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Background: COVID-19 infection can present with a heightened inflammatory state and platelet hyperactivation, however the roles of circulating extracellular vesicles (cEVs;pro-coagulant and pro-inflammatory mediators of intercellular communication) and the platelet releasate (PR;cargo released from activated platelets) remain uncharacterised. We hypothesised that the cEVs and PR proteomic signatures are altered in COVID-19 patients. Aim(s): To characterise and contrast paired cEVs and PR proteomes from COVID-19 patients and controls. Method(s): Ethical approval for this study was granted by the Mater Misericordiae University Hospital, Ireland. PR and platelet poor plasma (PPP) samples from COVID-19 patients requiring intensive care (severe, n = 6) or hospital care (non-severe, n = 6), and appropriate controls (n = 6 healthy controls and n = 5 COVID-negative hospitalised patients) were obtained with informed consent. cEVs were enriched from PPP by ultrafiltration. Samples were analysed by mass spectrometry and immunoassays. Result(s): Comparative statistical analysis revealed substantial overlap in the proteomic signatures of the cEVs and PR across COVID-19 patients and controls. Profound increases in circulating levels of pro-inflammatory proteins correlated with severity of infection, alongside significant dysregulation of proteins involved in blood coagulation including von Willebrand factor and fibrinogen. We also found evidence of 'spent' platelets in COVID-19 patients, with reduced platelet factor 4 (PF4) levels in the PR and concomitant increase of PF4 in plasma. Strikingly, several platelet-released proteins exhibited strong correlation with routinely obtained haematological parameters and together clearly differentiated between a severe and non-severe hospitalised COVID-19 patients. Conclusion(s): These preliminary data suggest that severe COVID-19 patients have a distinct cEV and PR profile and that proteomic signatures may be a useful tool in assessing the severity of COVID-19 when characterized in larger sample sizes. Our findings may lay the foundations to provide healthcare professionals with an adjunctive and minimally invasive tool towards assessing COVID-19 severity.
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Background: Thrombotic events are frequent and life-threating complications of COVID-19, but are also observed in patients with bacterial sepsis. Disseminated thrombosis may occur despite strict anticoagulation, suggesting that platelets play a direct, but yet undefined role. Several studies demonstrate altered platelet function in COVID-19, but the impact of platelets in COVID-19 and sepsis remains poorly understood. Aim(s): Platelet phenotype and function were comprehensively assessed in over 100 patients with either COVID-19 (non-ECMO, all-ICU, n = 23), bacterial infection without sepsis (SOFA-score < 2;n = 29), or sepsis/septic shock (SOFA-score >=2;n = 49) at multiple time points during the disease. Method(s): Patients were recruited at the local University Hospital (Ethical vote 94/19). Platelet phenotype and function were studied using flow cytometry (lumino-) aggregometry and whole-mount transmission electron-microscopy. Thrombus formation was investigated using a collagen-and tissue factor-coated flow chamber model at arterial shear rate (1000s-1). Thrombi were imaged by confocal microscopy. Result(s): Upon stimulation with ADP or CRP-XL platelets of infection patients without sepsis showed reduced PAC-1 binding and CD62P exposition. In sepsis patients reactivity was even more impaired and highly associated with disease severity (mean normalized geo-MFI PAC-1 infection: 0.56 vs sepsis: 0.25, p < 0.01;ROC-AUC: 0.76, p < 0.001). Intriguingly, platelets of COVID-19 patients were more responsive towards stimulation compared to comparably-ill ICU patients with sepsis. This relative hyper-reactivity was reflected by increased clot-formation in the flow chamber, compared to sepsis patients (mean surface coverage: 36% vs. 19%, p < 0.05). Thrombi of COVID-19 patients were platelet-rich with little fibrin, in contrast to healthy donors or sepsis patients showing increased amount of fibrin and less platelets. Subtherapeutic doses of GPIIb/IIIa blockers eptifibatide or tirofiban, which had minor effect in control blood, sufficiently prevented thrombus formation in COVID-19 samples under arterial flow. Conclusion(s): Our findings provide evidence that low dose GPIIb/ IIIa blockade might act as a powerful therapeutic tool in COVID-19 patients.
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Introduction: E-cigarette or vaping product use associated lung injury (EVALI) is a relatively new pulmonary syndrome linked to e-cigarette consumption. As of February 18th, 2020, a total of 2,807 hospitalized EVALI cases have been reported to the CDC. Among hospitalized EVALI cases, 15% (421 patients) were under the age of 18. Case Description: Patient is a 17-year-old previously healthy male who presented to the ED for a 3-day history of fever, progressively worsening nausea and vomiting, anorexia, dry cough, and night sweats. PMH was significant for COVID-19 infection in April 2021 and he was fully vaccinated for COVID-19 as of May 2021. Patient also noted 10 lbs. unintentional weight loss in the last month. Patient denied substance use or sexual activity. Family history was unremarkable. In the ED the patient was febrile and mildly tachycardic. Physical exam was grossly unremarkable including a normal lung exam. Relevant labs revealed a leukocytosis, hyponatremia, elevated ESR and CRP. SARS-COVID-2 PCR negative, SARS-COVID-2 IgG S1/S2 Spike protein positive, nucleocapsid negative. CXR, ECG, and RUQ U/S were unremarkable. Patient was subsequently admitted to the inpatient pediatric service for further management. During hospitalization the patient reported increased shortness of breath and pleuritic chest pain with SaO2 down to 86% on room air requiring supplemental oxygen. New social history obtained without family present revealed heavy vaping of nicotine and THC 'most days' for the past 3 years. Pediatric pulmonology was consulted and diagnosed the patient with EVALI and started him on methylprednisolone and a 5-day course of azithromycin for its anti-inflammatory effects. The patient was subsequently able to be weaned off oxygen and was discharged home on an oral prednisone taper and azithromycin after 6 days in the hospital. CXR 2 weeks after discharge was normal with complete resolution. Discussion: EVALI is mainly a diagnosis of exclusion and can mimic other infectious and rheumatologic conditions, therefore clinicians must maintain a high index of suspicion in order to make the diagnosis. Clinical manifestations of EVALI can include respiratory, gastrointestinal, and constitutional symptoms. The most frequently reported symptoms include shortness of breath, fever, cough, vomiting, diarrhea, dizziness, headache, tachycardia, and chest pain. Laboratory studies often show an elevated CRP and procalcitonin, leukocytosis, and a transaminitis. Radiographic features can include diffuse, bilateral, ground-glass infiltrates with basilar predominance and sub-pleural sparing. Conclusion: This case demonstrates the importance of obtaining a social history in a confidential environment in any adolescent case. When this was done on hospital day two, we learned of an extensive vaping history which helped us diagnose the patient with EVALI. In addition to drug use, clinicians should specifically ask about the use of e-cigarettes and vaping products since not all adolescents will divulge these details unless directly asked.
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Study Objectives: Due to their ubiquity, smartphone applications are becoming increasingly important for emergency response, including providing a means of mobilizing volunteer responders. Data from these applications may be useful for identifying potential disparities in emergency response by revealing geographic gaps and racial and income-based inequity in the availability of volunteers. This could in turn be used to create targeted interventions to increase equitable emergency response coverage. The purpose of our study was to examine associations between race, SES factors, and access to emergency resources using data from PulsePoint (PP), a smartphone-based emergency response application for public cardiac arrest. We sought to contextualize this investigation to the COVID-19 pandemic, to further understand how pandemic conditions may intersect with existing inequities. Methods: The PP responder position data from the Allegheny County PP deployment was aggregated into zip code-level totals from data samplings taken from August 2019 to May 2020 using geospatial informatics software (QGIS). These totals were stratified into pre- and intra-pandemic periods, as well as by racial and demographic characteristics obtained from the US Census Bureau. The change in available responders at the zip-code level, as well as the association between number of available responders and racial and demographic characteristics, were examined using Mann-Whitney U Tests due to non-normal distribution of responder counts. Results: The median (IQR) of available PP responders before and after the stay at home order were 67.4125 (116.9375) and 73.05 (127.95), respectively. Fifteen percent of zip codes in the Pittsburgh area have > 30% of African Americans with a median (IQR) of 280 (1488). This compared to 95.6% of zip codes in the Pittsburgh area that have > 30% of Caucasian-Americans with a median (IQR) of 8582 (12538). The median (IQR) for the percent below the poverty level for all zip codes was 9% (10.8%). The p-value of available PP responders before the shutdown for high-income vs. low-income zip codes was 0.493. The p-value of available PP responders after the shutdown for high-income vs. low-income zip codes was 0.197. Lastly, the p-values of available PP after the shutdown to zip codes with > 30% vs. <30% Caucasian-Americans and > 30% vs. <30% African Americans were -0.443 and 1.095, respectively. Conclusion: In summary, SES was associated with the number of PP responders at the zip code level in Allegheny county. Interestingly, the pandemic shifted the distribution of responders to a net increase in available responders which did not entirely differ by race, but by income.
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Background Hospitalised patients with severe COVID-19 (requiring critical care level support) appear to be at increased risk of thrombosis despite standard pharmacological thromboprophylaxis. The magnitude of thrombotic risk in patients with COVID-19 of moderate severity (not requiring critical care) is less clear. The optimal approach to thromboprophylaxis (and the role of intensified thromboprophylaxis) remains to be determined. Evidence of endothelial dysfunction has been widely reported in COVID-19 (particularly in severe COVID) and this may contribute to hypercoagulability. Aim To assess differences in patterns of hypercoagulability and endothelial dysfunction between a group of patients with moderate COVID-19 and a group of age-matched hospitalized patients (SARS-CoV-2 PCR negative) receiving low molecular weight heparin (LMWH) thromboprophylaxis. Methods Blood was collected from individuals admitted to hospital with COVID-19 of moderate severity (not requiring critical care level support) and a group of age-matched patients admitted with infective/inflammatory illness (SARS-CoV-2 PCR negative). All subjects received standard-dose LMWH thromboprophylaxis, with blood drawn at 12 hours post-dose (and with measurement of anti-FXa activity levels). Circulating levels of endothelial & fibrinolytic markers including ICAM, PAI-1, VCAM, soluble thrombomodulin (sTM), and tissue plasminogen activator (tPA) were determined by ELISA. Thrombin generation (TG) in platelet-poor plasma was assessed by calibrated automated thrombography in the presence of tissue factor (Final concentration, 1pM & 5pM), thrombomodulin (TM) (Final concentration, 6.25nM), and an inhibitory anti-tissue factor pathway inhibitor antibody (anti-TFPI;Final concentration 100μg/mL). Results 14 COVID-19 positive subjects and 11 hospitalized controls were recruited. There were no differences in mean age (69.7±4.5 vs 61.6±4.7 years;p= 0.2) or mean Body mass index (25.7±1.1 vs 22.7±1.2 Kg/m2;p=0.1) between groups. No COVID-19 patient or control required critical care support. In the COVID group, radiological evidence of pneumonitis [diffuse (n=3) or peripheral infiltrates (n=7)] was present in the majority of cases. None of the COVID-19 cases were requiring supplemental oxygen at the time of recruitment. All controls were admitted with either respiratory or urinary infection [radiological evidence of pneumonia in 4/11;supplemental oxygen requirement in 2/11, (28-36% FiO2 via nasal cannula)]. Plasma levels of sTM, ICAM, PAI-1 & VCAM were similar in both groups. Levels of t-PA were significantly higher in the COVID group (8.31±4.35 vs 4.91±2.37 ng/mL;p= 0.005). Despite similar plasma anti-Xa activity in both groups (0.06 vs 0.04 IU/mL;p=0.2), mean endogenous thrombin potential (ETP) was significantly higher in the COVID group (1929±119.7 vs 1528±138.9 nM*min;p=0.02), although peak thrombin was similar (173.6±26 vs 161.5±31nM). ETP-TM ratio was similar between groups (0.3±0.1 vs 0.2±0.1;p=0.3). Despite increased ETP, the lag time to thrombin generation was significantly prolonged in the COVID group (8.3±0.6 vs 5.8±0.5 mins, p= 0.006). This pattern has previously been observed in vascular diseases associated with altered plasma tissue factor pathway inhibitor (TFPI) activity. In the presence of an anti-TFPI antibody, the difference in lagtime between groups was attenuated (4.7±0.2 vs 3.5±0.1 mins;p= 0.002) and the difference in overall thrombin generation (delta TG) between both groups became significantly increased (Fig.1). Conclusion Plasma thrombin generation is enhanced in patients with non-severe COVID-19 despite pharmacological thromboprophylaxis. Endothelial dysfunction is also observed in this group and appears to modulate parameters of plasma thrombin generation. The clinical implications of these observations are not known although clinical studies of intensified thromboprophylaxis in attenuating thrombotic risk and other complications are ongoing. Fig 1. Inhibition of TFPI activity enhances thrombin generation in COVID-19. n the presence of an inhibitory anti-TFPI antibody, peak plasma thrombin generation was enhanced in COVID-19 in contrast to that observed among SARS-CoV-2 PCR negative hospitalised patients (339.6+25.2 vs 247.4+10.1, p=0.01). [Formula presented] Disclosures: Maguire: Actelion: Research Funding;Bayer Pharma: Research Funding. Ni Ainle: Daiichi-Sankyo: Research Funding;Actelion: Research Funding;Leo Pharma: Research Funding;Bayer Pharma: Research Funding. Kevane: Leo Pharma: Research Funding.
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Context. The Covid-19 pandemic is of unprecedented magnitude and has had major social and health consequences. Primary care professionals, mainly general practitioners, ensure the care of most patients with Covid-19. An early-stage treatment administered to patients with risk factors for developing a severe disease could reduce hospitalization and death rates. No treatment is currently validated in this indication. Objectives. To evaluate the safety and efficacy of experimental candidate agents delivered in outpatient settings to reduce the risk of hospitalization or death in at-risk patients with early-stage proven Covid-19 and no indication for hospital admission. Methods. Multicentric, open-label, multi-arm, multi-stage (MAMS) randomized controlled trial with a pilot tolerability and safety phase, and a clinical efficacy phase. Efficacy will be determined by the proportion of participants who have an indication for hospital admission, administration of acute oxygen therapy (because of Covid-19) or who decease between D0 and D14 in the experimental treatment group compared to the control group. Expected results. This trial will assess the tolerance and efficacy of diverse treatments administered at an early stage of Covid-19, in patients with risk factors of developing a severe disease. It will also provide information that can contribute to increase primary care actors' ability to conduct clinical trials at the national level.
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Background : Infection with SARS-CoV-2 leads to an altered hemostatic system and Covid-19 associated coagulopathy (CAC). Platelet counts remain overall unaltered, but thromboembolic events are frequently reported. Studies on the contribution of platelets to CAC are emerging but still lacking precise cohort comparison and broad analyses of platelet markers. Aims : We aimed to analyze platelet receptor expression and function on platelets and biomarkers in platelet-poor plasma to investigate the role of platelets in the onset of critical progression of CAC. Methods : Extensive platelet function analyses were performed on 34 critically-ill patients with Covid-19 and data was compared to sepsis patients ( n = 24) and non-SARS-CoV-2 acute infection ( n = 18). Tests included PFA-200, aggregometry, flow cytometry and whole mount TEM. Plasma levels of TPO, sCD62P and sGPVI were determined by ELISA. For all patients, relatives, and for healthy controls ( n = 10) informed consent was obtained. Results : While platelet counts in patients of our Covid-19 cohort were expectably unaltered, platelet function was severely impaired in multiple assays. Platelets failed to aggregate in response to ADP or TRAP-6 and could not activate integrin response or release α-granules. The amount of platelet-leukocyte aggregates was markedly elevated, indicating previous platelet activation in line with higher levels of sCD62P and sGPVI. Remarkably, we observed platelet exhaustion in Covid-19 patients using whole mount TEM by means of a lack of dense granules corroborating with impaired uptake of mepacrine. Conclusions : Our data imply that SARS-CoV-2 infection leads to a sub-threshold activation of platelets in a way that they become activated already before critical disease progression, without being cleared from the circulation, which is in striking contrast to sepsis. The platelet pool appears to be exhausted with detrimental consequences for thrombus stability and the risk of thromboembolic events. The mere platelet count in Covid-19 does thus not reflect progression to CAC, whereas platelet function is of high prognostic relevance.
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Background : COVID-19 confers an increased risk of thrombosis however the mechanisms underlying this coagulopathy and the optimal approach to thromboprophylaxis are unknown. Thrombotic risk is likely greatest among patients with severe COVID-19 requiring critical organ support however patients with moderate disease may be at risk and might also benefit from intensified thromboprophylaxis. Aims : To characterise plasma thrombin generation (TG) in patients with COVID-19 of moderate severity, treated with pharmacological thromboprophylaxis. Methods : Blood was collected from individuals admitted to hospital with COVID-19 of moderate severity (not requiring critical care support) and a group of age-matched patients admitted with infective/ inflammatory illness (negative for COVID-19). All subjects received standard dose low molecular weight heparin (LMWH) thromboprophylaxis with samples taken at time of predicted trough levels (confirmed by measuring anti-FXa activity). TG in platelet-poor plasma was determined by calibrated automated thrombography in the presence/absence of tissue factor (TF) (ppp-LOW reagent, 1 pM TF & 4 μM phospholipid;MP-reagent, 4 μM phospholipid;Thrombinoscope BV™). Results : Fourteen COVID-19 positive subjects and 11 hospitalised COVID-19 negative controls were recruited. Mean trough plasma anti-Xa activity was similar in both groups (0.06 vs 0.04 IU/mL;P = 0.2). In the presence of TF, mean endogenous thrombin potential was significantly higher in the COVID group in comparison to controls (1929 ± 119.7 vs 1528 ± 138.9 nM∗min;P = 0.02). Peak thrombin was also higher in COVID-19 (267.3 ± 22.2 vs 208.6 ± 17.8 nM;P = 0.06). Despite increased TG overall, lagtime to TG was significantly prolonged in COVID-19 (8.1 ± 0.5 vs 6.2 ± 0.5 mins;P = 0.02). No difference in any parameter of TG was observed between groups in the absence of TF. Conclusions : Despite pharmacological thromboprophylaxis plasma TG is enhanced in COVID-19. The underlying mechanisms remain to be elucidated. Specific clinical implications of increased TG despite pharmacological thromboprophylaxis have yet to be determined although clinical trials evaluating intensified anticoagulant regimens in a similar population are ongoing.
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Background : Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected over 100 million globally to date. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Several studies to date suggest a role for platelets in COVID-19-associated thrombosis. Aims : To assess the impact of COVID-19 on platelet activity and to characterise the proteome of the platelet releasate from COVID-19 patients, compared with healthy controls. Methods : Ethical approval was granted by the Institutional Review Board of the Mater Misericordiae University Hospital. Haematologic parameters of patients with severe COVID-19 disease (requiring intensive care;n = 34), with non-severe disease (not requiring intensive care;n = 20) and in general medical in-patients without COVID-19 ( n = 20) were assessed. Platelet function and activity were evaluated by secretion and platelet marker analysis ( n = 6 each cohort). The proteome of the platelet releasate was assessed using label-free mass spectrometry. Results : We demonstrated agonist-induced ADP release was 30-to-90 fold higher in COVID-19 patients compared with hospitalized controls (Fig. 1) and circulating levels of platelet-factor 4 (PF4), soluble P-selectin (sP-selectin) and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that COVID-19 patients possess hyperactive circulating platelets combined with a decreased activation threshold. Mass spectrometry analysis identified over 400 proteins from the releasate of COVID-19 patients and controls, including a multitude of inflammatory, vasoactive and vesicular proteins. The release of a subset of highly-relevant platelet proteins was modified based on the severity of COVID-19 infection. controls (Fig. 1) and circulating levels of platelet-factor 4 (PF4), soluble P-selectin (sP-selectin) and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that COVID-19 patients possess hyperactive circulating platelets combined with a decreased activation threshold. Mass spectrometry analysis identified over 400 proteins from the releasate of COVID-19 patients and controls, including a multitude of inflammatory, vasoactive and vesicular proteins. The release of a subset of highly-relevant platelet proteins was modified based on the severity of COVID-19 infection.
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Background: Little is known on what palliative care (PC) has been provided to patients with COVID-19. Aims: To understand what PC was provided nationwide to patients with COVID-19 and strategies implemented to overcome barriers during the pandemic. Methods: Semi-structured interviews were conducted with physicians across Canada about their experiences providing PC to patients with COVID-19. Thematic analysis was used to describe and interpret overarching themes. Results: Twelve specialized PC (SPC) and 11 primary PC (PPC) were interviewed. Interim analysis of 16 coded interviews demonstrated SPC and PPC physicians used traditional strategies (such as opioids, oxygen and serious illness conversations) to manage symptoms, support end of life, and engage patients and families in goals of care conversations (GOC). Neither SPC nor PPC indicated strong adoption of GOC and symptom management tools circulated early in the pandemic. Both SPC and PPC indicated a shift to virtual communication due to restrictive visitor policies, highlighting the need for distanced support and planned communication. Care coordination for PC patients was challenged by a lack of community resources, family infected with COVID-19, prolonged hospital stays, and increased number of PC patients discharged to rehabilitation services. New PC structures included;GOC teams that functioned in the emergency department and medicine floors, integrated clinical rounding by non-PC clinicians with PC teams, and hospital-based PC outreach to long term care. Strategies to improve PC implementation included: virtual technologies, team collaboration, patient and family engagement tools, and symptom management and GOC conversations tools. Conclusions: While PC management approaches to support patients with COVID-19 were mostly unchanged, new structures and strategies were developed to ensure patients and their families were provided with support.
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Background: Early diagnosis is key to the best treatment options and possible outcomes for cancer patients. However, the COVID19 pandemic has put a heavy burden on the US healthcare system, causing hospitals and medical centers to stop or delay routine cancer screenings such as mammograms, pap tests, colonoscopies, CT scans and PSA assays. Subsequently, cancer diagnostic testing and cancer patient care have also been disrupted. Methods: To determine the extent of cancer diagnostic testing that was impacted during the COVID 19 pandemic in 2020, we analyzed the changes in cancer test volume at NeoGenomics Laboratories Inc. between 2019 and 2020, and especially between March and June 2020. Unique patient test counts were categorized by cancer types as determined by the diagnostic ICD 10 code C00-D49 (with a minimum of 100 tests in 2019). Results: Comparing test volumes in 2020 to 2019, an overall decrease in tests ordered in 2020 was seen for multiple cancers. These cancers include malignant neoplasms of breast (16%) and malignant neoplasm of bronchus and lung (19%), followed by malignant neoplasm of colon, polycythemia vera, and Hodgkin lymphoma. In addition, a decrease in benign cancers, and decreases in benign neoplasm of colon, rectum, anus and anal canal was observed. To determine if the US stay-at-home order implemented between March and early June 2020 had affected test volume, month-to-month comparison shows the greatest impact in test volume in malignant neoplasm of breast: a 28% decrease comparing April 2020 to April 2019, and a 32% decrease comparing May 2020 to May 2019. Similarly, a 24% and 33% decrease were seen in malignant neoplasm of bronchus and lung for the same months. Individual tests specific for breast and lung cancer also showed similar decreases: 49- 56% decrease for Breast Triple Stain (CK5 + p63 + CK 8/18), 11-41% decrease for ER test, and up to 39% decrease for HER2 diagnostic tests. Tests for ALK fusions for lung cancer showed decreases in test volume ranging from 15% to 30% during April, May and June 2020 as compared to 2019. Interestingly, we found that the total test volumes for each age group (increments of 10 up to age 80) decreased April and May 2020 as well, compared to April and May 2019. We did not see a difference in test volume decreases based on patient gender. Conclusions: There was a decrease in cancer tests ordered during the pandemic in 2020 for most cancer types, with a large decrease found in breast, lung and colon cancer. The sharp decrease in breast cancer tests is important to note as breast cancer has recently been identified as the most diagnosed form of cancer, surpassing lung cancer. This impact in cancer testing may translate to delayed diagnosis and treatment options. It remains to be seen whether this will lead to more aggressive cancer treatments, or to a greater patient mortality. It is imperative that we continue to monitor and screen patients for cancer as the pandemic continues or during any healthcare crisis in the future.
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Introduction Même en période d’urgence épidémique, les essais cliniques randomisés restent la meilleure approche pour évaluer l’efficacité d’une intervention. Cependant différents défis méthodologiques se posent : pouvoir : – intégrer différentes stratégies thérapeutiques repositionnées ou innovantes adaptées aux connaissances émergentes lors de la conception et à différents stades de l’essai ;– écarter rapidement celles qui ne se révèlent pas prometteuses. Début 2021, aucun traitement n’est validé dans le traitement précoce de la COVID-19. Pourtant un tel traitement permettrait d’éviter les hospitalisations ou le décès. L’objectif de COVERAGE est d’évaluer la sécurité et l’efficacité de différents traitements ambulatoires pour diminuer le risque d’aggravation chez des patients fragiles avec facteurs de risque de gravité. Depuis sa mise en place de multiples adaptations ont pu être effectuées grâce au choix d’un schéma flexible. Méthodes COVERAGE est un essai multicentrique français de phase 3, de supériorité, contrôlé randomisé, ouvert à plusieurs bras parallèles (NCT04356495). Les patients – âge≥60 ans ou≥50 ans avec des comorbidités (ex : obésité) – présentant une COVID-19 sans critère d’hospitalisation sont randomisés (ratio 1) entre différentes stratégies expérimentales ou une stratégie contrôle. La randomisation est stratifiée sur le centre et d’autres facteurs de stratification peuvent être définis au cours du temps. Chaque stratégie thérapeutique peut être introduite dans tous ou certains centres à une période calendaire différente dans deux phases successives : d’abord une phase pilote (n=36) fondée sur un schéma de Fleming en une étape destinée à évaluer la tolérance et l’acceptabilité en traitement ambulatoire et à explorer les premiers paramètres d’évolution clinique ;puis, une phase d’efficacité (n=169) comparative utilisant un schéma adaptatif multi-bras multi-étape (MAMS) où chaque bras expérimental est comparé séparément aux participants du bras témoin unique inclus dans la même période calendaire pour éviter des biais de sélection et de confusion. Trois analyses intermédiaires (futilité±efficacité précoce) et une analyse finale seront effectuées pour le critère principal d’efficacité à j14, après l’inclusion de 30, 60, et 102 participants en phase d’efficacité. Chaque bras a un minimum de 36 participants (si arrêt après la phase pilote) et un maximum de 36+169 participants (si arrêt en fin de la phase d’efficacité). Le nombre total de patients inclus dans l’essai dépendra du nombre de bras, des décisions de passage de la phase pilote à la phase d’efficacité pour chaque stratégie, et de la durée de l’épidémie. Résultats Depuis mars 2020, plusieurs amendements au protocole ont permis de supprimer ou ajouter des bras, adapter les critères d’éligibilité et de stratification, effectuer une ouverture multicentrique progressive dans le cadre d’une extension nationale. En novembre 2020, COVERAGE s’est transformé en plateforme nationale dans le cadre de la stratégie REACTing pour optimiser les efforts de recherche français et a obtenu le label priorité nationale de recherche par le CAPNET. Fin janvier 2021, 112 participants étaient inclus et le recrutement continue. Conclusion L’essai COVERAGE a été construit pour s’adapter aux contraintes de la recherche clinique en période d’urgence épidémique. Le schéma adaptatif permettra d’évaluer la tolérance, la faisabilité ambulatoire et l’efficacité de différentes stratégies thérapeutiques précoces contre la COVID-19.
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Declaration de liens d'interets: Les auteurs declarent ne pas avoir de liens d'interets. Copyright © 2020