scholarly journals Optimization of sepsis therapy based on patient-specific digital precision diagnostics using next generation sequencing (DigiSep-Trial)—study protocol for a randomized, controlled, interventional, open-label, multicenter trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Thorsten Brenner ◽  
Annabell Skarabis ◽  
Philip Stevens ◽  
Jennifer Axnick ◽  
Peter Haug ◽  
...  
Keyword(s):  
Unit Length ◽  
Bloodstream Infections ◽  
Standard Of Care ◽  
Multicenter Trial ◽  
Intermediate Care ◽  
Open Label ◽  
Randomized Controlled ◽  
Link Type ◽  
Microbiological Analyses ◽  
Generation Sequencing

Abstract Background Sepsis is triggered by an infection and represents one of the greatest challenges of modern intensive care medicine. With regard to a targeted antimicrobial treatment strategy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the diagnostic gold standard, although they are characterized by numerous limitations. Culture-independent molecular diagnostic procedures represent a promising alternative. In particular, the plasmatic detection of circulating, cell-free DNA by next-generation sequencing (NGS) has shown to be suitable for identifying disease-causing pathogens in patients with bloodstream infections. Methods The DigiSep-Trial is a randomized, controlled, interventional, open-label, multicenter trial characterizing the effect of the combination of NGS-based digital precision diagnostics with standard-of-care microbiological analyses compared to solely standard-of-care microbiological analyses in the clinical picture of sepsis/septic shock. Additional anti-infective expert consultations are provided for both study groups. In 410 patients (n = 205 per arm) with sepsis/septic shock, the study examines whether the so-called DOOR-RADAR (Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk) score (representing a combined endpoint including the criteria (1) intensive/intermediate care unit length of stay, (2) consumption of antibiotics, (3) mortality, and (4) acute kidney injury (AKI)) can be improved by an additional NGS-based diagnostic concept. We also aim to investigate the cost-effectiveness of this new diagnostic procedure. It is postulated that intensive/intermediate care unit length of stay, mortality rate, incidence of AKI, the duration of antimicrobial therapy as well as the costs caused by complications and outpatient aftercare can be reduced. Moreover, a significant improvement in patient’s quality of life is expected. Discussion The authors´ previous work suggests that NGS-based diagnostics have a higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. In combination with the here presented DigiSep-Trial, this work provides the optimal basis to establish a new NGS-driven concept as part of the national standard based on the best possible evidence. Trial registrations DRKS-ID DRKS00022782. Registered on August 25, 2020 ClinicalTrials.govNCT04571801. Registered October 1, 2020

scholarly journals Unfractionated heparin in acute chest syndrome: a pilot feasibility randomized controlled trial of unfractionated heparin vs. standard of care in acute chest syndrome

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Craig D. Seaman ◽  
Enrico Novelli ◽  
Laura De Castro ◽  
Margaret V. Ragni
Keyword(s):  
Unfractionated Heparin ◽  
Large Scale ◽  
Controlled Trial ◽  
Standard Of Care ◽  
Phase Iii ◽  
Therapeutic Modality ◽  
Red Blood Cell Transfusion ◽  
Acute Chest Syndrome ◽  
Open Label ◽  
Randomized Controlled

Abstract Background Acute chest syndrome (ACS) is the leading cause of mortality in sickle cell disease (SCD). The pathogenesis of ACS is complex and not entirely understood with multiple etiologies likely contributing simultaneously. One particular etiology is pulmonary vascular occlusion due to thrombosis. Thus, anticoagulation is an attractive therapeutic modality. Methods This was a single-center, randomized controlled, open-label, pilot study to determine the feasibility of performing a larger multicenter phase III trial to assess the effects of unfractionated heparin (UFH) in ACS. Subjects were randomized within 24 h of diagnosis of ACS to one of two treatment arms, UFH, and standard of care (SOC), or no UFH and SOC. UFH was given intravenously for 7 days, or until discharge, if discharge was shorter than 7 days. SOC consisted of intravenous fluids, antibiotics, supplemental oxygen, analgesia, red blood cell transfusion, and exchange transfusion. Results From July 2014 to June 2018, a total of 7 patients underwent randomization (four patients received UFH in addition to SOC and 3 patients received SOC only). Two of the prespecified feasibility criteria were not met: the capacity to consent eligible individuals and the timely notification of hospitalized patients with ACS necessary to permit randomization within 24 h of diagnosis; thus, as a result of poor enrollment, the study was terminated early. The duration of hospitalization was 279.43 (SD 267.98) and 127.31 (SD 137.70) h in the UFH and SOC arms, respectively. The duration of hypoxemia, leukocytosis, fever, and moderate to severe pain was 117.52 (SD 60.52), 24.90 (SD 29.69), 117.52 (SD 60.52), and 117.52 (SD 60.52) h, respectively, in the UFH group, and 51.49 (SD 44.79), 0, 53.11 (SD 25.06), and 88.68 (SD 72.77) h, respectively, in the SOC group. No major bleeding was noted in either group. Conclusions Our study did not achieve prespecified feasibility criteria, resulting in poor enrollment and early termination, and serves to highlight some of the pitfalls experienced in clinical research in SCD. It did show the use of UFH without any major adverse events in 7 subjects. No future large-scale study is planned. Trials registration Registered at ClinicalTrials.gov (NCT #02098993) on March 28, 2014.

scholarly journals Convalescent plasma for hospitalized patients with COVID-19 and the effect of plasma antibodies: a randomized controlled, open-label trial

2021 ◽  
Author(s):  
Philippe Bégin ◽  
Jeannie Callum ◽  
Erin Jamulae Jamula ◽  
Richard Cook ◽  
Nancy M Heddle ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Controlled Trial ◽  
Harmful Effect ◽  
Standard Of Care ◽  
Hospitalized Patients ◽  
Open Label ◽  
Serious Adverse Events ◽  
Randomized Controlled ◽  
Negative Results ◽  
Intent To Treat

The efficacy of convalescent plasma for COVID-19 is unclear. While most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content may influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 days of respiratory symptom onset. Patients were allocated 2:1 to 500 mL of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 days. The effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. 940 patients were randomized and 921 patients were included in the intent-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) in the convalescent plasma arm and 86/307 (28.0%) in the standard of care arm; relative risk (RR) 1.16 (95% confidence interval (CI) 0.94-1.43; p=0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% vs. 26.4%; RR=1.27, 95% CI 1.02-1.57, p=0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standard log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (OR=0.74; 0.57-0.95 and OR=0.66; 0.50-0.87, respectively), while IgG against the full transmembrane Spike protein increased it (OR=1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 days among hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavourable antibody profiles may be associated with worse clinical outcomes compared to standard care.

scholarly journals Pharmacist-guided pre-emptive pharmacogenetic testing in antidepressant therapy (PrePGx): study protocol for an open-label, randomized controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Céline K. Stäuble ◽  
Markus L. Lampert ◽  
Samuel Allemann ◽  
Martin Hatzinger ◽  
Kurt E. Hersberger ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Antidepressant Treatment ◽  
Controlled Trial ◽  
Response Rates ◽  
Control Group ◽  
Open Label ◽  
Randomized Controlled ◽  
Link Type ◽  
Increased Risk ◽  
Antidepressant Pharmacotherapy

Abstract Background It is known that only 50% of patients diagnosed with major depressive disorders (MDD) respond to the first-line antidepressant treatment. Accordingly, there is a need to improve response rates to reduce healthcare costs and patient suffering. One approach to increase rates of treatment response might be the integration of pharmacogenetic (PGx) testing to stratify antidepressant drug selection. The goal of PGx assessments is to identify patients who have an increased risk to experience adverse drug reactions or non-response to specific drugs. Especially for antidepressants, there is compiling evidence on PGx influencing drug exposure as well as response. Methods This study is an open-label, randomized controlled trial conducted in two study centers in Switzerland: (1) the Psychiatric Clinic of Solothurn and (2) the Private Clinic Wyss in Münchenbuchsee. Adult inpatients diagnosed with a unipolar moderate or severe depressive episode are recruited at clinic admission and are included in the study. If the adjustment to a new antidepressant pharmacotherapy is necessary, the participants are randomized to either Arm A (intervention group) or Arm B (control group). If no new antidepressant pharmacotherapy is introduced the participants will be followed up in an observational arm. The intervention is the service of pharmacist-guided pre-emptive PGx testing to support clinical decision making on antidepressant selection and dosing. As a comparison, in the control group, the antidepressant pharmacotherapy is selected by the treating physician according to current treatment guidelines (standard of care) without the knowledge of PGx test results and support of clinical pharmacists. The primary outcome of this study compares the response rates under antidepressant treatment after 4 weeks between intervention and control arm. Discussion The findings from this clinical trial are expected to have a direct impact on inter-professional collaborations for the handling and use of PGx data in psychiatric practice. Trial registration ClinicalTrials.govNCT04507555. Registered on August 11, 2020. Swiss National Clinical Trials Portal SNCTP000004015. Registered August 18, 2020.

scholarly journals Convalescence plasma treatment of COVID-19: results from a prematurely terminated randomized controlled open-label study in Southern Sweden

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Karin Holm ◽  
Maria N. Lundgren ◽  
Jens Kjeldsen-Kragh ◽  
Oskar Ljungquist ◽  
Blenda Böttiger ◽  
...  
Keyword(s):  
Plasma Treatment ◽  
Viral Infections ◽  
Standard Of Care ◽  
Hospitalized Patients ◽  
Care Group ◽  
Open Label ◽  
Randomized Controlled ◽  
Oxygen Treatment ◽  
Randomized Controlled Studies ◽  
To Receive

Abstract Objective Convalescent plasma has been tried as therapy for various viral infections. Early observational studies of convalescent plasma treatment for hospitalized COVID-19 patients were promising, but randomized controlled studies were lacking at the time. The objective of this study was to investigate if convalescent plasma is beneficial to hospitalized patients with COVID-19. Results Hospitalized patients with confirmed COVID-19 and an oxygen saturation below 94% were randomized 1:1 to receive convalescent plasma in addition to standard of care or standard of care only. The primary outcome was number of days of oxygen treatment to keep saturation above 93% within 28 days from inclusion. The study was prematurely terminated when thirty-one of 100 intended patients had been included. The median time of oxygen treatment among survivors was 11 days (IQR 6–15) for the convalescent plasma group and 7 days (IQR 5–9) for the standard of care group (p = 0.4, median difference -4). Two patients in the convalescent plasma group and three patients in the standard of care group died (p = 0.64, OR 0.49, 95% CI 0.08–2.79). Thus no significant differences were observed between the groups. Trial registration ClinicalTrials NCT04600440, retrospectively registered Oct 23, 2020.

scholarly journals Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1797 ◽  
Author(s):  
Asgeir Store Jakola ◽  
Katja Werlenius ◽  
Munila Mudaisi ◽  
Sofia Hylin ◽  
Sara Kinhult ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Anticancer Agent ◽  
Controlled Trial ◽  
Progression Free Survival ◽  
Preliminary Evidence ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Randomized Controlled ◽  
Link Type ◽  
Methylguanine Methyltransferase

Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.

scholarly journals Prospective, Randomized, Parallel-Group, Open-Label Study to Evaluate the Efficacy and Safety of IMU-838, in Combination with Oseltamivir, in Adults with Coronavirus Disease 19 The IONIC Trial

2021 ◽  
Author(s):  
Kavi Sharma ◽  
Dr Lisa Berry ◽  
Dr Evangelos Vryonis ◽  
Dr Asad Ali ◽  
Dr Beatriz Lara ◽  
...  
Keyword(s):  
Clinical Improvement ◽  
Trial Design ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Therapeutic Effects ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Link Type ◽  
Discharge From Hospital

Background: Globally there is a scarcity of effective treatments for SARS-CoV-2 infections (causing COVID 19). Repurposing existing medications may offer the best hope for treating COVID 19 patients to curb the pandemic. IMU-838 is a dihydroorotate dehydrogenase (DHODH) inhibitor, which is an effective mechanism for antiviral effects against respiratory viruses. When used synergistically with Oseltamivir, therapeutic effects have been observed against influenza and SARS-CoV-2 in rodents.(13) The IONIC trial is a randomized control trial that will investigate whether time to clinical improvement in COVID 19 patients is improved following a 14 day course of IMU-838 + Oseltamivir versus Oseltamivir alone. Methods: IONIC trial is an open label study in which participants will be randomised 1:1 in two parallel arms; the intervention arm (IMU-838 + Oseltamivir) and control arm (Oseltamivir only). The primary outcome is time-to-clinical improvement; defined as the time from randomisation to: a 2-point improvement on WHO ordinal scale; discharge from hospital, or death (whichever occurs first). The study is sponsored by UHCW NHS Trust and funded by LifeArc. Discussion: The IONIC Protocol describes an overarching trial design to provide reliable evidence on the efficacy of IMU-838 (vidofludimus calcium) when delivered in combination with an antiviral therapy (Oseltamivir) [IONIC Intervention] for confirmed or suspected COVID-19 infection in adult patients receiving usual standard of care. Trial Registration: The trial was registered with EudraCT (2020-001805-21) on 09.04.2020 and ISRCTN on 23.09.2020 (ISRCTN53038326) and Clinicaltrials.gov on 17.08.2020 (NCT04516915) Strengths and Limitations: This study is the first to recruit participants in the trial exploring the effectiveness of IMU-838 in COVID-19. In addition, we believe it is the only trial exploring the effectiveness of IMU-838 in combination with Oseltamivir (Tamiflu) in patients with moderate to severe COVID-19. However, to make the trial design flexible due to the on-going pandemic the trial is un-blinded.

scholarly journals Evaluation of two family-based intervention programs for children affected by rare disease and their families – research network (CARE-FAM-NET): study protocol for a rater-blinded, randomized, controlled, multicenter trial in a 2x2 factorial design

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Johannes Boettcher ◽  
Bonnie Filter ◽  
Jonas Denecke ◽  
Amra Hot ◽  
Anne Daubmann ◽  
...  
Keyword(s):  
Rare Disease ◽  
Rare Diseases ◽  
Health Economic Evaluation ◽  
Multicenter Trial ◽  
Intervention Programs ◽  
Research Network ◽  
Treatment As Usual ◽  
Randomized Controlled ◽  
Link Type ◽  
Family Based

Abstract Background Families of children with rare diseases (i.e., not more than 5 out of 10,000 people are affected) are often highly burdened with fears, insecurities and concerns regarding the affected child and its siblings. Although families caring for children with rare diseases are known to be at risk for mental disorders, the evaluation of special programs under high methodological standards has not been conducted so far. Moreover, the implementation of interventions for this group into regular care has not yet been accomplished in Germany. The efficacy and cost-effectiveness of a family-based intervention will be assessed. Methods/design The study is a 2x2 factorial randomized controlled multicenter trial conducted at 17 study centers throughout Germany. Participants are families with children and adolescents affected by a rare disease aged 0 to 21 years. Families in the face-to-face intervention CARE-FAM, online intervention WEP-CARE or the combination of both will be treated over a period of roughly 6 months. Topics discussed in the interventions include coping, family relations, and social support. Families in the control condition will receive treatment as usual. The primary efficacy outcome is parental mental health, measured by the Structured Clinical Interview for DSM-IV (SCID-I) by blinded external raters. Further outcomes will be assessed from the parents’ as well as the children’s perspective. Participants are investigated at baseline, 6, 12 and 18 months after randomization. In addition to the assessment of various psychosocial outcomes, a comprehensive health-economic evaluation will be performed. Discussion This paper describes the implementation and evaluation of two family-based intervention programs for Children Affected by Rare Disease and their Family’s Network (CARE-FAM-NET) in German standard care. A methodologically challenging study design is used to reflect the complexity of the actual medical care situation. This trial could be an important contribution to the improvement of care for this highly burdened group. Trial registration German Clinical Trials Register: DRKS00015859 (registered 18 December 2018) and ClinicalTrials.gov: NCT04339465 (registered 8 April 2020). Protocol Version: 15 August 2020 (Version 6.1). Trial status: Recruitment started on 1 January 2019 and will be completed on 31 March 2021.

scholarly journals Chlorhexidine-impregnated sponge versus chlorhexidine gel dressing for short-term intravascular catheters: which one is better?

Critical Care ◽  
2020 ◽  
Vol 24 (1) ◽  
Author(s):  
Niccolò Buetti ◽  
Stéphane Ruckly ◽  
Carole Schwebel ◽  
Olivier Mimoz ◽  
Bertrand Souweine ◽  
...  
Keyword(s):  
Contact Dermatitis ◽  
Bloodstream Infections ◽  
Short Term ◽  
Cox Models ◽  
Randomized Controlled ◽  
Link Type ◽  
Skin Disinfection ◽  
Skin Antisepsis ◽  
Intravascular Catheters ◽  
Similar Risk

Abstract Background Chlorhexidine-gluconate (CHG) impregnated dressings may prevent catheter-related bloodstream infections (CRBSI). Chlorhexidine-impregnated sponge dressings (sponge-dress) and gel dressings (gel-dress) have never been directly compared. We used the data collected for two randomized-controlled trials to perform a comparison between sponge-dress and gel-dress. Methods Adult critically ill patients who required short-term central venous or arterial catheter insertion were recruited. Our main analysis included only patients with CHG-impregnated dressings. The effect of gel-dress (versus sponge-dress) on major catheter-related infections (MCRI) and CRBSI was estimated using multivariate marginal Cox models. The comparative risks of dressing disruption and contact dermatitis were evaluated using logistic mix models for clustered data. An explanatory analysis compared gel-dress with standard dressings using either CHG skin disinfection or povidone iodine skin disinfection. Results A total of 3483 patients and 7941 catheters were observed in 16 intensive care units. Sponge-dress and gel-dress were utilized for 1953 and 2108 catheters, respectively. After adjustment for confounders, gel-dress showed similar risk for MCRI compared to sponge-dress (HR 0.80, 95% CI 0.28–2.31, p = 0.68) and CRBSI (HR 1.13, 95% CI 0.34–3.70, p = 0.85), less dressing disruptions (OR 0.72, 95% CI 0.60–0.86, p < 0.001), and more contact dermatitis (OR 3.60, 95% CI 2.51–5.15, p < 0.01). However, gel-dress increased the risk of contact dermatitis only if CHG was used for skin antisepsis (OR 1.94, 95% CI 1.38–2.71, p < 0.01). Conclusions We described a similar infection risk for gel-dress and sponge-dress. Gel-dress showed fewer dressing disruptions. Concomitant use of CHG for skin disinfection and CHG-impregnated dressing may significantly increase contact dermatitis. Trials registration These studies were registered within ClinicalTrials.gov (numbers NCT01189682 and NCT00417235).

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Rituximab therapy for Graves’ orbitopathy – lessons from randomized control trials

2017 ◽  
Vol 176 (2) ◽  
pp. R101-R109 ◽  
Author(s):  
Marius N Stan ◽  
Mario Salvi
Keyword(s):  
Multicenter Trial ◽  
Clinical Activity ◽  
Open Label ◽  
Endocrine Disease ◽  
Randomized Controlled ◽  
Duration Of Disease ◽  
Graves Orbitopathy ◽  
Randomized Control ◽  
Post Hoc

Rituximab (RTX) use in open-label series has been associated with very encouraging responses in patients with active and moderate-to-severe Graves’ orbitopathy (GO). Recently, randomized controlled trials of RTX have been performed in such patients to answer the question of clinical efficacy and the safety profile of this agent. That data, reported separately, focused on Clinical Activity Score (CAS) and indicated in one trial a strong benefit of RTX in comparison with IV glucocorticoids, whereas the other trial noted the absence of a benefit by comparison with placebo. The outcome was reanalyzed post hoc here, using EUGOGO criteria, and the results were not significantly different. The authors comment further on the differences between the two trials regarding populations treated, methodology, analysis of outcomes and the adverse effect profile of RTX. The populations treated appear different with younger patients, lower TRAb and shorter duration of disease prevalent in the Italian trial, all elements favoring a better response. Smoking, usually diminishing a response, was also more prevalent in some patients. The combined outcome proposed by EUGOGO revealed similar results with CAS regarding RTX efficacy; yet, it might be a more comprehensive outcome. The adverse events of concern relate mainly to the risk of DON, which seems to be increased by the use of RTX in a certain subset of patients. Based on available data, a multicenter trial using the EUGOGO-proposed outcomes might be the next best step to define the role of RTX in GO therapy.

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