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1.
Lancet ; 398(10303): 856-869, 2021 09 04.
Article in English | MEDLINE | ID: covidwho-1397746

ABSTRACT

BACKGROUND: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer-BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. METHODS: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. FINDINGS: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. INTERPRETATION: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. FUNDING: UK Vaccine Task Force and National Institute for Health Research.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , Aged , Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , Equivalence Trials as Topic , Female , Humans , Immunization Schedule , Immunoglobulin G/blood , Intention to Treat Analysis , Male , Middle Aged , Single-Blind Method , Spike Glycoprotein, Coronavirus/immunology
2.
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
3.
Trials ; 22(1): 172, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1112448

ABSTRACT

OBJECTIVES: The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. TRIAL DESIGN: REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO2/FiO2 100-200 mmHg; • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. INTERVENTION AND COMPARATOR: Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. MAIN OUTCOMES: Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. RANDOMISATION: Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. BLINDING (MASKING): This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. TRIAL STATUS: This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. TRIAL REGISTRATION: The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. FULL PROTOCOL: The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19/therapy , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Respiration, Artificial , Respiratory Distress Syndrome/therapy , COVID-19/complications , Clinical Trials, Phase II as Topic , Disease Progression , Dose-Response Relationship, Drug , Equivalence Trials as Topic , Humans , Length of Stay , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/etiology , SARS-CoV-2
4.
Trials ; 22(1): 131, 2021 Feb 11.
Article in English | MEDLINE | ID: covidwho-1083070

ABSTRACT

OBJECTIVES: The main objective of this study is to evaluate the effect of intravenous lidocaine on gas exchange and inflammation in acute respiratory distress syndrome due or not to Covid-19 pneumonia. TRIAL DESIGN: This is a prospective monocentric, randomized, quadruple-blinded and placebo-controlled superiority trial. This phase 3 clinical study is based on two parallel groups received either intravenous lidocaine 2% or intravenous NaCl 0.9%. PARTICIPANTS: This study has been conducted at the University Hospitals of Strasbourg (medical and surgical Intensive Care Units in Hautepierre Hospital) since the 4th November 2020. The participants are 18 years-old and older, hospitalized in ICU for a moderate to severe ARDS according to the Berlin definition; they have to be intubated and sedated for mechanical protective ventilation. All participants are affiliated to the French Social security system and a dosage of beta HCG has to be negative for women of child bearing age . For the Covid-19 subgroup, the SARS-CoV2 infection is proved by RT-PCR <7 days before admission and/or another approved diagnostic technique and/or typical CT appearance pneumonia. The data are prospectively collected in e-Case Report Forms and extracted from clinical files. INTERVENTION AND COMPARATOR: The participants are randomised in two parallel groups with a 1:1 ratio. In the experimental group, patients receive intravenous lidocaine 2% (20mg/mL) (from FRESENIUS KABI France); the infusion protocol provide a bolus of 1 mg/kg (ideal weight), followed by 3 mg/kg/h for the first hour, 1.5 mg/kg/h for the second hour, 0.72 mg/kg/h for the next 22 hours and then 0.6 mg/kg/h for 14 days at most or 24 hours after extubation or ventilator-weaning. The patients in the control group receive intravenous NaCl 0.9% (9 mg/mL) (from Aguettant, France) as placebo comparator; the infusion protocol provide a bolus of 0.05 mL/kg (ideal weight), followed by 0.15 mL/kg/h for the first hour, 0.075 mL/kg/h for the second hour, 0.036 mL/kg/h for the next 22 hours, and the 0.03 mL/kg/h for up to 14 days or 24 hours after extubation or ventilator-weaning. Lidocaine level is assessed at H4, D2, D7 and D14 to prevent local anesthetics systemic toxicity. Clinical data and biological samples are collected to assess disease progression. MAIN OUTCOMES: The primary outcome is the evolution of alveolar-capillary gas exchange measured by the PaO2/FiO2 ratio after two days of treatment. The secondary endpoints of the study include the following: Evolution of PaO2/FiO2 ratio at admission and after 21 days of treatment Number of ventilator-free days Anti-inflammatory effects by dosing inflammatory markers at different timepoints (ferritin, bicarbonate, CRP, PCT, LDH, IL-6, Troponin HS, triglycerides, complete blood count, lymphocytes) Anti-thrombotic effects by dosing platelets, aPTT, fibrinogen, D-dimers, viscoelastic testing and identification of all thromboembolic events up to 4 weeks. Plasmatic concentration of lidocaine and albumin Incidence of adverse events like cardiac rhythm disorders, need of vasopressors, any modification of the QRS, QTc or PR intervals every day Ileus recovery time Consumption of hypnotics, opioids, neuromuscular blockers. Lengths of stay in the ICU, incidence of reintubation and complications due to intensive care unit care (mortality until 90 days, pneumothorax, bacterial pneumopathy, bronchospasm, cardiogenic shock, acute renal failure, need of renal dialysis, delirium, atrial fibrillation, stroke (CAM-ICU score), tetraplegia (MCR score)). Incidence of cough and sore throat at extubation or ventilator-weaning and within 24 hours. All these outcomes will be evaluated according to positivity to Sars-Cov-2. RANDOMISATION: The participants who meet the inclusion criteria and have signed written informed consent will be randomly allocated using a computer-generated random number to either intervention group or control group. The distribution ratio of the two groups will be 1:1, with a stratification according to positivity to Sars-Cov-2. BLINDING (MASKING): All participants, care providers, investigator and outcomes assessor are blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): We planned to randomize fifty participants in each group, 100 participants total. TRIAL STATUS: The amended protocol version 2.1 was approved by the Ethics Committee "Comité de Protection des Personnes Sud-Méditerranée II on January 8, 2021 and by the Commission Nationale de l'Informatique et des Libertés (CNIL) on November 10, 2020. The study is currently recruiting participants; the recruitment started in November 2020 and the planned recruitment period is three years. TRIAL REGISTRATION: The trial was registered on clinicaltrials.gov on October 30, 2020 and identified by number NCT04609865 . FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19/drug therapy , Lidocaine/therapeutic use , Respiratory Distress Syndrome/drug therapy , Voltage-Gated Sodium Channel Blockers/therapeutic use , Administration, Intravenous , COVID-19/blood , COVID-19/physiopathology , Clinical Trials, Phase III as Topic , Equivalence Trials as Topic , Humans , Inflammation/blood , Pulmonary Gas Exchange , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2 , Treatment Outcome
6.
Clin Trials ; 18(3): 335-342, 2021 06.
Article in English | MEDLINE | ID: covidwho-1063162

ABSTRACT

BACKGROUND: Recently emerging results from a few placebo-controlled randomized trials of COVID-19 vaccines revealed estimates of 62%-95% relative reductions in risk of virologically confirmed symptomatic COVID-19 disease, over approximately 2-month average follow-up period. Additional safe and effective COVID-19 vaccines are needed in a timely manner to adequately address the pandemic on an international scale. Such safe and effective vaccines would be especially appealing for international deployment if they also have favorable stability, supply, and potential for implementation in mass vaccination campaigns. Randomized trials provide particularly reliable insights about vaccine efficacy and safety. While enhanced efficiency and interpretability can be obtained from placebo-controlled trials, in settings where their conduct is no longer possible, randomized non-inferiority trials may enable obtaining reliable evaluations of experimental vaccines through direct comparison with active comparator vaccines established to have worthwhile efficacy. METHODS: The usual objective of non-inferiority trials is to reliably assess whether the efficacy of an experimental vaccine is not unacceptably worse than that of an active control vaccine previously established to be effective, likely in a placebo-controlled trial. This is formally achieved by ruling out a non-inferiority margin identified to be the minimum threshold for what would constitute an unacceptable loss of efficacy. This article not only investigates non-inferiority margins, denoted by δ, that address the usual objective of determining whether the experimental vaccine is "at least similarly effective to" the active comparator vaccine in the non-inferiority trial, but also develops non-inferiority margins, denoted by δo, intended to address the worldwide need for multiple safe and effective vaccines by satisfying the less stringent requirement that the experimental vaccine be "at least similarly effective to" an active comparator vaccine having efficacy that satisfies the widely accepted World Health Organization-Food and Drug Administration criteria for "worthwhile" vaccine efficacy. RESULTS: Using the margin δ enables non-inferiority trials to reliably evaluate experimental vaccines that truly are similarly effective to an active comparator vaccine having any level of "worthwhile" efficacy. When active comparator vaccines have efficacy in the range of 50%-70%, non-inferiority trials designed to use the margin δo have appealing properties, especially for experimental vaccines having true efficacy of approximately 60%. CONCLUSION: Non-inferiority trials using the proposed margins may enable reliable randomized evaluations of efficacy and safety of experimental COVID-19 vaccines. Such trials often require approximately two- to three-fold the person-years follow-up than a placebo-controlled trial. This could be achieved, without substantive increases in sample size, by increasing the average duration of follow-up from 2 months to approximately 4-6 months, assuming efficacy of the active comparator vaccine has been reliably evaluated over that longer duration.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Randomized Controlled Trials as Topic/methods , Equivalence Trials as Topic , Humans , Pandemics/prevention & control , SARS-CoV-2 , Sample Size , Single-Blind Method , Time Factors , Treatment Outcome
7.
BMJ Open ; 10(11): e041520, 2020 11 11.
Article in English | MEDLINE | ID: covidwho-920921

ABSTRACT

INTRODUCTION: Prone positioning (PP) is an effective first-line intervention to treat patients with moderate to severe acute respiratory distress syndrome (ARDS) receiving invasive mechanical ventilation, as it improves gas exchanges and reduces mortality. The use of PP in awake spontaneous breathing patients with ARDS secondary to COVID-19 was reported to improve oxygenation in few retrospective trials with small sample size. High-level evidence of awake PP for hypoxaemic patients with COVID-19 patients is still lacking. METHODS AND ANALYSIS: The protocol of this meta-trial is a prospective collaborative individual participant data meta-analysis of randomised controlled open label superiority trials. This design is particularly adapted to a rapid scientific response in the pandemic setting. It will take place in multiple sites, among others in USA, Canada, Ireland, France and Spain. Patients will be followed up for 28 days. Patients will be randomised to receive whether awake PP and nasal high flow therapy or standard medical treatment and nasal high flow therapy. Primary outcome is defined as the occurrence rate of tracheal intubation or death up to day 28. An interim analysis plan has been set up on aggregated data from the participating research groups. ETHICS AND DISSEMINATION: Ethics approvals were obtained in all participating countries. Results of the meta-trial will be submitted for publication in a peer-reviewed journal. Each randomised controlled trial was registered individually, as follows: NCT04325906, NCT04347941, NCT04358939, NCT04395144 and NCT04391140.


Subject(s)
Coronavirus Infections/therapy , Hypoxia/therapy , Oxygen Inhalation Therapy/methods , Patient Positioning/methods , Pneumonia, Viral/therapy , Prone Position , Betacoronavirus , COVID-19 , Cannula , Equivalence Trials as Topic , Humans , Meta-Analysis as Topic , Pandemics , Randomized Controlled Trials as Topic , SARS-CoV-2 , Wakefulness
8.
Trials ; 21(1): 770, 2020 Sep 09.
Article in English | MEDLINE | ID: covidwho-755207

ABSTRACT

OBJECTIVES: The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. TRIAL DESIGN: The OVID study is conducted as a multicentre open-label superiority randomised controlled trial. PARTICIPANTS: Inclusion Criteria 1. Signed patient informed consent after being fully informed about the study's background. 2. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment. 3. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature >37.5° C. 4. Ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves 5. Ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. 6. Ability to walk from car to study centre or reach it by wheelchair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. 7. Ability to self-administer prefilled enoxaparin injections after instructions received at the study centre or availability of a person living with the patient to administer enoxaparin. Exclusion Criteria 1. Any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior venous thromboembolism (VTE), acute confirmed symptomatic VTE, acute coronary syndrome. 2. Anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis: a. Any of the following events occurring in the prior 30 days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke, b. previous VTE, c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past 6 months, or recurrent, or metastatic, or inoperable. 3. Any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 30 days prior to randomization or sign of acute bleeding. 4. Intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial haemorrhage. 5. Haemoglobin <8 g/dL and platelet count <50 x 109 cells/L confirmed by recent laboratory test (<90 days). 6. Subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy. 7. Severe renal insufficiency (baseline creatinine clearance <30 mL/min calculated using the Cockcroft-Gault formula) confirmed by recent laboratory test (<90 days). 8. Contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity. 9. Current use of dual antiplatelet therapy. 10. Participation in other interventional studies over the past 30 days. 11. Non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment. 12. Cognitive impairment and/or inability to understand information provided in the study information. Patient enrolment will take place at seven Swiss centres, including five university hospitals and two large cantonal hospitals. INTERVENTION AND COMPARATOR: Patients randomized to the intervention group will receive subcutaneous enoxaparin at the recommended dose of 4,000 IU anti-Xa activity (40 mg/0.4 ml) once daily for 14 days. Patients randomized to the comparator group will receive no anticoagulation. MAIN OUTCOMES: Primary outcome: a composite of any hospitalization or all-cause death occurring within 30 days of randomization. SECONDARY OUTCOMES: (i) a composite of cardiovascular events, including deep vein thrombosis (including catheter-associated), pulmonary embolism, myocardial infarction/myocarditis, arterial ischemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischemic stroke within 14 days, 30 days, and 90 days of randomization; (ii) each component of the primary efficacy outcome, within 14 days, 30 days, and 90 days of randomization; (iii) net clinical benefit (accounting for the primary efficacy outcome, composite cardiovascular events, and major bleeding), within 14 days, 30 days, and 90 days of enrolment; (iv) primary efficacy outcome, within 14 days, and 90 days of enrolment; (v) disseminated intravascular coagulation (ISTH criteria, in-hospital diagnosis) within 14 days, 30 days, and 90 days of enrolment. RANDOMISATION: Patients will undergo block stratified randomization (by age: 50-70 vs. >70 years; and by study centre) with a randomization ratio of 1:1 with block sizes varying between 4 and 8. Randomization will be performed after the signature of the informed consent for participation and the verification of the eligibility criteria using the electronic data capture software (REDCAP, Vanderbilt University, v9.1.24). BLINDING (MASKING): In this open-label study, no blinding procedures will be used. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size calculation is based on the parameters α = 0.05 (2-sided), power: 1-ß = 0.8, event rate in experimental group, pexp = 0.09 and event rate in control group, pcon = 0.15. The resulting total sample size is 920. To account for potential dropouts, the total sample size was fixed to 1000 with 500 patients in the intervention group and 500 in the control group. TRIAL STATUS: Protocol version 1.0, 14 April 2020. Protocol version 3.0, 18 May 2020 Recruiting start date: June 2020. Last Patient Last Visit: March 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04400799 First Posted: May 26, 2020 Last Update Posted: July 16, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Anticoagulants/administration & dosage , Betacoronavirus/pathogenicity , Blood Coagulation/drug effects , Coronavirus Infections/drug therapy , Enoxaparin/administration & dosage , Pneumonia, Viral/drug therapy , Thrombosis/prevention & control , Anticoagulants/adverse effects , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Enoxaparin/adverse effects , Equivalence Trials as Topic , Host-Pathogen Interactions , Humans , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , SARS-CoV-2 , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/virology , Time Factors , Treatment Outcome
9.
Sensors (Basel) ; 20(17)2020 Aug 28.
Article in English | MEDLINE | ID: covidwho-740500

ABSTRACT

The non-invasive estimation of blood oxygen saturation (SpO2) by pulse oximetry is of vital importance clinically, from the detection of sleep apnea to the recent ambulatory monitoring of hypoxemia in the delayed post-infective phase of COVID-19. In this proof of concept study, we set out to establish the feasibility of SpO2 measurement from the ear canal as a convenient site for long term monitoring, and perform a comprehensive comparison with the right index finger-the conventional clinical measurement site. During resting blood oxygen saturation estimation, we found a root mean square difference of 1.47% between the two measurement sites, with a mean difference of 0.23% higher SpO2 in the right ear canal. Using breath holds, we observe the known phenomena of time delay between central circulation and peripheral circulation with a mean delay between the ear and finger of 12.4 s across all subjects. Furthermore, we document the lower photoplethysmogram amplitude from the ear canal and suggest ways to mitigate this issue. In conjunction with the well-known robustness to temperature induced vasoconstriction, this makes conclusive evidence for in-ear SpO2 monitoring being both convenient and superior to conventional finger measurement for continuous non-intrusive monitoring in both clinical and everyday-life settings.


Subject(s)
Ear Canal , Hypoxia/diagnosis , Monitoring, Physiologic/instrumentation , Oximetry/instrumentation , Photoplethysmography/instrumentation , Wearable Electronic Devices , Adult , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/therapy , Equivalence Trials as Topic , Feasibility Studies , Female , Fingers , Humans , Hypoxia/blood , Male , Monitoring, Physiologic/methods , Oximetry/methods , Oxygen/analysis , Oxygen/blood , Pandemics , Photoplethysmography/methods , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/therapy , SARS-CoV-2 , Young Adult
10.
Trials ; 21(1): 609, 2020 Jul 03.
Article in English | MEDLINE | ID: covidwho-630127

ABSTRACT

OBJECTIVES: To evaluate the therapeutic effects of ultra-short-wave diathermy (SWD) on COVID-19 pneumonia. The hypothesis is that SWD may minimise pneumonic inflammation and shorten the duration of the time to positive-to-negative conversion of COVID-19 nucleic acid test. TRIAL DESIGN: This is a single centre, 2-arm (1:1 ratio), evaluator blinded, parallel group design superiority randomised, controlled clinical trial. PARTICIPANTS: The inclusion criteria were: (1) Age 18-65 years, (2) COVID-19 nucleic acid test is positive, (3) Lung CT showed multiple patchy ground glass shadows or other typical manifestations of both lungs. The exclusion criteria were: (1) Patients who need ICU management, (2) Positive tests for other pathogens such as Tuberculosis, Mycoplasma, (3) Patients with respiratory failure or requiring mechanical ventilation, (4) Patients with metal implants or pacemakers, (5) Those with shock (6) Those that have bleeding tendency or active bleeding in the lungs, (7) Patients with multiple organ failure who need ICU monitoring and treatment, (8) Cancer patients and those with severe underlying diseases, (9) Pregnant or lactating women, (10) Patients with severe cognitive impairment who cannot follow the instructions to complete the treatment, (11) Those without signed informed consent and (12) Those with other contraindications to short wave. This study will be conducted in Tongji Hospital, Caidian, Wuhan, People's Republic of China. INTERVENTION AND COMPARATOR: The experimental group will be given the nationally recommended standard medical treatment + ultra-short-wave diathermy treatment. Ultra-short-wave therapy treatment will be performed through application of ultra-short-wave therapy machine electrodes on the anterior and posterior parts of the trunk for 10 minutes, twice a day for 12 consecutive days. The comparator will be the control, not receiving ultra-short-wave therapy, and will be given only the nationally recommended standard medical treatment. MAIN OUTCOMES: The primary outcome measures will be time to positive-to-negative conversion of COVID-19 nucleic acid test by pharyngeal swab, in days assessed at 7th, 14th ,21st and 28th days. The secondary outcome measures include nucleic acid test rate and recovery from symptoms, Vital signs assessment, Computed Tomography, Complete blood count, serum analysis and SIRS scale scores. Blinded evaluation will be at baseline (the day of starting ultra-short-wave diathermy) and after 28 days following the interventions. RANDOMISATION: A Randomization plan will be generated online on www.randomization.com using permuted blocks method, by a statistician who will not be part of the study. Small blocks of various sizes will be used. Patients will be randomized (1:1) between the experimental and control groups BLINDING (MASKING): This will be an evaluator blinded study. Due to the nature of the intervention, blinding of patients and healthcare workers is not possible. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 410 patients will be randomised in 1:1 ratio to two groups: experimental group (n=205) and control group (n=205). TRIAL STATUS: Protocol version 1 was approved on 02/12/2020. Recruitment for this trial began on 02/18/2020 and will be ongoing till the required sample size is reached. The analysis deadline is August 2020. TRIAL REGISTRATION: This randomised controlled trial has been prospectively registered with the Chinese Clinical Trials ( ChiCTR2000029972 ) on 17 February 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)
Betacoronavirus/pathogenicity , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Short-Wave Therapy , Adolescent , Adult , Aged , COVID-19 , China , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Equivalence Trials as Topic , Female , Host-Pathogen Interactions , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , SARS-CoV-2 , Short-Wave Therapy/adverse effects , Time Factors , Treatment Outcome , Young Adult
11.
Trials ; 21(1): 610, 2020 Jul 03.
Article in English | MEDLINE | ID: covidwho-629630

ABSTRACT

OBJECTIVES: As there is no treatment for COVID-19 with a proven mortality benefit at this moment in the pandemic, supportive management including mechanical ventilation is the core management in an intensive care unit (ICU). It is a challenge to provide consistent care in this situation, highly demanding and leading to potential staff shortages in ICU. We need to reduce unnecessary exposure of healthcare workers to the virus. This study aims to examine the impact of care using a non-invasive oscillating device (NIOD) for chest physiotherapy in the care of mechanically ventilated patients with COVID-19. In particular, we aim to explore if a NIOD performed by non-specialized personnel is not inferior to the standard chest physiotherapy (CPT) undertaken by physiotherapists caring for patients with COVID-19. TRIAL DESIGN: A pilot multicenter prospective crossover noninferiority randomized controlled trial. PARTICIPANTS: All mechanically ventilated patients with COVID-19 admitted to one of the two ICUs, and CPT ordered by the responsible physician. The participants will be recruited from two intensive care units in Canadian Academic Hospitals (one pediatric and one adult ICU). INTERVENTION AND COMPARATOR: We will implement NIOD and CPT alternatingly for 3 h apart over 3 h. We will apply a pragmatic design, so that other procedures including hypertonic saline nebulization, intermittent positive pressure ventilation, suctioning (e.g., oral or nasal), or changing the ventilator settings or modality (i.e., increasing positive end-expiratory pressure or changing the nasal mask to total face continuous positive airway pressure) can be provided at the direction of bedside intensivists in charge. MAIN OUTCOMES: The primary outcome measurement is the oxygenation level before and after the procedure (SpO2/FiO2 ratio). For cases with invasive ventilation (i.e., the use of an endotracheal tube to deliver positive pressure) and non-invasive ventilation, we will also document expiratory tidal volume, vital signs, and any related complications such as vomiting, hypoxemia, or unexpected extubation. We will collect the data before, 10 min after, and 30 min after the procedure. RANDOMIZATION: The order of the procedures (i.e., NIOD or CPT) will be randomly allocated using manual generated random numbers for each case. Randomization will be carried out by the independent research assistant in the study coordinating center by using opaque sealed envelopes, assigning an equal number of cases to each intervention arm. Stratification will be applied for age (> 18 years or ≤ 18 years of age) and the study sites. BLINDING (MASKING): No blinding will be performed. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): We estimate the necessary sample size as 25 for each arm (total 50 cases), with a power of 0.90 and an alpha of 0.05, with a non-inferiority design. TRIAL STATUS: The protocol version number 1 was approved on 27 March 2020. Currently, recruitment has not yet started, with the start scheduled by the mid-June 2020 and the end anticipated by December 2020. TRIAL REGISTRATION: ClinicalTrials.gov NCT04361435 . Registered on 28 April 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional File 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/therapy , Lung/virology , Physical Therapy Modalities , Pneumonia, Viral/therapy , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Critical Illness , Equivalence Trials as Topic , Host-Pathogen Interactions , Humans , Lung/physiopathology , Multicenter Studies as Topic , Pandemics , Physical Therapy Modalities/adverse effects , Physical Therapy Modalities/instrumentation , Pilot Projects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Prospective Studies , Quebec , Respiration, Artificial , SARS-CoV-2 , Time Factors , Treatment Outcome
12.
Trials ; 21(1): 422, 2020 May 24.
Article in English | MEDLINE | ID: covidwho-342726

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Alanine/administration & dosage , Alanine/adverse effects , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , China , Clinical Trials, Phase III as Topic , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Double-Blind Method , Equivalence Trials as Topic , Female , Humans , Infusions, Intravenous , Male , Multicenter Studies as Topic , Pandemics , Patient Safety , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Risk Assessment , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Time Factors , Treatment Outcome
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