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Preprint in English | Other preprints | ID: ppcovidwho-295990


ABSTRACT Background Globally there is a scarcity of effective treatments for SARS-CoV-2 infections (causing COVID 19). Repurposing existing medications may offer the best hope for treating COVID 19 patients to curb the pandemic. IMU-838 is a dihydroorotate dehydrogenase (DHODH) inhibitor, which is an effective mechanism for antiviral effects against respiratory viruses. When used synergistically with Oseltamivir, therapeutic effects have been observed against influenza and SARS-CoV-2 in rodents. (13) The IONIC trial is a randomized control trial that will investigate whether time to clinical improvement in COVID 19 patients is improved following a 14 day course of IMU-838 + Oseltamivir versus Oseltamivir alone. Methods IONIC trial is an open label study in which participants will be randomised 1:1 in two parallel arms;the intervention arm (IMU-838 + Oseltamivir) and control arm (Oseltamivir only). The primary outcome is time-to-clinical improvement;defined as the time from randomisation to: a 2-point improvement on WHO ordinal scale;discharge from hospital, or death (whichever occurs first). The study is sponsored by UHCW NHS Trust and funded by LifeArc. Discussion The IONIC Protocol describes an overarching trial design to provide reliable evidence on the efficacy of IMU-838 (vidofludimus calcium) when delivered in combination with an antiviral therapy (Oseltamivir) [ IONIC Intervention ] for confirmed or suspected COVID-19 infection in adult patients receiving usual standard of care. Trial Registration The trial was registered with EudraCT (2020-001805-21) on 09.04.2020 and ISRCTN on 23.09.2020 ( ISRCTN53038326 ) and on 17.08.2020 ( NCT04516915 ) Strengths and Limitations This study is the first to recruit participants in the trial exploring the effectiveness of IMU-838 in COVID-19. In addition, we believe it is the only trial exploring the effectiveness of IMU-838 in combination with Oseltamivir (Tamiflu) in patients with moderate to severe COVID-19. However, to make the trial design flexible due to the on-going pandemic the trial is un-blinded.

Int J Environ Res Public Health ; 18(17)2021 09 06.
Article in English | MEDLINE | ID: covidwho-1390649


Background: COVID-19 vaccination programmes offer hope for a potential end to the acute phase of the COVID-19 pandemic. We present perceptions following from a cohort of healthcare staff at the UK NHS hospital, which first initiated the BNT162b2 mRNA COVID-19 ("Pfizer") vaccination program. Methods: A paper-based survey regarding perceptions on the BNT162b2 mRNA COVID-19 vaccine was distributed to all healthcare workers at the University Hospitals Coventry & Warwickshire NHS Trust following receipt of the first vaccine dose. Results: 535 healthcare workers completed the survey, with a 40.9% response rate. Staff felt privileged to receive a COVID-19 vaccine. Staff reported that they had minimised contact with patients with confirmed or suspected COVID-19. Reported changes to activity following vaccination both at work and outside work were guarded. Statistically significant differences were noted between information sources used by staff groups and between groups of different ethnic backgrounds to inform decisions to receive vaccination. Conclusions: NHS staff felt privileged to receive the COVID-19 vaccine, and felt that their actions would promote uptake in the wider population. Concerns regarding risks and side effects existed, but were minimal. This research can be used to help inform strategies driving wider vaccine uptake amongst healthcare staff and the public.

COVID-19 , Vaccines , COVID-19 Vaccines , Delivery of Health Care , Hospitals, University , Humans , Pandemics , Perception , RNA, Messenger , SARS-CoV-2 , State Medicine , Vaccination
Lancet ; 396(10267): 1979-1993, 2021 12 19.
Article in English | MEDLINE | ID: covidwho-933547


BACKGROUND: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

COVID-19 Vaccines/administration & dosage , Immunogenicity, Vaccine , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/pharmacology , Female , Humans , Immunization, Secondary/adverse effects , Immunoglobulin G/blood , Immunoglobulin G/drug effects , Male , Middle Aged , SARS-CoV-2/drug effects , Single-Blind Method , Young Adult