4 results on '"Dennis Hadjiyiannakis"'
Search Results
2. Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial
- Author
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Saye H Khoo, Richard FitzGerald, Geoffrey Saunders, Calley Middleton, Shazaad Ahmad, Christopher J Edwards, Dennis Hadjiyiannakis, Lauren Walker, Rebecca Lyon, Victoria Shaw, Pavel Mozgunov, Jimstan Periselneris, Christie Woods, Katie Bullock, Colin Hale, Helen Reynolds, Nichola Downs, Sean Ewings, Amanda Buadi, David Cameron, Thomas Edwards, Emma Knox, I'ah Donovan-Banfield, William Greenhalf, Justin Chiong, Lara Lavelle-Langham, Michael Jacobs, Josh Northey, Wendy Painter, Wayne Holman, David G Lalloo, Michelle Tetlow, Julian A Hiscox, Thomas Jaki, Thomas Fletcher, Gareth Griffiths, Nicholas Paton, Fred Hayden, Janet Darbyshire, Amy Lucas, Ulrika Lorch, Andrew Freedman, Richard Knight, Stevan Julious, Rachel Byrne, Ana Cubas Atienzar, Jayne Jones, Chris Williams, Anna Song, Jan Dixon, Anja Alexandersson, Parys Hatchard, Emma Tilt, Andrew Titman, Ale Doce Carracedo, Vatsi Chandran Gorner, Andrea Davies, Louis Woodhouse, Nicola Carlucci, Emmanuel Okenyi, Marcin Bula, Kate Dodd, Jennifer Gibney, Lesley Dry, Zalina Rashid Gardner, Amin Sammour, Christine Cole, Tim Rowland, Maria Tsakiroglu, Vincent Yip, Rostam Osanlou, Anna Stewart, Ben Parker, Tolga Turgut, Afshan Ahmed, Kay Starkey, Sujamole Subin, Jennifer Stockdale, Lisa Herring, Jonathon Baker, Abigail Oliver, Mihaela Pacurar, Dan Owens, Alistair Munro, Gavin Babbage, Saul Faust, Matthew Harvey, Danny Pratt, Deepak Nagra, Aashish Vyas, Jaki, Thomas [0000-0002-1096-188X], and Apollo - University of Cambridge Repository
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Adult ,Male ,COVID-19 Vaccines ,Adolescent ,SARS-CoV-2 ,COVID-19 ,Bayes Theorem ,Antiviral Agents ,United Kingdom ,Infectious Diseases ,Treatment Outcome ,Double-Blind Method ,Humans ,Female - Abstract
Background: the antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19.Methods: this randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing.Findings: between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial.Interpretation: we found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive.Funding: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.
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- 2022
3. A Randomised -Controlled Phase 2 trial of Molnupiravir in Unvaccinated and Vaccinated Individuals with Early SARS-CoV-2
- Author
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Saye H Khoo, Richard FitzGerald, Geoffrey Saunders, Calley Middleton, Shazaad Ahmad, Christopher J Edwards, Dennis Hadjiyiannakis, Lauren Walker, Rebecca Lyon, Victoria Shaw, Pavel Mozgunov, Jimstan Periselneris, Christie Woods, Katie Bullock, Colin Hale, Helen Reynolds, Nichola Downs, Sean Ewings, Amanda Buadi, David Cameron, Thomas Edwards, Emma Knox, I’ah Donovan-Banfield, William Greenhalf, Justin Chiong, Lara Lavelle-Langham, Michael Jacobs, Wendy Painter, Wayne Holman, David G Lalloo, Michelle Tetlow, Julian A Hiscox, Thomas Jaki, Thomas Fletcher, and Gareth Griffiths
- Abstract
SummaryBackgroundMolnupiravir was licensed for treating high-risk patients with COVID-19 based on data from unvaccinated adults. AGILE CST-2 (NCT04746183) Phase II reports safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals.MethodsAdult out-patients with PCR-confirmed SARS-CoV-2 infection within five days of symptom onset were randomly assigned 1:1 to receive molnupiravir (800mg twice daily for five days) or placebo. The primary outcome was time to swab PCR-negativity, compared using a Bayesian model for estimating the probability of a superior virological response (Hazard Ratio>1) for molnupiravir over placebo. Secondary outcomes included change in viral titre at day 5, safety and tolerability, clinical progression and patient reported outcome measures. We analysed outcomes after the last participant reached day 29.FindingsOf 180 participants randomised (90 molnupiravir, 90 placebo), 50% were vaccinated. Infections with SARS-CoV-2 variants Delta (40%), Alpha (21%), Omicron (21%) and EU1 (16%) were represented. The median time to negative-PCR was 8 versus 11 days for molnupiravir and placebo (HR=1·30, 95% CrI 0·92-1·71, p=0·07 by Logrank and p=0·03 by Breslow-Gehan tests). Although small numbers precluded subgroup analysis, no obvious differences were observed between vaccinated and unvaccinated participants. Using a two-point prior the probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was just below our defined threshold of 80% for establishing superiority. Using an uninformative continuous prior, the probability of HR>1 was 94·7%. As an exploratory analysis, the change in viral titre on day 5 (end of treatment) was significantly greater with molnupiravir compared with placebo. A total of 4 participants reported severe adverse events (grade 3+), 3 of whom were in the placebo arm.InterpretationWe found molnupiravir to be well-tolerated, with evidence for high probability of antiviral efficacy in a population of vaccinated and unvaccinated individuals infected with a broad range of viral variants.FundingFunded by Ridgeback Biotherapeutics and UK National Institute for Health and Care Research infrastructure funding. The AGILE platform infrastructure is supported by the Medical Research Council (grant number MR/V028391/1) and the Wellcome Trust (grant number 221590/Z/20/Z).
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- 2022
4. Mainstreaming germline BRCA1/2 testing in non-mucinous epithelial ovarian cancer in the North West of England
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Andrew R Clamp, Gordon C Jayson, Martin Hogg, Sarah Moon, Doina Badea, Helene Schlecht, Fiona Lalloo, Elaine F. Harkness, Jurjees Hasan, Nicola Flaum, Dennis Hadjiyiannakis, Tara Clancy, Andrew J Wallace, George J Burghel, Claire Mitchell, Richard J. Edmondson, Robert D. Morgan, Emma J Crosbie, M Bulman, Emma R. Woodward, and D. Gareth Evans
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Adult ,medicine.medical_specialty ,Carcinoma, Ovarian Epithelial ,Article ,Germline ,Ovarian carcinoma ,Internal medicine ,Genetics ,medicine ,Humans ,Epithelial ovarian cancer ,Genetic Testing ,Risk threshold ,Germ-Line Mutation ,Genetics (clinical) ,Aged ,BRCA2 Protein ,Ovarian Neoplasms ,BRCA1 Protein ,business.industry ,Incidence (epidemiology) ,Middle Aged ,medicine.disease ,Serous fluid ,England ,North west ,Female ,Ovarian cancer ,business - Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1–2 and Periods 2–3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.
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- 2020
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