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Trials Aug 2023Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD),...
BACKGROUND
Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults.
METHODS
STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant's randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE.
DISCUSSION
Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children.
TRIAL REGISTRATION
The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354).
Topics: Adolescent; Young Adult; Humans; Child; Analgesics, Opioid; Saline Solution; Anemia, Sickle Cell; Academies and Institutes; Arginine; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase III as Topic
PubMed: 37587492
DOI: 10.1186/s13063-023-07538-z -
Journal of Cachexia, Sarcopenia and... Jun 2024Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate... (Review)
Review
Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety-nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C-reactive protein (n = 22, 42.3%), interleukin-6 (n = 16, 30.8%) and tumour necrosis factor-α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.
Topics: Cachexia; Humans; Neoplasms; Biomarkers; Clinical Trials as Topic
PubMed: 38783477
DOI: 10.1002/jcsm.13491 -
BMJ Open Aug 2023In locally recurrent rectal cancer (LRRC), surgery is a standard treatment for resectable disease. However, short-term and long-term outcomes are unsatisfactory due to...
Utility of circulating tumour DNA for prognosis and prediction of therapeutic effect in locally recurrent rectal cancer: study protocol for a multi-institutional, prospective observational study (JCOG1801A1, CAP-LR study).
INTRODUCTION
In locally recurrent rectal cancer (LRRC), surgery is a standard treatment for resectable disease. However, short-term and long-term outcomes are unsatisfactory due to the invasive nature of surgical procedures and the high proportion of local recurrence. Consequently, the identification of reliable prognostic and predictive biomarkers to guide treatment decisions may improve outcomes. The presence of circulating tumour DNA (ctDNA) in plasma after surgery may signify the presence of minimal residual disease (MRD) in various cancers. Therefore, we have launched a multi-institutional prospective observational study of ctDNA for MRD detection in conjunction with JCOG1801, a randomised, controlled phase III trial evaluating the efficacy of preoperative chemoradiotherapy (pre-CRT) compared with up-front surgery for LRRC (jRCTs031190076, NCT04288999).
METHODS AND ANALYSIS
JCOG1801A1 is the first correlative study that assesses ctDNA in LRRC patients enrolled in JCOG1801. Patients randomised to up-front surgery will provide whole blood samples at three time points (prior to surgery, after surgery and after postoperative chemotherapy); those to pre-CRT will provide at five time points (prior to pre-CRT, after pre-CRT, prior to surgery, after surgery and after postoperative chemotherapy). Cell-free DNA will be extracted from plasma and analysed by Guardant Reveal, a tumour tissue-agnostic assay that assesses both genomic alterations and methylation patterns to determine the presence or absence of ctDNA. We will compare the prognosis and treatment response of patients according to their ctDNA status after surgery and at other time points.
ETHICS AND DISSEMINATION
The study protocol received approval from the Institutional Review Board of National Cancer Center Hospital East on behalf of the participating institutions in February 2023. The study is conducted in accordance with the precepts established in the Declaration of Helsinki and Ethical Guidelines for Medical and Biological Research Involving Human Subjects. Written informed consent will be obtained from all eligible patients prior to registration.
Topics: Humans; Circulating Tumor DNA; Rectal Neoplasms; Prognosis; Health Facilities; Cell-Free Nucleic Acids; Randomized Controlled Trials as Topic; Clinical Trials, Phase III as Topic; Observational Studies as Topic; Multicenter Studies as Topic
PubMed: 37586869
DOI: 10.1136/bmjopen-2023-073217 -
Orphanet Journal of Rare Diseases Sep 2023When assessing the efficacy of a treatment in any clinical trial, it is recommended by the International Conference on Harmonisation to select a single meaningful...
BACKGROUND
When assessing the efficacy of a treatment in any clinical trial, it is recommended by the International Conference on Harmonisation to select a single meaningful endpoint. However, a single endpoint is often not sufficient to reflect the full clinical benefit of a treatment in multifaceted diseases, which is often the case in rare diseases. Therefore, the use of a combination of several clinically meaningful outcomes is preferred. Many methodologies that allow for combining outcomes in a so-called composite endpoint are however limited in a number of ways, not in the least in the number and type of outcomes that can be combined and in the poor small-sample properties. Moreover, patient reported outcomes, such as quality of life, often cannot be integrated in a composite analysis, in spite of their intrinsic value.
RESULTS
Recently, a class of non-parametric generalized pairwise comparisons tests have been proposed, which members do allow for any number and type of outcomes, including patient reported outcomes. The class enjoys good small-sample properties. Moreover, this very flexible class of methods allows for prioritizing the outcomes by clinical severity, allows for matched designs and for adding a threshold of clinical relevance. Our aim is to introduce the generalized pairwise comparison ideas and concepts for rare disease clinical trial analysis, and demonstrate their benefit in a post-hoc analysis of a small-sample trial in epidermolysis bullosa. More precisely, we will include a patient relevant outcome (Quality of life), in a composite endpoint. This publication is part of the European Joint Programme on Rare Diseases (EJP RD) series on innovative methodologies for rare diseases clinical trials, which is based on the webinars presented within the educational activity of EJP RD. This publication covers the webinar topic on composite endpoints in rare diseases and includes participants' response to a questionnaire on this topic.
CONCLUSIONS
Generalized pairwise comparisons is a promising statistical methodology for evaluating any type of composite endpoints in rare disease trials and may allow a better evaluation of therapy efficacy including patients reported outcomes in addition to outcomes related to the diseases signs and symptoms.
Topics: Humans; Clinical Relevance; Patient Reported Outcome Measures; Quality of Life; Rare Diseases; Clinical Trials as Topic
PubMed: 37658423
DOI: 10.1186/s13023-023-02819-x -
Trials Nov 2023Peritoneal dialysis (PD)-related infections, such as peritonitis, exit site, and tunnel infections, substantially impair the sustainability of PD. Accordingly,...
Multi-center, pragmatic, cluster-randomized, controlled trial of standardized peritoneal dialysis (PD) training versus usual care on PD-related infections (the TEACH-PD trial): trial protocol.
BACKGROUND
Peritoneal dialysis (PD)-related infections, such as peritonitis, exit site, and tunnel infections, substantially impair the sustainability of PD. Accordingly, PD-related infection is the top-priority research outcome for patients and caregivers. While PD nurse trainers teach patients to perform their own PD, PD training curricula are not standardized or informed by an evidentiary base and may offer a potential approach to prevent PD infections. The Targeted Education ApproaCH to improve Peritoneal Dialysis outcomes (TEACH-PD) trial evaluates whether a standardized training curriculum for PD nurse trainers and incident PD patients based on the International Society for Peritoneal Dialysis (ISPD) guidelines reduces PD-related infections compared to usual training practices.
METHODS
The TEACH-PD trial is a registry-based, pragmatic, open-label, multi-center, binational, cluster-randomized controlled trial. TEACH-PD will recruit adults aged 18 years or older who have not previously undergone PD training at 42 PD treatment units (clusters) in Australia and New Zealand (ANZ) between July 2019 and June 2023. Clusters will be randomized 1:1 to standardized TEACH-PD training curriculum or usual training practice. The primary trial outcome is the time to the first occurrence of any PD-related infection (exit site infection, tunnel infection, or peritonitis). The secondary trial outcomes are the individual components of the primary outcome, infection-associated catheter removal, transfer to hemodialysis (greater than 30 days and 180 days), quality of life, hospitalization, all-cause death, a composite of transfer to hemodialysis or all-cause death, and cost-effectiveness. Participants are followed for a minimum of 12 months with a targeted average follow-up period of 2 years. Participant and outcome data are collected from the ANZ Dialysis and Transplant Registry (ANZDATA) and the New Zealand Peritoneal Dialysis (NZPD) Registry. This protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.
DISCUSSION
TEACH-PD is a registry-based, cluster-randomized pragmatic trial that aims to provide high-certainty evidence about whether an ISPD guideline-informed standardized PD training curriculum for PD nurse trainers and adult patients prevents PD-related infections.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03816111. Registered on 24 January 2019.
Topics: Adult; Humans; Curriculum; Multicenter Studies as Topic; Peritoneal Dialysis; Peritonitis; Pragmatic Clinical Trials as Topic; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 37964367
DOI: 10.1186/s13063-023-07715-0 -
Trials Nov 2023Awareness with paralysis (AWP) is memory recall during neuromuscular blockade (NMB) and can cause significant psychological harm. Decades of effort and rigorous trials...
Awareness with paralysis and symptoms of post-traumatic stress disorder among mechanically ventilated emergency department survivors (ED-AWARENESS-2 Trial): study protocol for a pragmatic, multicenter, stepped wedge cluster randomized trial.
BACKGROUND
Awareness with paralysis (AWP) is memory recall during neuromuscular blockade (NMB) and can cause significant psychological harm. Decades of effort and rigorous trials have been conducted to prevent AWP in the operating room, where prevalence is 0.1-0.2%. By contrast, AWP in mechanically ventilated emergency department (ED) patients is common, with estimated prevalence of 3.3-7.4% among survivors given NMB. Longer-acting NMB use is a critical risk for AWP, and we have shown an association between ED rocuronium use and increased AWP prevalence. As NMB are given to more than 90% of ED patients during tracheal intubation, this trial provides a platform to test an intervention aimed at reducing AWP. The overall objective is to test the hypothesis that limiting ED rocuronium exposure will significantly reduce the proportion of patients experiencing AWP.
METHODS
This is a pragmatic, stepped wedge cluster randomized trial conducted in five academic EDs, and will enroll 3090 patients. Per the design, all sites begin in a control phase, under observational conditions. At 6-month intervals, sites sequentially enter a 2-month transition phase, during which we will implement the multifaceted intervention, which will rely on use of nudges and defaults to change clinician decisions regarding ED NMB use. During the intervention phase, succinylcholine will be the default NMB over rocuronium. The primary outcome is AWP, assessed with the modified Brice questionnaire, adjudicated by three independent, blinded experts. The secondary outcome is the proportion of patients developing clinically significant symptoms of post-traumatic stress disorder at 30 and 180 days after hospital discharge. We will also assess for symptoms of depression and anxiety, and health-related quality of life. A generalized linear model, adjusted for time and cluster interactions, will be used to compare AWP in control versus intervention phases, analyzed by intention-to-treat.
DISCUSSION
The ED-AWARENESS-2 Trial will be the first ED-based trial aimed at preventing AWP, a critical threat to patient safety. Results could shape clinical use of NMB in the ED and prevent more than 10,000 annual cases of AWP related to ED care.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT05534243 . Registered 06, September 2022.
Topics: Humans; Emergency Service, Hospital; Multicenter Studies as Topic; Paralysis; Quality of Life; Randomized Controlled Trials as Topic; Respiration, Artificial; Rocuronium; Stress Disorders, Post-Traumatic; Pragmatic Clinical Trials as Topic
PubMed: 38001507
DOI: 10.1186/s13063-023-07764-5 -
Trials Jul 2023Psychotic disorders often develop a chronic course with devastating consequences for individuals, families, and societies. Early intervention programs for people in the...
Enhancing educational and vocational recovery in adolescents and young adults with early psychosis through Supported Employment and Education (SEEearly): study protocol for a multicenter randomized controlled trial.
BACKGROUND
Psychotic disorders often develop a chronic course with devastating consequences for individuals, families, and societies. Early intervention programs for people in the first 5 years after the initial psychotic episode (early psychosis) can significantly improve the outcome and are therefore strongly recommended in national and international guidelines. However, most early intervention programs still focus on improving symptoms and relapse prevention, rather than targeting educational and vocational recovery. The aim of the present study is to explore the effects of Supported Employment and Education (SEE) following the Individual Placement and Support (IPS) model in people with early psychosis.
METHODS
The SEEearly trial compares treatment as usual (TAU) plus SEE to TAU alone in outpatient psychiatric settings. The study is a six-site, two-arm, single-blinded, superiority randomized controlled trial (RCT). Participants are randomly assigned (1:1) to the intervention or control group. Aiming to recruit 184 participants, with an assumed drop-out rate of 22%, we will be able to detect a 24% difference in the main outcome of employment/education with 90% power. We make assessments at baseline and at 6- and 12-month follow-ups. Outcome data on employment/education, medication, and current psychiatric treatment is obtained monthly through phone based short assessments. The primary outcome is steady participation for at least 50% of the 12-month follow-up in competitive employment and/or mainstream education. Secondary employment outcomes capture length of employment/education, time to first employment/education, monthly wages/educational attainment, and social return on investment (SROI). Secondary non-employment outcomes include subjective quality of life, psychopathology, substance use, relapse, hospitalization, and functional impairment. To be eligible, participants must be between 16 and 35 years, fulfill diagnostic criteria for early psychosis, and be interested in competitive employment and/or mainstream education.
DISCUSSION
In SEEearly, we hypothesize that participants with psychosis, who receive TAU plus SEE, present with better primary and secondary outcomes than participants, who receive TAU alone. Positive results of this study will justify SEE as an evidence-based strategy for clinical routine treatment in people with early psychosis.
TRIAL REGISTRATION
SEEearly was registered nationally and internationally in the German Clinical Trials Register (DRKS; identifier: DRKS00029660) on October 14, 2022.
Topics: Humans; Young Adult; Adolescent; Employment, Supported; Neoplasm Recurrence, Local; Psychotic Disorders; Educational Status; Substance-Related Disorders; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37400899
DOI: 10.1186/s13063-023-07462-2 -
Clinical Interventions in Aging 2023The availability of a simple and reliable marker of biological age might allow an acceleration of the research in the field of longevity extension. Previous studies...
Can We Slow Down Biological Age Progression? Study Protocol for the proBNPage Reduction (PBAR) Randomized, Double-Blind, Placebo-Controlled Trial (Effects of 4 "Anti-Aging" Food Supplements in Healthy Older Adults).
PURPOSE
The availability of a simple and reliable marker of biological age might allow an acceleration of the research in the field of longevity extension. Previous studies suggest that this marker might be the N-terminal of B-type natriuretic peptide precursor (NT-proBNP), from which proBNPage, a biological age surrogate, can be calculated. Objectives of the study: 1) To fine-tune the method of proBNPage progression assessment and 2) To establish whether 4 "anti-aging" treatments, which provided promising results in previous studies, can modify proBNPage progression.
PATIENTS AND METHODS
This is a double-blind randomized placebo-controlled clinical trial on 120 adults aged 65-80 years, free of cardiovascular diseases. Participants will be randomized into 3 groups: A) Coenzyme Q10 100 mg bid + Selenium 100 mcg; B) Resveratrol 350 mg bid + TA-65 (Astragalus Membranaceus extract) 100U; C) Placebo-1 bid + Placebo-2. They will be followed for 2 years and checked 8 times, to assess both proBNPage progression and treatment safety. Secondary variables (handgrip strength, aerobic capacity at the step test and quality of life) will also be assessed. Primary outcome will be the demonstration of significant changes of proBNPage, compared to baseline, in the 3 groups at 6, 12, 18 and 24 months. Secondary outcome will be the demonstration of similar changes of secondary variables. Statistical analyses will be mainly performed by repeated measures ANOVA (both according to intention to treat and per protocol) and paired t tests. The study was approved by the Ethics Committee Area Vasta Emilia Centro, Emilia-Romagna Region, ID: 64/2022/Sper/AOUBo. Trial registration: ClinicalTrials.gov, NCT05500742.
CONCLUSION
The use of proBNPage as a surrogate of biological age may prove an easy method to select anti-aging treatments worthy of further, more complex assessments.
Topics: Humans; Aged; Quality of Life; Hand Strength; Dietary Supplements; Aging; Cardiovascular Diseases; Double-Blind Method; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 37915546
DOI: 10.2147/CIA.S422371 -
Use of Statins in Heart Failure with Preserved Ejection Fraction: Current Evidence and Perspectives.International Journal of Molecular... May 2024Systemic inflammation and coronary microvascular endothelial dysfunction are essential pathophysiological factors in heart failure (HF) with preserved ejection fraction... (Review)
Review
Systemic inflammation and coronary microvascular endothelial dysfunction are essential pathophysiological factors in heart failure (HF) with preserved ejection fraction (HFpEF) that support the use of statins. The pleiotropic properties of statins, such as anti-inflammatory, antihypertrophic, antifibrotic, and antioxidant effects, are generally accepted and may be beneficial in HF, especially in HFpEF. Numerous observational clinical trials have consistently shown a beneficial prognostic effect of statins in patients with HFpEF, while the results of two larger trials in patients with HFrEF have been controversial. Such differences may be related to a more pronounced impact of the pleiotropic properties of statins on the pathophysiology of HFpEF and pro-inflammatory comorbidities (arterial hypertension, diabetes mellitus, obesity, chronic kidney disease) that are more common in HFpEF. This review discusses the potential mechanisms of statin action that may be beneficial for patients with HFpEF, as well as clinical trials that have evaluated the statin effects on left ventricular diastolic function and clinical outcomes in patients with HFpEF.
Topics: Humans; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Stroke Volume; Ventricular Function, Left; Clinical Trials as Topic
PubMed: 38732177
DOI: 10.3390/ijms25094958 -
BMC Cancer Aug 2023It is unknown if participation in a cancer clinical trial confers clinical benefits to patients. There is not enough scientific evidence in this regard and the available... (Observational Study)
Observational Study
BACKGROUND
It is unknown if participation in a cancer clinical trial confers clinical benefits to patients. There is not enough scientific evidence in this regard and the available publications are scarce and provide ambiguous and limited information.
OBJECTIVE
Compare overall and progression-free survival and response to treatment among those who met the eligibility criteria and accepted to participate and those who refused to participate in cancer clinical trials.
METHODS
An observational cross-sectional study with an analytical component was carried out, which included patients diagnosed with cancer who participated in phase III clinical trials and patients who, being eligible, refused to participate. The patients were cared for at the National Institute of Cancerology in Colombia between 2019 and 2022. Analysis of differences in proportions and means of sociodemographic and clinical variables was included; overall survival and progression-free survival time were described and the survival curves between groups were compared. Variables related to survival were determined using a Cox regression model and Hazard Ratios were calculated.
RESULTS
62 women and 50 men were included. In the women group, we found a statistical association between clinical trial participation and non-serious events adverse and progression. The stable disease and complete response were higher in participants than in refusers. The median progression-free survival for refusers was 7,4 m meantime for participants the median was not reached and 74,1% remained without progression at 28 months. In the men group, we also found a statistical association between clinical trial participation and the occurrence of non-serious events adverse meanwhile there were no significant differences in overall response, progression, and death, even though the proportion of progression was minor in participants 20% vs. refusers 26% respectively. The median survival was not reached for any group, even though in the participants group 55,2% were still alive at month 20 and in the refusers group still alive at 56,8% at month 45. Covariables included for the multivariate Cox regression only age had a statistical association with overall survival in the women's group and the men group any covariables reached statistical association.
CONCLUSION
It can be considered that participation in clinical trials could give participants a better response to treatment, without increasing the probability of death and with the probability of decreasing the progression of the disease. Participation in trials could improve the outcomes of clinical response rates, no change in overall survival, and progression-free.
Topics: Cross-Sectional Studies; Humans; Male; Female; Middle Aged; Aged; Regression Analysis; Clinical Trials, Phase III as Topic; Progression-Free Survival; Uterine Cervical Neoplasms; Prostatic Neoplasms; Survival Analysis
PubMed: 37612602
DOI: 10.1186/s12885-023-11305-3