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.

Outcome selection in primary care antimicrobial stewardship research

Clinical and antimicrobial stewardship (AMS) outcomes are highly relevant to pragmatic primary care trials, reflecting aspects, such as persistent symptoms and relapses, or antibiotic use and antimicrobial resistance. Sometimes both can be equally important. We present evidence demonstrating the wide range of outcome measures used in previous primary care trials and observe that there are no agreed standards for their design. We describe AMS interventions and outcomes in terms of intervention types and targets, and we make recommendations for future research designs. Specifically, we argue that: (i) where co-primary outcomes are considered appropriate, investigators should pre-specify interpretation of conflicting results; (ii) intervention evaluation should ensure prescriptions from sources outside of the usual provider are included in any AMS effectiveness measure; (iii) where possible, outcomes should include antimicrobial resistance; (iv) in some contexts, it may be necessary to include the antibiotics used within the intervention as part of the outcome; and (v) patient involvement is needed to establish the principles investigators should use when deciding whether the AMS or clinical outcomes should be prioritized.

558 Summarising the Reporting of Outcomes in Studies of Robot Assisted Cholecystectomy: A Systematic Review

Background Robot-assisted cholecystectomy (RC) has seen increasing adoption into clinical practice despite a lack of evidence to demonstrate superiority over conventional methods. Consistency in outcome selection, definition and reporting between studies is required for effective evidence synthesis and to minimise research waste. The aim of this study was to conduct an in-depth analysis of the outcomes reported in studies of RC. This work will inform the need for a core outcome set (COS). Method Systematic searches identified all published studies reporting RC, from inception to February 2020. Outcomes reported in each manuscript were recorded verbatim and categorised into domains. All outcomes were coded in duplicate. Where reported, the follow up period of each study was documented. Results Of 1425 abstracts screened, ninety studies met the criteria for inclusion. A total of 878 outcomes were reported. Each study included a median of 8 outcomes (range 3-26). Outcome selection was heterogeneous, with those relating to technical/operative factors (n = 383, 88 studies), complications (n = 245, 81 studies) and health economics (n = 139, 72 studies) used most frequently. No single outcome, or outcome domain, was reported in all studies. Only 30 studies reported a follow-up period, which ranged from 14 days to 46 months. In thirteen, the follow-up was for less than or equal to one month. Conclusions We identified significant heterogeneity in the selection and reporting of outcomes in studies of RC and support calls for standardisation and development of a COS.

Outcomes and measures of delirium interventional studies in palliative care to inform a core outcome set: A systematic review

Background: Trials of interventions for delirium in various patient populations report disparate outcomes and measures but little is known about those used in palliative care trials. A core outcome set promotes consistency of outcome selection and measurement. Aim: To inform core outcome set development by examining outcomes, their definitions, measures and time-points in published palliative care studies of delirium prevention or treatment delirium interventions. Design: Prospectively registered systematic review adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Data sources: We searched six electronic databases (1980–November 2020) for original studies, three for relevant reviews and the International Clinical Trials Registry Platform for unpublished studies and ongoing trials. We included randomised, quasi-randomised and non-randomised intervention studies of pharmacological and non-pharmacological delirium prevention and/or treatment interventions. Results: From 13/3244 studies (2863 adult participants), we identified 9 delirium-specific and 13 non-delirium specific outcome domains within eight Core Outcome Measures in Effectiveness Trials (COMET) taxonomy categories. There were multiple and varied outcomes and time points in each domain. The commonest delirium specific outcome was delirium severity ( n = 7), commonly using the Memorial Delirium Assessment Scale (6/8 studies, 75%). Four studies reported delirium incidence. Non-delirium specific outcomes included mortality, agitation, adverse events, other symptoms and quality of life. Conclusion: The review identified few delirium interventions with heterogeneity in outcomes, their definition and measurement, highlighting the need for a uniform approach. Findings will inform the next stage to develop consensus for a core outcome set to inform delirium interventional palliative care research.

A review of the Cochrane COVID-19 Study Register reveals inconsistency in the choice and measurement of SARS-CoV-2 infection outcomes in prevention trials

Background: Multiple studies are evaluating how to prevent SARS-CoV-2 infection. Interventions are wide ranging and include vaccines, prophylactic drugs, public health safety measures, and behavioural interventions. Heterogeneity in the outcomes measured and reported is leading to research waste and inefficiency, slowing worldwide identification and implementation of effective methods to prevent infection. A core outcome set (COS) for studies of interventions to prevent SARS-CoV-2 infection has recently been developed, identifying infection as a critical outcome to measure. This paper examines how SARS-CoV-2 infection outcomes are measured in registered COVID-19 prevention trials and considers how this can be improved. Methods: We searched the Cochrane COVID-19 Study Register to identify and review SARS-CoV-2 infection outcomes in prevention trials, including the rationale for choice of outcome measurement. We included phase 3 and 4 trials of COVID-19 prevention interventions. Early phase trials and studies relating to the transmission, treatment or management of COVID-19 were excluded. Results: We identified 430 entries in the register, of which 199 unique prevention trials were included across eight settings and 12 intervention types. Fifteen (8%) trials did not include any SARS-CoV-2 infection outcomes. The remaining 184 (92%) studies included a total of 268 SARS-CoV-2 infection outcomes, of which 32 (17%) did not specify how infection would be measured. Testing (i.e. formal diagnostic test) as a standalone method for determining infection was used in 57 (31%) trials, whereas defining infection by symptoms alone was used in 16 (9%) trials. All other trials (n=79, 43%) included multiple infection outcomes, defined in different ways. Discussion: There is considerable variation in how SARS-CoV-2 infection is measured within and across different interventions and settings. Furthermore, few studies report the rationale for outcome selection and measurement. Better transparency and standardisation of SARS-CoV-2 infection measurement is needed for the findings from prevention trials to inform decision-making.

Protocol for Light-Dark and Activity Rhythm Therapy for sleep: Feasibility and acceptability in Schizophrenia spectrum disorders (L-DART FitSz)

BackgroundSleep problems are common in people with diagnoses of schizophrenia spectrum disorders (> 50%), even during periods of relative stability of psychotic symptoms. Evidence suggests that people living with schizophrenia spectrum disorders are often keen to improve their sleep, but few non-pharmacological sleep treatments are available to patients in specialist mental health services. It has been proposed that occupational therapists may have the relevant skills for the delivery of behavioural sleep interventions. This mixed method, proof-of-concept study aims to assess the feasibility and acceptability of a new intervention, Light-Dark and Activity Rhythm Therapy (L-DART), to improve sleep in people with schizophrenia spectrum disorder diagnoses.MethodsA single group of 10 service users with schizophrenia spectrum diagnoses and self-reported problems with sleep onset, maintenance, timing or quality will be offered L-DART. L-DART will be delivered over 6–9 in person sessions and 3–6 phonecalls by an occupational therapist. Feasibility measures will comprise recruitment and retention logs, fidelity based on session records, adverse effects, and study attrition. Intervention uptake, engagement and adherence will be measured, and barriers to adherence explored. Acceptability will be assessed though quantitative satisfaction ratings and qualitative interviews. Activity patterns and dynamic light exposure will be measured, as well as self-reported sleep, wellbeing and functioning, to inform outcome selection in a larger trial.DiscussionThe findings will inform any necessary modifications to the intervention and its materials, enabling the development of a stage 2 manual and a therapist training package. The results will support the design of a randomised multi-therapist feasibility trial.Trial registrationISRCTN11998005, assigned registration on 17.02.2020

Methodology in core outcome set (COS) development: the impact of patient interviews and using a 5-point versus a 9-point Delphi rating scale on core outcome selection in a COS development study

Background As the development of core outcome sets (COS) increases, guidance for developing and reporting high-quality COS continues to evolve; however, a number of methodological uncertainties still remain. The objectives of this study were: (1) to explore the impact of including patient interviews in developing a COS, (2) to examine the impact of using a 5-point versus a 9-point rating scale during Delphi consensus methods on outcome selection and (3) to inform and contribute to COS development methodology by advancing the evidence base on COS development techniques. Methods Semi-structured patient interviews and a nested randomised controlled parallel group trial as part of the Pelvic Girdle Pain Core Outcome Set project (PGP-COS). Patient interviews, as an adjunct to a systematic review of outcomes reported in previous studies, were undertaken to identify preliminary outcomes for including in a Delphi consensus survey. In the Delphi survey, participants were randomised (1:1) to a 5-point or 9-point rating scale for rating the importance of the list of preliminary outcomes. Results Four of the eight patient interview derived outcomes were included in the preliminary COS, however, none of these outcomes were included in the final PGP-COS. The 5-point rating scale resulted in twice as many outcomes reaching consensus after the 3-round Delphi survey compared to the 9-point scale. Consensus on all five outcomes included in the final PGP-COS was achieved by participants allocated the 5-point rating scale, whereas consensus on four of these was achieved by those using the 9-point scale. Conclusions Using patient interviews to identify preliminary outcomes as an adjunct to conducting a systematic review of outcomes measured in the literature did not appear to influence outcome selection in developing the COS in this study. The use of different rating scales in a Delphi survey, however, did appear to impact on outcome selection. The 5-point scale demonstrated greater congruency than the 9-point scale with the outcomes included in the final PGP-COS. Future research to substantiate our findings and to explore the impact of other rating scales on outcome selection during COS development, however, is warranted.

Methodology in core outcome set (COS) development: the impact of patient interviews and using a 5-point versus a 9-point Delphi rating scale on core outcome selection in a COS development study.

Background: As the development of core outcome sets (COS) increases, guidance for developing and reporting high-quality COS continues to evolve; however, a number of methodological uncertainties still remain. The objectives of this study were: (1) to explore the impact of including patient interviews in developing a COS, (2) to examine the impact of using a 5-point versus a 9-point rating scale during Delphi consensus methods on outcome selection and (3) to inform and contribute to COS development methodology by advancing the evidence base on COS development techniques. Methods: Semi-structured patient interviews and a nested randomised controlled parallel group trial as part of the Pelvic Girdle Pain Core Outcome Set project (PGP-COS). Patient interviews, as an adjunct to a systematic review of outcomes reported in previous studies, were undertaken to identify preliminary outcomes for including in a Delphi consensus survey. In the Delphi survey, participants were randomised (1:1) to a 5-point or 9-point rating scale for rating the importance of the list of preliminary outcomes. Results: Four of the eight patient interview derived outcomes were included in the preliminary COS, however, none of these outcomes were included in the final PGP-COS. The 5-point rating scale resulted in twice as many outcomes reaching consensus after the 3-round Delphi survey compared to the 9-point scale. Consensus on all five outcomes included in the final PGP-COS was achieved by participants allocated the 5-point rating scale, whereas consensus on four of these was achieved by those using the 9-point scale. Conclusions: Using patient interviews to identify preliminary outcomes as an adjunct to conducting a systematic review of outcomes measured in the literature did not appear to influence outcome selection in developing the COS in this study. The use of different rating scales in a Delphi survey, however, did appear to impact on outcome selection. The 5-point scale demonstrated greater congruency than the 9-point scale with the outcomes included in the final PGP-COS. Future research to substantiate our findings and to explore the impact of other rating scales on outcome selection during COS development, however, is warranted.

Important research outcomes for treatment studies of perinatal depression: systematic overview and development of a core outcome set

Objective To develop a Core Outcome Set (COS) for treatment of perinatal depression Design Systematic overview of outcomes reported in the literature and consensus development study using a Delphi survey and modified nominal group technique. Setting International. Population Two hundred and twenty-two participants, representing thirteen countries. Methods A systematic overview of outcomes reported in recently published research, a two-round Delphi survey, a consensus meeting at which the final COS was decided. Main results In the literature search, 1772 abstracts were identified and evaluated, 284 papers/protocols were assessed in full and 165 studies were finally included in the review. In all, 106 outcomes were identified and thus included in the Delphi survey. 222 participants registered for the first round of the Delphi survey and 151 (68%) responded. In the second round, 123 (55%) participants responded. The following 9 outcomes were agreed upon for inclusion in the final COS: self-assessed symptoms of depression, diagnosis of depression by a clinician, parent to infant bonding, self-assessed symptoms of anxiety, quality of life, satisfaction with intervention, suicidal thoughts, attempted or committed suicide, thoughts of harming the baby, and adverse events. Conclusions The relevant stakeholders prioritised outcomes and reached consensus on a COS comprising nine outcomes. We hope that this COS will contribute to consistency and uniformity of outcome selection and reporting in future clinical trials involving treatment of perinatal depression Funding This article is adapted from a report by SBU, which provided funding for the study. Keywords: perinatal depression, postpartum depression, antenatal depression, COS