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1.
BMJ Open ; 12(4): e055123, 2022 04 19.
Article in English | MEDLINE | ID: covidwho-1868733

ABSTRACT

INTRODUCTION: Identifying and excluding coronary artery disease (CAD) in patients with atypical angina pectoris (AP) and non-specific thoracic complaints is a challenge for general practitioners (GPs). A diagnostic and prognostic tool could help GPs in determining the likelihood of CAD and guide patient management. Studies in outpatient settings have shown that the CT-based coronary calcium score (CCS) has high accuracy for diagnosis and exclusion of CAD. However, the CT CCS test has not been tested in a primary care setting. In the COroNary Calcium scoring as fiRst-linE Test to dEtect and exclude coronary artery disease in GPs patients with stable chest pain (CONCRETE) study, the impact of direct access of GPs to CT CCS will be investigated. We hypothesise that this will allow for early diagnosis of CAD and treatment, more efficient referral to the cardiologist and a reduction of healthcare-related costs. METHODS AND ANALYSIS: CONCRETE is a pragmatic multicentre trial with a cluster randomised design, in which direct GP access to the CT CCS test is compared with standard of care. In both arms, at least 40 GP offices, and circa 800 patients with atypical AP and non-specific thoracic complaints will be included. To determine the increase in detection and treatment rate of CAD in GP offices, the CVRM registration rate is derived from the GPs electronic registration system. Individual patients' data regarding cardiovascular risk factors, expressed chest pain complaints, quality of life, downstream testing and CAD diagnosis will be collected through questionnaires and the electronic GP dossier. ETHICS AND DISSEMINATION: CONCRETE has been approved by the Medical Ethical Committee of the University Medical Center of Groningen. TRIAL REGISTRATION NUMBER: NTR 7475; Pre-results.


Subject(s)
Coronary Artery Disease , General Practitioners , Angina Pectoris/complications , Angina Pectoris/diagnosis , Calcium , Chest Pain/diagnosis , Chest Pain/etiology , Coronary Angiography/methods , Coronary Artery Disease/complications , Coronary Artery Disease/diagnosis , Humans , Multicenter Studies as Topic , Pragmatic Clinical Trials as Topic , Predictive Value of Tests , Quality of Life , Randomized Controlled Trials as Topic
2.
Trials ; 23(1): 424, 2022 May 21.
Article in English | MEDLINE | ID: covidwho-1854863

ABSTRACT

BACKGROUND: The COVID-19 pandemic has considerably disrupted nearly all aspects of daily life, including healthcare delivery and clinical research. Because pragmatic clinical trials are often embedded within healthcare delivery systems, they may be at high risk of disruption due to the dual impacts on the conduct of both care and research. METHODS: We collected qualitative data using multiple methods to characterize the impact of COVID-19 on the research activities of 14 active pragmatic clinical trials in the National Institutes of Health (NIH) Health Care Systems Research Collaboratory. A COVID-19 impact questionnaire was administered electronically to principal investigators in June 2020. Text responses were analyzed thematically, and qualitative summaries were subsequently reviewed by five independent reviewers, who made iterative revisions. Additional COVID-19-related impacts were identified during virtual meetings with trial teams during April-July 2020 and combined with questionnaire responses for analysis. RESULTS: Impacts of the pandemic were broadly classified into two main types: healthcare operations and social distancing. In some instances, trial delays created statistical challenges, particularly with trials using stepped-wedge designs, and necessitated changing data collection strategies or modifying interventions. The majority of projects used existing stakeholder-driven approaches to adapt interventions. Several benefits of these adaptions were identified, including expanded outreach capabilities and ability to study virtual intervention delivery. All trial teams were able to adapt to pandemic-related modifications. CONCLUSION: In a group of 14 ongoing pragmatic clinical trials, there was significant impact of COVID-19 on trial activities. Engaging appropriate stakeholders was critical to designing and implementing trial modifications and making continued safe progress toward meeting research objectives.


Subject(s)
COVID-19 , Pragmatic Clinical Trials as Topic , COVID-19/epidemiology , Delivery of Health Care , Humans , National Institutes of Health (U.S.) , Pandemics , United States/epidemiology
3.
BMJ Open ; 12(2): e059711, 2022 Feb 24.
Article in English | MEDLINE | ID: covidwho-1807416

ABSTRACT

INTRODUCTION: Sleep-time blood pressure correlates more strongly with adverse cardiovascular events than does daytime blood pressure. The BedMed trial evaluates whether bedtime antihypertensive administration, as compared with conventional morning use, reduces major adverse cardiovascular events. METHODS AND ANALYSIS: DesignProspective randomised, open-label, blinded end-point trial.ParticipantsHypertensive primary care patients using blood pressure lowering medication and free from glaucoma.SettingCommunity primary care providers in 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba and Ontario) are mailing invitations to their eligible patients. Social media campaigns (Google, Facebook) are additionally running in the same provinces.InterventionConsenting participants are allocated via central randomisation to bedtime vs morning use of all antihypertensives.Follow-up(1) Telephone or email questionnaire at 1 week, 6 weeks, 6 months and every 6 months thereafter, and (2) accessing linked governmental healthcare databases tracking hospital and community medical services.Primary outcomeComposite of all-cause death, or hospitalisation for myocardial infarction/acute-coronary syndrome, stroke or congestive heart failure.Secondary outcomesEach primary outcome element on its own, all-cause hospitalisation or emergency department visit, long-term care admission, non-vertebral fracture, new glaucoma diagnosis, 18-month cognitive decline from baseline (via Short Blessed Test).Select other outcomesSelf-reported nocturia burden at 6 weeks and 6 months (no, minor or major burden), 1-year self-reported overall health score (EQ-5D-5L), self-reported falls, total cost of care (acute and community over study duration) and mean sleep-time systolic blood pressure after 6 months (via 24-hour monitor in a subset of 302 sequential participants).Primary outcome analysisCox proportional hazards survival analysis.Sample sizeThe trial will continue until a projected 254 primary outcome events have occurred.Current statusEnrolment ongoing (3227 randomised to date). ETHICS AND DISSEMINATION: BedMed has ethics approval from six research ethics review boards and will publish results in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02990663.


Subject(s)
Cardiovascular Diseases , Glaucoma , Alberta , Antihypertensive Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Glaucoma/chemically induced , Humans , Pragmatic Clinical Trials as Topic , Prospective Studies , Randomized Controlled Trials as Topic , Research Design , Risk Factors , Treatment Outcome
4.
Cancer Med ; 11(8): 1879-1890, 2022 04.
Article in English | MEDLINE | ID: covidwho-1802078

ABSTRACT

INTRODUCTION: During clinical follow-up it can be difficult to identify those head and neck cancer (HNC) patients who are coping poorly and could benefit from additional support. Health-related quality of life (HRQOL) questionnaires and prompt lists provide a means by which patients can express their perceived outcomes and raise concerns. The first aim of this secondary analysis following a randomized trial was to explore which patient characteristics, at around 3 months following treatment completion (baseline), best predict HRQOL 12 months later. The second aim was to attempt to ascertain which patients were most likely to benefit from using prompt list. METHODS: Cluster-controlled pragmatic trial data were analyzed. HRQOL was measured by the University of Washington Quality of life questionnaire (UW-QOLv4). The prompt list was the Patient Concerns Inventory (PCI-HN). RESULTS: The trial involved 15 eligible consultants and a median (inter-quartile range) of 16 (13-26) primary HNC patients per consultant, with 140 PCI patients and 148 controls. Baseline HRQOL was the dominant predictor of 12-month HRQOL with other predictors related to social, financial, and lifestyle characteristics as well as clinical stage and treatment. Although formal statistical tests for interaction were non-significant the trend in analyses over a range of outcomes suggested that patients with worse baseline HRQOL could benefit more from the PCI-HN. DISCUSSION: HRQOL early post-treatment is a key predictor of longer-term outcome. Measuring and using HRQOL and the PCI-HN are not only surrogates for predicting HRQOL at 15 months post-treatment, but also tools to help guide interventions.


Subject(s)
Head and Neck Neoplasms , Percutaneous Coronary Intervention , Controlled Clinical Trials as Topic , Head and Neck Neoplasms/therapy , Humans , Life Style , Pragmatic Clinical Trials as Topic , Quality of Life , Surveys and Questionnaires
6.
BMJ Open ; 11(12): e054550, 2021 12 30.
Article in English | MEDLINE | ID: covidwho-1592842

ABSTRACT

INTRODUCTION: Personal digital devices that provide health information, such as the Apple Watch, have developed an increasing array of cardiopulmonary tracking features which have received regulatory clearance and are directly marketed to consumers. Despite their widespread and increasing use, data about the impact of personal digital device use on patient-reported outcomes and healthcare utilisation are sparse. Among a population of patients with atrial fibrillation and/or atrial flutter undergoing cardioversion, our primary aim is to determine the impact of the heart rate measurement, irregular rhythm notification, and ECG features of the Apple Watch on quality of life and healthcare utilisation. METHODS AND ANALYSIS: We are conducting a prospective, open-label multicentre pragmatic randomised clinical trial, leveraging a unique patient-centred health data sharing platform for enrolment and follow-up. A total of 150 patients undergoing cardioversion for atrial fibrillation or atrial flutter will be randomised 1:1 to receive the Apple Watch Series 6 or Withings Move at the time of cardioversion. The primary outcome is the difference in the Atrial Fibrillation Effect on QualiTy-of-life global score at 6 months postcardioversion. Secondary outcomes include inpatient and outpatient healthcare utilisation. Additional secondary outcomes include a comparison of the Apple Watch ECG and pulse oximeter features with gold-standard data obtained in routine clinical care settings. ETHICS AND DISSEMINATION: The Institutional Review Boards at Yale University, Mayo Clinic, and Duke University Health System have approved the trial protocol. This trial will provide important data to policymakers, clinicians and patients about the impact of the heart rate, irregular rhythm notification, and ECG features of widely used personal digital devices on patient quality of life and healthcare utilisation. Findings will be disseminated to study participants, at professional society meetings and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04468321.


Subject(s)
Atrial Fibrillation , Atrial Flutter , Atrial Fibrillation/epidemiology , Atrial Fibrillation/therapy , Electric Countershock , Humans , Multicenter Studies as Topic , Pragmatic Clinical Trials as Topic , Prospective Studies , Quality of Life , Randomized Controlled Trials as Topic
7.
Contemp Clin Trials ; 111: 106619, 2021 12.
Article in English | MEDLINE | ID: covidwho-1574060

ABSTRACT

Characterizing the impacts of disruption attributable to the COVID-19 pandemic on clinical research is important, especially in pain research where psychological, social, and economic stressors attributable to the COVID-19 pandemic may greatly impact treatment effects. The National Institutes of Health - Department of Defense - Department of Veterans Affairs Pain Management Collaboratory (PMC) is a collective effort supporting 11 pragmatic clinical trials studying nonpharmacological approaches and innovative integrated care models for pain management in veteran and military health systems. The PMC rapidly developed a brief pandemic impacts measure for use across its pragmatic trials studying pain while remaining broadly applicable to other areas of clinical research. Through open discussion and consensus building by the PMC's Phenotypes and Outcomes Work Group, the PMC Coronavirus Pandemic (COVID-19) Measure was iteratively developed. The measure assesses the following domains (one item/domain): access to healthcare, social support, finances, ability to meet basic needs, and mental or emotional health. Two additional items assess infection status (personal and household) and hospitalization. The measure uses structured responses with a three-point scale for COVID-19 infection status and four-point ordinal rank response for all other domains. We recommend individualized adaptation as appropriate by clinical research teams using this measure to survey the effects of the COVID-19 pandemic on study participants. This can also help maintain utility of the measure beyond the COVID-19 pandemic to characterize impacts during future public health emergencies that may require mitigation strategies such as periods of quarantine and isolation.


Subject(s)
COVID-19 , Pragmatic Clinical Trials as Topic , Humans , Pandemics , Quarantine , Social Support , United States/epidemiology
8.
Contemp Clin Trials ; 112: 106633, 2022 01.
Article in English | MEDLINE | ID: covidwho-1525718

ABSTRACT

BACKGROUND: Older adults are at higher risk for cardiovascular disease and functional decline, often leading to deterioration and dependency. Cardiac rehabilitation (CR) provides opportunity to improve clinical and functional recovery, yet participation in CR decreases with age. Modified Application of CR in Older Adults (MACRO) is a National Institute on Aging (NIA)-funded pragmatic trial that responds to this gap by aiming to increase enrollment of older adults into CR and improving functional outcomes. This article describes the methodology and novel features of the MACRO trial. METHODS: Randomized, controlled trial of a coaching intervention (MACRO-I) vs. usual care for older adults (age ≥ 70 years) eligible for CR after an incident cardiac hospitalization. MACRO-I incorporates innovations including holistic risk assessments, flexible CR format (i.e., helping patients to select a CR design that aligns with their personal risks and preferences), motivational prompts, nutritional emphasis, facilitated deprescription, enhanced education, and home visits. Key modifications were necessitated by the COVID-19 pandemic, including switching from a performance-based primary endpoint (Short Physical Performance Battery) to a patient-reported measure (Activity Measure for Post-Acute Care Computerized Adaptive Testing). Changes prompted by COVID-19 maintain the original intent of the trial and provide key methodologic advantages. CONCLUSIONS: MACRO is exploring a novel individualized coaching intervention to better enable older patients to participate in CR. Due to COVID-19 many aspects of the MACRO protocol required modification, but the primary objective of the trial is maintained and the updated protocol will more effectively achieve the original goals of the study.


Subject(s)
COVID-19 , Cardiac Rehabilitation , Pandemics , Aged , COVID-19/epidemiology , Humans , Multicenter Studies as Topic , Pragmatic Clinical Trials as Topic , Randomized Controlled Trials as Topic
9.
Contemp Clin Trials ; 111: 106619, 2021 12.
Article in English | MEDLINE | ID: covidwho-1509630

ABSTRACT

Characterizing the impacts of disruption attributable to the COVID-19 pandemic on clinical research is important, especially in pain research where psychological, social, and economic stressors attributable to the COVID-19 pandemic may greatly impact treatment effects. The National Institutes of Health - Department of Defense - Department of Veterans Affairs Pain Management Collaboratory (PMC) is a collective effort supporting 11 pragmatic clinical trials studying nonpharmacological approaches and innovative integrated care models for pain management in veteran and military health systems. The PMC rapidly developed a brief pandemic impacts measure for use across its pragmatic trials studying pain while remaining broadly applicable to other areas of clinical research. Through open discussion and consensus building by the PMC's Phenotypes and Outcomes Work Group, the PMC Coronavirus Pandemic (COVID-19) Measure was iteratively developed. The measure assesses the following domains (one item/domain): access to healthcare, social support, finances, ability to meet basic needs, and mental or emotional health. Two additional items assess infection status (personal and household) and hospitalization. The measure uses structured responses with a three-point scale for COVID-19 infection status and four-point ordinal rank response for all other domains. We recommend individualized adaptation as appropriate by clinical research teams using this measure to survey the effects of the COVID-19 pandemic on study participants. This can also help maintain utility of the measure beyond the COVID-19 pandemic to characterize impacts during future public health emergencies that may require mitigation strategies such as periods of quarantine and isolation.


Subject(s)
COVID-19 , Pragmatic Clinical Trials as Topic , Humans , Pandemics , Quarantine , Social Support , United States/epidemiology
11.
Acta Anaesthesiol Scand ; 65(10): 1497-1504, 2021 11.
Article in English | MEDLINE | ID: covidwho-1327500

ABSTRACT

BACKGROUND: Coronavirus disease (COVID-19) primarily affects the lungs and lower airways and may present as hypoxaemic respiratory failure requiring admission to an intensive care unit (ICU) for supportive treatment. Here, supplemental oxygen remains essential for COVID-19 patient management, but the optimal dosage is not defined. We hypothesize that targeting an arterial partial pressure of oxygen of 8 kPa throughout ICU admission is superior to targeting 12 kPa. METHODS: The Handling Oxygenation Targets in ICU patients with COVID-19 (HOT-COVID) trial, is an investigator-initiated, pragmatic, multicentre, randomized, parallel-group trial comparing a lower oxygenation target versus a higher oxygenation target in adult ICU patients with COVID-19. The primary outcome is days alive without life-support (use of mechanical ventilation, renal replacement therapy or vasoactive therapy) at day 90. Secondary outcomes are 90-day and 1-year mortality, serious adverse events in the ICU and days alive and out of hospital in the 90-day period, health-related quality-of-life at 1 year, and health economic analyses. One-year follow-up of cognitive and pulmonary function is planned in a subgroup of Danish patients. We will include 780 patients to detect or reject an absolute increase in days alive without life-support of 7 days with an α of 5% and a ß of 20%. An interim analysis is planned after 90-day follow-up of 390 patients. CONCLUSIONS: The HOT-COVID trial will provide patient-important data on the effect of two oxygenation targets in ICU patients with COVID-19 and hypoxia. This protocol paper describes the background, design and statistical analysis plan for the trial.


Subject(s)
COVID-19 , Adult , COVID-19/therapy , Critical Care , Humans , Intensive Care Units , Lung , Multicenter Studies as Topic , Pragmatic Clinical Trials as Topic , Randomized Controlled Trials as Topic , Treatment Outcome
13.
Inflammopharmacology ; 29(4): 1075-1090, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1303331

ABSTRACT

This paper aims to summarize through meta-analyses the overall vaccine effectiveness of the BNT162b2 mRNA vaccine from observational studies. A systematic literature search with no language restriction was performed in electronic databases to identify eligible observational studies which reported the adjusted effectiveness of the BNT162b2 mRNA vaccine to prevent RT-PCR confirmed COVID-19. Meta-analyses with the random-effects model were used to calculate the pooled hazard ratio (HR) and pooled incidence rate ratio (IRR) at 95% confidence intervals, and the vaccine effectiveness was indicated as (pooled HR - 1)/HR or (pooled IRR - 1)/IRR. Nineteen studies were included for this meta-analysis. The meta-analysis revealed significant protective effect against RT-PCR confirmed COVID-19 ≥ 14 days after the first dose, with vaccine effectiveness of 53% (95% confidence interval 32-68%), and ≥ 7 days after the second dose, with vaccine effectiveness of 95% (95% confidence interval: 96-97%). Despite its effectiveness, reporting vaccine safety data by relevant stakeholders should be encouraged as BNT162b2 mRNA is a new vaccine that has not gained full approval. There have been limited data about vaccine effectiveness among immunocompromised patients; thus, the vaccine should be used cautiously in this patient population.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Observational Studies as Topic/methods , Pragmatic Clinical Trials as Topic/methods , COVID-19/diagnosis , COVID-19/epidemiology , Humans , Treatment Outcome
14.
Thromb Haemost ; 121(12): 1684-1695, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1171416

ABSTRACT

Coronavirus disease-2019 (COVID-19) has been associated with significant risk of venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality particularly among hospitalized patients with critical illness and elevated D-dimer (Dd) levels. Conflicting data have yet to elucidate optimal thromboprophylaxis dosing. HEP-COVID (NCT04401293) is a phase 3, multicenter, pragmatic, prospective, randomized, pseudo-blinded, active control trial to evaluate efficacy and safety of therapeutic-dose low-molecular-weight heparin (LMWH) versus prophylactic-/intermediate-dose LMWH or unfractionated heparin (UFH) for prevention of a primary efficacy composite outcome of VTE, ATE, and all-cause mortality 30 ± 2 days post-enrollment. Eligible patients have COVID-19 diagnosis by nasal swab or serologic testing, requirement for supplemental oxygen per investigator judgment, and Dd >4 × upper limit of normal (ULN) or sepsis-induced coagulopathy score ≥4. Subjects are randomized to enoxaparin 1 mg/kg subcutaneous (SQ)/two times a day (BID) (creatinine clearance [CrCl] ≥ 30 mL/min) or 0.5 mg/kg (CrCl 15-30 mL/min) versus local institutional prophylactic regimens including (1) UFH up to 22,500 IU (international unit) daily (divided BID or three times a day), (2) enoxaparin 30 and 40 mg SQ QD (once daily) or BID, or (3) dalteparin 2,500 IU or 5,000 IU QD. The principal safety outcome is major bleeding. Events are adjudicated locally. Based on expected 40% relative risk reduction with treatment-dose compared with prophylactic-dose prophylaxis, 308 subjects will be enrolled (assuming 20% drop-out) to achieve 80% power. Distinguishing design features include an enriched population for the composite endpoint anchored on Dd >4 × ULN, stratification by intensive care unit (ICU) versus non-ICU, and the ability to capture asymptomatic proximal deep venous thrombosis via screening ultrasonography prior to discharge.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Enoxaparin/administration & dosage , Thromboembolism/drug therapy , Anticoagulants/adverse effects , COVID-19/complications , COVID-19/diagnosis , Clinical Trials, Phase III as Topic , Enoxaparin/adverse effects , Humans , Pragmatic Clinical Trials as Topic , Prospective Studies , Risk Assessment , Risk Factors , Thromboembolism/diagnosis , Thromboembolism/etiology , Time Factors , Treatment Outcome , United States , Venous Thromboembolism/diagnosis , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
15.
Trials ; 22(1): 229, 2021 Mar 24.
Article in English | MEDLINE | ID: covidwho-1150419

ABSTRACT

Along with its heavy toll of morbidity and mortality, the coronavirus disease 2019 (COVID-19) pandemic exposed several limitations of the current global research response. The slow and inefficient process of carrying out traditional randomized clinical trials led regulatory authorities to hastily approve treatments and tests without sufficient evidence of safety and efficacy.We here outline issues with the current research platform, summarize shortcomings of traditional randomized clinical trials particularly apparent at the time of pandemics, and highlight the advantages of pragmatic clinical trials as an alternative to rapidly generate the needed clinical evidence. We further discuss barriers and challenges to pragmatic clinical trials implementation and explore opportunities for research institutions and regulatory authorities to facilitate widespread adoption of this vital research tool.As a subsequent wave of COVID-19, and/or another epidemic, are all but inevitable in our lifetime, we must ensure that our research infrastructure is conducive to carrying out pragmatic clinical trials to expeditiously generate the needed evidence and blunt the epidemic's toll on human lives and livelihoods.


Subject(s)
COVID-19/therapy , Pragmatic Clinical Trials as Topic , Research Design , COVID-19/diagnosis , Drug Approval , Evidence-Based Medicine , Humans
16.
Trials ; 22(1): 202, 2021 Mar 10.
Article in English | MEDLINE | ID: covidwho-1127720

ABSTRACT

OBJECTIVES: To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. TRIAL DESIGN: Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial PARTICIPANTS: The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: 1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2) Admitted to hospital for COVID-19; 3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: 1) pregnancy; 2) hemoglobin <80 g/L in the last 72 hours; 3) platelet count <50 x 109/L in the last 72 hours; 4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7) patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; 8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening; 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15) Imminent death according to the judgement of the most responsible physician; 16) enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. INTERVENTION AND COMPARATOR: Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. MAIN OUTCOMES: The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): 1. All-cause death 2. Composite of ICU admission or all-cause death 3. Composite of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; 5. Red blood cell transfusion (>1 unit); 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; 7. Renal replacement therapy; 8. Hospital-free days alive; 9. ICU-free days alive; 10. Ventilator-free days alive; 11. Organ support-free days alive; 12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 14. Heparin induced thrombocytopenia; 15. Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. RANDOMISATION: Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. BLINDING (MASKING): No blinding involved. This is an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. TRIAL STATUS: Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of 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)
Anticoagulants/therapeutic use , Blood Coagulation Disorders/drug therapy , COVID-19/drug therapy , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/complications , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , Clinical Trials, Phase III as Topic , Fibrin Fibrinogen Degradation Products/metabolism , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Hospitalization , Humans , Intensive Care Units/statistics & numerical data , Noninvasive Ventilation/statistics & numerical data , Pragmatic Clinical Trials as Topic , Randomized Controlled Trials as Topic , Respiration, Artificial/statistics & numerical data , SARS-CoV-2
17.
Trials ; 22(1): 186, 2021 Mar 05.
Article in English | MEDLINE | ID: covidwho-1119437

ABSTRACT

BACKGROUND: Depression and anxiety impact up to 1 in 5 pregnant and postpartum women worldwide. Yet, as few as 20% of these women are treated with frontline interventions such as evidence-based psychological treatments. Major barriers to uptake are the limited number of specialized mental health treatment providers in most settings, and problems with accessing in-person care, such as childcare or transportation. Task sharing of treatment to non-specialist providers with delivery on telemedicine platforms could address such barriers. However, the equivalence of these strategies to specialist and in-person models remains unproven. METHODS: This study protocol outlines the Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) randomized trial. SUMMIT is a pragmatic, non-inferiority test of the comparable effectiveness of two types of providers (specialist vs. non-specialist) and delivery modes (telemedicine vs. in-person) of a brief, behavioral activation (BA) treatment for perinatal depressive and anxiety symptoms. Specialists (psychologists, psychiatrists, and social workers with ≥ 5 years of therapy experience) and non-specialists (nurses and midwives with no formal training in mental health care) were trained in the BA protocol, with the latter supervised by a BA expert during treatment delivery. Consenting pregnant and postpartum women with Edinburgh Postnatal Depression Scale (EPDS) score of ≥ 10 (N = 1368) will be randomized to one of four arms (telemedicine specialist, telemedicine non-specialist, in-person specialist, in-person non-specialist), stratified by pregnancy status (antenatal/postnatal) and study site. The primary outcome is participant-reported depressive symptoms (EPDS) at 3 months post-randomization. Secondary outcomes are maternal symptoms of anxiety and trauma symptoms, perceived social support, activation levels and quality of life at 3-, 6-, and 12-month post-randomization, and depressive symptoms at 6- and 12-month post-randomization. Primary analyses are per-protocol and intent-to-treat. The study has successfully continued despite the COVID-19 pandemic, with needed adaptations, including temporary suspension of the in-person arms and ongoing randomization to telemedicine arms. DISCUSSION: The SUMMIT trial is expected to generate evidence on the non-inferiority of BA delivered by a non-specialist provider compared to specialist and telemedicine compared to in-person. If confirmed, results could pave the way to a dramatic increase in access to treatment for perinatal depression and anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT04153864 . Registered on November 6, 2019.


Subject(s)
Anxiety/therapy , Depression, Postpartum/therapy , Depression/therapy , Health Services Accessibility , Pregnancy Complications/therapy , Psychotherapy/methods , Telemedicine/methods , COVID-19 , Delivery of Health Care/methods , Equivalence Trials as Topic , Female , Humans , Maternal Health Services , Mental Health Services/organization & administration , Midwifery , Nurses , Pragmatic Clinical Trials as Topic , Pregnancy , Psychiatric Status Rating Scales , Psychiatry , Psychology , SARS-CoV-2 , Social Workers , Specialization
18.
Diabetes Metab Syndr ; 14(6): 1595-1602, 2020.
Article in English | MEDLINE | ID: covidwho-1059502

ABSTRACT

BACKGROUND & AIMS: Coronavirus disease 2019 (COVID-19) spreads rapidly and within no time, it has been declared a pandemic by the World Health Organization. Evidence suggests diabetes to be a risk factor for the progression and poor prognosis of COVID-19. Therefore, we aimed to understand the pooled prevalence of diabetes in patients infected with COVID-19. We also aimed to compute the risk of mortality and ICU admissions in COVID-19 patients with and without diabetes. METHODS: A comprehensive literature search was performed in PubMed to identify the articles reporting the diabetes prevalence and risk of mortality or ICU admission in COVID-19 patients. The primary outcome was to compute the pooled prevalence of diabetes in COVID-19 patients. Secondary outcomes included risk of mortality and ICU admissions in COVID-19 patients with diabetes compared to patients without diabetes. RESULTS: This meta-analysis was based on a total of 23007 patients from 43 studies. The pooled prevalence of diabetes in patients infected with COVID-19 was found to be 15% (95% CI: 12%-18%), p = <0.0001. Mortality risk was found to be significantly higher in COVID-19 patients with diabetes as compared to COVID-19 patients without diabetes with a pooled risk ratio of 1.61 (95% CI: 1.16-2.25%), p = 0.005. Likewise, risk of ICU admission rate was significantly higher in COVID-19 patients with diabetes as compared to COVID-19 patients without diabetes with a pooled risk ratio of 1.88 (1.20%-2.93%), p = 0.006. CONCLUSION: This meta-analysis found a high prevalence of diabetes and higher mortality and ICU admission risk in COVID-19 patients with diabetes.


Subject(s)
COVID-19/mortality , Cost of Illness , Diabetes Mellitus/mortality , Pragmatic Clinical Trials as Topic , COVID-19/diagnosis , Diabetes Mellitus/diagnosis , Hospitalization/trends , Humans , Intensive Care Units/trends , Pragmatic Clinical Trials as Topic/methods , Retrospective Studies
19.
Trials ; 22(1): 111, 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-1058269

ABSTRACT

OBJECTIVES: To evaluate whether a single high dose of oral cholecalciferol improves the respiratory outcomes as compared with placebo among adults COVID-19 patients at moderate risk of clinical complications. TRIAL DESIGN: The CARED trial is an investigator-initiated, multicentre, randomized, parallel, two-arm, sequential, double-blind and placebo-controlled clinical trial. It was planned as a pragmatic trial since the inclusion criteria are broad and the study procedures are as simple as possible, in order to be implemented in the routine clinical practice in general wards in the pandemic setting and a middle-income country context. The sequential design involves two stages. The first stage will assess the effects of vitamin D supplementation on blood oxygenation (physiological effects). The second stage will assess the effects on clinical outcomes. PARTICIPANTS: Participants of either gender admitted to general adult wards in 21 hospital sites located in four provinces of Argentina are invited to participate in the study if they meet the following inclusion criteria and none of the exclusion criteria: Inclusion criteria SARS-CoV-2 confirmed infection by RT-PCR; Hospital admission at least 24 hours before; Expected hospitalization in the same site ≥24 hours; Oxygen saturation ≥90% (measured by pulse oximetry) breathing ambient air; Age ≥45 years or at least one of the following conditions: ○ Hypertension; ○ Diabetes; ○ At least moderate COPD or asthma; ○ Cardiovascular disease (history of myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting or valve replacement surgery); ○ Body mass index ≥30; Willingness to sign informed consent (online supplementary material 1 and 2). EXCLUSION CRITERIA: Age <18 years; Women in childbearing age; >= 72 hs since current admission; Requirement for a high dose of oxygen (>5 litres/minute) or mechanical ventilation (non-invasive or invasive); History of chronic kidney disease requiring haemodialysis or chronic liver failure; Inability for oral intake. Chronic supplementation with pharmacological vitamin D; Current treatment with anticonvulsants; History of: ○ Sarcoidosis; ○ Malabsorption syndrome; ○ Known hypercalcemia or serum calcium >10.5 mg/dL; Life expectancy <6 months; Known allergy to study medication; Any condition at discretion of investigator impeding to understand the study and give informed consent. INTERVENTION AND COMPARATOR: The intervention consists in a single oral dose of 500.000 IU of commercially available cholecalciferol soft gel capsules (5 capsules of 100.000 IU) or matching placebo MAIN OUTCOMES: The primary outcome for the first stage is the change in the respiratory Sepsis-related Organ Failure Assessment (SOFAr) score between pre-treatment value and the worst value recorded during the first 7 seven days of hospitalization, the death or discharge, whichever occurs first. The SOFAr score measured as the ratio between the pulse oximetry saturation (SpO2) and FiO2 (27, 28) is used instead of the arterial partial pressure of oxygen (PaO2). SOFAr score is a 4-points scale, with higher values indicating deeper respiratory derangement as follows: 1 PaO2 <400; 2 PaO2 <300; 3 PaO2 <200; 4 PaO2 <100. The primary outcome for the second stage is the combined occurrence of requirement ≥40% of FiO2, invasive or non-invasive ventilation, up to 30 days or hospital discharge. RANDOMISATION: A computer-generated random sequence and the treatment assignment is performed through the web-based randomization module available in the electronic data capture system (Castor®). A randomization ratio 1:1, stratified and with permuted blocks was used. Stratification variables were diabetes (yes/no), age (≤60/>60 years) and the site. BLINDING (MASKING): Double-blind was achieved by using placebo soft gel capsules with the same organoleptic properties as the active medication. Central management of the medication is carried out by a pharmacist in charge of packaging the study drug in unblinded fashion, who have no contact with on-site investigators. Medication is packaged in opaque white bottles, each containing five soft gel capsules of the active drug or matching placebo, corresponding to complete individual treatment. Treatment codes are kept under the pharmacist responsibility, and all researchers are unaware of them. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The first stage is planned to include 200 patients (100 per group), the second stage is planned to include 1064 additional patients. The total sample size is 1264 patients. TRIAL STATUS: Currently the protocol version is the number 1.4 (from October 13th, 2020). The recruitment is ongoing since August 11th, 2020, and the first subject was enrolled on August 14th. Since then, 21 sites located in four provinces of Argentina were initiated, and 167 patients were recruited by January 11th, 2021. We anticipate to finish the recruitment for the first stage in mid-February, 2021, and in August, 2021 for the second stage. TRIAL REGISTRATION: The study protocol is registered in ClinicalTrials.gov (identifier number NCT04411446 ) on June 2, 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. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Subject(s)
COVID-19/diet therapy , COVID-19/epidemiology , Cholecalciferol/administration & dosage , Pandemics , SARS-CoV-2/genetics , Vitamins/administration & dosage , Aged , Aged, 80 and over , Argentina/epidemiology , COVID-19/complications , COVID-19/virology , Double-Blind Method , Female , Humans , Male , Middle Aged , Multicenter Studies as Topic , Patient Admission , Pragmatic Clinical Trials as Topic , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome
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