Outcome selection for tissue-agnostic drug trials for immune-mediated inflammatory diseases: a systematic review of core outcome sets and regulatory guidance

Background Tissue-agnostic drug development provides a paradigm shift in precision medicine and requires innovative trial designs. However, outcome selection for such trials can prove challenging. The objectives of this review were to: Identify and map core outcome sets (COS), across 11 immune-mediated inflammatory diseases (IMIDs) in order to facilitate the selection of relevant outcomes across the conditions for innovative trials of tissue-agnostic drug therapies. Compare outcomes or endpoints recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to identify and highlight similarities and differences. Methods The Core Outcome Measures in Effectiveness Trials (COMET), International Consortium for Health Outcomes Measurement (ICHOM), FDA and EMA databases were searched from inception to 28th December 2019. Two reviewers independently screened titles and abstracts of retrieved entries and conducted the subsequent full text screening. Hand searching of the reference lists and citation searching of the selected publications was conducted. The methodological quality of the included peer-reviewed articles was independently assessed by the reviewers based on the items of the COS–Standards for Development recommendations (COS–STAD) checklist. Core outcomes from the included publications were extracted and mapped across studies and conditions. Regulatory guidance from FDA and EMA, where available for clinical trials for the IMIDs, were obtained from their databases and recommendations on outcomes to measure directly compared. Results Forty-four COS publications were included in the final analysis. Outcomes such as disease activity, pain, fatigue, quality of life, physical function, work limitation/productivity, steroid use and biomarkers were recommended across majority of the conditions. There were significant similarities and differences in FDA and EMA recommendations. The only instance where either regulatory body directly referenced a COS was for jSLE—both referenced the Paediatric Rheumatology International Trials Organization (PRINTO) COS. Conclusions The findings from this systematic review provide valuable information to inform outcome selection in tissue-agnostic trials for IMIDs. There is a need for increased collaboration between regulators and COS developers and inclusion of regulators as key stakeholders in COS development to enhance the quality of COS. Trial registration Not registered.

Planning implementation and scale-up of physical activity interventions for people with walking difficulties: study protocol for the process evaluation of the ComeBACK trial

Background There is currently little evidence of planning for real-world implementation of physical activity interventions. We are undertaking the ComeBACK (Coaching and Exercise for Better Walking) study, a 3-arm hybrid Type 1 randomised controlled trial evaluating a health coaching intervention and a text messaging intervention. We used an implementation planning framework, the PRACTical planning for Implementation and Scale-up (PRACTIS), to guide the process evaluation for the trial. The aim of this paper is to describe the protocol for the process evaluation of the ComeBACK trial using the framework of the PRACTIS guide. Methods A mixed methods process evaluation protocol was developed informed by the Medical Research Council (MRC) guidance on process evaluations for complex interventions and the PRACTIS guide. Quantitative data, including participant questionnaires, health coach and administrative logbooks, and website and text message usage data, is being collected over the trial period. Semi-structured interviews and focus groups with trial participants, health coaches and health service stakeholders will explore expectations, factors influencing the delivery of the ComeBACK interventions and potential scalability within existing health services. These data will be mapped against the steps of the PRACTIS guide, with reporting at the level of the individual, provider, organisational and community/systems. Quantitative and qualitative data will elicit potential contextual barriers and facilitators to implementation and scale-up. Quantitative data will be reported descriptively, and qualitative data analysed thematically. Discussion This process evaluation integrates an evaluation of prospective implementation and scale-up. It is envisaged this will inform barriers and enablers to future delivery, implementation and scale-up of physical activity interventions. To our knowledge, this is the first paper to describe the application of PRACTIS to guide the process evaluation of physical activity interventions. Trial registration Australian and New Zealand Clinical Trials Registry (ANZCTR) Registration date: 10/12/2018.

Association between blood glucose levels and Glasgow Outcome Score in patients with traumatic brain injury: secondary analysis of a randomized trial

Background Blood glucose levels that are too high or too low after traumatic brain injury (TBI) negatively affect patient prognosis. This study aimed to demonstrate the relationship between blood glucose levels and the Glasgow Outcome Score (GOS) in TBI patients. Methods This study was based on a randomized, dual-center, open-label clinical trial. A total of 208 patients who participated in the randomized controlled trial were followed up for 5 years. Information on the disease, laboratory examination, insulin therapy, and surgery for patients with TBI was collected as candidate variables according to clinical importance. Additionally, data on 5-year and 6-month GOS were collected as primary and secondary outcomes, respectively. For multivariate analysis, a generalized additive model (GAM) was used to investigate relationships between blood glucose levels and GOS. The results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). We further applied a two- piecewise linear regression model to examine the threshold effect of blood glucose level and GOS. Results A total of 182 patients were included in the final analysis. Multivariate GAM analysis revealed that a bell-shaped relationship existed between average blood glucose level and 5-year GOS score or 6-month GOS score. The inflection points of the average blood glucose level were 8.81 (95% CI: 7.43–9.48) mmol/L considering 5-year GOS as the outcome and were 8.88 (95% CI 7.43−9.74) mmol/L considering 6-month GOS score as the outcome. The same analysis revealed that there was also a bell relationship between average blood glucose levels and the favorable outcome group (GOS score ≥ 4) at 5 years or 6 months. Conclusion In a population of patients with traumatic brain injury, blood glucose levels were associated with the GOS. There was also a threshold effect between blood glucose levels and the GOS. A blood glucose level that is either too high or too low conveys a poor prognosis. Trial registration ClinicalTrials.gov NCT02161055. Registered on 11 June 2014.

Effects of Bushen-Jiangya granules on blood pressure and pharmacogenomic evaluation in low-to-medium-risk hypertensive patients: study protocol for a randomized double-blind controlled trial

Introduction Hypertension is one of the most important risk factors for cardiovascular disease, and its control rates remain low worldwide. The most effective strategy is that patients with hypertension should be diagnosed and treated early. Preliminary studies showed that the Bushen Jiangya granule (BSJY) could suppress ventricular hypertrophy and inflammatory responses, lower blood pressure, and protect the target organs of hypertension. We designed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of BSJY in patients with low-to-medium risk hypertension. Methods and analysis This trial is a one-center, randomized, double-blind, placebo-controlled study. A total of 260 participants will be randomized in a 1:1 ratio to an experimental group (BSJY plus amlodipine) and a control group (placebo plus amlodipine). The trial cycle will last 8 weeks. The primary outcome is the change in 24-h average systolic and diastolic blood pressure. The secondary outcomes include heart rate variability, pharmacogenomic evaluation, improvement in TCM syndrome, and serum pro-inflammatory/anti-inflammatory cytokines between the two groups. The safety of medication will also be evaluated. All the data will be recorded in electronic case report forms and analyzed by SPSS V.22.0. Ethics and dissemination This study has been approved by the Research Ethics Committee of Guang’anmen Hospital, China Academy of Chinese Medical Sciences in Beijing, China (No. 2019-186-KY-01). The participants are volunteers, understand the process of this trial, and sign an informed consent. The results of this study will be disseminated to the public through peer-reviewed journals and academic conferences. Discussion We hypothesize that patients with low-to-medium-risk hypertension will benefit from BSJY. If successful, this study will provide evidence-based recommendations for clinicians. Trial registration Chinese Clinical Trial Registry ChiMCTR1900002876. Registered in November 2019

Effect of dexamethasone in patients with ARDS and COVID-19 (REMED trial)—study protocol for a prospective, multi-centre, open-label, parallel-group, randomized controlled trial

Background Since December 2019, SARS-CoV-2 virus has infected millions of people worldwide. In patients with COVID-19 pneumonia in need of oxygen therapy or mechanical ventilation, dexamethasone 6 mg per day is currently recommended. However, the dose of 6 mg of dexamethasone is currently being reappraised and may miss important therapeutic potential or may prevent potential deleterious effects of higher doses of corticosteroids. Methods REMED is a prospective, open-label, randomised controlled trial testing the superiority of dexamethasone 20 mg (dexamethasone 20 mg on days 1–5, followed by dexamethasone 10 mg on days 6–10) vs 6 mg administered once daily intravenously for 10 days in adult patients with moderate or severe ARDS due to confirmed COVID-19. Three hundred participants will be enrolled and followed up for 360 days after randomization. Patients will be randomised in a 1:1 ratio into one of the two treatment arms. The following stratification factors will be applied: age, Charlson Comorbidity Index, CRP levels and trial centre. The primary endpoint is the number of ventilator-free days (VFDs) at 28 days after randomisation. The secondary endpoints are mortality from any cause at 60 days after randomisation; dynamics of the inflammatory marker, change in WHO Clinical Progression Scale at day 14; and adverse events related to corticosteroids and independence at 90 days after randomisation assessed by the Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days. The study will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. Discussion We aim to compare two different doses of dexamethasone in patients with moderate to severe ARDS undergoing mechanical ventilation regarding efficacy and safety. Trial registration EudraCT No. 2020-005887-70. ClinicalTrials.gov NCT04663555. Registered on December 11, 2020

Measuring implementation fidelity in a cluster-randomized pragmatic trial: development and use of a quantitative multi-component approach

Background In pragmatic trials, on-site partners, rather than researchers, lead intervention delivery, which may result in implementation variation. There is a need to quantitatively measure this variation. Applying the Framework for Implementation Fidelity (FIF), we develop an approach for measuring variability in site-level implementation fidelity. This approach is then applied to measure site-level fidelity in a cluster-randomized pragmatic trial of Music & MemorySM (M&M), a personalized music intervention targeting agitated behaviors in residents living with dementia, in US nursing homes (NHs). Methods Intervention NHs (N = 27) implemented M&M using a standardized manual, utilizing provided staff trainings and iPods for participating residents. Quantitative implementation data, including iPod metadata (i.e., song title, duration, number of plays), were collected during baseline, 4-month, and 8-month site visits. Three researchers developed four FIF adherence dimension scores. For Details of Content, we independently reviewed the implementation manual and reached consensus on six core M&M components. Coverage was the total number of residents exposed to the music at each NH. Frequency was the percent of participating residents in each NH exposed to M&M at least weekly. Duration was the median minutes of music received per resident day exposed. Data elements were scaled and summed to generate dimension-level NH scores, which were then summed to create a Composite adherence score. NHs were grouped by tercile (low-, medium-, high-fidelity). Results The 27 NHs differed in size, resident composition, and publicly reported quality rating. The Composite score demonstrated significant variation across NHs, ranging from 4.0 to 12.0 [8.0, standard deviation (SD) 2.1]. Scaled dimension scores were significantly correlated with the Composite score. However, dimension scores were not highly correlated with each other; for example, the correlation of the Details of Content score with Coverage was τb = 0.11 (p = 0.59) and with Duration was τb = − 0.05 (p = 0.78). The Composite score correlated with CMS quality star rating and presence of an Alzheimer’s unit, suggesting face validity. Conclusions Guided by the FIF, we developed and used an approach to quantitatively measure overall site-level fidelity in a multi-site pragmatic trial. Future pragmatic trials, particularly in the long-term care environment, may benefit from this approach. Trial registration Clinicaltrials.gov NCT03821844. Registered on 30 January 2019, https://clinicaltrials.gov/ct2/show/NCT03821844.

Pneumococcal conjugate vaccination schedules in infants—acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study

Background Pneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial. Methods PVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative ‘1+1’ schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard ‘3+0’ schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. Discussion Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules. Trial registration International Standard Randomised Controlled Trial Number 72821613.

Design and rationale for a comparison study of Olmesartan and Valsartan On myocardial metabolism In patients with Dilated cardiomyopathy (OVOID) trial: study protocol for a randomized controlled trial

Background Dilated cardiomyopathy (DCMP) is characterized by ventricular chamber enlargement and systolic dysfunction which may cause heart failure. Patients with DCMP have overactivation of the renin-angiotensin-aldosterone systems, which can also adversely affect myocardial metabolism in heart failure. The impairment of myocardial metabolism can contribute to the progression of left ventricular remodeling and contractile dysfunction in heart failure. Although angiotensin II receptor blockers (ARBs) have been used to treat patients with DCMP, there has been no direct comparison of the efficacy of these agents. The objective of this study is to compare the effects of olmesartan and valsartan on myocardial metabolism in patients with DCMP. Methods/design The OVOID study (a comparison study of Olmesartan and Valsartan On myocardial metabolism In patients with Dilated cardiomyopathy) is designed as a non-blinded, open-label, parallel-group, prospective, randomized, controlled, multicenter clinical trial. A total of 40 DCMP patients aged between 20 and 85 years will be randomly allocated into the olmesartan or the valsartan group. 18F-fluoro-2-deoxyglucose (FDG) cardiac positron emission tomography (PET) will be performed at baseline and six months after receiving the study agent. The primary endpoint is myocardial glucose consumption per square meter, measured using 18F-FDG PET 6 months after receiving the study agent. Discussion The purpose of this trial is to compare the efficacy between olmesartan and valsartan in improving myocardial metabolism in DCMP patients. This will be the first randomized comparative study investigating the differential effects of ARBs on heart failure. Trial registration ClinicalTrials.govNCT04174456. Registered on 18 November 2019

Blood flow restriction with different load levels in patients with knee osteoarthritis: protocol of a randomized controlled trial

Background The effectiveness of blood flow restriction training (BFR) in elderly with knee osteoarthritis (OA) is comparable to performing high-intensity protocols (70 to 80% of 1 RM [repetition maximum]) that are known to be effective for improving the muscle strength of knee extensors, with the advantage of generating less particular rating of perceived exertion and pain immediately after training. However, despite being a promising alternative, little is known about the best way to apply the BFR, such as level of pressure and combination or not with other therapeutic modalities. The purpose of this study is to evaluate whether different levels of blood flow restriction with low load (BFR + LL) and no load (BFR + rest) are non-inferior to high-intensity resistance exercise (HIRE+BFRplacebo) for pain reduction in patients with knee OA. Methods/design This clinical trial is a non-inferiority, five-arm, randomized, active-controlled, single trial which will be carried out in 165 patients of both sexes with knee OA, aged 50 years and older. Participants will be randomly allocated into 5 exercise groups (40% of BFR + LL; 80% of BFR + LL; 40% of BFR + rest; 80% BFR + rest, and HIRE+BFR placebo). A mixed linear model will be used to examine the effect of group-by-time interaction on pain intensity on the WOMAC subscale (primary outcome) and on disease severity, physical functional data, balance data, quality of life, global perceived effect scale, and muscle strength (secondary outcomes). Participants will be analyzed for intention-to-treat, and the statistical assessor blinded to the groups. The collection of outcomes 72 h after completion of the 16 weeks of interventions will be the primary measurement point. Follow-up secondary timepoints will be collected at 20, 28, 40, 52, and 64 weeks after the end of interventions, except for pain during the training, which will be measured immediately at the end of each session. Only the comparison of the primary outcome between the HIRE group with each BFR group will be analyzed in the non-inferiority framework, the other comparisons between the BFR groups for the primary outcome, and all secondary outcomes will be interpreted in the superiority framework. Discussion The results of this clinical trial can point out more clearly to ways to optimize the BFR training with the minimum of pain immediately after training, which will allow the offer of an effective and more adherent strengthening training to patients with knee OA. Trial registration Registro Brasileiro de Ensaios Clínicos, RBR-93rx9q. Registered on 23 July 2020. Version 1.0.