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BMJ Paediatrics Open Nov 2023Food allergy is a major public health challenge in Australia. Despite widespread uptake of infant feeding and allergy prevention guidelines the incidence of peanut...
INTRODUCTION
Food allergy is a major public health challenge in Australia. Despite widespread uptake of infant feeding and allergy prevention guidelines the incidence of peanut allergy in infants has not fallen, and prevalence of peanut allergy in school-aged children continues to rise. Therefore, effective and accessible treatments for peanut allergy are required. There is high-quality evidence for efficacy of oral immunotherapy in children aged 4-17 years old; however, few randomised trials have investigated peanut oral immunotherapy (OIT) in young children. Furthermore, the use of food products for OIT with doses prepared and administered by parents without requiring pharmacy compounding has the potential to reduce costs associated with the OIT product.
METHODS AND ANALYSIS
Early Peanut Immunotherapy in Children is an open-label randomised controlled trial of peanut OIT compared with standard care (avoidance) to induce desensitisation in children aged 1-4 years old with peanut allergy. n=50 participants will be randomised 1:1 to intervention (daily peanut OIT for 12 months) or control (peanut avoidance). The primary outcome is the proportion of children in each group with a peanut eliciting dose >600 mg peanut protein as assessed by open peanut challenge after 12 months, analysed by intention to treat. Secondary outcomes include safety as assessed by frequency and severity of treatment-related adverse events, quality of life measured using age-appropriate food allergy-specific questionnaires and immunological changes during OIT.
ETHICS
The trial is approved by the Child and Adolescent Health Service Human Research Ethics Committee and prospectively registered with the Australia and New Zealand Clinical Trials Registry.
DISSEMINATION
Trial outcomes will be published in a peer-review journal and presented and local and national scientific meetings.
TRIAL REGISTRATION NUMBER
ACTRN12621001001886.
Topics: Child, Preschool; Humans; Infant; Administration, Oral; Arachis; Desensitization, Immunologic; Peanut Hypersensitivity; Quality of Life; Pragmatic Clinical Trials as Topic
PubMed: 37963680
DOI: 10.1136/bmjpo-2023-002294 -
Clinical and Translational Science Jun 2024Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of... (Randomized Controlled Trial)
Randomized Controlled Trial
Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.
Topics: Humans; Cytochrome P-450 CYP2D6; Selective Serotonin Reuptake Inhibitors; Pharmacogenomic Testing; Cytochrome P-450 CYP2C19; Depression; Prospective Studies; Female; Male; Pharmacogenomic Variants; Adult; Pragmatic Clinical Trials as Topic; Antidepressive Agents
PubMed: 38860639
DOI: 10.1111/cts.13822 -
BMC Cancer Feb 2024For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and... (Randomized Controlled Trial)
Randomized Controlled Trial
Alliance for clinical trials in Oncology (Alliance) trial A022101/NRG-GI009: a pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur).
BACKGROUND
For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed.
METHODS
The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility.
DISCUSSION
The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT05673148, registered December 21, 2022.
Topics: Humans; Prospective Studies; Radiosurgery; Colonic Neoplasms; Liver Neoplasms; Rectal Neoplasms
PubMed: 38350888
DOI: 10.1186/s12885-024-11899-2 -
Trials Jun 2023Pragmatic trials, because they study widely used treatments in settings of routine practice, require intensive participation from clinicians who determine whether... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pragmatic trials, because they study widely used treatments in settings of routine practice, require intensive participation from clinicians who determine whether patients can be enrolled. Clinicians are often conflicted between their therapeutic obligation to patients and their willingness to enroll them in trials in which treatments are randomly determined and thus potentially suboptimal. Refusal to enroll eligible patients can hinder trial completion and damage generalizability. In order to help evaluate and mitigate clinician refusal, this qualitative study examined how clinicians reason about whether to randomize eligible patients.
METHODS
We performed interviews with 29 anesthesiologists who participated in REGAIN, a multicenter pragmatic randomized trial comparing spinal and general anesthesia in hip fracture. Interviews included a chart-stimulated section in which physicians described their reasoning pertaining to specific eligible patients as well as a general semi-structured section about their views on clinical research. Guided by a constructivist grounded theory approach, we analyzed data via coding, synthesized thematic patterns using focused coding, and developed an explanation using abduction.
RESULTS
Anesthesiologists perceived their main clinical function as preventing peri- and intraoperative complications. In some cases, they used prototype-based reasoning to determine whether patients with contraindications should be randomized; in others, they used probabilistic reasoning. These modes of reasoning involved different types of uncertainty. In contrast, anesthesiologists expressed confidence about anesthetic options when they accepted patients for randomization. Anesthesiologists saw themselves as having a fiduciary responsibility to patients and thus did not hesitate to communicate their inclinations, even when this complicated trial recruitment. Nevertheless, they voiced strong support for clinical research, stating that their involvement was mainly hindered by production pressure and workflow disruptions.
CONCLUSIONS
Our findings suggest that prominent ways of assessing clinician decisions about trial randomization are based on questionable assumptions about clinical reasoning. Close examination of routine clinical practice, attuned to the features of clinical reasoning we reveal here, will help both in evaluating clinicians' enrollment determinations in specific trials and in anticipating and responding to them.
TRIAL REGISTRATION
Regional Versus General Anesthesia for Promoting Independence After Hip Fracture (REGAIN).
CLINICALTRIALS
gov NCT02507505. Prospectively registered on July 24, 2015.
Topics: Humans; Physicians; Hip Fractures; Qualitative Research; Clinical Reasoning
PubMed: 37365614
DOI: 10.1186/s13063-023-07445-3 -
Structural Heart : the Journal of the... Jul 2023Transcatheter aortic valve replacement (TAVR) is a treatment option for patients with symptomatic severe aortic stenosis across the entire spectrum of surgical risk.... (Review)
Review
Transcatheter aortic valve replacement (TAVR) is a treatment option for patients with symptomatic severe aortic stenosis across the entire spectrum of surgical risk. Recent trial data have led to the expansion of TAVR into lower-risk patients. With iterative technological advances and successive increases in procedural experience, the occurrence of complications following TAVR has declined. One of the most feared complications remains stroke, and patients consider stroke a worse outcome than death. There has therefore been great interest in strategies to mitigate the risk of stroke in patients undergoing TAVR. In this paper, we will discuss mechanisms and predictors of stroke after TAVR and describe the currently available cerebral embolic protection devices, including their design and relevant clinical studies pertaining to their use. We will also review the current overall evidence base for cerebral embolic protection during TAVR and ongoing randomized controlled trials. Finally, we will discuss our pragmatic recommendations for the use of cerebral embolic protection devices in patients undergoing TAVR.
PubMed: 37520138
DOI: 10.1016/j.shj.2023.100169 -
BMC Public Health Sep 2023Combining short-acting nicotine replacement therapy with varenicline increases smoking cessation rates compared with varenicline alone, but not all people tolerate these...
Effectiveness of nicotine salt vapes, cytisine, and a combination of these products, for smoking cessation in New Zealand: protocol for a three-arm, pragmatic, community-based randomised controlled trial.
BACKGROUND
Combining short-acting nicotine replacement therapy with varenicline increases smoking cessation rates compared with varenicline alone, but not all people tolerate these medications or find them helpful. We aim to investigate the therapeutic potential of an analogous combination, by evaluating the effectiveness, safety, and acceptability of combining nicotine salt e-cigarettes with cytisine, compared to nicotine salt e-cigarettes or cytisine only, on smoking abstinence at six months.
METHODS
A pragmatic, community-based, investigator-blinded, randomised superiority trial design will be utilised. Eligible participants will be people who smoke daily (N = 800, 90% power) from throughout New Zealand, who are: aged ≥ 18 years, motivated to quit in the next two weeks, able to provide online consent, willing to use e-cigarettes and/or cytisine, and have daily access to a mobile phone. Recruitment will utilise multi-media advertising. Participants will be randomised (3:3:2 ratio) to 12 weeks of: 1) e-cigarettes (closed pod system, 3% nicotine salt, tobacco flavour) plus cytisine; 2) e-cigarettes alone, or 3) cytisine alone. All groups will receive a six-month, text-message-based behavioural support programme. The primary outcome is self-reported, biochemically verified, continuous abstinence at six months post-quit date. Secondary outcomes, measured at quit date, then one, three, six, and 12 months post-quit date, include self-reported continuous abstinence, 7-day point prevalence abstinence, cigarettes smoked per day, withdrawal and urge to smoke, time to (re)lapse, treatment use and compliance, treatment crossover, dual-use, use of other cessation products, change in e-cigarette products, continuation of product use, acceptability, change in health state, health-related quality of life, change in body mass index, adverse events, and cost per quitter.
DISCUSSION
Pragmatic trials are of particular value as they reflect the 'real world' impact of interventions. The trial will provide some of the first evidence on the effectiveness of combining nicotine salt e-cigarettes with cytisine for smoking cessation, in a country with strong tobacco control policy. Findings will be incorporated into relevant systematic reviews, informing practice and policy.
TRIAL REGISTRATION
NCT05311085 ClinicalTrials.gov. Registered 5th April, 2022.
Topics: Humans; Nicotine; Smoking Cessation; Electronic Nicotine Delivery Systems; Vaping; New Zealand; Quality of Life; Varenicline; Tobacco Use Cessation Devices; Sodium Chloride, Dietary; Randomized Controlled Trials as Topic
PubMed: 37697327
DOI: 10.1186/s12889-023-16665-w -
Annals of the Rheumatic Diseases Mar 2024Treatment targets in systemic lupus erythematosus (SLE) have been validated in unselected-in terms of severity-cohorts, which limits their generalisability. We assessed...
Pragmatic targets for moderate/severe SLE and their implications for clinical care and trial design: sustained DORIS or LLDAS for at least 6 months is sufficient while their attainment for at least 24 months ensures high specificity for damage-free progression.
OBJECTIVES
Treatment targets in systemic lupus erythematosus (SLE) have been validated in unselected-in terms of severity-cohorts, which limits their generalisability. We assessed remission (Definition of Remission in SLE (DORIS)) and Lupus Low Disease Activity State (LLDAS) in a historical cohort of 348 patients with active moderate-to-severe disease and median follow-up of 5 years.
METHODS
Active SLE was defined as Physician Global Assessment ≥1.5 and/or SLE Disease Activity Index 2000 ≥6, requiring therapy intensification. DORIS/LLDAS, organ damage, flares and adverse events were monitored. Shared frailty survival, generalised linear models and K-means clustering were applied.
RESULTS
Sustained DORIS and LLDAS for ≥6 months occurred in 41.1% and 80.4%, respectively, and resulted in reduced damage accrual (HR: 0.58; 95% CI 0.36 to 0.93 and 0.61; 0.43 to 0.86) and severe flares (HR: 0.14; 0.08 to 0.27 and 0.19; 0.13 to 0.27). LLDAS without DORIS was also protective (HR: 0.65; 0.43 to 0.98 for damage, 0.49; 0.36 to 0.67 for flares). Models fitting increasing duration of targets showed that DORIS ≥50% and LLDAS ≥60% of time, or alternatively, ≥24 and ≥36 months, achieved optimal balance between feasibility (20.2-41.7%) and specificity (73.3-86.1%) for damage-free outcome. These targets were linked to reduced serious adverse events (risk ratio (RR): 0.56-0.71), hospitalisation (RR: 0.70) and mortality (RR: 0.06-0.13). Patients with predominant arthritis and mucocutaneous disease experienced reduced DORIS/LLDAS, compared with counterparts with major organ involvement. Conventional drugs were more frequently used in the former group, whereas potent immunosuppressive/biological agents in the latter.
CONCLUSIONS
In moderate-to-severe SLE, sustained DORIS/LLDAS for at least 6 months is sufficient, while attainment for at least 24 months ensures higher specificity for damage-free progression, thus facilitating treat-to-target strategies and clinical trials. Arthritis and skin disease represent unmet therapeutic needs that could benefit from novel biologics.
Topics: Humans; Arthritis; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Remission Induction; Severity of Illness Index; Skin Diseases; Clinical Trials as Topic
PubMed: 38233103
DOI: 10.1136/ard-2023-224919 -
European Heart Journal. Acute... Aug 2023Extracorporeal cardiopulmonary resuscitation is a promising treatment for refractory out-of-hospital cardiac arrest. Three recent randomized trials (ARREST trial, Prague... (Randomized Controlled Trial)
Randomized Controlled Trial
Extracorporeal cardiopulmonary resuscitation is a promising treatment for refractory out-of-hospital cardiac arrest. Three recent randomized trials (ARREST trial, Prague OHCA study, and INCEPTION trial) that addressed the clinical benefit of extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest yielded seemingly diverging results. The evidence for extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest, derived from three recent randomized controlled trials, is not contradictory but rather complementary. Excellent results can be achieved with a very high level of dedication, provided that strict selection criteria are applied. However, pragmatic implementation of extracorporeal cardiopulmonary resuscitation does not necessarily lead to improved outcome of refractory out-of-hospital cardiac arrest. Centres that are performing extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest or aspire to do so should critically evaluate whether they are able to meet the pre-requisites that are needed to conduct an effective extracorporeal cardiopulmonary resuscitation programme.
Topics: Humans; Cardiopulmonary Resuscitation; Out-of-Hospital Cardiac Arrest; Randomized Controlled Trials as Topic
PubMed: 37480551
DOI: 10.1093/ehjacc/zuad071 -
European Journal of Clinical Nutrition Dec 2023Evidence-based nutritional recommendations address the health impact of suboptimal nutritional status. Efficacy randomized controlled trials (RCTs) have traditionally... (Review)
Review
Evidence-based nutritional recommendations address the health impact of suboptimal nutritional status. Efficacy randomized controlled trials (RCTs) have traditionally been the preferred method for determining the effects of nutritional interventions on health outcomes. Nevertheless, obtaining a holistic understanding of intervention efficacy and effectiveness in real-world settings is stymied by inherent constraints of efficacy RCTs. These limitations are further compounded by the complexity of nutritional interventions and the intricacies of the clinical context. Herein, we explore the advantages and limitations of alternative study designs (e.g., adaptive and pragmatic trials), which can be incorporated into RCTs to optimize the efficacy or effectiveness of interventions in clinical nutrition research. Efficacy RCTs often lack external validity due to their fixed design and restrictive eligibility criteria, leading to efficacy-effectiveness and evidence-practice gaps. Adaptive trials improve the evaluation of nutritional intervention efficacy through planned study modifications, such as recalculating sample sizes or discontinuing a study arm. Pragmatic trials are embedded within clinical practice or conducted in settings that resemble standard of care, enabling a more comprehensive assessment of intervention effectiveness. Pragmatic trials often rely on patient-oriented primary outcomes, acquire outcome data from electronic health records, and employ broader eligibility criteria. Consequently, adaptive and pragmatic trials facilitate the prompt implementation of evidence-based nutritional recommendations into clinical practice. Recognizing the limitations of efficacy RCTs and the potential advantages of alternative trial designs is essential for bridging efficacy-effectiveness and evidence-practice gaps. Ultimately, this awareness will lead to a greater number of patients benefiting from evidence-based nutritional recommendations.
Topics: Humans; Nutritional Status; Research Design; Pragmatic Clinical Trials as Topic; Adaptive Clinical Trials as Topic
PubMed: 37715007
DOI: 10.1038/s41430-023-01330-7 -
Best Practice & Research. Clinical... Jul 2023The COVID-19 pandemic has had a profound global impact, affecting people's physical and mental health, and their social and economic circumstances. Mitigation measures... (Review)
Review
The COVID-19 pandemic has had a profound global impact, affecting people's physical and mental health, and their social and economic circumstances. Mitigation measures have disproportionately affected women. Studies have reported menstrual cycle and psychological disturbance associated with the pandemic. Pregnancy is a risk factor for severe COVID-19 disease. Reports have also demonstrated associations between COVID-19 infection, vaccination and Long COVID syndrome and reproductive health disturbance. However, studies are limited and there may be significant geographical variation. Also there is bias amongst published studies, and menstrual cycle data was not included in COVID-19 and vaccine trials. Longitudinal population based studies are required. In this review we discuss existing data, along with recommendations for further research required in this area. We also discuss a pragmatic approach to women presenting with reproductive health disturbance in the era of the pandemic, encompassing a multi-system assessment of psychological, reproductive health and lifestyle.
Topics: Pregnancy; Female; Humans; COVID-19; SARS-CoV-2; Pandemics; Post-Acute COVID-19 Syndrome; Reproductive Health
PubMed: 36990807
DOI: 10.1016/j.beem.2023.101760