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Expert Opinion on Pharmacotherapy 2023Behavioural symptoms are common manifestations of Parkinson's disease and include depression, anxiety, impulse control disorders, hallucinations, psychosis, and... (Review)
Review
INTRODUCTION
Behavioural symptoms are common manifestations of Parkinson's disease and include depression, anxiety, impulse control disorders, hallucinations, psychosis, and cognitive dysfunction. They remain inadequately addressed in many patients despite their relevance for quality of life and disability. This applies also to impulse control disorders where the most common approach in recent literature is to refrain from using dopamine agonists without consideration about their potential benefit on motor complications.
AREAS COVERED
We conducted a narrative review searching for articles on behavioral symptoms in Parkinson disease and selected those which included involved neurotransmitters such as dopamine, noradrenaline, serotonin, acetylcholine. We specifically focused our search on open-label and randomized double-blind studies and biomarkers which could best characterize these clinical manifestations.
EXPERT OPINION
Management of Parkinson disease behavioural manifestations lacks clear guidelines and standardized protocols beside general suggestions of dose adjustments in dopamine replacement therapy and use of antidepressants or antipsychotic drugs with little consideration of patients' age, sex, comorbidities, and motor status. We suggest a pragmatic approach which includes education of affected patients and caring people, dealing with complex cases by experienced multidisciplinary teams, use of cognitive behavioural therapy, and psychological counselling to complement drug treatment.
Topics: Humans; Parkinson Disease; Dopamine; Quality of Life; Psychotic Disorders; Antipsychotic Agents; Randomized Controlled Trials as Topic
PubMed: 37493445
DOI: 10.1080/14656566.2023.2240228 -
Journal of Cardiology Feb 2024Heart failure (HF) is a growing, global public health issue. Despite advances in HF care, many challenges remain and HF outcomes are poor. Some of the major reasons for... (Review)
Review
Heart failure (HF) is a growing, global public health issue. Despite advances in HF care, many challenges remain and HF outcomes are poor. Some of the major reasons for this are the lack of understanding and treatment for certain HF sub-types as well as the lack of implementation of treatment in areas where effective treatment exists. HF registries provide the opportunity to transform clinical research and patient care. Recently the registry-based randomized clinical trial has emerged as a pragmatic and inexpensive alternative to the gold standard in clinical trial design, the randomized controlled trial. Registries may also provide platforms for strategy trials, implementation trials, and screening. Using examples from the Swedish Heart Failure Registry and others, the present review provides insights into how registry-based research can address many of the unmet needs in HF.
Topics: Humans; Heart Failure; Treatment Outcome; Hospitalization; Registries; Sweden; Randomized Controlled Trials as Topic
PubMed: 37844799
DOI: 10.1016/j.jjcc.2023.10.006 -
Clinical Trials (London, England) Dec 2023The conceptual framework of pragmatism in clinical trials is explored using the American Society of Clinical Oncology's pragmatic, non-randomized, phase II, multi-center... (Clinical Trial)
Clinical Trial
The conceptual framework of pragmatism in clinical trials is explored using the American Society of Clinical Oncology's pragmatic, non-randomized, phase II, multi-center basket clinical trial, the Targeted Agent and Profiling Utilization Registry Study (NCT02693535) as a model. The Targeted Agent and Profiling Utilization Registry Study aims to identify signals of drug activity when Food and Drug Administration approved drugs are matched to pre-specified genomic targets in patients with advanced cancer outside of their approved indication(s). The objectives of the study are to generate evidence of potential signals of activity in targeted therapies prescribed in an off-label setting as well as to expose and educate community cancer centers to genomic testing and precision medicine through the study protocol. The principles of pragmatic trial design can be applied across a broad spectrum of evidence-generation strategies, from explanatory trials to real-world evidence studies, and are briefly discussed. American Society of Clinical Oncology's Targeted Agent and Profiling Utilization Registry Study falls closer to the pragmatic end of this spectrum as it seeks to assess the efficacy of Food and Drug Administration approved drugs used outside their approved indications under usual care conditions, yielding results generalizable to the population that would likely receive the intervention in practice, while still adhering to rigorous data quality standards. The Targeted Agent and Profiling Utilization Registry Study's pragmatic objectives, characteristics, strengths, and limitations in its implementation are discussed and demonstrate that a large, multi-center, precision medicine basket trial can be mounted in the context of community practice and can generate clinically useful information with minimal burden to patients and clinical trial sites.
Topics: Humans; Data Accuracy; Neoplasms; Research Design
PubMed: 37489819
DOI: 10.1177/17407745231182013 -
BMJ Open Sep 2023Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England....
Penicillin allergy status and its effect on antibiotic prescribing, patient outcomes and antimicrobial resistance (ALABAMA): protocol for a multicentre, parallel-arm, open-label, randomised pragmatic trial.
INTRODUCTION
Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims to determine if an intervention package, centred around a penicillin allergy assessment pathway (PAAP) initiated in primary care, is safe and effective in improving patient health outcomes and antibiotic prescribing.
METHODS AND ANALYSIS
The ALABAMA trial is a multicentre, parallel-arm, open-label, randomised pragmatic trial with a nested pilot study. Adults (≥18 years) with a penicillin allergy record and who have received antibiotics in the previous 24 months will be eligible for participation. Between 1592 and 2090 participants will be recruited from participating National Health Service general practices in England. Participants will be randomised to either usual care or intervention to undergo a pre-emptive PAAP using a 1:1 allocation ratio. The primary outcome measure is the percentage of treatment response failures within 28 days of an index prescription. 2090 and 1592 participants are estimated to provide 90% and 80% power, respectively, to detect a clinically important absolute difference of 7.9% in primary outcome at 1 year between groups. The trial includes a mixed-methods process evaluation and cost-effectiveness evaluation.
ETHICS AND DISSEMINATION
This trial has been approved by London Bridge Research Ethics Committee (ref: 19/LO/0176). It will be conducted in compliance with Good Clinical Practice guidelines according to the Declaration of Helsinki. Informed consent will be obtained from all subjects involved in the study. The primary trial results will be submitted for publication to an international, peer-reviewed journal.
TRIAL REGISTRATION
ISRCTN20579216.
Topics: Adult; Humans; Alabama; Anti-Bacterial Agents; Drug Hypersensitivity; Drug Resistance, Bacterial; Hypersensitivity; Multicenter Studies as Topic; Penicillins; Pilot Projects; Randomized Controlled Trials as Topic; State Medicine; Pragmatic Clinical Trials as Topic
PubMed: 37666558
DOI: 10.1136/bmjopen-2023-072253 -
Clinical and Experimental Emergency... Mar 2024The goal of a clinical study is to determine the factors associated with a disease and to assess the efficacy and safety of an investigational drug, procedure, or...
The goal of a clinical study is to determine the factors associated with a disease and to assess the efficacy and safety of an investigational drug, procedure, or device. Since clinical study designs vary due to unique requirements of individual studies, the aims of this report are to educate researchers on the different types of studies and to assist researchers in choosing the optimal study type to fulfill their individual requirements. Clinical studies are classified into the two main types, observational studies and clinical trials, depending on the presence or absence of an intervention. Observational studies include case-control studies, cohort studies, and cross-sectional studies. Case-control and cohort studies may be prospective or retrospective, and case-control studies may be nested or not. Clinical trials may be pragmatic and may be controlled or noncontrolled; randomized or nonrandomized; open label or blinded; and parallel, crossover, or factorial. These observational and clinical trial designs are reviewed. Each type of clinical study has advantages and disadvantages. Therefore, researchers must consider these in choosing the design best suited for achieving their study objectives.
PubMed: 37280050
DOI: 10.15441/ceem.23.036 -
American Journal of Respiratory and... Jul 2023Small trials and professional recommendations support mobilization interventions to improve recovery among critically ill patients, but their real-world effectiveness... (Randomized Controlled Trial)
Randomized Controlled Trial
Small trials and professional recommendations support mobilization interventions to improve recovery among critically ill patients, but their real-world effectiveness is unknown. To evaluate a low-cost, multifaceted mobilization intervention. We conducted a stepped-wedge cluster-randomized trial across 12 ICUs with diverse case mixes. The primary and secondary samples included patients mechanically ventilated for ⩾48 hours who were ambulatory before admission, and all patients with ICU stays ⩾48 hours, respectively. The mobilization intervention included ) designation and posting of daily mobilization goals; ) interprofessional closed-loop communication coordinated by each ICU's facilitator; and ) performance feedback. From March 4, 2019 through March 15, 2020, 848 and 1,069 patients were enrolled in the usual care and intervention phases in the primary sample, respectively. The intervention did not increase the primary outcome, patient's maximal Intensive Care Mobility Scale (range, 0-10) score within 48 hours before ICU discharge (estimated mean difference, 0.16; 95% confidence interval, -0.31 to 0.63; = 0.51). More patients in the intervention (37.2%) than usual care (30.7%) groups achieved the prespecified secondary outcome of ability to stand before ICU discharge (odds ratio, 1.48; 95% confidence interval, 1.02 to 2.15; = 0.04). Similar results were observed among the 7,115 patients in the secondary sample. The percentage of days on which patients received physical therapy mediated 90.1% of the intervention effect on standing. ICU mortality (31.5% vs. 29.0%), falls (0.7% vs. 0.4%), and unplanned extubations (2.0% vs. 1.8%) were similar between groups (all > 0.3). A low-cost, multifaceted mobilization intervention did not improve overall mobility but improved patients' odds of standing and was safe. Clinical trial registered with www.clinicaltrials.gov (NCT03863470).
Topics: Humans; Critical Illness; Intensive Care Units; Critical Care; Hospitalization; Patient Discharge
PubMed: 36996413
DOI: 10.1164/rccm.202209-1763OC -
Mayo Clinic Proceedings Nov 2023Pragmatic randomized clinical trials (pRCTs) have a unique set of considerations for data and safety monitoring. Because of their unconventional trial designs coupled... (Review)
Review
Pragmatic randomized clinical trials (pRCTs) have a unique set of considerations for data and safety monitoring. Because of their unconventional trial designs coupled with collection of multilevel data and implementation outcomes in real-world settings, thoughtful consideration is needed on the presentation of the trial design and accruing data to facilitate review and decision-making by the trial's data and safety monitoring board (DSMB). To our knowledge, there is limited information available in practical guidelines for generalists and medical general practitioners on what to monitor and to report to the DSMB during the conduct of pRCTs and what the DSMB should focus on in its review of reports. This article discusses these matters in the context of 3 case studies focusing on a set of critical data and safety monitoring questions that would be of interest to the generalist conducting pRCTs. In considering these questions, we provide tabular and graphical illustrations of how data can be presented to the DSMB while drawing attention to those areas that the DSMB should focus on in its review of the trial. The strategies and viewpoints discussed herein provide practical guidelines and can serve as a resource for the generalist conducting pRCTs.
Topics: Humans; Randomized Controlled Trials as Topic; Clinical Trials Data Monitoring Committees
PubMed: 37923529
DOI: 10.1016/j.mayocp.2023.02.019 -
BMJ Open Dec 2023Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol,...
Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK.
INTRODUCTION
Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care.
METHODS AND ANALYSIS
Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs.
ETHICS AND DISSEMINATION
The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov NCT03653832.
Topics: Adult; Humans; Propofol; Dexmedetomidine; Cost-Benefit Analysis; Clonidine; Critical Illness; Quality of Life; Adrenergic alpha-2 Receptor Agonists; Hypnotics and Sedatives; Pain; Intensive Care Units; United Kingdom; Respiration, Artificial; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase III as Topic
PubMed: 38072483
DOI: 10.1136/bmjopen-2023-078645 -
BMJ Open Sep 2023Corneal blindness is the third most frequent cause of blindness globally. Damage to the corneal endothelium is a leading indication for corneal transplantation, which is...
Belgian Endothelial Surgical Transplant of the Cornea (BEST cornea) protocol: clinical and patient-reported outcomes of Ultra-Thin Descemet Stripping Automated Endothelial Keratoplasty (UT-DSAEK) versus Descemet Membrane Endothelial Keratoplasty (DMEK) - a multicentric, randomised, parallel group...
OBJECTIVES
Corneal blindness is the third most frequent cause of blindness globally. Damage to the corneal endothelium is a leading indication for corneal transplantation, which is typically performed by lamellar endothelial keratoplasty. There are two conventional surgical techniques: Ultra-Thin Descemet Stripping Automated Endothelial Keratoplasty (UT-DSAEK) and Descemet Membrane Endothelial Keratoplasty (DMEK). The purpose of this study is to compare both techniques.
METHODS AND ANALYSIS
The trial compares UT-DSAEK and DMEK in terms of clinical and patient reported outcomes using a pragmatic, parallel, multicentric, randomised controlled trial with 1:1 allocation with a sample size of 220 participants across 11 surgical centres. The primary outcome is the change in best-corrected visual acuity at 12 months. Secondary outcomes include corrected and uncorrected vision, refraction, proportion of high vision, quality of life (EQ-5D-5L and VFQ25), endothelial cell counts and corneal thickness at 3, 6 and 12 months follow-up appointments. Adverse events will also be compared 12 months postoperatively.
ETHICS AND DISSEMINATION
The protocol was reviewed by ethical committees of 11 participating centres with the sponsor centre issuing the final definitive approval. The results will be disseminated at clinical conferences, by patient partner groups and open access in peer-reviewed journals.
GOVERNANCE OF THE TRIAL
Both, trial management group and trial steering committee, are installed with representatives of all stakeholders involved including surgeons, corneal bankers, patients and external experts.
TRIAL REGISTRATION NUMBER
NCT05436665.
Topics: Humans; Endothelium, Corneal; Belgium; Descemet Membrane; Quality of Life; Corneal Diseases; Corneal Transplantation; Cornea; Patient Reported Outcome Measures; Blindness; Randomized Controlled Trials as Topic
PubMed: 37714670
DOI: 10.1136/bmjopen-2023-072333 -
Trials Jul 2023Each year, 1 million children develop TB resulting in over 200,000 child deaths. TB preventive treatment (TPT) is highly effective in preventing TB but remains poorly... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Each year, 1 million children develop TB resulting in over 200,000 child deaths. TB preventive treatment (TPT) is highly effective in preventing TB but remains poorly implemented for household child contacts. Home-based child contact management and TPT services may improve access to care. In this study, we aim to evaluate the effectiveness and cost-effectiveness of home-based contact management with TPT initiation in two TB high-burden African countries, Ethiopia and South Africa.
METHODS
This pragmatic cluster randomized trial compares home-based versus facility-based care delivery models for contact management. Thirty-six clinics with decentralized TB services (18 in Ethiopia and 18 in South Africa) were randomized in a 1:1 ratio to conduct either home-based or facility-based contact management. The study will attempt to enroll all eligible close child contacts of infectious drug-sensitive TB index patients diagnosed and treated for TB by one of the study clinics. Child TB contact management, including contact tracing, child evaluation, and TPT initiation and follow-up, will take place in the child's home for the intervention arm and at the clinic for the control arm. The primary outcome is the cluster-level ratio of the number of household child contacts less than 15 years of age in Ethiopia and less than 5 years of age in South Africa initiated on TPT per index patient, comparing the intervention to the control arm. Secondary outcomes include child contact identification and the TB prevention continuum of care. Other implementation outcomes include acceptability, feasibility, fidelity, cost, and cost-effectiveness of the intervention.
DISCUSSION
This implementation research trial will determine whether home-based contact management identifies and initiates more household child contacts on TPT than facility-based contact management.
TRIAL REGISTRATION
NCT04369326 . Registered on April 30, 2020.
Topics: Child; Humans; Child, Preschool; Tuberculosis; South Africa; Ethiopia; Ambulatory Care Facilities; Clinical Protocols; Contact Tracing
PubMed: 37491264
DOI: 10.1186/s13063-023-07514-7