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Meta-analysis of the effectiveness of relapse prevention therapy for myelin-oligodendrocyte glycoprotein antibody-associated disease
Chang X, Zhang J, Li S, Wu P, Wang R, Zhang C, Wu Y
Multiple sclerosis and related disorders. 2023;72:104571
Abstract
BACKGROUND Approximately 40% of adults and 30% of children with Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) experience a relapsing course, but the optimal relapse prevention therapy remains unclear. A meta- analysis was conducted to investigate the efficacy of azathioprine (AZA), mycophenolate mofetil (MMF), rituximab (RTX), maintenance intravenous immunoglobulin (IVIG), and tocilizumab (TCZ) in prevention of attacks in MOGAD. METHODS English and Chinese-language articles published from January 2010 to May 2022 were searched in PubMed, Embase, Web of Science, Cochrane, Wanfang Data, China National Knowledge Infrastructure (CNKI), and China Science and Technology Journal Database (CQVIP). Studies with fewer than three cases were excluded. Meta-analysis of the relapse-free rate, the change of annualized relapse rate (ARR)and Expanded Disability Status Scale (EDSS) scores before and after treatment, and an age subgroup analysis was performed. RESULTS A total of 41 studies were included. Three were prospective cohort studies, one was an ambispective cohort study, and 37 were retrospective cohort studies or case series. Eleven, eighteen, eighteen, eight, and two studies were included in the meta-analysis for relapse-free probability after AZA, MMF, RTX, IVIG, and TCZ therapy, respectively. The proportions of patients without relapse after AZA, MMF, RTX, IVIG, and TCZ were 65% [95% confidence interval (CI):49%-82%]), 73% (95%CI:62%-84%), 66% (95%CI:55%-77%), 79% (95%CI:66%-91%), and 93% (95%CI:54%-100%), respectively. The relapse-free rate did not significantly differ between the children and adults treated with each medication. Six, nine, ten, and three studies were included in the meta-analysis for the change of ARR before and after AZA, MMF, RTX, and IVIG therapy, respectively. ARR was significantly decreased after AZA, MMF, RTX, and IVIG therapy with a mean reduction of 1.58 (95%CI: [-2.29--0.87]), 1.32 (95%CI: [-1.57--1.07]), 1.01 (95%CI: [-1.34--0.67]), and 1.84 (95%CI: [-2.66--1.02]), respectively. The change in ARR did not significantly differ between children and adults. CONCLUSIONS AZA, MMF, RTX, maintenance IVIG, and TCZ all reduce the risk of relapse in both pediatric and adult patients with MOGAD. The literatures included in the meta-analysis were mainly retrospective studies, so large randomized prospective clinical trials are needed to compare the efficacy of different treatments.
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Association of Convalescent Plasma Treatment With Clinical Status in Patients Hospitalized With COVID-19: A Meta-analysis
Troxel AB, Petkova E, Goldfeld K, Liu M, Tarpey T, Wu Y, Wu D, Agarwal A, Avendaño-Solá C, Bainbridge E, et al
JAMA network open. 2022;5(1):e2147331
Abstract
IMPORTANCE COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing. OBJECTIVE To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP. DATA SOURCES From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly. STUDY SELECTION Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally. DATA EXTRACTION AND SYNTHESIS A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board. MAIN OUTCOMES AND MEASURES Prespecified coprimary end points-the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model-were assessed clinically at 14 days after randomization. RESULTS Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics. CONCLUSIONS AND RELEVANCE This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.
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Prospective individual patient data meta-analysis: Evaluating convalescent plasma for COVID-19
Goldfeld KS, Wu D, Tarpey T, Liu M, Wu Y, Troxel AB, Petkova E
Statistics in Medicine. 2021
Abstract
As the world faced the devastation of the COVID-19 pandemic in late 2019 and early 2020, numerous clinical trials were initiated in many locations in an effort to establish the efficacy (or lack thereof) of potential treatments. As the pandemic has been shifting locations rapidly, individual studies have been at risk of failing to meet recruitment targets because of declining numbers of eligible patients with COVID-19 encountered at participating sites. It has become clear that it might take several more COVID-19 surges at the same location to achieve full enrollment and to find answers about what treatments are effective for this disease. This paper proposes an innovative approach for pooling patient-level data from multiple ongoing randomized clinical trials (RCTs) that have not been configured as a network of sites. We present the statistical analysis plan of a prospective individual patient data (IPD) meta-analysis (MA) from ongoing RCTs of convalescent plasma (CP). We employ an adaptive Bayesian approach for continuously monitoring the accumulating pooled data via posterior probabilities for safety, efficacy, and harm. Although we focus on RCTs for CP and address specific challenges related to CP treatment for COVID-19, the proposed framework is generally applicable to pooling data from RCTs for other therapies and disease settings in order to find answers in weeks or months, rather than years.
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Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial
Ortigoza MB, Yoon H, Goldfeld KS, Troxel AB, Daily JP, Wu Y, Li Y, Wu D, Cobb GF, Baptiste G, et al
JAMA internal medicine. 2021
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Abstract
IMPORTANCE There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. OBJECTIVE To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. DESIGN, SETTING, AND PARTICIPANTS CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. INTERVENTIONS A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline). MAIN OUTCOMES AND MEASURES The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8. RESULTS Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06). CONCLUSIONS AND RELEVANCE In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04364737.
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Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial
Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, et al
Jama. 2020
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Abstract
Importance: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed. Objective: To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19. Design, Setting, and Participants: Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled. Intervention: Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity. Main Outcomes and Measures: Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours. Results: Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, -10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83) (P for interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.65 [95% CI, 0.29-1.46]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.93]; P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18]; P < .001). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care. Conclusion and Relevance: Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000029757.
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Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19
Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, et al
Jama. 2020
Abstract
ImportanceConvalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed ObjectiveTo evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19 Design, Setting, and ParticipantsOpen-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020 The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation) The trial was terminated early after 103 of a planned 200 patients were enrolled InterventionConvalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity Main Outcomes and MeasuresPrimary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]) Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours ResultsOf 103 patients who were randomized (median age, 70 years;60 [58 3%] male), 101 (98 1%) completed the trial Clinical improvement occurred within 28 days in 51 9% (27/52) of the convalescent plasma group vs 43 1% (22/51) in the control group (difference, 8 8% [95% CI, −10 4% to 28 0%];hazard ratio [HR], 1 40 [95% CI, 0 79-2 49];P = 26) Among those with severe disease, the primary outcome occurred in 91 3% (21/23) of the convalescent plasma group vs 68 2% (15/22) of the control group (HR, 2 15 [95% CI, 1 07-4 32];P = 03);among those with life-threatening disease the primary outcome occurred in 20 7% (6/29) of the convalescent plasma group vs 24 1% (7/29) of the control group (HR, 0 88 [95% CI, 0 30-2 63];P = 83) (Pfor interaction = 17) There was no significant difference in 28-day mortality (15 7% vs 24 0%;OR, 0 65 [95% CI, 0 29-1 46];P = 30) or time from randomization to discharge (51 0% vs 36 0% discharged by day 28;HR, 1 61 [95% CI, 0 88-2 93];P = 12) Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87 2% of the convalescent plasma group vs 37 5% of the control group (OR, 11 39 [95% CI, 3 91-33 18];P < 001) Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care Conclusion and RelevanceAmong patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference Trial RegistrationChinese Clinical Trial Registry:ChiCTR2000029757
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A new nomogram for individualized prediction of the probability of hemorrhagic transformation after intravenous thrombolysis for ischemic stroke patients
Wu Y, Chen H, Liu X, Cai X, Kong Y, Wang H, Zhou Y, Zhu J, Zhang L, Fang Q, et al
BMC neurology. 2020;20(1):426
Abstract
BACKGROUND A reliable scoring tool to detect the risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis for ischemic stroke is warranted. The present study was designed to develop and validate a new nomogram for individualized prediction of the probability of hemorrhagic transformation (HT) in patients treated with intravenous (IV) recombinant tissue plasminogen activator (rt-PA). METHODS We enrolled patients who suffered from acute ischemic stroke (AIS) with IV rt-PA treatment in our emergency green channel between August 2016 and July 2018. The main outcome was defined as any type of intracerebral hemorrhage according to the European Cooperative Acute Stroke Study II (ECASS II). All patients were randomly divided into two cohorts: the primary cohort and the validation cohort. On the basis of multivariate logistic model, the predictive nomogram was generated. The performance of the nomogram was evaluated by Harrell's concordance index (C-index) and calibration plot. RESULTS A total of 194 patients with complete data were enrolled, of whom 131 comprised the primary cohort and 63 comprised the validation cohort, with HT rate 12.2, 9.5% respectively. The score of chronic disease scale (CDS), the global burden of cerebral small vascular disease (CSVD), National Institutes of Health Stroke Scale (NIHSS) score ≥ 13, and onset-to-treatment time (OTT) ≥ 180 were detected important determinants of ICH and included to construct the nomogram. The nomogram derived from the primary cohort for HT had C- Statistics of 0.9562 and the calibration plot revealed generally fit in predicting the risk of HT. Furthermore, we made a comparison between our new nomogram and several other risk-assessed scales for HT with receiver operating characteristic (ROC) curve analysis, and the results showed the nomogram model gave an area under curve of 0.9562 (95%CI, 0.9221-0.9904, P < 0.01) greater than HAT (Hemorrhage After Thrombolysis), SEDAN (blood Sugar, Early infarct and hyper Dense cerebral artery sign on non-contrast computed tomography, Age, and NIHSS) and SPAN-100 (Stroke Prognostication using Age and NIHSS) scores. CONCLUSIONS This proposed nomogram based on the score of CDS, the global burden of CSVD, NIHSS score ≥ 13, and OTT ≥ 180 gives rise to a more accurate and more comprehensive prediction for HT in patients with ischemic stroke receiving IV rt-PA treatment.
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Neuroprotective effects of erythropoietin in patients with carbon monoxide poisoning
Pang L, Bian M, Zang XX, Wu Y, Xu DH, Dong N, Wang ZH, Yan BL, Wang DW, Zhao HJ, et al
Journal of Biochemical & Molecular Toxicology. 2013;27((5):):266-71.
Abstract
The purpose of this study was to evaluate the efficacy of erythropoietin (EPO) for treating patients with carbon monoxide (CO) poisoning. We conducted a randomized, prospective study of 103 patients with CO poisoning in two groups: an EPO group (n = 54; patients received EPO) and a placebo group (n = 49; patients received normal saline). The study endpoints were the functional outcome at day 30 (the Barthel index and neurologic sequelae), National Institutes of Health Stroke Scale (NIHSS) score, and the levels of S-100. At 18 days, the NIHSS score improved significantly and S-100 levels significantly decreased in patients in the EPO group. At 30 days, patients in the EPO group had a superior Barthel index and fewer patients had delayed neurologic sequelae (DNS). This study demonstrated that early administration of EPO to patients with CO poisoning improved neurological outcomes and reduced the incidence of DNS. 2013 Wiley Periodicals, Inc.