Regional effects on efficacy and safety of vilobelimab in mechanically ventilated patients with severe COVID-19

Introduction: Poor outcomes in COVID-19 patients (pt) are associated with C5a-C5aR axis activation. A C5a-specific monoclonal antibody, vilobelimab (VILO), improves outcomes in critically ill COVID-19 pt in a Phase 3 randomized, double-blind, placebo (PLC)- controlled study [1]. Method(s): COVID-19 pt within 48 h of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or PLC at a 1:1 ratio on top of standard of care. Predefined subgroup analyses by region and country were performed. Result(s): Forty-six (46) hospitals on 4 continents randomized 369 pt: VILO (n = 178), PLC (n = 191). VILO significantly reduced 28- (HR 0.67;95% CI 0.48-0.96;p = 0.027) and 60-Day mortality (HR 0.67;95% CI 0.48-0.93, p = 0.0163) using a predefined, unstratified per protocol analysis. Mortality rates at 28- and 60-days and VILO treatment effects, however, differed substantially between regions: Western Europe HR for 60-day mortality 0.59 [0.37-0.95], South Africa plus Russian Federation HR 0.62 [0.28-1.38] and South America HR 0.80 [0.46-1.39] (Fig. 1). The weak signal in South America is predominately driven by Brazil (n = 74), which showed a significant age imbalance with a median 9-years younger PLC group (44.5-years-old vs 53.5-years-old) with low 60-day mortality of ~ 32.5% in the PLC group versus ~ 43.3% in Western Europe. Adjusting for age group categories (<= 30, 31-40, 41-50, 51-60, > 60;Cox regression) for 60-day mortality changed the HR in Brazil (0.96 [0.44-2.10] for continuous age-adjustment) to values near the estimate for the entire study population (HR 0.77 [0.35-1.69] for age in categories), suggesting a by chance imbalance and not a statistically evident weaker effect in Brazil. Conclusion(s): Regional efficacy differences between the rest of the world and South America were driven by age imbalances between treatment groups, which do not diminish the robust efficacy signal for VILO in severe COVID-19.