Query: Convalescent plasma for  COVID-19 Clinical trials

title: A Scoping Review of Registered Clinical Trials of Convalescent Plasma for COVID 19 and a Framework for Accelerated Synthesis of Trial Evidence (FAST Evidence)
abstract: Many parallel studies of convalescent plasma with modest enrolment projections have been launched for the treatment of COVID 19. By pooling data from multiple parallel studies that are similar, we can increase the effective sample size and achieve enough statistical power to determine effectiveness more quickly through metanalysis. A scoping review of registered clinical trials of convalescent plasma for COVID 19 was conducted to assess the feasibility of performing a rapid and timely metanalysis that will support accelerated review for approval and implementation.  Trials were included if they utilized convalescent plasma to treat or prevent COVID 19. Forty eight registered trials (projected to enroll more than 5000 subjects) of convalescent plasma were identified and included for analysis. The majority of studies (33 studies with 4440 projected enrolment) will address the treatment of severe and/or critical cases of COVID 19. Twenty nine studies are controlled and 17 of these are reported as actively recruiting. The combined enrolment of patients from similar studies should be sufficient to determine meaningful improvements in mortality, rates of admission to intensive care and need for mechanical ventilation by the end of 2020 sooner than any individual study could determine effectiveness. Accessing supplemental outcome data from investigators may be needed, however, to align reporting of some outcomes from these studies. Heterogeneity in product potency due to different antibody titers is anticipated and studies using conventional treatment as controls instead of placebo may complicate our understanding of efficacy. Convalescent plasma is being tested in ongoing controlled studies, largely to treat severe and/or critical cases of COVID 19. Sufficient combined power to detect clinically important reductions in multiple outcomes, including mortality, is expected by September 2020. Regulatory approval, funding and implementation by blood operators could be accelerated by planned metanalysis as study results become available.

title: Convalescent Plasma for COVID 19: A multicenter, randomized clinical trial
abstract: Passive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID 19 for which evidence from controlled clinical trials is lacking.  We conducted a multi center, randomized clinical trial in patients hospitalized for COVID 19. All patients received standard of care treatment, including off label use of marketed medicines, and were randomized 1:1 to receive one dose (250 300 mL) of CP from donors with IgG anti SARS CoV 2. The primary endpoint was the proportion of patients in categories 5, 6 or 7 of the COVID 19 ordinal scale at day 15.  The trial was stopped after first interim analysis due to the fall in recruitment related to pandemic control. With 81 patients randomized, there were no patients progressing to mechanical ventilation or death among the 38 patients assigned to receive plasma (0% versus 6 out of 43 patients (14% progressing in control arm. Mortality rates were 0% vs 9.3% at days 15 and 29 for the active and control groups, respectively (log rank p=0.056) No significant differences were found in secondary endpoints. At inclusion, patients had a median time of 8 days (IQR, 6 9) of symptoms and 49,4% of them were positive for anti SARS CoV 2 IgG antibodies.  Convalescent plasma could be superior to standard of care in avoiding progression to mechanical ventilation or death in hospitalized patients with COVID 19. The strong dependence of results on a limited number of events in the control group prevents drawing firm conclusions about CP efficacy from this trial. (Funded by Instituto de Salud Carlos III; NCT04345523)

title: CONVALESCENT PLASMA FOR COVID 19 INFECTION: EVIDENCE AND CLINICAL APPLICATION
abstract: Corona virus disease 2019 (COVID 19) is caused by severe acute respiratory syndrome corona virus 2 (SARS CoV2) and has currently affected 11 million people worldwide with 0.53 million deaths. While there is ongoing trials and research for newer therapeutic options including antivirals (remdesivir) anti interleukin 6 (tocilizumab) vaccines and antimalarials; there is renewed interest in the use of old therapeutic tools as well. Convalescent plasma has been used historically for measles, poliomyelitis, Spanish flu pandemic, severe acute respiratory syndrome (SARS1) and Ebola epidemics with conflicting results. With widespread use of convalescent plasma throughout the world as investigational drug for COVID 19, it is important to review past experience with its use in various outbreaks, potential role in COVID 19, and clinical application during current pandemic and challenges faced by resource constrained countries.

title: Randomization amid a pandemic a critical appraisal regarding convalescent plasma therapy clinical trials for COVID 19 patients
abstract: The novel coronavirus disease (COVID 19) is spreading rapidly, a pandemic that has already affected millions of people across the world Currently there are no vaccines or drugs approved for COVID 19 Initial data which are coming from large clinical trials using Hydroxychloroquine, Lopinavir/Ritonavir, Remdesevir, and Favipiravir are not satisfactory against COVID 19 till now and we are in the midst of a worldwide public health threat In this context human convalescent plasma is considered as an option for treatment of COVID 19 disease Convalescent plasma therapy is a classic adaptive immunotherapy which involves the administration of antibodies against COVID 19 to a COVID 19 patient for the purpose of treating the viral disease Over the last two decades, convalescent plasma therapy was used for the treatment of 2003 SARS CoV 1 epidemic, 2009 2010 H1N1 influenza virus pandemic, the 2012 Middle East Respiratory Syndrome (MERS) CoV epidemic and 2014 2016 Ebola epidemic

title: Evidence favouring the efficacy of convalescent plasma for COVID 19 therapy
abstract: To determine the effect of COVID 19 convalescent plasma on mortality, we aggregated patient outcome data from randomized clinical trials, matched control, and case series studies. Fixed effects analyses demontrated that hospitalized COVID 19 patients transfused with convalescent plasma exhibited a a57% reduction in mortality rate (13% compared to matched patients receiving standard treatments (25% OR: 0.43, P 0.001) These data provide evidence favouring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized COVID 19 patients.

title: Convalescent plasma for COVID 19: Promising, not proven
abstract: While promising, convalescent plasma remains experimental and is not proven effective for COVID 19. In addition, many questions remain regarding the accuracy and predictive value of antibody testing of donors and patients, optimal donor selection, optimal timing, and selection of patients most likely to benefit. Until these questions are answered, convalescent plasma should ideally be used in the context of well designed clinical trials. The evidence is suggestive but weak. Trials are ongoing.

title: Convalescent plasma to treat critically ill patients with COVID 19: framing the need for randomised clinical trials
abstract: We are in a severe acute respiratory distress syndrome coronavirus 2 (SARS CoV 2) pandemic, causing coronavirus disease (COVID 19) SARS CoV 2 is an enveloped RNA virus with cell entry facilitated by spike (S) protein that has a cleavage site at the S1 S2 boundary and other structural proteins such as membrane (M) envelope (E) and nucleocapsid (N) proteins [1] Currently, there are two lineages of SARS CoV 2 virus infecting humans, with similar virulence and clinical outcomes, derived from a common ancestor that originated in December 2019 in Wuhan [1, 2] Most patients who recover from SARS CoV 2 illness will develop antibodies and memory lymphocytes against these proteins, which gives them immunity  In this editorial, we discuss the biological, operational, and methodological questions that arise when designing a randomised controlled trial (RCT) of convalescent plasma in COVID 19.

title: Development of a Database of Registered Clinical Trials Using Convalescent Plasma for Treatment of COVID 19: Is Data Harmonization Possible?
abstract: COVID 19 convalescent plasma (CCP) is a promising therapeutic option, but efficacy remains unknown In response to the emerging pandemic, multiple clinical trials assessing the efficacy and/or safety of CCP were registered in quick succession on ClinicalTrials gov (CTG) However, concern is growing that several trials may not reach stated enrollment goals We hypothesize that data harmonization among these trials may yield meaningful data that could not be obtained from underpowered individual trials We have developed a multidimensional grid of relevant US clinical trials, with the goal of determining if data harmonization can be achievable by identifying common data standards  All US trials registered on CTG as of 5/30/20 with CCP as treatment for COVID 19 patients were considered for inclusion Studies were excluded if they were designed solely for compassionate use (expanded access) assessed the feasibility of CCP collection or delivery per se (no treatment endpoint) were exclusively in children, or were duplicates Key parameters such as study design, patient population(s) and clinical and laboratory endpoints were extracted Trials were grouped based on target patient populations and study design  Between 3/22/20 and 5/30/20, 37 trials involving CCP were registered on CTG 12 were excluded based on above criteria The remaining 25 trials were organized based on patient populations and study design, yielding five distinct groups: (A) double blind randomized control trials (DBRCT) involving outpatients (N=4)(B) DBRCTs involving inpatients (N=6)(C) randomized open label trials involving inpatients (N=2)(D) single arm open label trials involving inpatients (N=10)(E) single arm open label trials involving both inpatients and outpatients (N=3) Among the 12 trials randomizing to two arms (groups A, B, C) the non intervention arm varied (standard plasma, 5% albumin, LR, "standard care" Among the 21 studies involving inpatients (groups B E) both clinical severity of patients enrolled, and outcomes analyzed varied greatly  Meaningful groupings of CCP clinical trials based on common parameters were developed in the above framework Overlaps as well as sources of heterogeneity among trials were identified This framework allows the generation of preliminary recommendations to facilitate data harmonization across trials that may face accrual problems Prospective pre statistical harmonization of data across clinical trials by adoption of common data standards, including inclusion and exclusion criteria, study populations, intervention protocols, outcome measures and data dictionaries, can facilitate pooling of data and improve statistical power Both trial level and individual patient level meta analyses may be employed as statistical strategies to analyze data

title: Convalescent Plasma for COVID 19: back to the future
abstract: The global pandemic of the new coronavirus SARS CoV 2 not only has medical, economic and social but also historical significance. In many parts of the world, the exponential epidemic curve of cases has overwhelmed hospital services. The primary pulmonary viral infection has required supportive care with oxygen and, if needed, mechanical ventilation and clinical teams around the world have successfully cared for hundreds of thousands of severely ill patients. However, there is currently no specific antiviral therapy that is proven to reduce mortality, although many putative antiviral and anti inflammatory regimes are being tested in large randomised clinical trials. The lack of a specific therapy has caused some sense of hopelessness in clinical staff, trepidation in the wider public and has not made plotting a route out of lockdown any easier. However, the most promising therapy at the moment may be one of the oldest. It is one where transfusion services and hospital blood banks play a direct role in identifying donors, testing, manufacturing and issuing products. It is also one where patients who have had COVID 19 can donate plasma, which can be used as a therapy for new patients who present with the disease. Convalescent plasma treatment, containing polyclonal antibody (Ab) has been used to treat severe viral pneumonia during previous pandemics. In fact, it has been used intermittently for over a century, including patients treated during the era of the Spanish Influenza pandemic in the early 20th century. Although all the studies conducted at that time had significant methodological flaws, and none were randomised, they suggested a reduction in mortality. In the more recent past, convalescent plasma has been used to treat H1N1 influenza and, more relevantly, SARS CoV infections in 2003, with evidence of some considerable benefit cited in a systematic review, especially if convalescent plasma was given earlier in the course of the disease (within the first 14 days of symptoms) Convalescent plasma has already been used in observational studies of patients with severe COVID 19. However, a systematic review of the evidence has shown that the conclusions about the effectiveness and safety of convalescent plasma in people with COVID 19 that can be drawn from these studies are limited. There have been only eight uncontrolled studies published, including a total of 32 participants. Some of the results reported in these studies are consistent with increased viral clearance and recovery from the disease. In some way, it is remarkable that such a potentially useful treatment has not been rigorously tested to allow definition of evidencebased guidelines for its tactical use in epidemics and for strategic planning for the collection of convalescent plasma to be incorporated into pandemic planning. Lack of evidence for a promising treatment is not unusual, but convalescent plasma has faced the challenge of always being very difficult to collect enough of during a pandemic to provide plasma to treat large number of patients. The other problem has been the lack of a co ordinated national and international response to allow rapid and timely randomised controlled trials to take place. The present COVID 19 epidemic has already been of such duration and magnitude to allow collection and use of plasma. However, it still takes considerable co ordination to complete large scale trials in a short time. A recent report of 5000 patients treated with convalescent plasma in the United States, almost entirely for compassionate use, suggested that convalescent plasma is safe, with no obvious cases of Ab dependent enhancement of disease. However, without data on control patients, it is impossible to be confident whether convalescent plasma is either safe or effective in the treatment of COVID 19. A more rigorous assessment of the role of convalescent plasma is underway. At the last count, 22 randomised trials around the world had been registered on trial registries. Two living systematic reviews of convalescent plasma will assess the benefits of treating people who have been diagnosed with COVID 19 and the benefits of preventative treatment for people at high risk of getting COVID 19. In the United Kingdom, the Office of Life Sciences, NHS Blood and Transplant (NHSBT) and the Department of Health and Social Care (DHSC) have proposed and planned a new programme to collect high volumes of plasma. The work is funded as a new PS20 million project by the DHSC. The strategy is to build up the collection of plasma from convalescent donors to provide enough plasma not only for two large scale randomised controlled trials to assess the efficacy and safety of convalescent plasma, but also to provide enough plasma to treat hospitalised and/or intensive care patients with COVID 19 if the randomised controlled trials do show efficacy. Within six weeks, NHSBT has set up what is effectively a new production line with workstreams reaching out to potential donors who were admitted to hospital and/or testing positive for COVID 19 and those who had symptoms consistent with the disease. NHSBT has established the collection of over 5000 units a week by rearranging work with existing donor centres, building three new collection centres in London, training over 200 newly recruited staff by donor centre staff and the core nursing team and defining new manufacturing processes and new methods to evaluate the quantity and quality of anti SARS CoV 2 antibodies. These are certainly challenging targets, and we have been faced with high on session deferral rates as we are plasmapheresing many first time donors who have recently recovered from serious infection. We are bringing deferral rates down and increasing the proportion of Received: 19 May 2020  20 May 2020

title: Passive immunotherapy with convalescent plasma against COVID 19? What about the evidence base and clinical trials?