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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-333040

ABSTRACT

Rationale: The COVID-19 pandemic disrupted non-COVID critical care trials globally as intensive care units (ICUs) prioritized patient care and COVID-specific research. The international randomized controlled trial CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) was forced to halt recruitment at all sites in March 2020, creating immediate challenges. We applied the CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstance) guidance to report the impact of the pandemic on CYCLE and describe our mitigation approaches. Methods On March 23, 2020, the CYCLE Methods Centre distributed a standardized email to determine the number of patients still in-hospital and those requiring imminent 90-day endpoint assessments. We assessed protocol fidelity by documenting attempts to provide the in-hospital randomized intervention (cycling or routine physiotherapy), collect the primary outcome (physical function 3-days post-ICU discharge), and 90-day outcomes. We advised sites to prioritize data for the study’s primary outcome. We sought feedback on pandemic barriers related to trial procedures. Results As of March 17, 2020, 197 patients (of 360 planned) had been randomized;26 (13.2%) remained in hospital or were pending 90-day assessments. From 15 active sites (12 Canada, 2 US, 1 Australia), we identified 5 patients still receiving the study intervention in ICUs, 6 requiring primary outcomes, and 17 requiring 90-day assessments. All ICU interventions (5/5, 100%), 5/6 (83%) of primary outcomes, and all (17/17, 100%) 90-day assessments were attempted. Out of the 6 primary outcomes, one site was unable to attempt due to a temporary institutional ban on direct patient contact for non-COVID research, 2 were attempted but not completed due to reasons unrelated to the pandemic, and 3 were completed. Our main mitigation strategies included identifying patients at risk for protocol deviations, communicating early and frequently with sites, monitoring patient progress, data entry, and validation, and providing guidance for conducting some research activities remotely. Conclusions We retained all enrolled patients with minimal missing data using several time-sensitive strategies. Although CONSERVE recommends reporting only major modifications incurred by extenuating circumstances, we suggest that there are other benefits to reporting mitigation strategies with the goal of improving research transparency and trial management. Trial Registration: NCT03471247

2.
N Engl J Med ; 2022 Mar 30.
Article in English | MEDLINE | ID: covidwho-1768965

ABSTRACT

BACKGROUND: The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear. METHODS: We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2-positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 µg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization. RESULTS: A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Findings were similar to the primary analysis in a modified intention-to-treat analysis that included only patients who received at least one dose of ivermectin or placebo (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and in a per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). There were no significant effects of ivermectin use on secondary outcomes or adverse events. CONCLUSIONS: Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.).

3.
BMJ Open ; 12(2): e053642, 2022 02 16.
Article in English | MEDLINE | ID: covidwho-1691312

ABSTRACT

INTRODUCTION: Diabetes mellitus is the most common endocrine disorder in children, and the prevalence of paediatric type 1 and type 2 diabetes continue to rise globally. Diabetes clinical care programs pivoted to virtual care with the COVID-19 pandemic-driven social distancing measures. Yet, the impact of virtual care on health-related quality of life in children living with diabetes remains unclear. This protocol reports on the methods that will be implemented to conduct a systematic review to assess the health-related quality of life and metabolic health impacts of virtual diabetes care. METHODS AND ANALYSIS: We will search MEDLINE, Embase, EMCare, PsycInfo, Web of Science, and the grey literature for eligible studies. We will screen title, abstract, and full-text papers for potential inclusion and assess the risk of bias and the overall confidence in the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. A meta-analysis will be conducted if two studies report similar populations, study designs, methods, and outcomes.This systematic review will summarise the health-related quality of life outcomes for virtual diabetes care delivery models. ETHICS AND DISSEMINATION: No ethics approval is required for this systematic review protocol as it does not include patient data. The systematic review will be published in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42021235646.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Child , Humans , Meta-Analysis as Topic , Pandemics , Quality of Life , Research Design , SARS-CoV-2 , Systematic Reviews as Topic
4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-319954

ABSTRACT

Background: Although vaccines are currently available for coronavirus disease 2019 (COVID-19), there remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as treatments for early COVID-19 among outpatients at a high risk for severe complications. Methods: The TOGETHER Trial is an international (currently in Brazil and Africa), multi-center platform adaptive randomized, placebo-controlled, clinical trial. Patients are included if they are at least 18 years of age, have a positive antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and have an indication for high risk of disease severity, including co-morbidities, older age, or high body mass index. Eligible patients are randomized with equal chance to an investigational product (IP) or to placebo. The primary endpoint is hospitalization due to clinical worsening of COVID-19 or emergency room required observation for more than 6 hours up to 28 days after randomization. Key secondary endpoints include viral clearance, clinical improvement, hospitalization for any cause, mortality for any cause, and safety and tolerability of each IP. Scheduled interim analyses are conducted and reviewed by the Data and Safety Monitoring Committee (DSMC), who make recommendations on continuing or stopping each IP. The platform adaptive design go-no-go decision rules are extended to dynamically incorporate external evidence on COVID-19 interventions from ongoing independent randomized clinical trials. Discussion: Results from this trial will assist in the identification of therapeutics for COVID-19 that can easily be scaled in low- and middle-income settings. The novel methodological extension of the platform adaptive design to dynamically incorporate external evidence is one of the first of its kind and may provide highly valuable information for all COVID-19 trials going forward. Clinicaltrials.gov registration: NCT04727424 (27/01/2021)

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-316581

ABSTRACT

Background: HIV self-testing (HIVST) is one of the recommended approaches for HIV testing services, particularly for helping reach populations who would not normally access facility-based HIV testing. HIVST must be tailored to different populations to ensure uptake. Objective: The main objective of this study was to develop an acceptable HIVST delivery strategy to help improve urban men’s engagement with HIV services. Methods: : We invited key stakeholders for urban men’s HIV services to participate in a co-creation workshop aimed at developing HIVST delivery approaches for urban men, using eThekwini municipality as a study setting. We conducted purposive sampling to include health care users and health care providers, representing a range of views across the public sector and voluntary sector. We employed the Nominal Group Technique (NGT) method for data collection. The NGT workshop was conducted in two consecutive phases: phase one was focused on determining barriers for men’s engagement with the current/facility-based HIV testing services;phase two was aimed at determining HIVST delivery strategies. We used the results of the NGT to design a tailored HIVST strategy for urban men in eThekwini District. Results: : Participants identified the following psychological factors as the most important barriers to uptake of HIV testing services by urban men: stigma, ignorance about the importance of testing and testing process as well as fear of positive test results. Key stakeholders suggested internal motivation strategies as a potentially effective approach to support HIVST delivery strategy. Guided by the NGT results, we designed a HIVST delivery strategy that is supported by a risk communication approach. Conclusion: We designed an evidence-based risk communication mobile health (mHealth) strategy coupled with SARS COV-2 self-testing tailored to improve men’s uptake of HIVST. A follow-up study to evaluate the feasibility of implementing these approaches is recommended.

6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314458

ABSTRACT

Background: . This paper presents, for the first time, the Epidemic Volatility Index (EVI), a conceptually simple, early warning tool for emerging epidemic waves. Methods: . EVI is based on the volatility of the newly reported cases per unit of time, ideally per day, and issues an early warning when the rate of the volatility change exceeds a threshold. Results: . Results from the COVID-19 epidemic in Italy and New York are presented here, while daily updated predictions for all world countries and each of the United States are available online. Interpretation . EVI’s application to data from the current COVID-19 pandemic revealed a consistent and stable performance in terms of detecting oncoming waves. The application of EVI to other epidemics and syndromic surveillance tasks in combination with existing early warning systems will enhance our ability to act fast and optimize containment of outbreaks.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314433

ABSTRACT

Background: COVID-19 is a rapidly spreading disease that is causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. Several vaccines have been accepted by regulatory authorities, but their individual and relative efficacy and adverse effects remain unclear.Methods: We conducted a systematic review of randomised clinical trials with network meta-analysis and Trial Sequential Analysis (TSA). Searches were made in CENTRAL, MEDLINE, Embase, and other sources from inception to May 12, 2021 for randomised clinical trials, assessing vaccines for COVID-19 . At least two independent reviewers screened studies, extracted data, and assessed the risk of bias. Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events.Findings We identified 22 trials;19 trials randomising 144 434 participants were included in our analyses. mRNA vaccines (efficacy 95%, 95% confidence interval (CI) 92% to 97%;69 285 participants;2 trials;GRADE: moderate certainty) and viral vector vaccines (efficacy 68%, 95% CI 61% to 74%;71 401 participants;5 trials;GRADE: low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio (RR) 0·25, 95% CI 0·09 to 0·67;67 563 participants;3 trials, GRADE: low certainty), but data on mRNA vaccines are still imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence indicated rare serious adverse events. mRNA and viral vector vaccines increased the risk of non-serious adverse events. Interpretation The evidence suggests that mRNA vaccines and viral vector vaccines are effective in preventing COVID-19. mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. mRNA vaccines and viral vector vaccines increase the risks of rare serious adverse events according to observational evidence. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines. Registration Information: PROSPERO CRD42020196492. Funding Information: The Copenhagen Trial Unit funded the wages for the authors affiliated with the Copenhagen Trial Unit. None of the authors received any specific funding related to the review. Declaration of Interests: The authors declare that they have no known competing interests.

8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314432

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes corona virus disease 2019 (COVID-19) which has rapidly spread worldwide. Several human randomized clinical trials assessing potential vaccines are currently underway. There is an urgent need for a living systematic review that continuously assesses the beneficial and harmful effects of all available vaccines for COVID-19. Methods: /design: We will conduct a living systematic review based on searches of major medical databases (e.g. MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and conduct risk of bias assessments. We will include randomized clinical trials comparing any vaccine aiming to prevent COVID-19 (including but not limited to messenger RNA;DNA;non-replicating viral vector;replicating viral vector;inactivated virus;protein subunit;dendritic cell;other vaccines) with any comparator (placebo;‘active placebo’;no intervention;standard care;an ‘active’ intervention;another vaccine for COVID-19) for participants in all age groups.Primary outcomes will be all-cause mortality;a diagnosis of COVID-19;and serious adverse events. Secondary outcomes will be quality of life, and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, Trial Sequential Analyses, network meta-analyses, and individual patient data meta-analyses. Within-study bias will be assessed using Cochrane risk of bias tool. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Confidence in Network Meta-Analysis (CINeMA) approaches will be used to assess certainty of evidence. Observational studies describing harms identified during the search for trials will also be included and described and analyzed separately. Discussion: COVID-19 has become a pandemic with substantial mortality. A living systematic review assessing the beneficial and harmful effects of different vaccines is urgently needed. This living systematic review will regularly inform best practice in vaccine prevention and clinical research of this highly prevalent disease. Systematic review registration: PROSPERO CRD42020196492

9.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-307209

ABSTRACT

Background: Despite the expectations regarding the effectiveness of chloroquine (CQ) and hydroxychloroquine (HCQ) for coronavirus disease (COVID-19) management, concerns about their adverse events have remained. Objectives: The objective of this systematic review was to evaluate the safety of CQ and HCQ from malarial and non-malarial randomized clinical trials (RCTs). Methods: : The primary outcomes were the frequencies of serious adverse events (SAEs), retinopathy, and cardiac complications. Search strategies were applied to MEDLINE, EMBASE, LILACS, CENTRAL, Scopus, and Trip databases. We used random-effects model to pool results across studies and Peto one-step odds ratio (OR) for event rates below 1 %. Both-armed zero-event studies were excluded from the meta-analyses. We used the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate the certainty of evidence. Results: : Ninety-two RCTs were included. We found no significant difference between CQ/HCQ and control (placebo or non-CQ/HCQ) in the frequency of SAEs (OR: 0.98, 95 % confidence interval [CI]: 0.71–1.36, 25 trials, 11,605 participants, moderate certainty of evidence). No clear relationship was observed between CQ/HCQ and retinopathy (OR: 1,63, 95 % CI: -0.4–6.57, 5 trials, 344 participants, very low certainty of evidence). There was a low certainty of evidence of the effect of CQ/HCQ versus control on cardiac complications (Relative risk: 1.48, 95 % CI: 1.1–1.98, 8 trials, 5,970 participants). Conclusions: : CQ and HCQ might be safe, with low frequency of SAEs on malarial and non-malarial conditions. No clear effect of their use on the incidence of retinopathy and cardiac complications was observed.The protocol for this systematic review was registered with PROSPERO (registration number : CRD42020177818)

10.
Eur J Rheumatol ; 2022 Feb 14.
Article in English | MEDLINE | ID: covidwho-1687311

ABSTRACT

OBJECTIVES: The experiences of children with pediatric rheumatic diseases (PRD) during the initial phase of the COVID-19 pandemic have not been well-documented. We sought to determine the effects of the COVID-19 pandemic on protective behaviors, healthcare access, medication management, and education among an international cross-sectional parental survey of children with PRDs. METHODS: The COVID-19 Global Rheumatology Alliance Patient Experience Survey was distributed online, and parents of children with parental-reported PRD, with or without COVID-19 infection, were eligible to enroll. Respondents described their child's demographics, adoptions of protective behaviors, healthcare access, changes to immunosuppression, and disruptions in schooling. RESULTS: A total of 427 children were included in the analyses. The most common rheumatic disease was juvenile idiopathic arthritis (40.7%), and most children were taking conventional synthetic diseasemodifying antirheumatic drugs (DMARDs) (54.6%) and/or biologic DMARDs (51.8%). A diagnosis of COVID-19 was reported in five children (1.2%), none of whom required hospitalization. Seventeen children (4.0%) had stopped or delayed their drugs due to concern for immunosuppression, most commonly glucocorticoids. Almost all families adopted behaviors to protect their children from COVID-19, including quarantining, reported by 96.0% of participants. In addition, 98.3% of full-time students experienced disruptions in their education, including cancelations of classes and transitions to virtual classrooms. CONCLUSION: Despite the low numbers of children with PRDs who developed COVID-19 in this cohort, most experienced significant disruptions in their daily lives, including quarantining and interruptions in their education. The drastic changes to these children's environments on their future mental and physical health and development remain unknown.

11.
PLoS One ; 17(1): e0260733, 2022.
Article in English | MEDLINE | ID: covidwho-1643240

ABSTRACT

BACKGROUND: COVID-19 is rapidly spreading causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. METHODS AND FINDINGS: Our objective was to assess the effectiveness and safety of COVID-19 vaccines through analyses of all currently available randomized clinical trials. We searched the databases CENTRAL, MEDLINE, Embase, and other sources from inception to June 17, 2021 for randomized clinical trials assessing vaccines for COVID-19. At least two independent reviewers screened studies, extracted data, and assessed risks of bias. We conducted meta-analyses, network meta-analyses, and Trial Sequential Analyses (TSA). Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events. We assessed the certainty of evidence with GRADE. We identified 46 trials; 35 trials randomizing 219 864 participants could be included in our analyses. Our meta-analyses showed that mRNA vaccines (efficacy, 95% [95% confidence interval (CI), 92% to 97%]; 71 514 participants; 3 trials; moderate certainty); inactivated vaccines (efficacy, 61% [95% CI, 52% to 68%]; 48 029 participants; 3 trials; moderate certainty); protein subunit vaccines (efficacy, 77% [95% CI, -5% to 95%]; 17 737 participants; 2 trials; low certainty); and viral vector vaccines (efficacy 68% [95% CI, 61% to 74%]; 71 401 participants; 5 trials; low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio, 0.25 [95% CI 0.09 to 0.67]; 67 563 participants; 3 trials, low certainty), but comparable data on inactivated, mRNA, and protein subunit vaccines were imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence suggested rare serious adverse events. All the vaccines increased the risk of non-serious adverse events. CONCLUSIONS: The evidence suggests that all the included vaccines are effective in preventing COVID-19. The mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/epidemiology , COVID-19/prevention & control , SARS-CoV-2/pathogenicity , /administration & dosage , COVID-19/mortality , COVID-19/pathology , COVID-19 Vaccines/adverse effects , Humans , Network Meta-Analysis , Randomized Controlled Trials as Topic , SARS-CoV-2/immunology , Survival Analysis , Treatment Outcome , Vaccines, Inactivated , Vaccines, Subunit , /adverse effects
12.
BMJ Open ; 11(12), 2021.
Article in English | ProQuest Central | ID: covidwho-1592612

ABSTRACT

IntroductionTreatment of bipolar disorder is the focus of several clinical trials, however the understanding of the outcomes for establishing treatment effectiveness within these trials is limited. Further, there is limited literature which reports on the outcomes considered to be important to patients, indicating that patient perspectives are often not considered when selecting outcomes of effectiveness within trials. This protocol describes a systematic review which aims to describe the outcomes being used within trials to measure treatment effectiveness, commenting on the inclusion of patient-important outcomes within previous trials.Methods and analysisThis protocol is reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols statement. OVID MEDLINE, OVID Embase, OVID APA PsycINFO, Web of Science, the Wiley Cochrane Library, ClinicalTrials.gov and the International Clinical Trials Registry Platform databases will be searched for eligible studies. Screening, full-text and data extraction stages will be completed in duplicate using the Covidence platform for systematic reviews. Eligible studies will include clinical trials of interventions in bipolar disorder, in order to identify outcomes used to assess treatment effectiveness, and qualitative studies, to determine which outcomes have been reported as important by patients. Risk of bias for included studies will be assessed using the Cochrane Risk of Bias Tool for randomised controlled trials, and the Newcastle-Ottawa Scale for observational research.Ethics and disseminationThis review will involve dissemination to key stakeholders, including primary end users such as patients, clinicians and trialists. Knowledge translation tools will be generated to share the relevant conclusions of this review. Results will be communicated to the scientific community through peer-reviewed publications, conferences and workshops. No ethics approval will be sought as this study is based on literature.PROSPERO registration numberCRD42021214435.

13.
Lancet Glob Health ; 10(1): e42-e51, 2022 01.
Article in English | MEDLINE | ID: covidwho-1586173

ABSTRACT

BACKGROUND: Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. METHODS: This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing. FINDINGS: The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18-102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52-0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53-0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21-0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36-1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01-0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups. INTERPRETATION: Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. FUNDING: FastGrants and The Rainwater Charitable Foundation. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.


Subject(s)
COVID-19/drug therapy , Emergency Medical Services/statistics & numerical data , Fluvoxamine/therapeutic use , Hospitalization/statistics & numerical data , Adult , Aged , Aged, 80 and over , Brazil , Double-Blind Method , Female , Fluvoxamine/adverse effects , Humans , Male , Middle Aged , SARS-CoV-2 , Serotonin Uptake Inhibitors/adverse effects , Serotonin Uptake Inhibitors/therapeutic use , Treatment Outcome
14.
J Med Case Rep ; 15(1): 586, 2021 Dec 13.
Article in English | MEDLINE | ID: covidwho-1571926

ABSTRACT

BACKGROUND: Psychiatric disorders increase risk of neuropsychiatric disease and poor outcomes, yet little is known about the neuropsychiatric manifestations of COVID-19 in the psychiatric population. The primary objective is to synthesize neuropsychiatric outcomes of COVID-19 in people with preexisting psychiatric disorders. METHODS: Data were collected during an ongoing review of the impact of pandemics on people with existing psychiatric disorders. All study designs and gray literature were included. Medline, PsychInfo, CINAHL, EMBASE, and MedRx were searched from inception to September 1 2020. Risk of bias was assessed using a published tool that can accommodate all study types. Two independent authors screened the studies and extracted data. Data were narratively synthesized, as there were insufficient data to meta-analyze. Evidence was appraised according to GRADE. RESULTS: Four case reports were included, comprising 13 participants from three countries. Many large-sample, relevant papers were omitted for not reporting psychiatric history, despite reporting other comorbidities. Included participants (n = 13) were hospitalized with COVID-19 and appeared to meet criteria for delirium. Myoclonus, rigidity, and alogia were also reported. The most commonly reported preexisting psychiatric diagnoses were mood disorders, schizophrenia, and alcohol use disorder. CONCLUSIONS: People with preexisting psychiatric disorders may experience delirium, rigidity, myoclonus, and alogia during COVID-19 infection; although higher quality and longitudinal data are needed to better understand these phenomena. Relevant COVID-19 literature does not always report psychiatric history, despite heightened neuropsychiatric vulnerability within this population. TRIAL REGISTRATION:  PROSPERO (CRD42020179611).


Subject(s)
COVID-19 , Delirium , Bias , Delirium/epidemiology , Humans , Pandemics , SARS-CoV-2
15.
Lancet Reg Health Am ; 6: 100142, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1568912

ABSTRACT

Background: Observational studies have postulated a therapeutic role of metformin in treating COVID-19. We conducted an adaptive platform clinical trial to determine whether metformin is an effective treatment for high-risk patients with early COVID-19 in an outpatient setting. Methods: The TOGETHER Trial is a placebo-controled, randomized, platform clinical trial conducted in Brazil. Eligible participants were symptomatic adults with a positive antigen test for SARS-CoV-2. We enroled eligible patients over the age of 50 years or with a known risk factor for disease severity. Patients were randomly assigned to receive either placebo or metformin (750 mg twice daily for 10 days or placebo, twice daily for 10 days). The primary outcome was hospitalization defined as either retention in a COVID-19 emergency setting for > 6 h or transfer to tertiary hospital due to COVID-19 at 28 days post randomization. Secondary outcomes included viral clearance at day 7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian framework to determine probability of success of the intervention compared to placebo. Findings: The TOGETHER Trial was initiated June 2, 2020. We randomized patients to metformin starting January 15, 2021. On April 3, 2021, the Data and Safety Monitoring Committee recommended stopping enrollment into the metformin arm due to futility. We recruited 418 participants, 215 were randomized to the metformin arm and 203 to the placebo arm. More than half of participants (56.0%) were over the age of 50 years and 57.2% were female. Median age was 52 years. The proportion of patients with the primary outcome at 28 days was not different between the metformin and placebo group (relative risk [RR] 1.14[95% Credible Interval 0.73; 1.81]), probability of superiority 0.28. We found no significant differences between the metformin and placebo group on viral clearance through to day 7 (Odds ratio [OR], 0.99, 95% Confidence Intervals 0.88-1.11) or other secondary outcomes. Interpretation: In this randomized trial, metformin did not provide any clinical benefit to ambulatory patients with COVID-19 compared to placebo, with respect to reducing the need for retention in an emergency setting or hospitalization due to worsening COVID-19. There were also no differences between metformin and placebo observed for other secondary clinical outcomes.

16.
Sci Rep ; 11(1): 23775, 2021 12 10.
Article in English | MEDLINE | ID: covidwho-1565730

ABSTRACT

Early warning tools are crucial for the timely application of intervention strategies and the mitigation of the adverse health, social and economic effects associated with outbreaks of epidemic potential such as COVID-19. This paper introduces, the Epidemic Volatility Index (EVI), a new, conceptually simple, early warning tool for oncoming epidemic waves. EVI is based on the volatility of newly reported cases per unit of time, ideally per day, and issues an early warning when the volatility change rate exceeds a threshold. Data on the daily confirmed cases of COVID-19 are used to demonstrate the use of EVI. Results from the COVID-19 epidemic in Italy and New York State are presented here, based on the number of confirmed cases of COVID-19, from January 22, 2020, until April 13, 2021. Live daily updated predictions for all world countries and each of the United States of America are publicly available online. For Italy, the overall sensitivity for EVI was 0.82 (95% Confidence Intervals: 0.75; 0.89) and the specificity was 0.91 (0.88; 0.94). For New York, the corresponding values were 0.55 (0.47; 0.64) and 0.88 (0.84; 0.91). Consecutive issuance of early warnings is a strong indicator of main epidemic waves in any country or state. EVI's application to data from the current COVID-19 pandemic revealed a consistent and stable performance in terms of detecting new waves. The application of EVI to other epidemics and syndromic surveillance tasks in combination with existing early warning systems will enhance our ability to act swiftly and thereby enhance containment of outbreaks.


Subject(s)
COVID-19/epidemiology , Pandemics , Humans , Italy/epidemiology , New York/epidemiology , Predictive Value of Tests , Time Factors
17.
J Addict Med ; 2021 Nov 16.
Article in English | MEDLINE | ID: covidwho-1522355

ABSTRACT

OBJECTIVES: The opioid use disorder (OUD) crisis in North America has become "an epidemic within a pandemic" in the context of the COVID-19 virus. We aimed to explore the association between the COVID-19 pandemic and changes in opioid use patterns among patients receiving treatment for OUD. METHODS: We used prospectively collected data from 456 patients attending 31 opioid agonist clinics across Ontario, Canada. All included participants underwent routine urine drug screens (UDSs) both before and after the onset of the COVID-19 pandemic. A paired sample t-test was used to compare the proportion of opioid-positive UDSs collected pre- and post-pandemic, and linear regression analysis was used to explore factors associated with this change. RESULTS: Participants had a mean age of 39.9 years (standard deviation = 10.9), 52% were male, and 81% were receiving methadone treatment. The percentage of opioid-positive UDSs increased significantly during the pandemic, on average by 10.6% (95% confidence interval [CI] 8.17, 12.95, P < 0.001). Continued opioid use before the pandemic was associated with 9.43% increase, on average, in the percentage of opioid-positive UDSs during the pandemic (95% CI 3.79, 15.07). Self-reported past-month cocaine (adjusted beta-coefficient 6.83, 95% CI 0.92, 12.73) and amphetamine (adjusted beta-coefficient 13.13, 95% CI 5.15, 21.1) use at study entry were also associated with increases in opioid-positive UDSs. CONCLUSIONS: Increased opioid use is one measure of the negative impact the COVID-19 pandemic has had on individuals with OUD, an already marginalized population. Understanding factors associated with worse outcomes is essential to ensuring that treatment programs appropriately adapt to better serve this population during the pandemic.

18.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-292195

ABSTRACT

Background: There remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as treatments for early COVID-19 among outpatients at a high risk for severe complications.Methods: : The TOGETHER Trial is a multi-center platform adaptive randomized, placebo-controlled, clinical trial. Patients are included if they are at least 18 years of age, have a positive antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and have an indication for high risk of disease severity, including co-morbidities, older age, or high body mass index. Eligible patients are randomized with equal chance to an investigational product (IP) or to placebo.The primary endpoint is hospitalization defined as either retention in a COVID-19 emergency setting for greater than 6 hours or transfer to tertiary hospital due to COVID-19. Secondary outcomes include mortality, adverse events, adherence, and viral clearance. Scheduled interim analyses are conducted and reviewed by the Data and Safety Monitoring Committee (DSMC), who make recommendations on continuing or stopping each IP. The platform adaptive design go-no-go decision rules are extended to dynamically incorporate external evidence on COVID-19 interventions from ongoing independent randomized clinical trials.Discussion: Results from this trial will assist in the identification of therapeutics for the treatment of early diagnosed COVID-19. The novel methodological extension of the platform adaptive design to dynamically incorporate external evidence is one of the first of its kind and may provide highly valuable information for all COVID-19 trials going forward.Clinicaltrials.gov registration: NCT04727424 (27/01/2021)

19.
Syst Rev ; 10(1): 294, 2021 11 04.
Article in English | MEDLINE | ID: covidwho-1504827

ABSTRACT

BACKGROUND: Despite the expectations regarding the effectiveness of chloroquine (CQ) and hydroxychloroquine (HCQ) for coronavirus disease (COVID-19) management, concerns about their adverse events have remained. OBJECTIVES: The objective of this systematic review was to evaluate the safety of CQ and HCQ from malarial and non-malarial randomized clinical trials (RCTs). METHODS: The primary outcomes were the frequencies of serious adverse events (SAEs), retinopathy, and cardiac complications. Search strategies were applied to MEDLINE, EMBASE, LILACS, CENTRAL, Scopus, and Trip databases. We used a random-effects model to pool results across studies and Peto's one-step odds ratio (OR) for event rates below 1%. Both-armed zero-event studies were excluded from the meta-analyses. We used the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate the certainty of evidence. RESULTS: One hundred and six RCTs were included. We found no significant difference between CQ/HCQ and control (placebo or non-CQ/HCQ) in the frequency of SAEs (OR: 0.98, 95% confidence interval [CI]: 0.76-1.26, 33 trials, 15,942 participants, moderate certainty of evidence). However, there was a moderate certainty of evidence that CQ/HCQ increases the incidence of cardiac complications (RR: 1.62, 95% CI: 1.10-2.38, 16 trials, 9908 participants). No clear relationship was observed between CQ/HCQ and retinopathy (OR: 1.63, 95% CI: - 0.4-6.57, 5 trials, 344 participants, very low certainty of evidence). CONCLUSIONS: CQ and HCQ probably do not increase SAEs, with low frequency of these adverse events on malarial and non-malarial conditions. However, they may increase cardiac complications especially in patients with COVID-19. No clear effect of their use on the incidence of retinopathy was observed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020177818.


Subject(s)
COVID-19 , Hydroxychloroquine , COVID-19/drug therapy , Chloroquine/adverse effects , Humans , Hydroxychloroquine/adverse effects , Randomized Controlled Trials as Topic , SARS-CoV-2
20.
Lancet Glob Health ; 10(1): e42-e51, 2022 01.
Article in English | MEDLINE | ID: covidwho-1492864

ABSTRACT

BACKGROUND: Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. METHODS: This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing. FINDINGS: The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18-102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52-0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53-0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21-0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36-1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01-0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups. INTERPRETATION: Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. FUNDING: FastGrants and The Rainwater Charitable Foundation. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.


Subject(s)
COVID-19/drug therapy , Emergency Medical Services/statistics & numerical data , Fluvoxamine/therapeutic use , Hospitalization/statistics & numerical data , Adult , Aged , Aged, 80 and over , Brazil , Double-Blind Method , Female , Fluvoxamine/adverse effects , Humans , Male , Middle Aged , SARS-CoV-2 , Serotonin Uptake Inhibitors/adverse effects , Serotonin Uptake Inhibitors/therapeutic use , Treatment Outcome
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