The Dedicated Imaging Post-Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) trial protocol: a multicentre, randomised trial of salvage radiotherapy versus surveillance for low-risk biochemical recurrence after radical prostatectomy.

BACKGROUND: Salvage radiation therapy (SRT) and surveillance for low-risk prostate-specific antigen (PSA) recurrence have competing risks and benefits. The efficacy of early SRT to the prostate bed with or without pelvic lymph nodes compared to surveillance in patients with PSA recurrence after radical prostatectomy and no identifiable recurrent disease evident on prostate specific membrane antigen-positron emission tomography/computer tomography (PSMA-PET/CT) is unknown. STUDY DESIGN: The Dedicated Imaging Post-Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) is an open-label, multicentre, randomised Phase II trial. ENDPOINTS: The primary endpoint is 3-year event-free survival, with events comprising one of PSA recurrence (PSA ≥0.2 ng/mL higher than baseline), radiological evidence of metastatic disease, or initiation of systemic or other salvage treatments. Secondary endpoints include patient-reported outcomes, treatment patterns, participant perceptions, and cost-effectiveness. ELIGIBILITY CRITERIA: Eligible participants have PSA recurrence of prostate cancer after radical prostatectomy, defined by serum PSA level of 0.2-0.5 ng/mL, deemed low risk according to modified European Association of Urology biochemical recurrence risk criteria (International Society for Urological Pathology Grade Group ≤2, PSA doubling time >12 months), with no definite/probable recurrent prostate cancer on PSMA-PET/CT. PATIENTS AND METHODS: A total of 100 participants will be recruited from five Australian centres and randomised 1:1 to SRT or surveillance. Participants will undergo 6-monthly clinical evaluation for up to 36 months. Androgen-deprivation therapy is not permissible. Enrolment commenced May 2023. TRIAL REGISTRATION: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN: ACTRN12622001478707).

Preventing smoking initiation in adolescents living in vulnerable socioeconomic conditions: Study protocol of the KickAsh!-intervention.

AIMS: Adolescents living in vulnerable socioeconomic conditions are confronted with tobacco-related health disparities. As school-based interventions appear to be less effective among these youngsters, other approaches are necessary. One promising avenue is youth social work settings that offer sport and recreational activities (SR-settings). SR-settings have been examined as a levering context for health promotion, but evidence regarding smoking prevention is currently lacking. METHODS: This study describes the protocol of a non-randomised cluster controlled trial evaluating a smoking prevention intervention for adolescents. At least 24 SR-settings are needed for the intervention and control group. A mixed-method design will be used. Quantitative measures will be used to assess effectiveness, involving validated questionnaires on smoking initiation behaviour and influencing factors (i.e. attitude, self-efficacy, social influence and risk perception). In addition, feasibility will be assessed with regard to intervention fidelity, dose and reach. Data will be collected at baseline, three and nine months following the intervention. To gain deeper understanding on the impact and underlying processes of the intervention, we will conduct qualitative interviews with users (adolescents) and implementers (youth workers within the SR-settings) of the intervention. CONCLUSIONS: Conducting this trial will offer novel insights into the effectiveness of a smoking prevention intervention designed for adolescents living in vulnerable socioeconomic conditions. A mixed-method design will enable to measure impact, implementation and underlying processes of the intervention. Overall, this design will enhance our understanding on the suitability of SR-settings as contexts for smoking prevention initiatives targeting hard-to-reach youth. This trial is registered on Clinicaltrials.gov: NCT05920772.

Telehealth utilization in gynecologic oncology clinical trials.

OBJECTIVE: Prior to the COVID-19 pandemic, telehealth visits and remote clinical trial operations (such as local collection of laboratory tests or imaging studies) were underutilized in gynecologic oncology clinical trials. Current literature on these operational changes provides anecdotal experience and expert opinion with few studies describing patient-level safety data. We aimed to evaluate the safety and feasibility of telehealth and remote clinical trial operations during the COVID-19 Pandemic. METHODS: Gynecologic oncology patients enrolled and actively receiving treatment on a clinical trial at a single, academic institution during the designated pre-Telehealth and Telehealth periods were identified. Patients with at least 1 provider or research coordinator telehealth visit were included. Patient demographics, health system encounters, adverse events, and protocol deviations were collected. Pairwise comparisons were performed between the pre-Telehealth and Telehealth period with each patient serving as their own control. RESULTS: Thirty-one patients met inclusion criteria. Virtual provider visits and off-site laboratory testing increased during the Telehealth period. Delays in provider visits, imaging, and laboratory testing did not differ between time periods. Total and minor protocol deviations increased in incidence during the Telehealth period and were due to documentation of telehealth and deferment of non-therapeutic testing. Major protocol deviations, emergency department visits, admissions, and severe adverse events were of low incidence and did not differ between time periods. CONCLUSIONS: Telehealth and remote clinical trial operations appeared safe and did not compromise clinical trial protocols in a small, single institutional study. Larger scale evaluations of such trial adaptations should be performed to determine continued utility following the Pandemic.

bTUNED: transcutaneous tibial nerve stimulation for neurogenic lower urinary tract dysfunction.

OBJECTIVE: To present the protocol for a randomized controlled trial (RCT) evaluating the efficacy and safety of transcutaneous tibial nerve stimulation (TTNS) for refractory neurogenic lower urinary tract dysfunction (NLUTD). STUDY DESIGN AND RESULTS: bTUNED (bladder and TranscUtaneous tibial Nerve stimulation for nEurogenic lower urinary tract Dysfunction) is an international multicentre, sham-controlled, double-blind RCT investigating the efficacy and safety of TTNS. The primary outcome is success of TTNS, defined as improvements in key bladder diary variables at study end compared to baseline values. The focus of the treatment is defined by the Self-Assessment Goal Achievement (SAGA) questionnaire. Secondary outcomes are the effect of TTNS on urodynamic, neurophysiological, and bowel function outcome measures, as well as the safety of TTNS. CONCLUSIONS: A total of 240 patients with refractory NLUTD will be included and randomized 1:1 into the verum or sham TTNS group from March 2020 until August 2026. TTNS will be performed twice a week for 30 min during 6 weeks. The patients will attend baseline assessments, 12 treatment visits and follow-up assessments at the study end.

Effects of a cognitive stimulation program on physical and cognitive dimensions in community-dwelling faller older adults with cognitive impairment: study protocol.

BACKGROUND: Cognitive functioning is an important dimension among the elderly. Cognitive maintenance is vital for aging due to its association with autonomy and independence. Considering the importance of preventive programs in older adults' health, this study aims to share an intervention protocol of a falls prevention program for community-dwelling faller older adults with cognitive impairment. METHODS: This is the protocol of an experimental and longitudinal study, consisting of cognitive stimulation associated with physical exercise in a 16-week fall prevention program. For cognitive intervention, the APG Cognitive Training Protocol will be used. Participants will be assessed pre-and post-intervention and will be randomly allocated to experimental or control groups. The screening protocol is composed of the TUG, FES-I, LAWTON & BRODY, ACE-R, GAI and fall survey instruments, focusing on the assessment of balance and mobility, fear of falling, performance on IADL, cognitive and anxiety tracking, respectively. DISCUSSION: This study can determine the long-term effects of multimodal cognitive training, providing evidence for its replication in the provision of care for the elderly. The objective is to promote improvements in the cognitive performance, mobility and balance of the elderly, with a focus on reducing the number of falls, fractures, hospitalizations and institutionalization, serving as an alternative to interrupt the cycle of falls. TRIAL REGISTRATION: The research was approved by the Research Ethics Committee with Human Beings at the Federal University of São Carlos, CAAE: 3654240.9.0000.5504 and Brazilian Registry of Clinical Trials (REBEC) RBR-3t85fd, registered on the 25th of September, 2020.

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol.

BACKGROUND: Peripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC. METHODS: 200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000 mg/day) or placebo to evaluate the effect of metformin on functional status, PAD progression, cardiovascular disease events, and systemic inflammation. The primary outcome is 180-day maximum walking distance on the 6-min walk test (6MWT). Secondary outcomes include additional assessments of functional status (cardiopulmonary exercise testing, grip strength, Walking Impairment Questionnaires), health related quality of life (SF-36, VascuQoL), macro- and micro-vascular assessment of lower extremity blood flow (ankle brachial indices, pulse volume recording, EndoPAT), cardiovascular events (amputations, interventions, major adverse cardiac events, all-cause mortality), and measures of systemic inflammation. All outcomes will be assessed at baseline, 90 and 180 days of study drug exposure, and 180 days following cessation of study drug. We will evaluate the primary outcome with linear mixed-effects model analysis with covariate adjustment for baseline 6MWT, age, baseline ankle brachial indices, and smoking status following an intention to treat protocol. DISCUSSION: MOBILE IC is uniquely suited to evaluate the use of metformin to improve both systematic inflammatory responses, cellular energetics, and functional outcomes in patients with PAD and IC. TRIAL REGISTRATION: The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.

Now is the time to fix the evidence generation system.

Despite enormous advances in biomedical science, corresponding improvements in health outcomes lag significantly. This is particularly true in the United States, where life expectancy trails far behind that of other high-income countries. In addition, substantial disparities in life expectancy and other health outcomes exist as a function of race, ethnicity, wealth, education, and geographic location. A major reformation of our national system for generating medical evidence-the clinical research enterprise-is needed to facilitate the translation of biomedical research into useful products and interventions. Currently, premarket systems for generating and evaluating evidence work reasonably well, but the postmarket phase is disaggregated and often fails to answer essential questions that must be addressed to provide optimal clinical care and public health interventions for all Americans. Solving these problems will require a focus on three key domains: (1) improving the integration of and access to high-quality data from traditional clinical trials, electronic health records, and personal devices and wearable sensors; (2) restructuring clinical research operations to support and incentivize the involvement of patients and frontline clinicians; and (3) articulating ethical constructs that enable responsible data sharing to support improved implementation. Finally, we must also address the systemic tendency to optimize individual components of the clinical research enterprise without considering the effects on the system as a whole. Overcoming suboptimization by creating incentives for integration and sharing will be essential to achieve more timely and equitable improvement in health outcomes.

The Targeted Agent and Profiling Utilization Registry Study: A pragmatic 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.

Treating nightmares in posttraumatic stress disorder with dronabinol: study protocol of a multicenter randomized controlled study (THC PTSD-trial).

BACKGROUND: Distressing nightmares are a core symptom of posttraumatic stress disorder (PTSD) and contribute to psychiatric comorbidity, impaired physical health and decreased social functioning. No specific pharmacological treatment for PTSD-related nightmares is yet approved. Preliminary clinical data indicate that cannabinoid agonists can improve nightmares and overall PTSD symptoms in patients with PTSD. The primary objective of the study is to examine the efficacy of oral dronabinol (BX-1) versus placebo in reducing nightmares in patients with PTSD. The secondary objectives of the study are to examine the efficacy of oral BX-1 in reducing other PTSD symptoms. METHODS: The study is designed as a multi-centric, double-blind, randomized (1:1), placebo-controlled, parallel group interventional trial. Eligible patients will be randomized to BX-1 or placebo, receiving a once-daily oral dose before bedtime for 10 weeks. Primary efficacy endpoint is the Clinician-Administered PTSD Scale (CAPS-IV) B2 score for the last week, measuring frequency and intensity of nightmares. Secondary efficacy endpoints are other disorder-specific symptoms in patients with PTSD. Further, tolerability and safety of dronabinol will be assessed. DISCUSSION: This randomized controlled trial will provide evidence whether treating patients with PTSD and nightmares with dronabinol is safe and efficacious. TRIAL REGISTRATION: NCT04448808, EudraCT 2019-002211-25.

Exergames improves cognitive functions in adolescents with depression: study protocol of a prospective, assessor-blind, randomized controlled trial.

BACKGROUND: Depression is a condition that imposes a significant disease burden, with cognitive impairment being one of its costly symptoms. While cognitive rehabilitation is crucial, it is also challenging. Although some studies have investigated the impact of exergames on cognitive function improvement, these have primarily focused on the elderly population, with limited attention given to individuals with depression. Consequently, this study aims to investigate the effects of exergames on cognitive functions in adolescents with depression and compare the effectiveness of exergames with traditional exercise. METHOD: The present investigation is a single-center randomized controlled trial that employs the ANOVA method to calculate the sample size using G*Power software, assuming a 25% dropout rate. The study enrolls fifty-four eligible patients with depression who are randomly allocated to one of three treatment groups: the exergames group, which receives standard treatment and exergames intervention; the exercise group, which receives standard treatment and traditional exercise intervention; and the control group, which receives standard treatment exclusively. The study provides a comprehensive regimen of 22 supervised exercise and exergame sessions over an 8-week period, with a frequency of twice per week for the initial two weeks and three times per week for the subsequent six weeks. The researchers gather cognitive, mood, and sleep metrics at the onset of the first week, as well as at the conclusion of the fourth and eighth weeks. The researchers employ a wearable device to track participants' heart rate during each intervention session and evaluate the Borg Rating of Perceived Exertion scale at the conclusion of each session. DISCUSSION: The findings from this study make several contributions to the current literature. First, this study comprehensively reports the efficacy of an exergames intervention for multidimensional symptoms in adolescents with depression. Second, this study also compares the efficacy of exergames with that of traditional exercise. These findings provide a theoretical basis for the use of exergames as an adjunctive intervention for depression and lay the groundwork for future research. TRIAL REGISTRATION: This trial is registered with the Chinese Clinical Trials Registry (Registration number: ChiCTR2100052709; Registration Status: Prospective registration;) 3/11/2021, URL:    http://www.chictr.org.cn/edit.aspx?pid=135663&htm=4 .

Protocol for a multicenter study on effectiveness and economics of the Back At work After Surgery (BAAS): a clinical pathway for knee arthroplasty.

BACKGROUND: Optimizing return to work (RTW) after knee arthroplasty (KA) is becoming increasingly important due to a growing incidence of KA and poor RTW outcomes after KA. We developed the Back At work After Surgery (BAAS) clinical pathway for optimized RTW after KA. Since the effectiveness and cost analysis of the BAAS clinical pathway are still unknown, analysis on effectiveness and costs of BAAS is imperative. METHOD: This protocol paper has been written in line with the standards of Standard Protocol Items: Recommendations for Interventional Trails. To assess the effectiveness and cost-effectiveness for RTW, we will perform a multicenter prospective cohort study with patients who decided to receive a total KA (TKA) or an unicompartmental KA (UKA). To evaluate the effectiveness of BAAS regarding RTW, a comparison to usual care will be made using individual patient data on RTW from prospectively performed cohort studies in the Netherlands. DISCUSSION: One of the strengths of this study is that the feasibility for the BAAS clinical pathway was tested at first hand. Also, we will use validated questionnaires and functional tests to assess the patient's recovery using robust outcomes. Moreover, the intervention was performed in two hospitals serving the targeted patient group and to reduce selection bias and improve generalizability. The limitations of this study protocol are that the lead author has an active role as a medical case manager (MCM) in one of the hospitals. Additionally, we will use the data from other prospective Dutch cohort studies to compare our findings regarding RTW to usual care. Since we will not perform an RCT, we will use propensity analysis to reduce the bias due to possible differences between these cohorts. TRAIL REGISTRATION: This study was retrospectively registered at clinicaltrails.gov ( https://clinicaltrials.gov/ct2/show/NCT05690347 , date of first registration: 19-01-2023).

Ultrasound-guided PIVC insertion: a randomised controlled trial protocol.

Ultrasound-guided insertion of peripheral intravenous catheters (PIVCs) is an alternative to traditional anatomical landmark-based insertion. However, data on its performance in paediatric patients of varying levels of difficult intravenous access are limited. The researchers hypothesise that ultrasound-guided PIVC insertion will increase first-attempt success compared with landmark technique. This randomised, parallel-group, single-centre, superiority trial commenced recruiting in July 2021, including hospitalised children (aged 0 (>37 weeks gestation) to 18 years) requiring a PIVC. It will recruit 180 children, stratified by degree of perceived difficulty, and centrally randomised into two groups (ratio 1:1). The primary outcome is first-attempt PIVC insertion success. Secondary outcomes include total number of PIVC insertion attempts, PIVC insertion failure, post-insertion complications, dwell time, patient/parent satisfaction, and healthcare costs. The current study will inform the superiority of ultrasound-guided PIVC insertion in comparison with landmark technique. Adoption by healthcare facilities might improve patient outcomes and decrease healthcare costs.

Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by high mean pulmonary arterial pressure (≥ 20 mmHg) and remodeling of the vascular arteries. Approved therapies improve symptoms and delay clinical worsening in the long term, but they do not relieve acute exertional symptoms. RT234, a drug/device combination (Respira Therapeutics, Palo Alto, CA, USA) that delivers the phosphodiesterase 5 inhibitor vardenafil to the lungs via inhalation, has been shown to reduce pulmonary vascular resistance in patients with PAH. This study aims to evaluate whether RT234 can increase oxygen capacity during cardiopulmonary exercise testing (CPET) in patients with PAH. METHODS: This prospective, multi-center, open-label, two-cohort, dose-escalation, phase IIb trial in patients with PAH will evaluate the safety and efficacy of RT234 in improving exercise parameters. The trial began in September 2020 and is expected to be completed by early 2024. Patients eligible for enrollment will have a right heart catheterization-confirmed diagnosis of PAH, a 6-minute walking distance of ≥ 150 m, a minute ventilation/carbon dioxide production slope of ≥ 36, and will be on up to three stable oral and/or inhaled (not parenteral) PAH-specific background therapies. The estimated sample size is 86 patients, who will be divided into two dose cohorts. Cohort 1 will receive 0.5 mg RT234, and cohort 2 will receive 1.0 mg RT234. Each cohort will contain two subgroups based on the number of PAH background medications (up to two vs three). The trial will assess patients' changes from baseline in peak oxygen consumption (VO2) during CPET 30 minutes after a single dose of 0.5 mg or 1.0 mg RT234, the change in the 6-minute walking distance, and the pharmacokinetics and safety profile of single doses of RT234. CONCLUSION: This is the first trial involving an as-needed medication for PAH. The trial will provide insights into the safety and efficacy of as-needed RT234 in treating the acute symptoms of PAH during exercise and will inform the design of further trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04266197.

Single fraction ablative preoperative radiation treatment for early-stage breast cancer: the CRYSTAL study - a phase I/II clinical trial protocol.

BACKGROUND: Breast-conserving surgery (BCS) and whole breast radiation therapy (WBRT) are the standard of care for early-stage breast cancer (BC). Based on the observation that most local recurrences occurred near the tumor bed, accelerated partial breast irradiation (APBI), consisting of a higher dose per fraction to the tumor bed over a reduced treatment time, has been gaining ground as an attractive alternative in selected patients with low-risk BC. Although more widely delivered in postoperative setting, preoperative APBI has also been investigated in a limited, though increasing, and number of studies. The aim of this study is to test the feasibility, safety and efficacy of preoperative radiotherapy (RT) in a single fraction for selected BC patients. METHODS: This is a phase I/II, single-arm and open-label single-center clinical trial using CyberKnife. The clinical investigation is supported by a preplanning section which addresses technical and dosimetric issues. The primary endpoint for the phase I study, covering the 1st and 2nd year of the research project, is the identification of the maximum tolerated dose (MTD) which meets a specific target toxicity level (no grade 3-4 toxicity). The primary endpoint for the phase II study (3rd to 5th year) is the evaluation of treatment efficacy measured in terms of pathological complete response rate. DISCUSSION: The study will investigate the response of BC to the preoperative APBI from different perspectives. While preoperative APBI represents a form of anticipated boost, followed by WBRT, different are the implications for the scientific community. The study may help to identify good responders for whom surgery could be omitted. It is especially appealing for patients unfit for surgery due to advanced age or severe co-morbidities, in addition to or instead of systemic therapies, to ensure long-term local control. Moreover, patients with oligometastatic disease synchronous with primary BC may benefit from APBI on the intact tumor in terms of tumor progression free survival. The study of response to RT can provide useful information about BC radiobiology, immunologic reactions, genomic expression, and radiomics features, to be tested on a larger scale. TRIAL REGISTRATION: The study was prospectively registered at clinicaltrials.gov ( NCT04679454 ).

c4c: Paediatric pharmacovigilance: Methodological considerations in research and development of medicines for children - A c4c expert group white paper.

Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population-specific factors (e.g., more frequent use of off-label/unlicensed drugs). In recognition of these challenges, a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life-cycle of medicinal products which are described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development, safety data collection and analysis. Furthermore, they describe the specific details of post-marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record-linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit-risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life-cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs.

Can telerehabilitation services combined with caregiver-mediated exercises improve early supported discharge services poststroke? A study protocol for a multicentre, observer-blinded, randomized controlled trial.

BACKGROUND: Recovery of walking ability is an important goal for patients poststroke, and a basic level of mobility is critical for an early discharge home. Caregiver-mediated exercises could be a resource-efficient strategy to augment exercise therapy and improve mobility in the first months poststroke. A combination of telerehabilitation and face-to-face support, blended care, may empower patient-caregiver dyads and smoothen the transition from professional support to self-management. The Armed4Stroke study aims to investigate the effects of a caregiver-mediated exercise program using a blended care approach in addition to usual care, on recovery of mobility in the first 6 months poststroke. METHODS: A multicentre, observer-blinded randomized clinical trial in which 74 patient-caregiver dyads will be enrolled in the first 3 months poststroke. Dyads are randomly allocated to a caregiver-mediated exercises intervention or to a control group. The primary endpoint is the self-reported mobility domain of the Stroke Impact Scale. Secondary endpoints include care transition preparedness and psychological functioning of dyads, length of inpatient stay, gait-related measures and extended ADL of patients, and caregiver burden. Outcomes are assessed at enrolment, end of treatment and 6 months follow-up. RESULTS: During 8 weeks, caregivers are trained to become an exercise coach using a blended care approach. Dyads will receive a tailor-made, progressive training program containing task-specific exercises focusing on gait, balance, physical activity and outdoor activities. Dyads are asked to perform the training program a minimum of 5 times a week for 30 min per session, supported by a web-based telerehabilitation system with instruction videos and a messaging environment to communicate with their physiotherapist. CONCLUSIONS: We hypothesize that the Armed4Stroke program will increase self-reported mobility and independence in ADL, facilitating an early discharge poststroke. In addition, we hypothesize that active involvement of caregivers and providing support using blended care, will improve the care transition when professional support tapers off. Therefore, the Armed4Stroke program may complement early supported discharge services. TRIAL REGISTRATION: Netherlands Trial Register, NL7422 . Registered 11 December 2018.

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .

Clinical and virological outcomes with baloxavir compared with oseltamivir in pediatric patients aged 6 to < 12 years with influenza: an open-label, randomized, active-controlled trial protocol.

BACKGROUND: Children with influenza virus infections are prone to complications and are common sources of influenza transmission. Baloxavir marboxil inhibits cap-dependent endonuclease and was approved for influenza treatment in adolescent, adult, and pediatric patients in Japan. The miniSTONE-2 study included pediatric patients with influenza (1 to < 12 years) and demonstrated similar median times to alleviation of signs and symptoms of influenza with a single dose of baloxavir granules (weight < 20 kg: 2 mg/kg, ≥ 20 kg: 40 mg) and oseltamivir. Although the baloxavir dose in miniSTONE-2 was higher than the Japanese-approved dose, baloxavir exposure in miniSTONE-2 was similar to Japanese pediatric patients who receive the Japanese-approved dose. This study will be the first randomized active-controlled study in pediatric patients with influenza using the Japanese-approved dose of baloxavir. METHODS: This is a multicenter, open-label, randomized, active-controlled trial in which 200 Japanese subjects aged 6 to < 12 years with influenza virus infection are randomly allocated (2:1) to a single dose of baloxavir at the approved dose in Japan (weight ≥ 10 to < 20 kg: 10 mg, ≥ 20 to < 40 kg: 20 mg, ≥ 40 kg: 40 mg) or oseltamivir twice daily for 5 days. The primary clinical endpoint is the time to illness alleviation of influenza, from administration of baloxavir or oseltamivir until the following criteria were met and sustained for at least 21.5 h (24 h-10%): cough and nasal discharge/nasal congestion rated as absent or mild axillary body temperature < 37.5 °C. The primary analysis population is the intention-to-treat infected population, which includes all pediatric subjects who receive at least one dose of study drug and have confirmed influenza virus infection by reverse transcription-polymerase chain reaction. The safety population includes all subjects who receive at least one dose of study drug. DISCUSSION: No comparative studies have been conducted to confirm the efficacy and safety of baloxavir versus a comparator in pediatric patients with influenza infection in Japan. The outcomes from this trial will provide evidence on the efficacy and safety of baloxavir as an antiviral treatment option for Japanese pediatric patients with influenza infection. Trial registration Japan Registry of Clinical Trials: jRCTs011200011. Registered November 2020. ( https://rctportal.niph.go.jp/en/ ).

Supporting participation in paid work of cancer survivors and their partners in the Netherlands: protocol of the SusTained Employability in cancer Patients and their partnerS (STEPS) multi-centre randomized controlled trial and cohort study.

BACKGROUND: Many cancer survivors experience physical and/or psychosocial problems affecting return to work (RTW) and work retention. Current interventions on RTW lack evidence regarding effectiveness, while interventions for work retention are missing. Partners of cancer survivors may also experience work- and health-related outcomes; yet, these consequences are not well understood. Here, the protocol of the STEPS study is described. The study aims are to: 1) evaluate the (cost-)effectiveness of a rehabilitation program for RTW and work retention in cancer survivors, and 2) assess health- and work-related outcomes among cancer survivors' partners. METHODS: In a multicentre Randomized Controlled Trial (RCT), 236 working-age cancer survivors with an employment contract will be randomly allocated to a usual care group or an intervention group receiving a multidisciplinary rehabilitation program, combining occupational therapy facilitating work retention (e.g., energy management and self-efficacy training) and reintegration consultation addressing work-related issues (e.g., RTW planning and discussing workplace or task modifications with the supervisor). Alongside the RCT, a prospective cohort study will be conducted among cancer survivors' partners (n = 267). Participants in the RCT and cohort study will be asked to complete questionnaires at baseline, and after six and 12 months, assessing work- and health-related outcomes. Generalized estimating equations will be used to assess intervention's effectiveness, compared to usual care, regarding primary (i.e., working hours per week) and secondary outcomes. Also economic and process evaluations will be performed. For the cohort study, logistic or linear regression modelling will be applied assessing work- and health-related outcomes (primary outcome: working hours) of cancer survivors' partners, and what factors predict these outcomes. RESULTS: The study is planned to start in September 2021; results are expected in 2023. CONCLUSION: Compared to usual care, the STEPS intervention is hypothesized to be (cost-)effective and the intervention could be a valuable addition to standard care helping cancer survivors to sustain employment. Further, it is expected that living with a cancer survivor has a substantial impact on work and health of partners, while specific groups of partners that are at particular risk for this impact are likely to be identified. TRIAL REGISTRATION: Dutch Trial Register ( NTR;NL9094 ; 15-12-2020).

Clinical trial design: Past, present, and future in the context of big data and precision medicine.

Clinical trials are fundamental for advances in cancer treatment. The traditional framework of phase 1 to 3 trials is designed for incremental advances between regimens. However, our ability to understand and treat cancer has evolved with the increase in drugs targeting an expanding array of therapeutic targets, the development of progressively comprehensive data sets, and emerging computational analytics, all of which are reshaping our treatment strategies. A more robust linkage between drugs and underlying cancer biology is blurring historical lines that define trials on the basis of cancer type. The complexity of the molecular basis of cancer, coupled with manifold variations in clinical status, is driving the individually tailored use of combinations of precision targeted drugs. This approach is spawning a new era of clinical trial types. Although most care is delivered in a community setting, large centers support real-time multi-omic analytics and their integrated interpretation by using machine learning in the context of real-world data sets. Coupling the analytic capabilities of large centers to the tailored delivery of therapy in the community is forging a paradigm that is optimizing service for patients. Understanding the importance of these evolving trends across the health care spectrum will affect our treatment of cancer in the future and is the focus of this review.