Multiple Randomized Controlled Trial Design Research Articles

Randomized feasibility trial of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program

BackgroundThe Scleroderma Patient-centered Intervention Network (SPIN) developed an online self-management program (SPIN-SELF) designed to improve disease-management self-efficacy in people with systemic sclerosis (SSc, or scleroderma). The aim of this study was to evaluate feasibility aspects for conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF Program.MethodsThis feasibility trial was embedded in the SPIN Cohort and utilized the cohort multiple RCT design. In this design, at the time of cohort enrollment, cohort participants consent to be assessed for trial eligibility and randomized prior to being informed about the trial. Participants in the intervention arm are informed and provide consent, but not the control group. Forty English-speaking SPIN Cohort participants from Canada, the USA, or the UK with low disease-management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale [SEMCD] score ≤ 7) who were interested in using an online self-management program were randomized (3:2 ratio) to be offered the SPIN-SELF Program or usual care for 3 months. Program usage was examined via automated usage logs. User satisfaction was assessed with semi-structured interviews. Trial personnel time requirements and implementation challenges were logged.ResultsOf 40 SPIN Cohort participants randomized, 26 were allocated to SPIN-SELF and 14 to usual care. Automated eligibility and randomization procedures via the SPIN Cohort platform functioned properly, except that two participants with SEMCD scores > 7 (scores of 7.2 and 7.3, respectively) were included, which was caused by a system programming error that rounded SEMCD scores. Of 26 SPIN Cohort participants offered the SPIN-SELF Program, only 9 (35%) consented to use the program. Usage logs showed that use of the SPIN-SELF Program was low: 2 of 9 users (22%) logged into the program only once (median = 3), and 4 of 9 (44%) accessed none or only 1 of the 9 program’s modules (median = 2).ConclusionsThe results of this study will lead to substantial changes for the planned full-scale RCT of the SPIN-SELF Program that we will incorporate into a planned additional feasibility trial with progression to a full-scale trial. These changes include transitioning to a conventional RCT design with pre-randomization consent and supplementing the online self-help with peer-facilitated videoconference-based groups to enhance engagement.Trial registrationclinicaltrials.gov, NCT03914781. Registered 16 April 2019.

The Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program: protocol for a two-arm parallel partially nested randomized controlled feasibility trial with progression to full-scale trial

BackgroundSystemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary).MethodsThis study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort (http://www.spinsclero.com/en/cohort) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important modifications, thereby requiring a re-set for the full-scale trial. Otherwise, the full-scale RCT will proceed, and outcome data from the feasibility portion will be utilized in the full-scale trial. In the full-scale RCT, 524 participants will be recruited.DiscussionThe SPIN-SELF Program may improve disease management self-efficacy, patient activation, social appearance anxiety, and functional health outcomes in people with SSc. SPIN works with partner patient organizations around the world to disseminate its programs free-of-charge.Trial registrationClinicalTrials.govNCT04246528. Registered on 27 January 2020

CHI study: protocol for an observational cohort study on ageing and mental health in community-dwelling older adults

IntroductionAgeing is associated with a multitude of healthcare issues including dementia, depression, frailty, morbidity associated with chronic disease and high healthcare utilisation. With Singapore’s population projected to age significantly over...

Factors associated with patient-reported likelihood of using online self-care interventions: a Scleroderma Patient-centered Intervention Network (SPIN) cohort study

ObjectivesThe Scleroderma Patient-centered Intervention Network (SPIN) Cohort uses the cohort multiple randomised controlled trial design to embed trials of online self-care interventions for people living with systemic sclerosis (SSc; scleroderma)....

Frailty Intervention Trial iN End-Stage patientS on haemodialysis (FITNESS): study protocol for a randomised controlled trial

BackgroundFrailty is a state of low physiological reserve and multi-systemic dysregulation that leads to susceptibility to external stressors; it is associated with adverse outcomes. North American data suggest that haemodialysis recipients are more likely to be frail than the general population, although data on UK cohorts are lacking. Furthermore, with a multitude of assessment tools, it is difficult for the clinician to ascertain which is most suitable for this population. The FITNESS Study aims to measure the prevalence and outcomes associated with frailty in a large UK haemodialysis cohort to determine the optimum frailty tool as defined by predictive value for mortality/hospitalisation and to conduct a feasibility study exploring a multi-disciplinary clinical intervention to improve frailty among haemodialysis recipients.Methods/designThe study will follow a cohort multiple randomised controlled trial design; the initial cohort study will identify participants to be invited into a subsequent open-label randomised controlled trial. Eligible patients will be identified and recruited from their usual haemodialysis session. They will be invited to complete tasks and questionnaires collecting data on sarcopenia, immunosenescence, mood, cognition, disability, and comorbidity. Fifty pre-frail participants with suitable English proficiency will be randomly selected from this cohort to participate in the randomised controlled trial phase of the study. Further stratified randomisation will occur to assign these 50 participants to active or passive groups. The active group will receive a psychologically supported, patient-centred, multi-disciplinary intervention into frailty, in what we believe to be a first within this patient group. The control group will receive usual haemodialysis standard of care. All participants will be followed up using electronic patient records for outcomes to include hospitalisation and mortality. Primary outcomes for this phase of the study will be feasibility and tolerability of the clinical intervention study.DiscussionThe study will collect data on multiple aspects of frailty allowing for a rich dataset for detailed analysis. We believe this will be the first study to explore a psychologically supported, patient-centred intervention in this patient group.Trial registrationClinicaltrials.gov, NCT03071107. Registered on 6 March 2017.

Investigation of the “m” in the cmRCT (cohort multiple randomized controlled trial) design revealed dependence between trial results

Investigation of the “m” in the cmRCT (cohort multiple randomized controlled trial) design revealed dependence between trial results

The cohort multiple randomized controlled trial design was found to be highly susceptible to low statistical power and internal validity biases

ObjectivesThe “cohort multiple randomized controlled trial” (cmRCT) is a recent innovation by which novel interventions are trialed within large longitudinal cohorts of patients to gain efficiencies and align trials more closely to standard clinical practice. The use of cmRCTs is outpacing its methodological understanding, and more appropriate methods for designing and analyzing such trials are urgently needed. Study Design and SettingWe established the UK Comprehensive Longitudinal Assessment of Salford Integrated Care cohort of 4,377 patients with long-term conditions within which we are conducting a cmRCT (“Proactive Telephone Coaching and Tailored Support”) of telephone-based health coaching. ResultsWe identify some key methodological challenges to the use of the cmRCT in actual practice. Principal are issues around statistical power, sample size, and treatment effect estimation, for which we provide appropriate methods. Sampling procedures commonly applied in conventional RCTs can result in unintentional selection bias. The fixed data collection points that feature in cmRCTs can also threaten validity. ConclusionThe cmRCT may offer advantages over conventional trial designs. However, a cmRCT requires appropriate power calculation, sampling, and analysis procedures; else, studies may be underpowered or subject to validity biases. We offer solutions to some of the key issues, but further methodological investigations are needed. Cohort multiple RCT–specific Consolidated Standards of Reporting Trials guidance may be indicated.

Benefits and challenges of using the cohort multiple randomised controlled trial design for testing an intervention for depression

BackgroundTrials which test the effectiveness of interventions compared with the status quo frequently encounter challenges. The cohort multiple randomised controlled trial (cmRCT) design is an innovative approach to the design and conduct of pragmatic trials which seeks to address some of these challenges.Main textIn this article, we report our experiences with the first completed randomised controlled trial (RCT) using the cmRCT design. This trial—the Depression in South Yorkshire (DEPSY) trial—involved comparison of treatment as usual (TAU) with TAU plus the offer of an intervention for people with self-reported long-term moderate to severe depression. In the trial, we used an existing large population-based cohort: the Yorkshire Health Study. We discuss our experiences with recruitment, attrition, crossover, data analysis, generalisability of results, and cost. The main challenges in using the cmRCT design were the high crossover to the control group and the lower questionnaire response rate among patients who refused the offer of treatment. However, the design did help facilitate efficient and complete recruitment of the trial population as well as analysable data that were generalisable to the population of interest. Attrition rates were also smaller than those reported in other depression trials.ConclusionThis first completed full trial using the cmRCT design testing an intervention for self-reported depression was associated with a number of important benefits. Further research is required to compare the acceptability and cost effectiveness of standard pragmatic RCT design with the cmRCT design.Trial registrationISRCTN registry: ISRCTN02484593. Registered on 7 Jan 2013.

Abstract CT067: The Prospective Dutch ColoRectal Cancer Cohort (PLCRC): a prospective nationwide observational cohort study providing the infrastructure for registry based trials

Abstract Background: Colorectal cancer (CRC) was once considered a single entity, but now appears to exist of multiple, often molecular defined, subclasses. These subclasses have implications for treatment, and hamper the feasibility of prospective randomized clinical trials which require large sample sizes. To anticipate further developments and to obtain more detailed insight in the outcome of daily practice, the Prospective Dutch CRC cohort (PLCRC) was initiated. In this prospective observational multicenter cohort, patients with all stages of colorectal cancer are included, and clinical data, tissue, blood samples and patient-reported outcome measures are collected. The cohort serves as an infrastructure for registry based trials in the Netherlands (CRC incidence approximately 16.000 patients per year). Methods: Patients ≥18 years with histologically proven stage I-IV CRC are eligible to participate. The informed consent includes consent for systematic collection of long-term clinical data and optionally 1) standardized collection of tissue and blood samples; 2) being informed when clinically relevant DNA mutations are detected; 3) patient-reported outcome questionnaires; and 4) invitation for future interventional studies according to (amongst others) the cohort multiple randomized controlled trial design (cmRCT). Results: In 2016 the number of participating hospitals increased from 6 to 17. The number of included patients roughly doubled to more than 1100 patients. The PLCRC infrastructure is used in the execution of fifteen studies, which amongst others focus on the prognostic value of circulating tumor DNA, the quality of life during treatment with new compounds and the influence of nutrition on treatment outcome. The studies use the option to repeatedly withdraw blood, send out PROMs and/or randomize patients according to the cmRCT design. The study populations in the substudies vary from newly diagnosed stage 2 colon cancer to non-liver limited metastatic CRC. In 2017, at least 20 hospitals which are currently in the initiation process will be added with which a 50% coverage of the Dutch hospitals will be reached. Conclusions: PLCRC provides long-term clinical data, tissue, blood samples and patient-reported outcome measures of a large cohort of patients with colorectal cancer. The cohort will be representative of the colorectal cancer population in the Netherlands. Multiple studies are ongoing making use of the infrastructure provided. These studies will make it possible to optimize treatment for specific small subgroups. Citation Format: Geraldine Vink, Robert Coebergh van den Braak, Haiko Bloemendal, Veerle Coupé, Marloes Elferink, Frans Erdkamp, Helma van Grevenstein, Jan-Willem de Groot, Jan Ijzermans, Martijn Intven, Maartje Los, Mirre de Noo, Martijn van Oijen, Cornelis Punt, Ron Rietbroek, Wilfried Roeloffzen, Anandi Schiphorst, Huig Schipper, Hein Stockmann, Manuel Tjin-a-Ton, Ankie van der Velden, Marlies Verhaar, Wouter Vles, David Zimmerman, Gerrit Meijer, Miriam Koopman. The Prospective Dutch ColoRectal Cancer Cohort (PLCRC): a prospective nationwide observational cohort study providing the infrastructure for registry based trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT067. doi:10.1158/1538-7445.AM2017-CT067

Promising alternative for classic randomized controlled trials: first experience with the cohort multiple randomized controlled trial design in the oncologic setting

Promising alternative for classic randomized controlled trials: first experience with the cohort multiple randomized controlled trial design in the oncologic setting

Evaluation of biases present in the cohort multiple randomised controlled trial design: a simulation study

BackgroundThe cohort multiple randomised controlled trial (cmRCT) design provides an opportunity to incorporate the benefits of randomisation within clinical practice; thus reducing costs, integrating electronic healthcare records, and improving external validity. This study aims to address a key concern of the cmRCT design: refusal to treatment is only present in the intervention arm, and this may lead to bias and reduce statistical power.MethodsWe used simulation studies to assess the effect of this refusal, both random and related to event risk, on bias of the effect estimator and statistical power. A series of simulations were undertaken that represent a cmRCT trial with time-to-event endpoint. Intention-to-treat (ITT), per protocol (PP), and instrumental variable (IV) analysis methods, two stage predictor substitution and two stage residual inclusion, were compared for various refusal scenarios.ResultsWe found the IV methods provide a less biased estimator for the causal effect when refusal is present in the intervention arm, with the two stage residual inclusion method performing best with regards to minimum bias and sufficient power. We demonstrate that sample sizes should be adapted based on expected and actual refusal rates in order to be sufficiently powered for IV analysis.ConclusionWe recommend running both an IV and ITT analyses in an individually randomised cmRCT as it is expected that the effect size of interest, or the effect we would observe in clinical practice, would lie somewhere between that estimated with ITT and IV analyses. The optimum (in terms of bias and power) instrumental variable method was the two stage residual inclusion method. We recommend using adaptive power calculations, updating them as refusal rates are collected in the trial recruitment phase in order to be sufficiently powered for IV analysis.

Comparing conVEntional RadioTherapy with stereotactIC body radiotherapy in patients with spinAL metastases: study protocol for an randomized controlled trial following the cohort multiple randomized controlled trial design.

BackgroundStandard radiotherapy is the treatment of first choice in patients with symptomatic spinal metastases, but is only moderately effective. Stereotactic body radiation therapy is increasingly used to treat spinal metastases, without randomized evidence of superiority over standard radiotherapy. The VERTICAL study aims to quantify the effect of stereotactic radiation therapy in patients with metastatic spinal disease.Methods/designThis study follows the ‘cohort multiple Randomized Controlled Trial’ design. The VERTICAL study is conducted within the PRESENT cohort. In PRESENT, all patients with bone metastases referred for radiation therapy are enrolled. For each patient, clinical and patient-reported outcomes are captured at baseline and at regular intervals during follow-up. In addition, patients give informed consent to be offered experimental interventions. Within PRESENT, 110 patients are identified as a sub cohort of eligible patients (i.e. patients with unirradiated painful, mechanically stable spinal metastases who are able to undergo stereotactic radiation therapy). After a protocol amendment, also patients with non-spinal bony metastases are eligible. From the sub cohort, a random selection of patients is offered stereotactic radiation therapy (n = 55), which patients may accept or refuse. Only patients accepting stereotactic radiation therapy sign informed consent for the VERTICAL trial. Non-selected patients (n = 55) receive standard radiotherapy, and are not aware of them serving as controls. Primary endpoint is pain response after three months. Data will be analyzed by intention to treat, complemented by instrumental variable analysis in case of substantial refusal of the stereotactic radiation therapy in the intervention arm.DiscussionThis study is designed to quantify the treatment response after (stereotactic) radiation therapy in patients with symptomatic spinal metastases. This is the first randomized study in palliative care following the cohort multiple Randomized Controlled Trial design. This design addresses common difficulties associated with classic pragmatic randomized controlled trials, such as disappointment bias in patients allocated to the control arm, slow recruitment, and poor generalizability.Trial registrationThe Netherlands Trials Register number NL49316.041.14. ClinicalTrials.gov registration number NCT02364115. Date of trial registration February 1, 2015.

Prospective Dutch colorectal cancer cohort: an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research

Background: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients’ outcomes. With only 5–15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG).Methods/design: The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I–IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria.Results: Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients.Conclusion: This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

Abstract 1827: The prospective Dutch colorectal cancer cohort: A prospective nation-wide observational cohort study

Abstract The increasingly complex subclassification of tumors based on clinical and molecular characteristics, as well as the large sample sizes needed for clinical trials, pose new challenges to the recruitment of patients for studies. Currently, less than 10% of all cancer patients are enrolled in clinical trials, limiting their external validity, but also leaving room for improvement in the recruitment of patients. Clinical trials are often complicated by low inclusion rates, inadequate data collection, high non-completion rates and costs, and often provide insufficient data for post-hoc subgroup analyses. We believe that a prospective observational cohort study can provide standardized and validated collection of clinical data, tissue and blood samples and patient-reported outcome measures, and can improve patient recruitment for clinical trials. The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nation-wide observational cohort study in the Netherlands, a country with a yearly colorectal cancer incidence of 15,000 patients. The goal of the study is to facilitate future basic, translational and clinical research in the field of colorectal cancer for both national and international research groups with short or absent inclusion periods, even for studies with stringent inclusion criteria. All patients > 18 years with histologically proven colorectal cancer are asked to participate. Four essential features characterize the study: 1) a patient-centered informed-consent approach; 2) a framework to systematically collect long-term clinical follow-up and patient-reported outcomes; 3) an infrastructure for the standardized collection and storage of tissue and blood samples and 4) efficient recruitment for clinical trials which is facilitated by the innovative cohort multiple randomized controlled trial (cmRCT) design. The cmRCT design allows patients to participate in multiple non-conflicting clinical trials. We believe that the key to the development of a sustainable cohort study is the collaboration with existing organizations using their expertise, and preventing duplicate data entry and unnecessary costs. To these ends, close collaborations with other national initiatives, like the national cancer registry (hosted by IKNL), the national pathology registry PALGA, and the national biobanking infrastructure BBMRI-NL have been established. An effective governance structure to secure the privacy of patients and hospitals, and to facilitate research is needed. This study will provide long-term clinical data, tissue and blood samples, and patient-reported outcome measures collected under a broad informed consent, of a large cohort of patients with colorectal cancer. The available data and tissue will facilitate basic, translational and clinical research. Furthermore, the design of this cohort study can be used as an example for other tumor types. Citation Format: Robert R.J. Coebergh van den Braak, Geraldine R. Vink, Martijn G.H. van Oijen, Mirre E. de Noo, Sophie A. Kurk, Maarten J.P. Burbach, Alice M. Couwenberg, Anne M. May, Helena M. Verkooijen, Gerrit A. Meijer, Miriam Koopman. The prospective Dutch colorectal cancer cohort: A prospective nation-wide observational cohort study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1827.

The cohort multiple randomized controlled trial design: a valid and efficient alternative to pragmatic trials?

Randomized controlled trials (RCTs)-the gold standard for evaluating the effects of medical interventions-are notoriously challenging in terms of logistics, planning and costs. The cohort multiple randomized controlled trial approach is designed to facilitate randomized trials for pragmatic evaluation of (new) interventions and is a promising variation from conventional pragmatic RCTs. In this paper, we evaluate methodological challenges of conducting an RCT within a cohort. We argue that equally valid results can be obtained from trials conducted within cohorts as from pragmatic RCTs. However, whether this design is more efficient compared with conducting a pragmatic RCT depends on the amount and nature of non-compliance in the intervention arm.

The impact of retractor SPONGE-assisted laparoscopic surgery on duration of hospital stay and postoperative complications in patients with colorectal cancer (SPONGE trial): study protocol for a randomized controlled trial.

BackgroundTo achieve an adequate visual working field during laparoscopic colorectal surgery without disturbance of the small intestine, patients are positioned in the Trendelenburg position. This position results in hemodynamic changes that may increase the risk of cardiopulmonary complications and prolonged hospital stay. Recently, an intraoperative retractor sponge was introduced as an alternative to the Trendelenburg position during laparoscopic surgery.The objective of this trial is to study the impact of the use of an intraoperative retractor sponge on the duration of the hospital stay and risk of perioperative complications in patients undergoing laparoscopic surgery for colorectal cancer.Methods/designThe SPONGE trial is a monocenter study and follows the cohort multiple randomized controlled trial (cmRCT) design. It will be conducted within a multicenter prospective observational cohort of colorectal cancer patients of all stages, for whom longitudinal clinical data and patient-reported outcomes are collected. Patients within the cohort, who will undergo laparoscopic surgery for distal colon or rectal cancer, are eligible for inclusion and form a subcohort. From this subcohort, a 1:1 random sample will be offered to undergo surgery with the use of the retractor sponge. Patients from the subcohort who are not selected will undergo standard treatment, that is, surgery in the Trendelenburg position. The primary endpoint is the duration of the postoperative hospital stay. Secondary outcomes are duration of surgery; intraoperative blood loss and fluid balance; and postoperative body temperature, oxygenation and complications. Both arms require 94 patients.DiscussionThis study is the first randomized controlled trial to evaluate the effect of sponge-assisted laparoscopic colorectal surgery in comparison with standard Trendelenburg position on hospital stay and peri- and postoperative complications. Results of this study will also be relevant for other surgical procedures in the pelvic region. The present study is the second randomized controlled trial according to the cmRCT design, which is embedded within our colorectal cancer cohort.Trial registration numberClinicalTrials.gov NCT02574013. Registered 27 September 2015.

Modern clinical research: How rapid learning health care and cohort multiple randomised clinical trials complement traditional evidence based medicine

ABSTRACTBackground. Trials are vital in informing routine clinical care; however, current designs have major deficiencies. An overview of the various challenges that face modern clinical research and the methods that can be exploited to solve these challenges, in the context of personalised cancer treatment in the 21st century is provided.Aim. The purpose of this manuscript, without intending to be comprehensive, is to spark thought whilst presenting and discussing two important and complementary alternatives to traditional evidence-based medicine, specifically rapid learning health care and cohort multiple randomised controlled trial design. Rapid learning health care is an approach that proposes to extract and apply knowledge from routine clinical care data rather than exclusively depending on clinical trial evidence, (please watch the animation: http://youtu.be/ZDJFOxpwqEA). The cohort multiple randomised controlled trial design is a pragmatic method which has been proposed to help overcome the weaknesses of conventional randomised trials, taking advantage of the standardised follow-up approaches more and more used in routine patient care. This approach is particularly useful when the new intervention is a priori attractive for the patient (i.e. proton therapy, patient decision aids or expensive medications), when the outcomes are easily collected, and when there is no need of a placebo arm.Discussion. Truly personalised cancer treatment is the goal in modern radiotherapy. However, personalised cancer treatment is also an immense challenge. The vast variety of both cancer patients and treatment options makes it extremely difficult to determine which decisions are optimal for the individual patient. Nevertheless, rapid learning health care and cohort multiple randomised controlled trial design are two approaches (among others) that can help meet this challenge.

Improving recruitment of older people to clinical trials: use of the cohort multiple randomised controlled trial design

There is widespread evidence of under-recruitment of older people to research studies, notably randomised controlled trials of interventions. Study exclusion criteria, ethical dilemmas, patient preference, risk of bias and challenges for treatment comparisons are particular problems faced by researchers. This article describes how more widespread use of the cohort multiple randomised controlled trial (cmRCT) design in ageing research may help address many of these problems. The original key features of the cmRCT design are a large observational cohort of people with the condition of interest (e.g. frailty) with regular measurement of outcomes for the whole cohort. For each RCT eligible patients are identified and a random selection offered the trial intervention; their outcomes are compared with those eligible patients not offered the intervention. Relevant assents are obtained at baseline to enable future involvement in a range of potential trials. Where possible, the follow-up schedule is aligned with the key time points for assessment in future trials and includes the key baseline descriptors, and primary and secondary outcomes. The cmRCT approach also enables detailed observational and qualitative research for the chosen condition of interest, and might include the establishment of research biobanks to better align basic science, epidemiological, qualitative and clinical trial research.

A familial risk enriched cohort as a platform for testing early interventions to prevent severe mental illness.

BackgroundSevere mental illness (SMI), including schizophrenia, bipolar disorder and severe depression, is responsible for a substantial proportion of disability in the population. This article describes the aims and design of a research study that takes a novel approach to targeted prevention of SMI. It is based on the rationale that early developmental antecedents to SMI are likely to be more malleable than fully developed mood or psychotic disorders and that low-risk interventions targeting antecedents may reduce the risk of SMI.Methods/DesignFamilies Overcoming Risks and Building Opportunities for Well-being (FORBOW) is an accelerated cohort study that includes a large proportion of offspring of parents with SMI and embeds intervention trials in a cohort multiple randomized controlled trial (cmRCT) design. Antecedents are conditions of the individual that are distressing but not severely impairing, predict SMI with moderate-to-large effect sizes and precede the onset of SMI by at least several years. FORBOW focuses on the following antecedents: affective lability, anxiety, psychotic-like experiences, basic symptoms, sleep problems, somatic symptoms, cannabis use and cognitive delay. Enrolment of offspring over a broad age range (0 to 21 years) will allow researchers to draw conclusions on a longer developmental period from a study of shorter duration. Annual assessments cover a full range of psychopathology, cognitive abilities, eligibility criteria for interventions and outcomes. Pre-emptive early interventions (PEI) will include skill training for parents of younger children and courses in emotional well-being skills based on cognitive behavioural therapy for older children and youth. A sample enriched for familial risk of SMI will enhance statistical power for testing the efficacy of PEI.DiscussionFORBOW offers a platform for efficient and unbiased testing of interventions selected according to best available evidence. Since few differences exist between familial and ’sporadic’ SMI, the same interventions are likely to be effective in the general population. Comparison of short-term efficacy of PEI on antecedents and the long term efficacy for preventing the onset of SMI will provide an experimental test of the etiological role of antecedents in the development of SMI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-014-0344-2) contains supplementary material, which is available to authorized users.

SP0194 Leveraging an Innovative TRIAL Design for A Rare Disease Context: the Cohort Multiple RCT (CMRCT) Design

Pragmatic randomized controlled trials (RCTs) are considered the gold standard for determining the effectiveness of interventions in actual clinical practice. Traditionally designed pragmatic RCTs have high internal validity, but have...