Recommendations For Future Trials Research Articles

Advancing Delirium Treatment Trials in Older Adults: Recommendations for Future Trials From the Network for Investigation of Delirium: Unifying Scientists (NIDUS).

To summarize the delirium treatment trial literature, identify the unique challenges in delirium treatment trials, and formulate recommendations to address each in older adults. A 39-member interprofessional and international expert working group of clinicians (physicians, nurses, and pharmacists) and nonclinicians (biostatisticians, epidemiologists, and trial methodologists) was convened. Four expert panels were assembled to explore key subtopics (pharmacological/nonpharmacologic treatment, methodological challenges, and novel research designs). To provide background and context, a review of delirium treatment randomized controlled trials (RCTs) published between 2003 and 2023 was conducted and evidence gaps were identified. The four panels addressed the identified subtopics. For each subtopic, research challenges were identified and recommendations to address each were proposed through virtual discussion before a live, full-day, and in-person conference. General agreement was reached for each proposed recommendation across the entire working group via moderated conference discussion. Recommendations were synthesized across panels and iteratively discussed through rounds of virtual meetings and draft reviews. We identified key evidence gaps through a systematic literature review, yielding 43 RCTs of delirium treatments. From this review, eight unique challenges for delirium treatment trials were identified, and recommendations to address each were made based on panel input. The recommendations start with design of interventions that consider the multifactorial nature of delirium, include both pharmacological and nonpharmacologic approaches, and target pathophysiologic pathways where possible. Selecting appropriate at-risk patients with moderate vulnerability to delirium may maximize effectiveness. Targeting patients with at least moderate delirium severity and duration will include those most likely to experience adverse outcomes. Delirium severity should be the primary outcome of choice; measurement of short- and long-term clinical outcomes will maximize clinical relevance. Finally, plans for handling informative censoring and missing data are key. By addressing key delirium treatment challenges and research gaps, our recommendations may serve as a roadmap for advancing delirium treatment research in older adults.

A roadmap for research in post-stroke fatigue: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue.

A roadmap for research in post-stroke fatigue: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue.

Device-based interventions that seek to restore bilateral and binaural hearing in adults with single-sided deafness: a conceptual analysis

Single-sided deafness (SSD) is defined by severe-to-profound sensorineural hearing loss in one ear only. This article outlines the etiologies and associated functional, psychological, social, and other consequences of SSD in adulthood. The available hearing aids and auditory implants for SSD are described, alongside an overview of the methods adopted by clinicians and researchers to define and measure their benefits and harms. Current concepts and issues to consider in the field of rerouting and restoring device-based interventions are explored. A contemporary overview of the current challenges in outcome measurement of all available interventions in the field is also provided, and cost effectiveness of SSD interventions is discussed briefly. This article therefore proves a comprehensive summary of the current knowledge on interventions and outcome measurement for SSD for those interested or actively working in the field, and recommendations for future trials. These include recommendations on the timescale of measurements, long-term benefits (or harms), cost utility, and the use of the internationally agreed core outcome domain set for all future clinical trials of device-based interventions for SSD.

Production acceptance trial of indigenous manufactured helmet: Field experience and lessons drawn

Effective trial of indigenously developed flying clothing like a helmet on aircrew is important before final acceptance. The prototype indigenously designed helmet by an Indian manufacturer was subjected to a final Production Acceptance Trial (PAT) at a flying base for operational capability. Ground and in-flight evaluation of helmet was conducted involving aircrew. Most of the parameters for trials were satisfactory. Certain observations were brought out by the aircrew and trial team, which were later rectified by the manufacturer. The rectified helmet was subjected to repeat PAT and finally accepted for bulk production. This paper highlights the importance of such trials, lessons drawn, and recommendations for future trials.

The feasibility of a multidomain dementia risk reduction randomised controlled trial for people experiencing cognitive decline: the Body, Brain, Life for Cognitive Decline (BBL-CD)

Objectives To evaluate the feasibility of a proof-of-concept multidomain dementia risk reduction intervention. Method An 8-week, parallel-group RCT, focused on increasing adherence to lifestyle domains of Mediterranean diet (MeDi), Physical Activity (PA), and Cognitive Engagement (CE). Feasibility was evaluated against the Bowen Feasibility Framework objectives of: Acceptability of the intervention, compliance with the protocol, and efficacy of the intervention to change behaviour in the three domains of interest. Results High acceptability of the intervention was demonstrated through a participant retention rate of 80.7% (Intervention: 84.2%; Control: 77.4%). Compliance to the protocol was strong with 100% of participants completing all educational modules and all MeDi and PA components, with 20% compliance for CE. Linear mixed models demonstrated efficacy to change behaviour through significant effects of adherence to MeDi (χ2 = 16.75, df = 3, p < .001) and CE (χ2 = 9.83, df = 3, p =.020), but not PA (χ2 = 4.48, df = 3, p =.211). Conclusion Overall the intervention was shown to be feasible. Recommendations for future trials in this area are: The implementation of practical, one-on-one sessions as they are more effective than passive education at eliciting behaviour change; use of booster sessions to increase likelihood of lifestyle changes being sustained; and collection of qualitative data to identify barriers to change.

Maintaining Integrity of Worldwide FINGER Clinical Trials During the COVID-19 Pandemic

The COVID-19 pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions. World-Wide FINGERS international network convened a forum for researchers to discuss statistical design and analysis issues they faced during the pandemic. We report experiences of three trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials. The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessments protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within site stratification, interim power projections, and sensitivity analyses. Robust approaches to study design and analysis are critical to negotiate issues related to the intervention.

Short-term music therapy treatment for adolescents with depression – A pilot study

Music therapy holds promising potential to support adolescents with depression mastering developmental tasks as well as improving emotion regulation. The objective of the present pilot study was to assess the feasibility, acceptance and potential effectiveness of a theory driven music therapy treatment plan for youth with depression. The treatment aimed to reduce severity of depression and to improve emotion regulation and health related quality of life. Hair cortisol concentration served as an additional biological marker for bodily stress. In an outpatient center, adolescents with depression received 12 single sessions of music therapy. A prospective, single-arm repeated-measures design (pre-, post-, follow-up) was used to examine acceptance, feasibility, and outcome measures. Nine adolescents were included in analyses. The music therapy treatment plan seems to be feasible and well accepted by adolescents. The results of analyses indicate improvements regarding depressive symptoms, positive coping with difficult emotions and health-related quality of life in included patients. The beneficial effects were not shown to be fully sustained in the follow-up. The results suggest that music therapy caused no harm and might have contributed to the improvement of clinical outcomes in the mildly to moderately adolescents with depression. Several recommendations for future trials in this field are reported. ● Design of the pilot study is feasible, recruitment is of major importance. ● The music therapy treatment plan was well accepted by adolescents with depression. ● Severity of depression decreased while attending the program & increased afterwards. ● Other significant changes were seen in emotion regulation and self-perception.

Moving Beyond 3+3: The Future of Clinical Trial Design.

Misgivings have been raised about the operating characteristics of the canonical 3+3 dose-escalation phase I clinical trial design. Yet, the traditional 3+3 design is still the most commonly used. Although it has been implied that adhering to this design is due to a stubborn reluctance to adopt change despite other designs performing better in hypothetical computer-generated simulation models, the continued adherence to 3+3 dose-escalation phase I strategies is more likely because these designs perform the best in the real world, pinpointing the correct dose and important side effects with an acceptable degree of precision. Beyond statistical simulations, there are little data to refute the supposed shortcomings ascribed to the 3+3 method. Even so, to address the unique nuances of gene- and immune-targeted compounds, a variety of inventive phase 1 trial designs have been suggested. Strategies for developing these therapies have launched first-in-human studies devised to acquire a breadth of patient data that far exceed the size of a typical phase I design and blur the distinction between dose selection and efficacy evaluation. Recent phase I trials of promising cancer therapies assessed objective tumor response and durability at various doses and schedules as well as incorporated multiple expansion cohorts spanning a variety of histology or biomarker-defined tumor subtypes, sometimes resulting in U.S. Food and Drug Administration approval after phase I. This article reviews recent innovations in phase I design from the perspective of multiple stakeholders and provides recommendations for future trials.

A systematic review of Tuina for irritable bowel syndrome: Recommendations for future trials

This systematic review assessed whether Tuina (therapeutic massage) is more effective and safer than no treatment or routine medical treatment for irritable bowel syndrome (IBS). Eleven databases were searched for randomized controlled trials of IBS diagnosed based on Manning or Rome criteria. Tuina with or without routine treatments (RTs) was tested against RTs. The Cochrane risk of bias was evaluated for each trial. RevMan 5.3 was used to conduct a meta-analysis. A total of 8 trials (5 IBS-diarrhea and 3 IBS-constipation) with 545 participants using 8 different manipulations were included. All trials were published in Chinese. For overall symptom improving rate (> 30 % improvement in overall symptom scores), it had not been shown that Tuina was significantly better than RTs (RR 1.23, 95 % CI 0.94-1.60, 197 participants, 3 studies, I2 = 65 %) for IBS-diarrhea, and Tuina combined with RTs showed more benefit than RTs alone (RR 1.29, 95 % CI 1.08-1.54, 115 participants, 3 studies) for IBS-diarrhea. All trials did not report adverse effect in relation to Tuina. Risk of bias was generally unclear across all domains. Tuina combined with RTs may be superior to RTs for improving overall symptom of IBS-diarrhea. Due to the existing methodological issues and the heterogeneity of Tuina manipulation, current findings need to be confirmed in large scale, multicenter, and robust randomized trials (especially on outcome assessing blinding and allocation concealment).

Functional mode of action of ASP5736, a selective 5-HT5A receptor antagonist for treatment of cognitive dysfunction in schizophrenia

Docosahexaenoic acid (DHA) is an omega-3 long-chain polyunsaturated fatty acid that accumulates in neural tissues during intrauterine development, particularly in the frontal lobes of the brain. The frontal lobes are responsible for a suite of cognitive abilities referred to as ‘executive functions.’ Executive function skills include attention, working memory (the ability to mentally manipulation information), and inhibitory control (the ability to control or supress inappropriate actions).In this chapter, we briefly review the development of the human brain and the accumulation of DHA in the brain. The main focus is on summarizing the evidence from randomized controlled trials that have supplemented pregnant women with DHA and measured the effects on children’s executive functions. We provide details of the different assessments of executive function that have been used in trials, and summarize the evidence base with respect to dose of DHA used in trials and age when executive functions are measured. We conclude with some recommendations for future trials in this area.

Perceptions of Massage Therapists Participating in a Randomized Controlled Trial.

Clinical practice and randomized trials often have disparate aims, despite involving similar interventions. Attitudes and expectancies of practitioners influence patient outcomes, and there is growing emphasis on optimizing provider-patient relationships. In this study, we evaluated the experiences of licensed massage therapists involved in a randomized controlled clinical trial using qualitative methodology. Seven massage therapists who were interventionists in a randomized controlled trial participated in structured interviews approximately 30 minutes in length. Interviews focused on their experiences and perceptions regarding aspects of the clinical trial, as well as recommendations for future trials. Transcribed interviews were analyzed for emergent topics and themes using standard qualitative methods. Six themes emerged. Therapists discussed 1) promoting the profession of massage therapy through research, 2) mixed views on using standardized protocols, 3) challenges of sham interventions, 4) participant response to the sham intervention, 5) views on scheduling and compensation, and 6) unanticipated benefits of participating in research. Therapists largely appreciated the opportunity to promote massage through research. They demonstrated insight and understanding of the rationale for a clinical trial adhering to a standardized protocol. Evaluating the experiences and ideas of complementary and alternative medicine practitioners provides valuable insight that is relevant for the implementation and design of randomized trials.

Comparing treatment fidelity between study arms of a randomized controlled clinical trial for stroke family caregivers

Objective: To compare treatment fidelity among treatment arms in the Telephone Assessment and Skill-Building Kit study for stroke caregivers (TASK II) with respect to: 1) protocol adherence; 2) intervention dosage and 3) nurse intervener perspectives. Design: A randomized controlled clinical trial design. Setting: Urban, community, midwestern United States. Subjects: A total of 254 stroke caregivers (mean ±SD age, 54.4 ±11.8 years), 55 (22.0%) males and 199 (78.4%) females) randomized to the TASK II intervention (n=123) or an Information, Support, and Referral comparison group (n=131). Interventions: TASK II participants received the TASK II Resource Guide; Information, Support, and Referral participants received a standard caregiver brochure. At approximately 8 weeks after discharge, both groups received 8 weekly calls from a nurse, with a booster call 4 weeks later. Measures: Protocol adherence was evaluated with the TASK II Checklist for Monitoring Adherence. Intervention dosage was measured by the number of minutes caregivers spent reading materials and talking with the nurse. Nurse intervener perspectives were obtained through focus groups. Results: Protocol adherence was 80% for the TASK II and 92% for the Information, Support, and Referral. As expected, intervention dosage differed between TASK II and Information, Support, and Referral with respect to caregiver time spent reading materials (t=-6.49; P<.001) and talking with the nurse (t=-7.38; P<.001). Focus groups with nurses yielded further evidence for treatment fidelity and recommendations for future trials. Conclusions: These findings substantiate treatment fidelity in both study arms of the TASK II stroke caregiver intervention trial (NIH R01NR010388; ClinicalTrials.govNCT01275495).

Nutritional interventions in sarcopenia: a critical review.

The aim of the present paper is to critically review the details of the published nutrition intervention trials, with and without exercise, targeting sarcopenia. Sarcopenia is the loss of muscle mass, strength and/or performance with age. Since amino acids and energy are required for muscle synthesis it is possible that nutritional intake influences sarcopenia. Nutritional studies are challenging to carry out because of the complexity of modulating dietary intake. It is very difficult to change one nutrient without influencing many others, which means that many of the published studies are problematic to interpret. The studies included evaluate whole protein, essential amino acids and β-hydroxyl β-methylbutyrate (HMB). Whole-protein supplementation failed to show a consistent effect on muscle mass, strength or function. This can be explained by the variations in study design, composition of the protein supplement and the failure to monitor voluntary food intake, adherence and baseline nutritional status. Essential amino-acid supplements showed an inconsistent effect but there are only two trials that have significant differences in methodology and the supplement used. The HMB studies are suggestive of a beneficial effect on older adults, but larger well-controlled studies are required that measure outcomes relevant to sarcopenia, ideally in sarcopenic populations. The issues of timing and distribution of protein intake, and increased splanchnic amino-acid sequestration are discussed, and recommendations for future trials are made.

Supportive care for men with prostate cancer: why are the trials not working? A systematic review and recommendations for future trials.

Men with prostate cancer are likely to have a long illness and experience psychological distress for which supportive care may be helpful. This systematic review describes the evidence for effectiveness and cost-effectiveness of supportive care for men with prostate cancer, taking into account treatment pathway and components of interventions. MEDLINE, EMBASE, CINAHL, CENTRAL, and Psychinfo were searched from inception––July 2013 for randomized controlled trials and controlled trials. Two authors independently assessed risk of bias and extracted data. Twenty-six studies were included (2740 participants). Interventions were delivered pre and during (n = 12), short-term (n = 8), and longer term (18 months) (n = 5) after primary treatment. No interventions were delivered beyond this time. Few trials recruited ethnic minorities and none recruited men in same sex relationships. Intervention components included information, education, health professional discussion, homework, peer discussion, buddy support, cognitive behavioral therapy, cognitive restructuring, psychoeducation, Reiki and relaxation. Most interventions were delivered for 5–10 weeks. Risk of bias of trials was assessed as unclear for most domains due to lack of information. The majority of trials measuring quality of life and depression found no effect. Relatively few trials measured anxiety, coping skills and self-efficacy, and the majority found no effect. No cost data were available. Trials of supportive care for men with prostate cancer cover a range of interventions but are limited by population diversity, inconsistent measurement and reporting of outcomes, and inability to assess risk of bias. Recommendations on design and conduct of future trials are presented.

Vitamin D and Cognition: Recommendations for Future Trials

Vitamin D and Cognition: Recommendations for Future Trials

What Is the Evidence for the Treatment of Asthma with Homeopathy?

A review of the medical evidence base on the treatment of asthma with homeopathic remedies has been conducted with the aim to determine if there are any indications for the effectiveness of the treatment of asthma with homeopathy. A non-exhaustive list of 32 research papers has been examined of which four were systematic reviews, seven RCTs, nine observational and qualitative studies, five pilot and open studies and case studies of 147 cases. Research outcomes considered to be highest in the hierarchy of evidence are mostly negative or inconclusive, whereas all others are positive. This clearly identified trend is analysed against trial designs and treatments strategy. It was found that usually the designs of RCTs limit the full evaluation of the effect of a homeopathic prescription and recommendations for future trials and research designs are made. The encouraging findings for homeopathy coming from well-constructed RCTs and observational studies should be considered more seriously and more trials and studies are recommended in order to replicate such findings.

Correlation of Human and Horse Heart Rates During Equine-Assisted Therapy Sessions with At-Risk Youths: A Pilot Study

Minimal research has been done to examine the cause of the positive results of animal-assisted therapy. This study examines the correlation between horse and human heart rate, an involuntary stress response, which may allow the mechanisms of potential therapeutic benefits to be further understood. Horse and human heart rates were recorded during equine-assisted therapy sessions, compared, and the significance of human/horse heart rate correlation was documented. Results indicate that each incidence of correlating changes in the heart rates appeared to be the result of external stimuli. Findings are discussed and recommendations for future trials with controlled environments are made.

The role of pharmacogenomics in metastatic renal cell carcinoma

Pharmacogenomics is the study of how variation in the genetic background affects an individual's response to a specific drug and/or its metabolism. Using knowledge about the genes which produce the enzymes that metabolize a specific drug, a physician may decide to raise or lower the dose, or even change to a different drug. Targeted therapy with tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors has led to a substantial improvement in the standard of care for patients with advanced or metastatic renal cell carcinoma (RCC). Although few studies have identified biomarkers that predict the response of targeted drugs in the treatment of metastatic RCC, some associations have been found. Several studies have identified genetic polymorphisms with implications in the pharmacokinetics and/or pharmacodynamics of TKIs and mTOR inhibitors and which are associated with a prolonged progression-free survival and/or overall survival in patients with metastatic RCC. Among the genes of interest, we should consider IL8, FGFR2, VEGFA, FLT4, and NR1I2. In this review, we discuss single nucleotide polymorphisms (SNPs) associated with outcome and toxicity following targeted therapies and provide recommendations for future trials to facilitate the use of SNPs in personalized therapy for this disease.

Evidence to support tooth brushing in critically ill patients.

Tooth brushing in critically ill patients has been advocated by many as a standard of care despite the limited evidence to support this practice. Attention has been focused on oral care as the evidence accumulates to support an association between the bacteria in the oral microbiome and those respiratory pathogens that cause pneumonia. It is plausible to assume that respiratory pathogens originating in the oral cavity are aspirated into the lungs, causing infection. A recent study of the effects of a powered toothbrush on the incidence of ventilator-associated pneumonia was stopped early because of a lack of effect in the treatment group. This review summarizes the evidence that supports the effectiveness of tooth brushing in critically ill adults and children receiving mechanical ventilation. Possible reasons for the lack of benefit of tooth brushing demonstrated in clinical trials are discussed. Recommendations for future trials in critically ill patients are suggested. With increased emphasis being placed on oral care, the evidence that supports this intervention must be evaluated carefully.