Cohort Multiple Randomised Controlled Trial Research Articles

Strategic Multimodal Intervention in at‐risk Elderly Indians for Prevention of Dementia (SMRUTHI INDIA): A cohort multiple randomised controlled trial (cmRCT)

AbstractBackgroundThe major burden of dementia will be falling on Low and middle‐income countries in the next few decades. One of the major strategies to counter the rise in dementia burden is primary prevention, especially in at‐risk elderly individuals.MethodStrategic Multimodal Intervention in at‐risk Elderly Indians for Prevention of Dementia (SMRUTHI INDIA) is designed as a Cohort Multiple Randomised Controlled Trial (cmRCT) under a prospective community‐based cohort in rural India with long‐term follow‐up over many years. The rural cohort will be established in four zones of India, under the Indian Council of Medical Research (ICMR), Model Rural Health Research Units (MRHRUs) at Himachal Pradesh (North), Tripura (East), Rajasthan (West) and Karnataka (South). We plan to recruit 10000 participants with age > = 55 years and CAIDE score > = 6. SMRUTHI INDIA will be established in 2 phases. Phase 1 involves establishing a cohort (phase 1a) and development, followed by validation of the multimodal care bundle (phase 1 b). The care bundle preparation will have a development phase, acceptability and adaptability phase followed by feasibility testing involving a pilot RCT in a single centre. Phase 2 involves testing multiple interventions in cmRCT, and the first intervention to be tested will be the multimodal care bundle. The primary outcome will be the incidence of all‐cause dementia.ResultSMRUTHI INDIA will establish in parallel a large prospective rural cohort of at‐risk elderly in India and develop a culturally adapted and context‐specific multimodal care bundle. At the end of Phase 1, we will have the results of the pilot RCT on the feasibility of multimodal care bundle.ConclusionSMRUTHI INDIA is a landmark cohort multiple randomised controlled trial (cmRCT) which will assess multiple interventions for the primary prevention of dementia for the first time in India.Funding: Department of Health Research, Indian Council of Medical Research (ICMR)

PSMA-PET/CT-Guided Intensification of Radiation Therapy for Prostate Cancer (PSMAgRT): Findings of Detection Rate, Effect on Cancer Management, and Early Toxicity From a Phase 2 Randomized Controlled Trial

Prostate-specific membrane antigen (PSMA) ligand positron emission tomography (PET) is increasingly integrated in prostate cancer management because of its diagnostic performance. We sought to evaluate the effect of PSMA-PET/computed tomography (CT)-guided intensification of radiation therapy (PSMAgRT) on patient outcomes. Here, we report secondary trial endpoints including the rate of new lesion detection, effect on prostate cancer management, and treatment-related toxicities. In this phase 2 cohort multiple randomized controlled trial across 2 institutions, men with prostate cancer planned for RT were randomly selected for PSMAgRT across 4 strata: oligometastatic, high risk (Cancer of the Prostate Risk Assessment ≥6 or cN1), salvage post-RT, and salvage postprostatectomy (RP). Primary endpoint was failure-free survival at 5 years, with analysis pending further follow-up. Secondary endpoints included new lesion detection yield of PSMA-PET/CT, acute and delayed toxicities, effect on prostate cancer management, and health-related quality-of-life outcomes. This trial is registered with ClinicalTrials.gov, identifier NCT03525288, companion to registry NCT03378856. Between May 2018 and February 2021, 262 patients were enrolled and randomized. Nine patients were later excluded (5 control, 4 PSMAgRT), leaving 253 patients for analysis (23 oligometastatic, 86 high risk, 16 salvage post-RT, and 128 salvage post-RP). New lesions were detected in 45.5% of oligometastatic, 39.5% of high risk, 14.3% of salvage post-RT, and 51.6% of salvage post-RP. Overall, PSMA-PET/CT led to intensification of RT in over half of patients (52.0%), with minimal intensification of systemic therapy (4.0%). With a median follow-up of 12.9 months, this intensification was associated with 3 attributable grade 3+ events (2.5% of patients undergoing PSMAgRT) but no difference in the rate of grade 2+ events attributable to RT compared with controls (43%, both arms). In this randomized trial, PSMA-PET/CT led to intensification of RT in more than half of patients. Longer follow-up is required to determine whether this intensification translates to effect on cancer control and long-term toxicity and health-related quality-of-life outcomes.

Randomized controlled trial of an internet-based self-guided hand exercise program to improve hand function in people with systemic sclerosis: the Scleroderma Patient-centered Intervention Network Hand Exercise Program (SPIN-HAND) trial

BackgroundSystemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. Functional impairment of hands is common. The Scleroderma Patient-centered Intervention Network (SPIN)-HAND trial compared effects of offering access to an online self-guided hand exercise program to usual care on hand function (primary) and functional health outcomes (secondary) in people with SSc with at least mild hand function limitations.MethodsThe pragmatic, two-arm, parallel-group cohort multiple randomized controlled trial was embedded in the SPIN Cohort. Cohort participants with Cochin Hand Function Scale (CHFS) scores ≥ 3 and who indicated interest in using the SPIN-HAND Program were randomized (3:2 ratio) to an offer of program access or to usual care (targeted N = 586). The SPIN-HAND program consists of 4 modules that address (1) thumb flexibility and strength; (2) finger bending; (3) finger extension; and (4) wrist flexibility and strength. The primary outcome analysis compared CHFS scores 3 months post-randomization between participants offered versus not offered the program. Secondary outcomes were CHFS scores 6 months post-randomization and functional health outcomes (Patient-Reported Outcomes Measurement Information System profile version 2.0 domain scores) 3 and 6 months post-randomization.ResultsIn total, 466 participants were randomized to intervention offer (N = 280) or usual care (N = 186). Of 280 participants offered the intervention, 170 (61%) consented to access the program. Of these, 117 (69%) viewed at least one hand exercise instruction video and 77 (45%) logged into the program website at least 3 times. In intent-to-treat analyses, CHFS scores were 1.2 points lower (95% CI − 2.8 to 0.3) for intervention compared to usual care 3 months post-randomization and 0.1 points lower (95% CI − 1.8 to 1.6 points) 6 months post-randomization. There were no statistically significant differences in other outcomes.ConclusionThe offer to use the SPIN-HAND Program did not improve hand function. Low offer uptake, program access, and minimal usage among those who accessed the program limited our ability to determine if using the program would improve function. To improve engagement, the program could be tested in a group format or as a resource to support care provided by a physical or occupational therapist.Trial registrationNCT03419208. Registered on February 1, 2018.

From the identification of biopsychosocial risk factors to an increase in pain-related self-efficacy (IDRIS) – The online-based conveyance of an explanatory model for chronic back pain: Study protocol of a cohort multiple randomized controlled trial

BackgroundBack pain has a high global prevalence and carries a substantial risk for chronification. Biopsychosocial factors are assumed to be critical in the transition from acute to chronic back pain. Digital interventions are a promising tool to educate patients about their complaints. Thus, providing patients with an explanatory model regarding their individual risk factors in the early stage of their complaints via the internet might thus be a valuable approach in treatment. ObjectivesThe objectives of the present online study are to investigate the influence of a personalized psychoeducational intervention on self-efficacy and functioning and to examine biopsychosocial risk factors for symptom chronification. The intervention is based on a current model summarizing the empirical knowledge on relevant factors for persistent somatic symptoms, which has not been studied in back pain patients yet. MethodsAn observational cohort of patients with acute and subacute back pain (N = 564) will be asked about biopsychosocial risk factors via online survey at baseline, 4-week, and 12-week follow-up. Within this cohort, a randomly selected group of 132 participants (intervention group) with psychological burden (MCS-12 score of the SF-12 ≤ 50) and relevant somatic symptom intensity and interference (mean sum score of two numeric rating scales ≥5) and no prior psychotherapeutic treatment will be offered a personalized explanatory model in the form of an animated psychoeducational video. The video will be personalized in terms of participants' individual symptom profile and will be made accessible to watch online for 7 days. Participants will be compared to a control group receiving no treatment regarding change in pain-specific self-efficacy after 1 month as primary outcome, and change in functioning after 1 and 3 months, respectively, as secondary outcomes. Acceptance and usefulness of the intervention will be evaluated using the number of video views and a numeric rating scale. DiscussionThis is the first investigation of a personalized, video-animated online psychoeducation based on patients' individual risk factors for the chronification of back pain and the first systematic evaluation of the risk factors included in a comprehensive aetiological model on persistent somatic symptoms in back pain patients. This way, this study contributes to the understanding of cross-disorder psychopathological factors and a stronger consideration of biopsychosocial factors in the treatment of persistent somatic symptoms. If proven effective, the internet-based intervention will make an important contribution to the early treatment of back pain. Ethical approvalThe study was approved by the Local Psychological Ethics Committee (LPEK) at the Center for Psychosocial Medicine of the University Medical Center Hamburg-Eppendorf. Trial registrationThe study was registered at the German Clinical Trials Register in December 2021 (registration trial number: DRKS00025445).

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

PROState Pathway Embedded Comparative Trial: The IP3-PROSPECT study

IntroductionThe traditional double blind RCT is the ‘gold standard’ trial design. For a variety of reasons, these designs often fail to accrue enough participants to conclude. This is particularly challenging in localized prostate cancer. The cohort multiple randomised controlled trial (cmRCT) trial design may represent an alternative approach to delivering robust comparative data in prostate cancer. Patients and methodsIP3-PROSPECT is a cmRCT designed to test multiple prostate cancer interventions from eligible men in one cohort. Key to the design is two points of consent. First, at point of consent one, men referred for prostate cancer investigations are invited to join the cohort. They may then be randomly invited at a later date to consider an intervention at point of consent two. In the pilot phase we will test the acceptability and feasibility of developing the cohort. ResultsAcceptability and feasibility of the study will be measured by a combination of quantitative and qualitative methods. The primary outcome measure is the rate of consent to inclusion to the IP3-PROSPECT cohort. Secondary outcome measures include the completeness of data collection at sites and return rates of patient questionnaires. We will also interview patients and healthcare professionals to explore their thoughts on the implementation, practicality and efficiency of IP3-PROSPECT. ConclusionThe IP3-PROSPECT study will evaluate the cmRCT design in prostate cancer. Initially we will pilot the design, assessing for acceptability and feasibility. The cmRCT is an innovative design that offers potential for building a modern comparative evidence base for prostate cancer.

Изменения иммунитета и микроциркуляции в почках на фоне лечения гнойного пиелонефрита

Aim. To assess alterations of immune status and blood microcirculation in patients with purulent pyelonephritis during treatment. Methods. The prospective cohort multiple randomized controlled trial was carried out at the Department of Urology and Andrology at the Municipal Hospital No. 11 (Barnaul) in 2016-2019. A total of 94 patients aged 20–60 diagnosed with purulent pyelonephritis were treated during this period. The study was approved by the Ethics Committee of the Altai State Medical University (protocol No. 14 dated November 18, 2016). The informed consent was submitted by all participants. During the study, two groups were formed, which included patients already diagnosed with purulent pyelonephritis and patients with a suspicion on purulent process based on clinical, laboratory and functional tests data. The patients were randomized and divided into two groups in accordance with the methods used. The first group, showing no clinical and laboratory response to therapy, underwent surgery (n=47), the second group received cryoprcipitate together with standard conservative treatment for purulent pyelonephritis (n=47). All the cohorts were similar in age, gender and ethnicity. The patients’ immune status was estimated: IgM, IgG and IgA-based enzyme immunoassay tests were performed using the Immunoscreen-G, M, A-EIA-BEST kit by Vector-Best (Novosibirsk); serum interleukin-1β, interleukin-6, TNF-α and urine interleukin-8 levels were assayed using the Interleukin-8-EIA-BEST, Interleukin-1β-EIA-BEST, Alpha-TNF-EIA-BEST and Interleukin-6-EIA-BEST kits (Vector-Best, Russia, 2011). In addition to a number of instrumental tests, blood microcirculation in the zone of inflammation was assessed using the LAKK-2 analyzer in the projections of kidneys. The immune status markers were assessed upon admission and on day 6–7 of hospital stay. Each and every patient received complex conservative treatment. The patients received antibacterial therapy during an average of 3–4 days after their body temperature was back to normal. Results. Immune status assessment in group 1 patients revealed multidirectional alterations in immunoglobulin levels: significantly increased level serum Ig G and Ig M and decreased level of Ig A indicated the impaired humoral immunity. On day 9 of treatment the patients of group 1 still showed decreased level of Ig A. Their Ig G became even higher, and the level Ig M showed a decreasing trend. Upon admission, the serum levels of proinflammatory cytokines in patients of group 1 were more than twice as high as the control level, which could be considered the natural consequence of the observed infectious process in the urinary tract. On day 9 of treatment serum levels of proinflammatory cytokines became significantly lower: urine IL-8 level declined to 10.01±0.86 pg/mL, blood IL-6 level declined to 12.04±0.81 pg/mL, IL-1 level declined to 10.67±1.07 pg/mL, and TNF-α level declined to 4.75±0.40 pg/mL. However, the latter failed to reach the physiologically normal level, which indicated the incomplete reversal of inflammation in the urinary tract against the background of using the selected treatment approach. Blood microcirculation assessment using Laser Doppler flowmetry (LDF) prior to prescribing therapy to patients of group 1 revealed the following basal blood flow indicators: decreased shunt blood flow, reduced average blood flow, index of microcirculation efficiency, myogenic tone and fluctuations in erythrocyte flow, as well as elevated coefficient of variation and neurogenic tone compared to control and comparison groups. After surgery used as an adjunct to the complex treatment the significantly increased index of microcirculation efficiency, elevated average blood flow, increased neurogenic tone, reduced shunt blood flow and myogenic tone were observed. The listed indicators showed a positive trend, but failed to reach the physiologically normal level. Kidney inflammation persisted despite surgical and antibacterial treatment. Group 2. Assessment of group 2 patients prior to prescribing drug therapy revealed the pronounced serum immunoglobulin level alterations. Serum Ig G and Ig M levels were increased compared to control group, and the Ig A level was decreased, which indicated the humoral immunity impairment. Assessment of immunoglobulin levels after treatment showed they were back to normal, which indicated complete restoration of humoral immune response. In patients of group 2, cytokine profile analysis was performed prior to prescribing drug therapy supplemented by cryoprcipitate, and on day 9 of treatment. Thus, prior to complex treatment, the patients’ serum and urine levels of proinflammatory cytokines were more than twice as high as the control level, which was due to ongoing inflammatory process, and the urine IL-8 level was twice as high as the control level. Drug therapy with the use of cryoprcipitate resulted in recovery of IL-1β, TNF-α, IL-6 and IL-8 levels to physiologically normal levels obtained by examination of healthy individuals. This indicates complete reversal of inflammation in the urinary tract against the background of using the selected treatment approach. Assessment of microcirculation in the surface projections of kidneys by LDF revealed alterations in basal blood flow similar to those observed in patients of group 1. The average blood flow, shunt blood flow, neurogenic tone and index of microcirculation efficiency decreased significantly, and the myogenic tone increased. On day 9 of treatment the significantly increased average blood flow, index of microcirculation efficiency, neurogenic tone and shunt blood flow were observed. Myogenic tone dropped to physiologically normal level. Based on the alterations observed, the improved blood circulation in the ischemic zone and reduced hypoxia in the affected area of the kidneys can be reported.

Promotion of mental health in young adults via mobile phone app: study protocol of the ECoWeB (emotional competence for well-being in Young adults) cohort multiple randomised trials

BackgroundPromoting well-being and preventing poor mental health in young people is a major global priority. Building emotional competence (EC) skills via a mobile app may be an effective, scalable and acceptable way to do this. However, few large-scale controlled trials have examined the efficacy of mobile apps in promoting mental health in young people; none have tailored the app to individual profiles.Method/designThe Emotional Competence for Well-Being in Young Adults cohort multiple randomised controlled trial (cmRCT) involves a longitudinal prospective cohort to examine well-being, mental health and EC in 16–22 year olds across 12 months. Within the cohort, eligible participants are entered to either the PREVENT trial (if selected EC scores at baseline within worst-performing quartile) or to the PROMOTE trial (if selected EC scores not within worst-performing quartile). In both trials, participants are randomised (i) to continue with usual practice, repeated assessments and a self-monitoring app; (ii) to additionally receive generic cognitive-behavioural therapy self-help in app; (iii) to additionally receive personalised EC self-help in app. In total, 2142 participants aged 16 to 22 years, with no current or past history of major depression, bipolar disorder or psychosis will be recruited across UK, Germany, Spain, and Belgium. Assessments take place at baseline (pre-randomisation), 1, 3 and 12 months post-randomisation. Primary endpoint and outcome for PREVENT is level of depression symptoms on the Patient Health Questionnaire-9 at 3 months; primary endpoint and outcome for PROMOTE is emotional well-being assessed on the Warwick-Edinburgh Mental Wellbeing Scale at 3 months. Depressive symptoms, anxiety, well-being, health-related quality of life, functioning and cost-effectiveness are secondary outcomes. Compliance, adverse events and potentially mediating variables will be carefully monitored.ConclusionsThe trial aims to provide a better understanding of the causal role of learning EC skills using interventions delivered via mobile phone apps with respect to promoting well-being and preventing poor mental health in young people. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective Mobile-health public health strategies for preventing poor mental health and promoting well-being.Trial registrationClinicalTrials.gov (www.clinicaltrials.org). Number of identification: NCT04148508 November 2019.

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...

The Scleroderma Patient-Centered Intervention Network Self-Management Program: Protocol for a Randomized Feasibility Trial.

BackgroundSystemic sclerosis (SSc), or scleroderma, is a rare disease that often results in significant disruptions to activities of daily living and can negatively affect physical and psychological well-being. Because there is no known cure, SSc treatment focuses on reducing symptoms and disability and improving health-related quality of life (HRQoL). Self-management programs are known to increase self-efficacy for disease management in many chronic diseases. The Scleroderma Patient-centered Intervention Network (SPIN) developed a Web-based self-management program (SPIN self-management; SPIN-SELF) to increase self-efficacy for disease management and to improve HRQoL for patients with SSc.ObjectiveThe proposed study aims to assess the feasibility of conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF program by evaluating the trial implementation processes, required resources and management, scientific aspects, and participant acceptability and usage of the SPIN-SELF program.MethodsThe SPIN-SELF feasibility trial will be conducted via the SPIN Cohort. The SPIN Cohort was developed as a framework for embedded pragmatic trials using the cohort multiple RCT design. In total, 40 English-speaking SPIN Cohort participants with low disease management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale score ≤7), who have indicated interest in using a Web-based self-management program, will be randomized with a 3:2 ratio into the SPIN-SELF program or usual care for 3 months. Feasibility outcomes include trial implementation processes, required resources and management, scientific aspects, and patient acceptability and usage of the SPIN-SELF program.ResultsEnrollment of the 40 participants occurred between July 5, 2019, and July 27, 2019. By November 25, 2019, data collection of trial outcomes was completed. Data analysis is underway, and results are expected to be published in 2020.ConclusionsThe SPIN-SELF program is a self-help tool that may improve disease-management self-efficacy and improve HRQoL in patients with SSc. The SPIN-SELF feasibility trial will ensure that trial methodology is robust, feasible, and consistent with trial participant expectations. The results will guide adjustments that need to be implemented before undertaking a full-scale RCT of the SPIN-SELF program.International Registered Report Identifier (IRRID)DERR1-10.2196/16799

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.

Improving care for older people with long-term conditions and social care needs in Salford: the CLASSIC mixed-methods study, including RCT

BackgroundThe Salford Integrated Care Programme (SICP) was a large-scale transformation project to improve care for older people with long-term conditions and social care needs. We report an evaluation of the ability of the SICP to deliver an enhanced experience of care, improved quality of life, reduced costs of care and improved cost-effectiveness.ObjectivesTo explore the process of implementation of the SICP and the impact on patient outcomes and costs.DesignQualitative methods (interviews and observations) to explore implementation, a cohort multiple randomised controlled trial to assess patient outcomes through quasi-experiments and a formal trial, and an analysis of routine data sets and appropriate comparators using non-randomised methodologies.SettingSalford in the north-west of England.ParticipantsOlder people aged ≥ 65 years, carers, and health and social care professionals.InterventionsA large-scale integrated care project with three core mechanisms of integration (community assets, multidisciplinary groups and an ‘integrated contact centre’).Main outcome measuresPatient self-management, care experience and quality of life, and health-care utilisation and costs.Data sourcesProfessional and patient interviews, patient self-report measures, and routine quantitative data on service utilisation.ResultsThe SICP and subsequent developments have been sustained by strong partnerships between organisations. The SICP achieved ‘functional integration’ through the pooling of health and social care budgets, the development of the Alliance Agreement between four organisations and the development of the shared care record. ‘Service-level’ integration was slow and engagement with general practice was a challenge. We saw only minor changes in patient experience measures over the period of the evaluation (both improvements and reductions), with some increase in the use of community assets and care plans. Compared with other sites, the difference in the rates of admissions showed an increase in emergency admissions. Patient experience of health coaching was largely positive, although the effects of health coaching on activation and depression were not statistically significant. Economic analyses suggested that coaching was likely to be cost-effective, generating improvements in quality of life [mean incremental quality-adjusted life-year gain of 0.019, 95% confidence interval (CI) –0.006 to 0.043] at increased cost (mean incremental total cost increase of £150.58, 95% CI –£470.611 to £711.776).LimitationsThe Comprehensive Longitudinal Assessment of Salford Integrated Care study represents a single site evaluation, with consequent limits on external validity. Patient response rates to the cohort survey were < 40%.ConclusionsThe SICP has been implemented in a way that is consistent with the original vision. However, there has been more rapid success in establishing new integrated structures (such as a formal integrated care organisation), rather than in delivering mechanisms of integration at sufficient scale to have a large impact on patient outcomes.Future workFurther research could focus on each of the mechanisms of integration. The multidisciplinary groups may require improved targeting of patients or disease subgroups to demonstrate effectiveness. Development of a proven model of health coaching that can be implemented at scale is required, especially one that would provide cost savings for commissioners or providers. Similarly, further exploration is required to assess the longer-term benefits of community assets and whether or not health impacts translate to reductions in care use.Trial registrationCurrent Controlled Trials ISRCTN12286422.FundingThis project was funded by the NIHR Health Services and Delivery Research programme and will be published in full inHealth Services and Delivery Research; Vol. 6, No. 31. See the NIHR Journals Library website for further project information.

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

Effectiveness of a healthy lifestyle intervention for chronic low back pain: a randomised controlled trial.

We assessed the effectiveness of a 6-month healthy lifestyle intervention, on pain intensity in patients with chronic low back pain who were overweight or obese. We conducted a pragmatic randomised controlled trial, embedded within a cohort multiple randomised controlled trial of patients on a waiting list for outpatient orthopaedic consultation at a tertiary hospital in NSW, Australia. Eligible patients with chronic low back pain (>3 months in duration) and body mass index ≥27 kg/m and <40 kg/m were randomly allocated, using a central concealed random allocation process, to receive advice and education and referral to a 6-month telephone-based healthy lifestyle coaching service, or usual care. The primary outcome was pain intensity measured using an 11-point numerical rating scale, at baseline, 2 weeks, and monthly for 6 months. Data analysis was by intention-to-treat according to a prepublished analysis plan. Between May 13, 2015, and October 27, 2015, 160 patients were randomly assigned in a 1:1 ratio to the intervention or usual care. We found no difference between groups for pain intensity over 6 months (area under the curve, mean difference = 6.5, 95% confidence interval -8.0 to 21.0; P = 0.38) or any secondary outcome. In the intervention group, 41% (n = 32) of participants reported an adverse event compared with 56% (n = 45) in the control group. Our findings show that providing education and advice and telephone-based healthy lifestyle coaching did not benefit patients with low back pain who were overweight or obese, compared with usual care. The intervention did not influence the targeted healthy lifestyle behaviours proposed to improve pain in this patient group.

Telephone-based weight loss support for patients with knee osteoarthritis: a pragmatic randomised controlled trial

To determine the effectiveness of telephone-based weight loss support in reducing the intensity of knee pain in patients with knee osteoarthritis, who are overweight or obese, compared to usual care. We conducted a parallel randomised controlled trial (RCT), embedded within a cohort multiple RCT of patients on a waiting list for outpatient orthopaedic consultation at a tertiary referral hospital in NSW, Australia. Patients with knee osteoarthritis, classified as overweight or obese [body mass index (BMI) between ≥27kg/m2 and <40kg/m2] were randomly allocated to receive referral to an existing non-disease specific government funded 6-month telephone-based weight management and healthy lifestyle service or usual care. The primary outcome was knee pain intensity measured using an 11-point numerical rating scale (NRS) over 6-month follow-up. A number of secondary outcomes, including self-reported weight were measured. Data analysis was by intention-to-treat according to a pre-published analysis plan. Between May 19 and June 30 2015, 120 patients were randomly assigned to the intervention (59 analysed, one post-randomisation exclusion) or usual care (60 analysed). We found no statistically significant between group differences in pain intensity [area under the curve (AUC), mean difference 5.4, 95%CI:-13.7 to 24.5, P=0.58] or weight change at 6 months (self-reported; mean difference-0.4, 95%CI:-2.6 to 1.8, P=0.74). Among patients with knee osteoarthritis who are overweight, telephone-based weight loss support, provided using an existing 6-month weight management and healthy lifestyle service did not reduce knee pain intensity or weight, compared with usual care. ACTRN12615000490572.

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.

The effects of exercise on the quality of life of patients with breast cancer (the UMBRELLA Fit study): study protocol for a randomized controlled trial

BackgroundMeta-analyses of randomized controlled trials (RCTs) have shown that exercise has beneficial effects on quality of life (QoL) in patients with breast cancer. However, these effects were often small. Blinding in an exercise trial is not possible, which has the possible disadvantage of difficult accrual, drop-out after randomization to control and contamination between study groups (controls adopting the behaviour of the intervention group). The cohort multiple randomized controlled trial (cmRCT) is an alternative for conventional RCTs and has the potential to overcome these disadvantages.MethodsThis cmRCT will be performed within the Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA). Patients with breast cancer who visit the radiotherapy department of the University Medical Center Utrecht are asked to participate in UMBRELLA. Patients give consent for collection of medical information, providing patient-reported outcomes through regular questionnaires and randomization into future intervention studies. Patients who fulfill the UMBRELLA Fit study eligibility criteria (12 to 18 months post inclusion in UMBRELLA, low physical activity level) will be randomly allocated to the intervention or control group (1:1 ratio). Patients randomized to the intervention group will be offered a 12-week exercise programme. The control group will not be informed. Regular cohort measurements will be used for outcome assessment. Feasiblity (including participation, contamination, generalizability and retention) of the cmRCT design and effects of the intervention on QoL will be evaluated.DiscussionWe will examine the feasibility of the cmRCT design in exercise-oncology research and compare this with conventional RCTs. Furthermore, the effectiveness of an exercise intervention on the QoL of patients with breast cancer in the short term (6 months) and long term (24 months) will be studied.Trial registrationNetherlands Trial Register, NTR5482/NL.52062.041.15. Retrospectively registered on 7 December 2015.

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.