Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial.

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.

Estimated Prevalence of and Factors Associated With Clinically Significant Anxiety and Depression Among US Adults During the First Year of the COVID-19 Pandemic.

Importance: Claims of dramatic increases in clinically significant anxiety and depression early in the COVID-19 pandemic came from online surveys with extremely low or unreported response rates. Objective: To examine trend data in a calibrated screening for clinically significant anxiety and depression among adults in the only US government benchmark probability trend survey not disrupted by the COVID-19 pandemic. Design, Setting, and Participants: This survey study used the US Centers for Disease Control and Prevention Behavioral Risk Factor Surveillance System (BRFSS), a monthly state-based trend survey conducted over the telephone. Participants were adult respondents in the 50 US states and District of Columbia who were surveyed March to December 2020 compared with the same months in 2017 to 2019. Exposures: Monthly state COVID-19 death rates. Main Outcomes and Measures: Estimated 30-day prevalence of clinically significant anxiety and depression based on responses to a single BRFSS item calibrated to a score of 6 or greater on the 4-item Patient Health Questionnaire (area under the receiver operating characteristic curve, 0.84). All percentages are weighted based on BRFSS calibration weights. Results: Overall, there were 1 429 354 respondents, with 1 093 663 in 2017 to 2019 (600 416 [51.1%] women; 87 153 [11.8%] non-Hispanic Black; 826 334 [61.5%] non-Hispanic White; 411 254 [27.8%] with college education; and 543 619 [56.8] employed) and 335 691 in 2020 (182 351 [51.3%] women; 25 517 [11.7%] non-Hispanic Black; 250 333 [60.5%] non-Hispanic White; 130 642 [29.3%] with college education; and 168 921 [54.9%] employed). Median within-state response rates were 45.9% to 49.4% in 2017 to 2019 and 47.9% in 2020. Estimated 30-day prevalence of clinically significant anxiety and depression was 0.4 (95% CI, 0.0 to 0.7) percentage points higher in March to December 2020 (12.4%) than March to December 2017 to 2019 (12.1%). This estimated increase was limited, however, to students (2.4 [95% CI, 0.8 to 3.9] percentage points) and the employed (0.9 [95% CI, 0.5 to 1.4] percentage points). Estimated prevalence decreased among the short-term unemployed (-1.8 [95% CI, -3.1 to -0.5] percentage points) and those unable to work (-4.2 [95% CI, -5.3 to -3.2] percentage points), but did not change significantly among the long-term unemployed (-2.1 [95% CI, -4.5 to 0.5] percentage points), homemakers (0.8 [95% CI, -0.3 to 1.9] percentage points), or the retired (0.1 [95% CI, -0.6 to 0.8] percentage points). The increase in anxiety and depression prevalence among employed people was positively associated with the state-month COVID-19 death rate (1.8 [95% CI, 1.2 to 2.5] percentage points when high and 0.0 [95% CI, -0.7 to 0.6] percentage points when low) and was elevated among women compared with men (2.0 [95% CI, 1.4 to 2.5] percentage points vs 0.2 [95% CI, -0.1 to 0.6] percentage points), Non-Hispanic White individuals compared with Hispanic and non-Hispanic Black individuals (1.3 [95% CI, 0.6 to 1.9] percentage points vs 1.1 [95% CI, -0.2 to 2.5] percentage points and 0.7 [95% CI, -0.1 to 1.5] percentage points), and those with college educations compared with less than high school educations (2.5 [95% CI, 1.9 to 3.1] percentage points vs -0.6 [95% CI, -2.7 to 1.4] percentage points). Conclusions and Relevance: In this survey study, clinically significant US adult anxiety and depression increased less during 2020 than suggested by online surveys. However, this modest aggregate increase could mask more substantial increases in key population segments (eg, first responders) and might have become larger in 2021 and 2022.

How COVID-19 has impacted immunisation service delivery in Australia: a national study.

OBJECTIVE: The objective of this study was to determine the impact the COVID-19 pandemic had on the delivery of adult, maternal and childhood immunisation services in Australia in 2020 prior to the rollout of COVID-19 vaccines, and to understand the adaptations made at a service delivery level that may have contributed to the successful delivery of immunisation services during the first year of the pandemic. METHODS: An electronic survey was sent to immunisation providers and pharmacists in all states and territories in Australia between November 2020 and December 2020. It explored interruption to the delivery of immunisation services, strategies implemented to maintain services, prioritisation of populations, and self-reported challenges and solutions initiated by providers. RESULTS: A total of 850 people responded to the survey. Of these, the most common professional groups identified were pharmacists followed by nurse immunisers, nurses/midwives and general practitioners. Several changes were implemented including relocation of vaccination clinics, change to bookings rather than walk-in appointments, infection prevention measures, clients waiting in cars pre- and post-vaccination and reduced observation period post-vaccination. CONCLUSION: The pandemic has provided opportunities for services to trial new and innovative strategies such as electronic pre-assessment, electronic consent and drive-through vaccination services. IMPLICATIONS FOR PUBLIC HEALTH: Immunisation providers mostly viewed these changes positively and intend to continue many post-pandemic. The experience gained from the trialling of these strategies may be adapted for vaccine delivery and National Immunisation Program vaccines beyond the pandemic.

The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis.

BACKGROUND: Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. METHODS AND FINDINGS: Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (-1.2 ms, -3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. CONCLUSIONS: While caution is advised in the use of amodiaquine in patients aged ≥12 years with concomitant use of heart rate-reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.

An adaptive randomised placebo controlled phase II trial of antivirals for COVID-19 infection (VIRCO): A structured summary of a study protocol for a randomised controlled trial.

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.