scholarly journals Usefulness of convalescent plasma transfusion for the treatment of severely ill COVID-19 patients in Pakistan

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tehmina Nafees Sonia Khan ◽  
Samina Naz Mukry ◽  
Shahtaj Masood ◽  
Lubna Meraj ◽  
Bikha Ram Devrajani ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Sofa Score ◽  
Statistical Tests ◽  
Multiorgan Failure ◽  
Clinical Status ◽  
Secondary Endpoint ◽  
Trial Registration ◽  
Open Label ◽  
Search Result ◽  
Link Type

Abstract Background Convalescent plasma(CP) was utilized as potential therapy during COVID-19 pandemic in Pakistan. The study aimed at appraisal of CP transfusion safety and usefulness in COVID pneumonia. Methods Single arm, MEURI study design of non-randomized open label trial was conducted in five centers. Patients werecategorized as moderately severe, severe, and critical. The primary endpoint was a) improvement in clinical status and change in category of disease severity; secondary endpoint was b) CP ability to halt disease progression to invasive ventilation. CP transfused to hospitalized patients. Statistical tests including median (interquartile ranges), Mann-Whitney U test, Fisher’s exact test using SPSS ver. 23, ANOVA and Chi-square test were applied for the analysis of results parameters before and after CP treatment. SOFA score was applied for multiorgan failure in severe and critical cases. Results A total of 50 adult patients; median age 58.5 years (range: 29–92 years) received CP with infusion titers; median 1:320 U/mL (Interquartile range 1:80–1:320) between April 4 to May 5, 2020. The median time from onset of symptoms to enrollment in trial was 3 to 7 days with shortness of breath and lung infiltration as severity criterion. In 35 (70%) recipients, oxygen saturation improved from 80 to 95% within 72h, with resolution of lung infiltrates. Primary endpoint was achieved in 44 (88%) recipients whereas secondary endpoint was achieved in 42 (84%). No patient experienced severe adverse events. A high SOFA score (> 7) correlated with deaths in severe and critical patients. Eight (16%) patients expired due to comorbidities; cardiac arrest in 2 (4%), multiorgan failure secondary to cytokine storm in 5 (10%) and ventilator associated complications in 1 (2%). Conclusion CP transfusion can be used as a safe and useful treatment in moderately severe and severe patients. Trial registration The trial registration number is NCT04352751 (https://www.irct.ir/search/result?query=IRCT20200414047072N1). Trial Registration date is 28th April 2020.

scholarly journals A novel MSC-based immune induction strategy for ABO-incompatible liver transplantation: a phase I/II randomized, open-label, controlled trial

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yingcai Zhang ◽  
Jiebin Zhang ◽  
Huimin Yi ◽  
Jun Zheng ◽  
Jianye Cai ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Hepatic Failure ◽  
Therapeutic Option ◽  
Controlled Trial ◽  
Trial Registration ◽  
Biliary Complications ◽  
Open Label ◽  
Antibody Mediated Rejection ◽  
Link Type ◽  
Induction Strategy

Abstract Background ABO-incompatible liver transplantation (ABO-i LT) has become a rescue therapeutic option for patients with severe hepatic failure. Although the use of rituximab greatly reduces the morbidity of antibody-mediated rejection (AMR), severe adverse effects, such as infection and biliary complications, still seriously threaten the survival of transplant recipients. The aim of this study was to evaluate the safety and feasibility of using mesenchymal stem cells (MSCs) to replace rituximab in ABO-i LT. Methods Twenty-two patients with severe hepatic failure undergoing ABO-i LT were enrolled and randomly divided into two groups: the MSC group and the rituximab group. The safety of the application of MSCs and the incidence of allograft rejection, including antibody-mediated rejection (AMR) and acute cellular rejection (ACR), were evaluated in both groups at the 2-year follow-up period as primary endpoints. Recipients and graft survival and other postoperative complications were compared as secondary endpoints. Results No severe MSC-related adverse events were observed during the trial. MSC treatment yielded comparable, if not better, results than rituximab at decreasing the incidence of acute rejection (9.1% vs 27.3%). Inspiringly, compared to those in the rituximab group, the rates of biliary complications (0% vs 45.5%) and infection (9.1% vs 81.8%) were significantly decreased in the MSC group. In addition, there were no significant differences in 2-year graft and recipient survival between the two groups (81.8% vs 72.7%). Conclusions Our data show that MSC transfusion is comparable to rituximab treatment for AMR prophylaxis following ABO-i LT. Additionally, the results indicate that MSCs are more beneficial to the prevention of infection and biliary complications and may be introduced as a novel immunosuppressive approach for ABO-i LT. Trial registration Trial registration: chictr.org.cn, ChiCTR2000037732. Registered 31 August 2020- Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=57074.

scholarly journals Otitis media outcomes of a combined 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine and 13-valent pneumococcal conjugate vaccine schedule at 1-2-4-6 months: PREVIX_COMBO, a 3-arm randomised controlled trial

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Amanda Jane Leach ◽  
Edward Kim Mulholland ◽  
Mathuram Santosham ◽  
Paul John Torzillo ◽  
Peter McIntyre ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Otitis Media ◽  
Conjugate Vaccine ◽  
Otitis Media With Effusion ◽  
Controlled Trial ◽  
Acute Otitis Media ◽  
Trial Registration ◽  
Open Label ◽  
Suppurative Otitis Media ◽  
Link Type

Abstract Background Aboriginal children living in Australian remote communities are at high risk of early and persistent otitis media, hearing loss, and social disadvantage. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are the primary pathogens. We compared otitis media outcomes in infants randomised to either a combination of Synflorix™ (PHiD-CV10, with protein D of NTHi) and Prevenar13™ (PCV13, with 3, 6A, and 19A), with recommended schedules for each vaccine alone. We previously reported superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months. Methods In an open-label superiority trial, we randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to either Prevenar13™ (P) at 2–4-6 months (_PPP), Synflorix™ (S) at 2–4-6 months (_SSS), or Synflorix™ at 1–2-4 months plus Prevenar13™ at 6 months (SSSP). Ears were assessed using tympanometry at 1 and 2 months, combined with otoscopy at 4, 6, and 7 months. A worst ear diagnosis was made for each child visit according to a severity hierarchy of normal, otitis media with effusion (OME), acute otitis media without perforation (AOMwoP), AOM with perforation (AOMwiP), and chronic suppurative otitis media (CSOM). Results Between September 2011 and September 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(141). Ear assessments were successful in 96% scheduled visits. At 7 months prevalence of any OM was 91, 86, and 90% in the _PPP, _SSS, and SSSP groups, respectively. There were no significant differences in prevalence of any form of otitis media between vaccine groups at any age. Combined group prevalence of any OM was 43, 57, 82, 87, and 89% at 1, 2, 4, 6, and 7 months of age, respectively. Of 388 infants with ear assessments at 4, 6 and 7 months, 277 (71.4%) had OM that met criteria for specialist referral; rAOM, pOME, or CSOM. Conclusions Despite superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months, there were no significant differences in prevalence of otitis media nor healthy ears throughout the first months of life. Trial registration ACTRN12610000544077 registered 06/07/2010 and ClinicalTrials.govNCT01174849 registered 04/08/2010.

scholarly journals Tolerogenic nanoparticles mitigate the formation of anti-drug antibodies against pegylated uricase in patients with hyperuricemia

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Earl Sands ◽  
Alan Kivitz ◽  
Wesley DeHaan ◽  
Sheldon S. Leung ◽  
Lloyd Johnston ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Standard Of Care ◽  
Secondary Endpoint ◽  
Dependent Manner ◽  
Open Label ◽  
Biologic Drugs ◽  
Double Blind ◽  
Open Label Study ◽  
Phase 1B ◽  
Dose Dependent

AbstractBiologic drugs have transformed the standard of care for many diseases. However, many biologics induce the formation of anti-drug antibodies (ADAs), which can compromise their safety and efficacy. Preclinical studies demonstrate that biodegradable nanoparticles-encapsulating rapamycin (ImmTOR), but not free rapamycin, mitigate the immunogenicity of co-administered biologic drugs. Here we report the outcomes from two clinical trials for ImmTOR. In the first ascending dose, open-label study (NCT02464605), pegadricase, an immunogenic, pegylated uricase enzyme derived from Candida utilis, is assessed for safety and tolerability (primary endpoint) as well as activity and immunogenicity (secondary endpoint); in the second single ascending dose Phase 1b trial (NCT02648269) composed of both a double-blind and open-label parts, we evaluate the safety of ImmTOR (primary endpoint) and its ability to prevent the formation of anti-drug antibodies against pegadricase and enhance its pharmacodynamic activity (secondary endpoint) in patients with hyperuricemia. The combination of ImmTOR and pegadricase is well tolerated. ImmTOR inhibits the development of uricase-specific ADAs in a dose-dependent manner, thus enabling sustained enzyme activity and reduction in serum uric acid levels. ImmTOR may thus represent a feasible approach for preventing the formation of ADAs to a broad range of immunogenic biologic therapies.

scholarly journals D-galactose supplementation in individuals with PMM2-CDG: results of a multicenter, open label, prospective pilot clinical trial

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Peter Witters ◽  
Hans Andersson ◽  
Jaak Jaeken ◽  
Laura Tseng ◽  
Clara D. M. van Karnebeek ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Pilot Trial ◽  
Congenital Disorder ◽  
Trial Registration ◽  
Symptomatic Therapy ◽  
Supportive Treatment ◽  
Open Label ◽  
Congenital Disorder Of Glycosylation ◽  
Link Type ◽  
Clinical Changes

AbstractPMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) with only symptomatic therapy. Some CDG have been successfully treated with D-galactose. We performed an open-label pilot trial with D-galactose in 9 PMM2-CDG patients. Overall, there was no significant improvement but some milder patients did show positive clinical changes; also there was a trend toward improved glycosylation. Larger placebo-controlled studies are required to determine whether D-galactose could be used as supportive treatment in PMM2-CDG patients.Trial registration ClinicalTrials.gov Identifier: NCT02955264. Registered 4 November 2016, https://clinicaltrials.gov/ct2/show/NCT02955264

scholarly journals Anakinra To Prevent Respiratory Failure In COVID-19

2020 ◽  
Author(s):  
Evdoxia Kyriazopoulou ◽  
Periklis Panagopoulos ◽  
Simeon Metallidis ◽  
George N. Dalekos ◽  
Garyfallia Poulakou ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Sofa Score ◽  
Early Recognition ◽  
Prospective Trial ◽  
Standard Of Care ◽  
Hazard Ratio ◽  
Open Label ◽  
Urokinase Plasminogen Activator Receptor ◽  
Link Type ◽  
Anakinra Treatment

ABSTRACTIntroductionThe management of pneumonia caused by SARS-CoV-2 should rely on early recognition of the risk for progression to severe respiratory failure (SRF) and its prevention. We investigated if early suPAR (soluble urokinase plasminogen activator receptor)-guided anakinra treatment could prevent COVID-19-assocated SRF.MethodsIn this open-label prospective trial, 130 patients admitted with SARS-CoV-2 pneumonia SARS-CoV-2 and suPAR levels ≥6 μg/l were assigned to subcutaneous anakinra 100mg once daily for 10 days. The primary outcome was the incidence of SRF at day 14. Secondary outcomes were 30-day mortality, changes in sequential organ failure assessment (SOFA) score, of cytokine-stimulation pattern and of circulating inflammatory mediators. Equal number of propensity score-matched comparators for comorbidities, severity on admission and standard-of care (SOC) were studied.ResultsThe incidence of SRF was 22.3% (95% CI, 16.0-30.2%) among anakinra-treated patients and 59.2% (95% CI, 50.6-67.3%; P: 4.6 x 10−8) among SOC comparators (hazard ratio, 0.30; 95%CI, 0.20-0.46). 30-day mortality was 11.5% (95% CI, 7.1-18.2%) and 22.3% (95% CI, 16.0-30.2%) respectively (hazard ratio 0.49; 95% CI 0.25-0.97%; P: 0.041). Anakinra treatment was associated with decrease in SOFA score and in circulating interleukin (IL)-6, sCD163 and sIL2-R; the serum IL-10/IL-6 ratio on day 7 was inversely associated with the change in SOFA score. Duration of stay at the intensive care unit and at hospital was shortened compared to the SOC group; the cost of hospitalization was decreased.ConclusionsEarly suPAR-guided anakinra treatment is associated with decrease of the risk for SRF and restoration of the pro- /anti-inflammatory balance.Trial RegistrationClinicalTrials.gov, NCT04357366

scholarly journals Community control strategies for scabies: A cluster randomised noninferiority trial

PLoS Medicine ◽  
2021 ◽  
Vol 18 (11) ◽  
pp. e1003849
Author(s):  
Myra Hardy ◽  
Josaia Samuela ◽  
Mike Kama ◽  
Meciusela Tuicakau ◽  
Lucia Romani ◽  
...  
Keyword(s):  
Large Scale ◽  
Control Strategies ◽  
Risk Difference ◽  
Trial Registration ◽  
Community Control ◽  
Open Label ◽  
Middle Income ◽  
Link Type ◽  
Cluster Randomised ◽  
Lower Baseline

Background Scabies is a neglected tropical disease hyperendemic to many low- and middle-income countries. Scabies can be successfully controlled using mass drug administration (MDA) using 2 doses of ivermectin-based treatment. If effective, a strategy of 1-dose ivermectin-based MDA would have substantial advantages for implementing MDA for scabies at large scale. Methods and findings We did a cluster randomised, noninferiority, open-label, 3-group unblinded study comparing the effectiveness of control strategies on community prevalence of scabies at 12 months. All residents from 35 villages on 2 Fijian islands were eligible to participate. Villages were randomised 1:1:1 to 2-dose ivermectin-based MDA (IVM-2), 1-dose ivermectin-based MDA (IVM-1), or screen and treat with topical permethrin 5% for individuals with scabies and their household contacts (SAT). All groups also received diethylcarbamazine and albendazole for lymphatic filariasis control. For IVM-2 and IVM-1, oral ivermectin was dosed at 200 μg/kg and when contraindicated substituted with permethrin. We designated a noninferiority margin of 5%. We enrolled 3,812 participants at baseline (July to November 2017) from the 35 villages with median village size of 108 (range 18 to 298). Age and sex of participants were representative of the population with 51.6% male and median age of 25 years (interquartile range 10 to 47). We enrolled 3,898 at 12 months (July to November 2018). At baseline, scabies prevalence was similar in all groups: IVM-2: 11.7% (95% confidence interval (CI) 8.5 to 16.0); IVM-1: 15.2% (95% CI 9.4 to 23.8); SAT: 13.6% (95% CI 7.9 to 22.4). At 12 months, scabies decreased substantially in all groups: IVM-2: 1.3% (95% CI 0.6 to 2.5); IVM-1: 2.7% (95% CI 1.1 to 6.5); SAT: 1.1% (95% CI 0.6 to 2.0). The risk difference in scabies prevalence at 12 months between the IVM-1 and IVM-2 groups was 1.2% (95% CI −0.2 to 2.7, p = 0.10). Limitations of the study included the method of scabies diagnosis by nonexperts, a lower baseline prevalence than anticipated, and the addition of diethylcarbamazine and albendazole to scabies treatment. Conclusions All 3 strategies substantially reduced prevalence. One-dose was noninferior to 2-dose ivermectin-based MDA, as was a screen and treat approach, for community control of scabies. Further trials comparing these approaches in varied settings are warranted to inform global scabies control strategies. Trial registration Clinitrials.gov NCT03177993 and ANZCTR N12617000738325.

scholarly journals Evaluation of Convalescent Plasma versus Standard of Care for the Treatment of COVID-19 in Hospitalazed Patients: study protocol for a phase 2 randomized, open-label, controlled, multicenter trial

2020 ◽  
Author(s):  
Elena Diago-Sempere ◽  
Jose Luis Bueno ◽  
Aranzazu Sancho-Lopez ◽  
Elena Munez-Rubio ◽  
Ferran Torres ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Respiratory Infections ◽  
Controlled Trial ◽  
Viral Disease ◽  
Adult Patients ◽  
Trial Registration ◽  
Ordinal Scale ◽  
Efficacy And Safety ◽  
Open Label ◽  
Link Type

Background: COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. At the time this clinical trial was planned, there were no available vaccine or therapeutic agents with proven efficacy, but the severity of the condition prompted the use of several pharmacological and non-pharmacological interventions. It has long been hypothesized that the use of convalescent plasma (CP) from infected patients who have developed an effective immune response is likely to be an option for the treatment of patients with a variety of severe acute respiratory infections (SARI) of viral etiology. The aim of this study is to assess the efficacy and safety of convalescent plasma in adult patients with severe COVID-19 pneumonia. Methods/Design: The ConPlas-19 study is a multicenter, randomized, open-label controlled trial. The protocol has been prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. The study has been planned to include 278 adult patients hospitalized with severe COVID-19 infection not requiring mechanical ventilation (invasive or non-invasive). Subjects are randomly assigned in a 1:1 ratio (139 per treatment arm), stratified by center, to receive intravenously administered CP (single infusion) plus SOC or SOC alone, and are to be followed for 30 days. The primary endpoint of the study is the proportion of patients that progress to categories 5, 6 or 7 (on the 7-point ordinal scale proposed by the WHO) at day 15. Interim analyses for efficacy and/or futility will be conducted once 20%, 40%, and 60% of the planned sample size are enrolled and complete D15 assessment. Discussion: This clinical trial is designed to evaluate the efficacy and safety of passive immunotherapy with convalescent plasma for the treatment of adult patients hospitalized with COVID-19. The results of this study are expected to contribute to establishing the potential place of CP in the therapeutics for a new viral disease. Trial registration: Trial registration at clinicaltrials.gov; Registration Number: NCT04345523; https://clinicaltrials.gov/ct2/show/NCT04345523; Registered on 30 March, 2020. First posted date: April 14, 2020. Keywords: COVID-19, randomized, controlled trial, protocol, convalescent plasma (CP), antibodies.

scholarly journals Early Anakinra Treatment for COVID-19 Guided by Urokinase Plasminogen Receptor

2021 ◽  
Author(s):  
Evdoxia Kyriazopoulou ◽  
Garyfallia Poulakou ◽  
Haralampos Milionis ◽  
Simeon Metallidis ◽  
Georgios Adamis ◽  
...  
Keyword(s):  
Sofa Score ◽  
Clinical Performance ◽  
Severe Disease ◽  
Clinical Status ◽  
Multicenter Trial ◽  
World Health ◽  
Open Label ◽  
Urokinase Plasminogen Activator Receptor ◽  
Absolute Decrease ◽  
Anakinra Treatment

Background In a previous open-label trial, early anakinra treatment guided by elevated soluble urokinase plasminogen activator receptor (suPAR) prevented progression of COVID-19 pneumonia into respiratory failure. Methods In the SAVE-MORE multicenter trial, 594 hospitalized patients with moderate and severe COVID-19 pneumonia and plasma suPAR 6 ng/ml or more and receiving standard-of-care were 1:2 randomized to subcutaneous treatment with placebo or 100 mg anakinra once daily for 10 days. The primary endpoint was the overall clinical status of the 11-point World Health Organization ordinal Clinical Performance Scale (WHO-CPS) at day 28. The changes of the WHO-CPS and of the sequential organ failure assessment (SOFA) score were the main secondary endpoints. Results Anakinra-treated patients were distributed to lower strata of WHO-CPS by day 28 (adjusted odds ratio-OR 0.36; 95%CI 0.26-0.50; P<0.001); anakinra protected from severe disease or death (6 or more points of WHO-CPS) (OR: 0.46; P: 0.01). The median absolute decrease of WHO-CPS in the placebo and anakinra groups from baseline was 3 and 4 points respectively at day 28 (OR 0.40; P<0.0001); and 2 and 3 points at day 14 (OR 0.63; P: 0.003); the absolute decrease of SOFA score was 0 and 1 points (OR 0.63; P: 0.004). 28-day mortality decreased (Hazard ratio: 0.45; P: 0.045). Hospital stay was shorter. Conclusions Early start of anakinra treatment guided by suPAR provides 2.78 times better improvement of overall clinical status in moderate and severe COVID-19 pneumonia. (Sponsored by the Hellenic Institute for the Study of Sepsis ClinicalTrials.gov identifier, NCT04680949)

scholarly journals Single-arm, open-label, multicentre first in human study to evaluate the safety and performance of dural sealant patch in reducing CSF leakage following elective cranial surgery: the ENCASE trial

BMJ Open ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. e049098
Author(s):  
Tristan Van Doormaal ◽  
Menno R Germans ◽  
Mariska Sie ◽  
Bart Brouwers ◽  
Andrew Carlson ◽  
...  
Keyword(s):  
Adverse Events ◽  
Primary Endpoint ◽  
User Satisfaction ◽  
Neurosurgical Procedures ◽  
Open Label ◽  
Cranial Surgery ◽  
Dural Closure ◽  
Handling Characteristics ◽  
Csf Leakage ◽  
And Performance

ObjectiveThe dural sealant patch (DSP) is designed for watertight dural closure after cranial surgery. The goal of this study is to assess, for the first time, safety and performance of the DSP as a means of reducing cerebrospinal fluid (CSF) leakage in patients undergoing elective cranial intradural surgery with a dural closure procedure.DesignFirst in human, open-label, single-arm, multicentre study with 360-day (12 months) follow-up.SettingThree large tertiary reference neurosurgical centres, two in the Netherlands and one in Switzerland.ParticipantsForty patients undergoing elective cranial neurosurgical procedures, stratified into 34 supratentorial and six infratentorial trepanations.InterventionEach patient received one DSP after cranial surgery and closure of the dura mater with sutures.Outcome measuresPrimary composite endpoint was occurrence of one of the following events: postoperative percutaneous CSF leakage, intraoperative leakage at 20 cm H2O positive end-expiratory pressure or postoperative wound infection. Overall success was defined as achieving the primary endpoint in no more than two patients. Secondary endpoints were device-related serious adverse events or adverse events (AEs), pseudomeningocele and thickness of dura+DSP. Additional endpoints were reoperation in 30 days and user satisfaction.ResultsNo patients met the primary endpoint. No device-related (serious) AEs were observed. There were two incidences of self-limiting pseudomeningocele as confirmed on MRI. Thickness of dura and DSP were (mean±SD) 3.5 mm±2.0 at day 7 and 2.1 mm±1.2 at day 90. No patients were reoperated within 30 days. Users reported a satisfactory design and intuitive application.ConclusionsDSP, later officially named Liqoseal, is a safe and potentially efficacious device for reducing CSF leakage after intracranial surgery, with favourable clinical handling characteristics. A randomised controlled trial is needed to assess Liqoseal efficacy against the best current practice for reducing postoperative CSF leakage.Trial registration numberNCT03566602.

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