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1.
EClinicalMedicine ; 54: 101703, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2082840

ABSTRACT

Background: Well tolerated antivirals administered early in the course of COVID-19 infection when the viremia is highest could prevent progression to severe disease. Favipiravir inhibits SARS-CoV-2 viral replication in vitro with evidence of clinical benefit in open label trials. Placebo controlled studies of people with early symptomatic COVID-19 with regular assessments of SARS-CoV-2 viral load can determine if it has an antiviral effect and improves clinical outcomes. Methods: People with PCR-confirmed COVID-19 and 5 days or less of symptoms were randomised 1:1 to favipiravir 1800 mg on day 1, then 800 mg twice daily or matched placebo for 14 days. SARS-CoV-2 viral load was quantitated from second daily self-collected nose-throat swabs while receiving study drug. The primary endpoint was time to virological cure defined as 2 successive swabs negative for SARS-CoV-2 by PCR and secondary outcomes were progression of disease severity, symptom resolution and safety. Findings: Between 31 July 2020 and 19 September 2021, 200 people were enrolled (199 in the community, 1 in hospital) with 190 receiving one or more doses of drug (modified intention to treat [mITT] population). There was no difference in time to virological cure (Log-rank p=0.6 comparing Kaplan Meier curves), progression to hospitalisation (14 favipiravir, 9 placebo; p=0.38), time to symptom resolution (cough, fever, sore throat) and there were no deaths. 51 people related an adverse event that was possibly drug related, but these were evenly distributed (n=24 favipiravir, n=27 placebo). Sensitivity analyses where the definition of virological cure was changed to: a single negative PCR, exclude datapoints based on the presence or absence of human DNA in the swab, a SARS-CoV-2 viral load < 300 copies/mL being considered negative all demonstrated no difference between arms. Interpretation: Favipiravir does not improve the time to virological cure or clinical outcomes and shows no evidence of an antiviral effect when treating early symptomatic COVID-19 infection. Funding: The study was supported in part by grants from the Commonwealth Bank Australia, the Lord Mayor's Charitable Foundation, Melbourne Australia and the Orloff Family Charitable Trust, Melbourne, Australia. JHM is supported by the Medical Research Future Fund, AYP, JT are supported by the Australian National Health and Medical Research Council.

2.
Intern Med J ; 52(2): 214-222, 2022 02.
Article in English | MEDLINE | ID: covidwho-1700926

ABSTRACT

BACKGROUND: The COVID-19 pandemic has generated significant debate about how emerging infections can be treated in the absence of evidence-based therapies to combat disease. In particular, the use of off-label therapies outside of a clinical trial setting has been controversial. AIM: To longitudinally study policies and prescribing practices pertaining to therapies for COVID-19 in Australian health services during 2020. METHODS: Prospective data were collected from participating Australian health services who may care for patients with COVID-19 via an electronic portal. A single informant from each health service was emailed a survey link at regular intervals. Information was sought regarding changes to COVID-19 policy at their service and use of therapies for COVID-19. RESULTS: Overall, 78 hospitals were represented from 39 respondents with longitudinal data collection from May to December 2020. All Australian states/territories were represented with the majority (34/39; 87%) of respondents located in a major city. Just over half (20/39) of respondents had a written policy for COVID-19 therapy use at their health service at survey enrolment and policies changed frequently throughout the pandemic. Therapy use outside of a clinical trial was reported in 54% of health services, most frequently in Victoria, correlating with higher numbers of COVID-19 cases. At study commencement, hydroxychloroquine was most frequently used, with corticosteroids and remdesivir use increasingly throughout the study period. CONCLUSION: Our results reflect the reactive nature of prescribing of therapies for COVID-19 and highlight the importance of evidence-based guidelines to assist prescribers.


Subject(s)
COVID-19 , Australia/epidemiology , Health Services , Humans , Pandemics , Policy , Prospective Studies , SARS-CoV-2 , Surveys and Questionnaires
3.
Infection ; 49(3): 401-410, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1002187

ABSTRACT

COVID-19 is an infectious disease caused by a novel ß-coronavirus, belonging to the same subgenus as the Severe Acute Respiratory Syndrome (SARS) virus. Remdesivir, an investigational broad-spectrum antiviral agent has previously demonstrated in vitro activity against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and in vivo efficacy against other related coronaviruses in animal models. Its safety profile has been tested in a compassionate use setting for patients with COVID-19. The current therapeutic studies demonstrate clinical effectiveness of remdesivir in COVID-19 patients by shortening time to clinical recovery, and hospital stay. In this review, we critically analyze the current evidence of remdesivir against COVID-19 and dissect the aspects over its safety and efficacy. Based on existing data, remdesivir can be regarded as a potential therapeutic agent against COVID-19. Further large-scale, randomized placebo-controlled clinical trials are, however, awaited to validate these findings.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , Animals , COVID-19/epidemiology , Humans , SARS-CoV-2/drug effects , Time Factors , Treatment Outcome
4.
Trials ; 21(1): 847, 2020 Oct 13.
Article in English | MEDLINE | ID: covidwho-858487

ABSTRACT

OBJECTIVES: Primary objective: To determine the efficacy of a candidate antiviral on time to virological cure compared to standard of care within 14 days of randomisation Secondary objectives: • To determine the safety of the antiviral • To determine the clinical benefit of the antiviral over placebo according to the WHO 7-point ordinal scale • To determine the clinical benefit of the antiviral over placebo on time to resolution of clinical symptoms • To determine the effect of the antiviral over placebo on biomarkers of inflammation and immune activation TRIAL DESIGN: This is a multi-centre, triple-blind, randomised placebo controlled phase II, 2-arm trial with parallel-group design with allocation ratio 1:1. PARTICIPANTS: Inclusion Criteria: • Provision of informed consent by the participant • Age ≥18 years • Confirmed SARS-CoV-2 by nucleic acid testing in the past 5 days • COVID-19 related symptom initiation within 5 days • Female patients of childbearing potential must have a negative pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 1 week following the last dose of study treatment. EXCLUSION CRITERIA: • Known allergy to the study medication • Is on another clinical trial investigating an antiviral treatment for COVID-19 • Pregnancy • Patients with severe hepatic dysfunction equivalent to Grade C in the Child-Pugh classification • Patients with renal impairment requiring dialysis • Is deemed by the Investigator to be ineligible for any reason Participants will be recruited from, and the study visits will take place at Alfred Hospital, Monash Health, Austin Health in Victoria, Australia for hospitalised participants as well as recruitment in the community in participants homes for eligible people not requiring hospitalisation. INTERVENTION AND COMPARATOR: The first candidate antiviral is favipiravir Arm 1: Favipiravir 1800 mg favipiravir BD on Day 1 followed by 800 mg BD favipiravir for the next 13 days. Arm 2: Placebo MAIN OUTCOMES: Primary outcome: Time to virological cure as defined by 2 successive throat (or combined nose/throat) swabs negative for SARS-CoV-2 by nucleic acid testing during the 14 days after enrolment. RANDOMISATION: Randomisation performed at the Alfred Hospital Clinical Trials Pharmacy using computer generated block-randomisation lists with 6 participants per block. Within each block half of the participants will be randomised to the candidate antiviral and the other half to placebo. Randomisation is stratified by study site, with participants enrolled in the community considered as a study site. BLINDING (MASKING): Study participants, study investigators and the study statistician will be blinded to treatment allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The study aims to recruit 190 people (95/arm) with the first candidate antiviral favipiravir TRIAL STATUS: Protocol version 2.0 Dated 31-Jul-2020. Recruitment will take place between July 2020 and December 2020. TRIAL REGISTRATION: clinicaltrials.gov NCT04445467 First posted 24-Jun-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Pyrazines/therapeutic use , Amides/adverse effects , Antiviral Agents/adverse effects , Australia/epidemiology , Betacoronavirus/genetics , Biomarkers/metabolism , COVID-19 , Clinical Protocols , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Female , Hospitalization/statistics & numerical data , Humans , Male , Pandemics , Placebos/administration & dosage , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Pyrazines/adverse effects , SARS-CoV-2 , Safety , Treatment Outcome
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