Effects of exercise in breast cancer patients: implications of the trials within cohorts (TwiCs) design in the UMBRELLA Fit trial

Purpose The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of exercise on quality of life (QoL) and fatigue in inactive breast cancer survivors. Methods UMBRELLA Fit was conducted within the prospective UMBRELLA breast cancer cohort. Patients provided consent for future randomization at cohort entry. We randomized inactive patients 12–18 months after cohort enrollment. The intervention group (n = 130) was offered a 12-week supervised exercise intervention. The control group (n = 130) was not informed and received usual care. Six-month exercise effects on QoL and fatigue as measured in the cohort were analyzed with intention-to-treat (ITT), instrumental variable (IV), and propensity scores (PS) analyses. Results Fifty-two percent (n = 68) of inactive patients accepted the intervention. Physical activity increased in patients in the intervention group, but not in the control group. We found no benefit of exercise for dimensions of QoL (ITT difference global QoL: 0.8, 95% CI = − 2.2; 3.8) and fatigue, except for a small beneficial effect on physical fatigue (ITT difference: − 1.1, 95% CI = − 1.8; − 0.3; IV: − 1.9, 95% CI = − 3.3; − 0.5, PS: − 1.2, 95% CI = − 2.3; − 0.2). Conclusion TwiCs gave insight into exercise intervention acceptance: about half of inactive breast cancer survivors accepted the offer and increased physical activity levels. The offer resulted in no improvement on QoL, and a small beneficial effect on physical fatigue. Trial registration Netherlands Trial Register (NTR5482/NL.52062.041.15), date of registration: December 07, 2015.

Prospective bladder cancer infrastructure for experimental and observational research on bladder cancer: study protocol for the ‘trials within cohorts’ study ProBCI

IntroductionA better understanding of the molecular profile of bladder tumours, the identification of novel therapeutic targets, and introduction of new drugs and has renewed research interest in the field of bladder cancer. We describe the design and setup of a Dutch Prospective Bladder Cancer Infrastructure (ProBCI) as a means to stimulate and accelerate clinically meaningful experimental and observational research.Methods and analysisProBCI entails an open cohort of patients with bladder cancer in which the trials within cohorts (TwiCs) design can be embedded. Physicians in participating hospitals prospectively recruit invasive (≥T1) patients with bladder cancer on primary diagnosis for inclusion into the study. Extensive clinical data are collected and updated every 4 months, along with patient-reported outcomes and biomaterials. Informed consent includes participation in TwiCs studies and renewed contact for future studies. Consent for participation in questionnaires and molecular analyses that may yield incidental findings is optional.Ethics and disseminationThe Dutch ProBCI is a unique effort to construct a nation-wide cohort of patients with bladder cancer including clinical data, patient-reported outcomes and biomaterial, to facilitate observational and experimental research. Data and materials are available for other research groups on request through www.probci.nl. Ethics approval was obtained from METC Utrecht (reference: NL70207.041.19).Trial registration numberNCT04503577.

Treating to target in psoriatic arthritis: assessing real-world outcomes and optimising therapeutic strategy for adults with psoriatic arthritis—study protocol for the MONITOR-PsA study, a trials within cohorts study design

Background The Tight Control of psoriatic arthritis (TICOPA) trial confirmed improved clinical outcomes with a treat to target (T2T) strategy in psoriatic arthritis (PsA). This consisted of 4-weekly review and escalation of ‘step up’ therapy (single disease modifying therapy (DMARD), combination DMARDs and then biologics) based on remission criteria. Based on this, a T2T approach is supported by European PsA treatment recommendations. However, it is not commonly implemented in routine care primarily due to feasibility and cost concerns. In the TICOPA trial, the same treatment regime was used for all participants regardless of their disease profile. Despite the recognition of PsA as a highly heterogeneous condition, no studies have tailored which drugs are used depending on disease severity. The cohort will establish real world outcomes for the T2T approach in PsA and also form the basis of a trials within cohorts (TWiCs) design to test alternative therapeutic approaches within embedded clinical trials providing an evidence base for treatment strategy in PsA. Methods The Multicentre Observational Initiative in Treat to target Outcomes in Psoriatic Arthritis (MONITOR-PsA) cohort will apply a T2T approach within routine care. It will recruit newly diagnosed adult patients with PsA starting systemic therapies. The cohort is observational allowing routine therapeutic care within NHS clinics but a T2T approach will be supported when monitoring treatment within the cohort. Eligible participants will be adults (≥18 years) with active PsA with ≥ 1 tender or swollen joints or enthesis who have not previously had treatment with DMARDs for articular disease. Discussion This study is the first TWiC designed to support a fully powered randomised drug trial. The results from the observational cohort will be compared with those observed in the TICOPA trial investigating the clinical effectiveness and health care costs of the pragmatic T2T approach. Nested trials will provide definitive RCT evidence establishing the optimal management of PsA within the T2T approach. The TWiCs design allows robust generalizability to routine healthcare, avoids disappointment bias, aids recruitment and in future will allow assessment of longer-term outcomes. Trial registration ClinicalTrials.gov NCT03531073. Retrospectively registered on 21 May 2018.