Zelen Design Research Articles

Economic evaluation of intensive home treatment in comparison to care as usual alongside a randomised controlled trial.

There is a dearth of research on the cost-effectiveness of intensive home treatment (IHT), an alternative to psychiatric hospitalisation for patients experiencing psychiatric crises. We therefore present a health economic evaluation alongside a pre-randomised controlled trial of IHT compared to care as usual (CAU). Patients were pre-randomised to IHT or CAU using a double-consent open-label Zelen design. For the cost-utility analysis, the EuroQol 5-dimensional instrument was used. The cost-effectiveness was assessed using the Brief Psychiatric Rating Scale (BPRS). Data of 198 patients showed that each additional QALY gained from offering IHT instead of CAU was on average associated with an extra cost of €48,003. There is a 38% likelihood that IHT will lead to more QALYs at lower costs compared to CAU. An improvement of one additional point on the BPRS by offering IHT instead of CAU was associated with an extra cost of €19,203. There is a 38% likelihood that IHT will lead to higher BPRS score improvements at lower costs. Based on the NICE willingness-to-pay threshold of £30,000 (€35,000) per QALY, IHT could potentially be considered cost-effective with a likelihood of 55-60% when viewed from a societal perspective, and > 75% from a health care perspective. IHT appears slightly more attractive in terms of cost-utility and cost-effectiveness than CAU, although differences in both costs and effects are small especially when viewed from the societal costs perspective. From the health care sector costs perspective, IHT has a higher probability of being cost-effective compared to CAU. Netherlands Trial Register: NTR6151.

Reanalysis of a Randomized Controlled Trial on Promoting Influenza Vaccination in General Practice Waiting Rooms: A Zelen Design.

In 2014–2015, we conducted a randomized controlled trial (RCT) assessing the effect of an advertising campaign for influenza vaccination using posters and pamphlets in general practitioner (GP) waiting rooms. No effect of the intervention could be demonstrated, but the immunization uptake increased in both arms of the study. In 2019, we deepened the investigations explaining the increased uptake conducting a registry-based 4/2/1 cluster RCT designed by Zelen with two extra years of follow-up of the study cohort. The study population included 23,024 patients eligible to be vaccinated who were registered with 175 GPs. The main outcome remained the number of vaccination units delivered per study group. Data were extracted from the SNIIRAM warehouse claim database for the Lille-Douai district (northern France). No difference in vaccination uptake was found in the Zelen versus the control group of the initial RCT. Overall, the proportion of vaccinated patients increased in the cohort from 51.4% to 70.4% over the three years. Being vaccinated the previous year was a strong predictor of being vaccinated in a subsequent year. The increase in vaccination uptake, especially among people older than 65, can be explained by a cohort effect. Health promotion and the promotion of primary health care may play an important role in this increase.

Using the external auditory canal skin graft of the healthy side to treat unilateral congenital aural atresia: preliminary results of clinical research

Objective: To investigate whether the contralateral normal external auditory canal (EAC) skin graft can maintain the ear canal health after EAC reconstruction in unilateral congenital aural atresia (CAA) cases. Methods: A Zelen design randomized controlled study was used to collect unilateral CAA patients for EAC reconstruction prospectively (clinical trial registration number: ChiCTR2000032103). The patients were randomly divided into the control group and the trial group. The trial group used the contralateral normal EAC skin graft group (transplant part of the contralateral normal EAC skin to repair the atresia side for unilateral CAA patients), the control group all used scalp blade thick skin. We observed the EAC health and hearing results of the two groups after EAC reconstruction. Results: A total of 13 cases were enrolled from July 2020 to August 2021. There were eight patients in the trial group, including six males and two females, with an average age of 22.3 years (14-36 years). There were two patients with CAA on the left and six patients on the right. The average follow-up time was 8.8 months (4-14 months). There were five patients in the control group, all cases were male with an average age of 16.2 years (12-20 years). There were four patients with CAA on the left and one patient on the right. The average follow-up time was 7.0 months (2-14 months). In the trial group, eight cases of reconstructed EAC epithelium were healthy, one patient had cicatricial stenosis of EAC opening and lateralization of the tympanic membrane. The other patient had cicatricial stenosis of reconstructed EAC, this case also had scar hyperplasia of the contralateral EAC opening but recovered after soft packing and triamcinolone acetonide injection treatment. The healthy side EAC of the rest trial group had no scarring stenosis or local bone hyperplasia during long-term follow-up. In the control group, one patient was lost to follow-up and the other four patients had dry ears of reconstructed EAC, but easily to form crusts and needed to be cleaned repeatedly, one patient had lateralization of the tympanic membrane, the EAC epithelium was not healthy for long-term follow-up. The incidence of complications related to EAC reconstruction was lower than previous studies (χ²=5.55, P=0.018), and the average postoperative Air-Bone Gap increased (18.8±10.0)dB. Conclusion: By optimizing the EAC reconstruction technology, the health of the reconstructed EAC is improved compared with the previous study. After active intervention and treatment, there should be no scarring stenosis or local bone hyperplasia on the contralateral side EAC.

Early Detection Initiative: A randomized controlled trial of algorithm-based screening in patients with new onset hyperglycemia and diabetes for early detection of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the only leading cause of cancer death without an early detection strategy. In retrospective studies, 0.5–1% of subjects >50 years of age who newly develop biochemically-defined diabetes have been diagnosed with PDAC within 3 years of meeting new onset hyperglycemia and diabetes (NOD) criteria. The Enriching New-onset Diabetes for Pancreatic Cancer (ENDPAC) algorithm further risk stratifies NOD subjects based on age and changes in weight and diabetes parameters. We present the methodology for the Early Detection Initiative (EDI), a randomized controlled trial of algorithm-based screening in patients with NOD for early detection of PDAC. We hypothesize that study interventions (risk stratification with ENDPAC and imaging with Computerized Tomography (CT) scan) in NOD will identify earlier stage PDAC. EDI uses a modified Zelen's design with post-randomization consent. Eligible subjects will be identified through passive surveillance of electronic medical records and eligible study participants randomized 1:1 to the Intervention or Observation arm. The sample size is 12,500 subjects. The ENDPAC score will be calculated only in those randomized to the Intervention arm, with 50% (n = 3125) expected to have a high ENDPAC score. Consenting subjects in the high ENDPAC group will undergo CT imaging for PDAC detection and an estimate of potential harm. The effectiveness and efficacy evaluation will compare proportions of late stage PDAC between Intervention and Observation arm per randomization assignment or per protocol, respectively, with a planned interim analysis. The study is designed to improve the detection of sporadic PDAC when surgical intervention is possible.

Effectiveness of a Nurse-Led Multidisciplinary Intervention vs Usual Care on Advance Care Planning for Vulnerable Older Adults in an Accountable Care Organization

Advance care planning (ACP), especially among vulnerable older adults, remains underused in primary care. Additionally, many ACP initiatives fail to integrate directly into the electronic health record (EHR), resulting in infrequent and disorganized documentation. To determine whether a nurse navigator-led ACP pathway combined with a health care professional-facing EHR interface improves the occurrence of ACP discussions and their documentation within the EHR. This was a randomized effectiveness trial using the Zelen design, in which patients are randomized prior to informed consent, with only those randomized to the intervention subsequently approached to provide informed consent. Randomization began November 1, 2018, and follow-up concluded November 1, 2019. The study population included patients 65 years or older with multimorbidity combined with either cognitive or physical impairments, and/or frailty, assessed from 8 primary care practices in North Carolina. Participants were randomized to either a nurse navigator-led ACP pathway (n = 379) or usual care (n = 380). The primary outcome was documentation of a new ACP discussion within the EHR. Secondary outcomes included the usage of ACP billing codes, designation of a surrogate decision maker, and ACP legal form documentation. Exploratory outcomes included incident health care use. Among 759 randomized patients (mean age 77.7 years, 455 women [59.9%]), the nurse navigator-led ACP pathway resulted in a higher rate of ACP documentation (42.2% vs 3.7%, P < .001) as compared with usual care. The ACP billing codes were used more frequently for patients randomized to the nurse navigator-led ACP pathway (25.3% vs 1.3%, P < .001). Patients randomized to the nurse navigator-led ACP pathway more frequently designated a surrogate decision maker (64% vs 35%, P < .001) and completed ACP legal forms (24.3% vs 10.0%, P < .001). During follow-up, the incidence of emergency department visits and inpatient hospitalizations was similar between the randomized groups (hazard ratio, 1.17; 95% CI, 0.92-1.50). A nurse navigator-led ACP pathway integrated with a health care professional-facing EHR interface increased the frequency of ACP discussions and their documentation. Additional research will be required to evaluate whether increased EHR documentation leads to improvements in goal-concordant care. ClinicalTrials.gov Identifier: NCT03609658.

Internet and Telerehabilitation-Delivered Management of Rotator Cuff-Related Shoulder Pain (INTEL Trial): Randomized Controlled Pilot and Feasibility Trial.

BackgroundRotator cuff–related shoulder pain (RCRSP) is a common and disabling musculoskeletal condition. Internet-based and telerehabilitation delivery of recommended care may improve access to care and improve adherence and outcomes.ObjectiveThe primary aim of this pilot randomized controlled trial was to assess the feasibility of a 12-week internet-delivered intervention for RCRSP comparing advice only, recommended care, and recommended care with group-based telerehabilitation.MethodsReporting was in accordance with the Consolidated Standards of Reporting Trials (CONSORT) checklist for pilot and feasibility trials. People with a primary complaint of RCRSP for 3 months or longer were identified via a paid Facebook strategy. Screening involved an online questionnaire followed by a 20-minute telehealth assessment. Participants were randomly allocated (via a Zelen design) to receive (1) advice only, (2) recommended care (internet-delivered evidence-based exercise and education), or (3) recommended care and telerehabilitation (including a weekly group teleconference session). Progression criteria for a full-scale trial included (1) recruitment of 20% or greater of eligible participants, (2) acceptable adherence (two or more of the three prescribed weekly sessions) among 70% or greater of participants, (3) 80% or greater retention of participants, (4) absence of intervention-related serious adverse events, and (5) 80% or greater response rates to questionnaires. Secondary clinical and patient knowledge outcomes were collected (via email or text) at baseline, six weeks, and 12 weeks (for clinical and patient knowledge), and within-group change was reported descriptively.ResultsWe enrolled 36 of 38 (95%) eligible participants and all participants were recruited within a 3-week period. Of the 36 participants, 12 participants were allocated to each of the three trial arms. The mean age of participants was between 51 and 56 years, and 83% (10/12) to 92% (11/12) were female. Retention at the 12-week endpoint was 94% (34/36) and response to email questionnaires at other time points was 83% or greater. We found acceptable adherence (defined as greater than 70% of participants performing exercise 2 or 3 times/week) in the recommended care group with telerehabilitation but not in the recommended care group without telerehabilitation. There was a total of 24 adverse events over 108 person-months of observation. All adverse events were mild or moderate (mainly muscle and shoulder symptoms), with the exception of one instance of elective surgery (unrelated to the person’s shoulder condition).ConclusionsOur prespecified success criteria were met or exceeded, but there was a gender imbalance toward women. It is feasible to progress to a fully powered trial, but strategies to address the gender imbalance need to be implemented.Trial RegistrationAustralian New Zealand Clinical Trials Registry (ACTRN12620000248965); https://tinyurl.com/yy6eztf5

Effects of telephone-based health coaching on patient-reported outcomes and health behavior change: A randomized controlled trial.

ObjectiveTelephone based health coaching (TBHC) seems to be a promising approach to foster self-management in patients with chronic conditions. The aim of this study was to evaluate the effectiveness of a TBHC on patient-reported outcomes and health behavior for people living with chronic conditions in Germany.MethodsPatients insured at a statutory health insurance were randomized to an intervention group (IG; TBHC) and a control group (CG; usual care), using a stratified random allocation before giving informed consent (Zelen’s single-consent design). The TBHC was based on motivational interviewing, goal setting, and shared decision-making and carried out by trained nurses. All outcomes were assessed yearly for three years. We used mixed effects models utilizing all available data in a modified intention-to-treat sample for the main analysis. Participants and study centers were included as random effects. All models were adjusted for age, education and campaign affiliation.ResultsOf the 10,815 invited patients, 4,283 returned their questionnaires at baseline. The mean age was 67.23 years (SD = 9.3); 55.5% were female. According to the model, TBHC was statistically significant superior to CG regarding 6 of 19 outcomes: physical activity in hours per week (p = .030) and in metabolic rate per week (p = .048), BMI (p = .009) (although mainly at baseline), measuring blood pressure (p< .001), patient activation (p< .001), and health literacy (p< .001). Regarding stages of change (p = .005), the IG group also showed statistically different results than the CG group, however the conclusion remains inconclusive. Within-group contrasts indicating changes from baseline to follow-ups and significant between-group comparisons regarding these changes supported the findings. Standardized effect sizes were small. TBHC did not show any effect on mental QoL, health status, alcohol, smoking, adherence, measuring blood sugar, foot monitoring, anxiety, depression and distress. Campaign-specific subgroup effects were detected for ‘foot monitoring by a physician’ and ‘blood sugar measurement’.ConclusionTBHC interventions might have small effects on some patient reported and behavioral outcomes.Practice implicationsFuture research should focus on analyzing which intervention components are effective and who profits most from TBHC interventions.RegistrationGerman Clinical Trials Register (Deutsches Register Klinischer Studien; DRKS): DRKS00000584

Fatigue, quality of life and physical fitness following an exercise intervention in multiple myeloma survivors (MASCOT): an exploratory randomised Phase 2 trial utilising a modified Zelen design

BackgroundExercise may improve fatigue in multiple myeloma survivors, but trial evidence is limited, and exercise may be perceived as risky in this older patient group with osteolytic bone destruction.MethodsIn this Phase 2 Zelen trial, multiple myeloma survivors who had completed treatment at least 6 weeks ago, or were on maintenance only, were enrolled in a cohort study and randomly assigned to usual care or a 6-month exercise programme of tailored aerobic and resistance training. Outcome assessors and usual care participants were masked. The primary outcome was the FACIT-F fatigue score with higher scores denoting less fatigue.ResultsDuring 2014–2016, 131 participants were randomised 3:1 to intervention (n = 89) or usual care (n = 42) to allow for patients declining allocation to the exercise arm. There was no difference between groups in fatigue at 3 months (between-group mean difference: 1.6 [95% CI: −1.1–4.3]) or 6 months (0.3 [95% CI: −2.6–3.1]). Muscle strength improved at 3 months (8.4 kg [95% CI: 0.5–16.3]) and 6 months (10.8 kg [95% CI: 1.2–20.5]). Using per-protocol analysis, cardiovascular fitness improved at 3 months (+1.2 ml/kg/min [95% CI: 0.3–3.7]). In participants with clinical fatigue (n = 17), there was a trend towards less fatigue with exercise over 6 months (6.3 [95% CI: −0.6–13.3]). There were no serious adverse events.ConclusionsExercise appeared safe and improved muscle strength and cardiovascular fitness, but benefits in fatigue appeared limited to participants with clinical fatigue at baseline. Future studies should focus on patients with clinical fatigue.Clinical trial registrationThe study was registered with ISRCTN (38480455) and is completed.

The adapted Zelen was a feasible design to trial exercise in myeloma survivors

ObjectivesWe used a method rarely seen in cancer behavioral trials to explore methods of overcoming difficulties often seen in randomized controlled trials. We report our experiences of the adapted Zelen design, so that other researchers can consider this approach for behavioral trials. Study Design and SettingThe adapted Zelen design was used to explore the effects of exercise on multiple myeloma patients fatigue, quality of life, and physical outcomes. All participants consented to an observational cohort study of lifestyle factors but were unaware of subsequent randomization to remain in cohort only group or be offered an exercise intervention requiring second consent. ResultsThere was lower than expected uptake to the exercise offered group (57%), so the length of recruitment increased from 24 to 29 months to ensure power was reached. At enrollment, patients were unaware of the potential increased commitment, and as a result, 62% of participants allocated to the intervention declined because of the extra time/travel commitment required. This emulates clinical settings and suggests improvements in intervention delivery are required. Our findings suggest that the adapted Zelen design may be useful in limiting dropout of controls due to dissatisfaction from group allocation, or contamination of control arm. ConclusionFuture use of this design warrants careful consideration of the study resources and recruitment time frames required but holds potential value in reducing contamination, control group dissatisfaction, and resulting dropout. Adapted Zelen design reduces selection bias and therefore gives clinicians a better understanding of acceptability in clinical settings. Future studies should evaluate control group experiences of the design and formally record contamination throughout the study to confirm its acceptability.

Fatigue, Quality of Life, and Physical Fitness Following an Exercise Intervention in Survivors of Multiple Myeloma: A Randomised Controlled Trial Using a Zelen Design

▪Background. The benefit of exercise on fatigue and wellbeing in patients with solid tumours (breast, prostate, colorectal) is supported by some randomised controlled trials (RCT). In multiple myeloma (myeloma), osteolytic bone destruction causes persistent pain and fracture risk, leading to reduced physical functioning, and barriers to exercise. There is a paucity of research in this patient group. We aimed to test the efficacy of a previously piloted exercise intervention in a randomised controlled trial in myeloma survivors.Methods. MASCOT used a double-consent adapted Zelen design to reduce contamination of control group, often found in RCT. Eligible patients had completed chemotherapy and had at least stable disease for ≥6 weeks. Screening for fracture risk was carried out by multi-disciplinary team. After initial consent to a lifestyle cohort study and completion of baseline tests, subjects were randomised to exercise intervention (re-consented) or control (usual care). Control subjects were not informed of the randomisation, and not re-consented. The 12-week intervention was tailored aerobic and resistance exercises with behavioural support and home exercise. Subjects attended weekly supervised gym sessions in weeks 1-12, and then monthly until 6 months. All subjects were assessed at 3, 6 and 12 months. The primary outcome was between group differences in fatigue (Functional Assessment of Chronic Illness Therapy, FACIT-F) change at 3 months. Regression models were run with the 3-or 6-month fatigue as the dependent variable, with the baseline values and trial arm allocation as independent variables, with same methodology for secondary endpoints (QOL, physical fitness, muscle strength, body composition).Results. From June 2014 to November 2016, 138 patients consented to the cohort study, of whom 131 were randomised (control, 42, intervention 89). Time from last treatment was 15 months (median, range: 2-251), median age was 63yrs (35-86), 55% were male and 67% had bone disease. Of 89 participants randomised to the intervention, 51(57%) consented; main reasons for declining were number of visits and/or travel distance. Median attendance at sessions was 75%, and 40 completed the programme at 3 months. 3- and 12-month follow-up was 88%, 95% and 63%, 74% respectively, for exercise and control. Forty participants with complete cases in each arm were included in the analyses (per protocol).Baseline levels of fatigue were similar in the exercise and control groups (40.8±7.8, 41.7±10.7); with 7(17%) and 10(24%) subjects reporting clinical fatigue (score<34). Groups were matched for all other variables. There was no between group difference in fatigue at 3-months (2.14, 95%CI -0.51,4.79, p=0.1) or 6-months. We found no between-group differences in physical functioning, emotional functioning, anxiety, or depression at 3 or 6 months. VO2peak improved significantly at 3-months(p=0.024) but not at 6-months(p=0.26). Leg muscle strength improved at 6-months(p=0.027), with a trend for improvement at 3 months(p=0.052). Trends to improvement in physical activity self-efficacy(p=0.053) and body fat percentage(p=0.051) at 3 months were not seen at 6 months.Because the trial included patients who did not have clinical fatigue at baseline, hence limited scope for improvement in this endpoint, we undertook subgroup analysis of patients with clinical fatigue at baseline. Here, patients who completed the exercise intervention reported feeling less tired (less fatigue) at 3 months, which was maintained at 6- and 12-months. (Figure). They also had improved leg strength at each time point (Figure), which was not seen in the control arm. A similar pattern was observed for VO2peak .In interviews, participants voiced a sense of achievement, their confidence to exercise under supervision and were pleased to have the opportunity to improve their physical wellbeing.Conclusion. Benefits in fatigue appeared limited to subjects with clinical fatigue at baseline, although improvements in muscle strength and fitness were seen in the group as a whole, and patient testimonies were positive. Future research should consider modifying the intervention delivery format to reduce barriers to recruitment and attendance and incorporate fatigue screening before enrolment. DisclosuresRabin:Takeda: Consultancy, Other: Travel support , Speakers Bureau; Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Other: Travel support, Speakers Bureau. Popat:Amgen: Honoraria. Yong:TAkeda: Honoraria, Research Funding; janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Research Funding.

A personalized self-management and intensive spa therapy intervention for musculoskeletal disorders of the upper extremities contributes to reduce disability: A randomized controlled trial

Musculoskeletal disorders (MSDs) constitute a major occupational health problem in the working population. MSDs manifest as localized pain or functional difficulty in one or more anatomical areas, such as the cervical spine, shoulder, elbow, hand, and wrist. Although physical exercise is widely recommended, few studies with a good level of evidence have enabled us to base a complete, well-constructed intervention on exercise that can be offered as secondary prevention in these disorders. A prospective, multicenter, comparative, randomized study using Zelen's design. This study falls under active prevention of MSDs of the upper extremities. Participants are workers aged between 18 and 65 years, with any type of job or workstation, with or without a history of sick leave. The primary aim is to show the superiority at 3 months of a combination of spa therapy, exercise, and self-management workshops for 6 days over self-management workshops in terms of employee functional capacity in personal and professional daily life (QUICK DASH scale). We included 148 patients, 73 assigned to the intervention group and 75 to the control group. At 3 months, the total score of functional disability assessed by QUICK DASH decreased in both groups. This reduction was higher in the intervention group (−10.04 ± 15.83) versus control group (−5.57 ± 13.45). We noticed a non-significant decrease for QUICK DASH total score ( P = 0.10). However, the field specifically assessing disabilities in physical activities; QUICK DASH sport; had significantly decreased in the intervention group (−14.58 ± 21.49) versus control group (−6.72 ± 19.04) ( P = 0.02). The originality of this intervention lies, in its short, intensive format, which is compatible with remaining in work; and in its multidisciplinary approach. This trial demonstrates the benefits of a short course of spa therapy combined with a personalized self-management program on the functional capacity in their daily life.

Impact of the ESDM on the development of children with ASD in a European French-speaking population: First results of the intervention implementation

Introduction Early intervention for autism spectrum disorder (ASD) in the European French-speaking countries is heterogeneous and poorly evaluated to date. Early intervention units applying the Early Start Denver Model (ESDM) for toddlers and young children with ASD have been created in France and Belgium to improve this situation. It is essential to evaluate this intervention for the political decision-making process regarding ASD interventions in European French-speaking countries. We selected the implementation of a 12-hour ESDM intervention for children with ASD over a 2-year period as part of the IDEA trial. This ESDM intervention can be complex to implement. It is subject to many organizational constraints. It relies on a strong involvement of both ESDM professional teams and parents to implement this individual intervention adapted to each child. It is therefore important at this stage of the IDEA study to evaluate the ESDM intervention implementation. Methods The IDEA trial is an ongoing multicentre, randomised controlled trial, using a two-stage Zelen design. Children included are aged 15 to 36 months, diagnosed with ASD and with a Developmental Quotient (DQ) of 30 or above on the Mullen Scale of Early Learning (MSEL). We use a stratified minimisation randomisation at a ratio 1:2 in favour of the control group. The sample size requires is 180 children (120 in the control and 60 in the intervention group). The intervention evaluated is a 12-hour per week ESDM by trained therapists (10 hours in the centre and 2 hours in the toddlers’ natural environment). The control group receives care available in the community. Our aim was to evaluate the ESDM intervention implementation for children in the intervention group, by evaluating the number of sessions and the number of hours ESDM conducted and analyzing reasons for absence and organization of centers. Results To date, 131 children have been included: 88 randomized children in the control group, 43 randomized in the intervention group. At inclusion, children’ characteristics in the intervention group were mean age 29.8 months, the level of behavioral change and severity of autistic symptoms at ADOS score of 7.6 (max score 10.0) and developmental quotient at Mullen score of 45.9 (max score 59.1). ESDM intervention sessions were completed for 65% of the children. Seventy-five percent of the reasons for cancellation were related to the organization of ESDM professional teams (holidays, training/absences of professionals). The average number of intervention hours delivered was of 8 hours per week. The average number of hours delivered increased (from 6.6 hours to 9.6 hours per week) during the months of ESDM intervention implementation, suggesting a gradual implementation. Conclusions The evaluation of the intervention implementation showed that children received on average 4 hours less ESDM intervention than initially planned by the protocol. The reasons for canceling sessions related to families are limited (25%), which shows a strong motivation and involvement on their part. The results highlight the factors limiting the ESDM intervention implementation (necessary adaptation period, organizational constraints of the professional teams).

Intensive home treatment for patients in acute psychiatric crisis situations: a multicentre randomized controlled trial

BackgroundHospitalization is a common method to intensify care for patients experiencing a psychiatric crisis. A short-term, specialised, out-patient crisis intervention by a Crisis Resolution Team (CRT) in the Netherlands, called Intensive Home Treatment (IHT), is a viable intervention which may help reduce hospital admission days. However, research on the (cost-)effectiveness of alternatives to hospitalisation such as IHT are scarce. In the study presented in this protocol, IHT will be compared to care-as-usual (CAU) in a randomized controlled trial (RCT). CAU comprises low-intensity outpatient care and hospitalisation if necessary. In this RCT it is hypothesized that IHT will reduce inpatient days by 33% compared to CAU while safety and clinical outcomes will be non-inferior. Secondary hypotheses are that treatment satisfaction of patients and their relatives are expected to be higher in the IHT condition compared to CAU.MethodsA 2-centre, 2-arm Zelen double consent RCT will be employed. Participants will be recruited in the Amsterdam area, the Netherlands. Clinical assessments will be carried out at baseline and at 6, 26 and 52 weeks post treatment allocation. The primary outcome measure is the number of admission days. Secondary outcomes include psychological well-being, safety and patients’ and their relatives’ treatment satisfaction. Alongside this RCT an economic evaluation will be carried out to assess the cost-effectiveness and cost-utility of IHT compared to CAU.DiscussionRCTs on the effectiveness of crisis treatment in psychiatry are scarce and including patients in studies performed in acute psychiatric crisis care is a challenge due to the ethical and practical hurdles. The Zelen design may offer a feasible opportunity to carry out such an RCT. If our study finds that IHT is a safe and cost-effective alternative for CAU it may help support a further decrease of in-patient bed days and may foster the widespread implementation of IHT by mental health care organisations internationally.Trial registrationThe trial is registered in the Netherlands Trial Register as # NTR-6151. Registered 23 November 2016.

Impact of the Early Start Denver Model on the cognitive level of children with autism spectrum disorder: study protocol for a randomised controlled trial using a two-stage Zelen design

IntroductionEarly intervention for autism spectrum disorder (ASD) in the European French-speaking countries is heterogeneous and poorly evaluated to date. Early intervention units applying the Early Start Denver Model (ESDM) for...

Population-based outreach versus care as usual to prevent suicide attempt: study protocol for a randomized controlled trial.

BackgroundSuicide remains the 10th-ranked most frequent cause of death in the United States, accounting for over 40,000 deaths per year. Nonfatal suicide attempts lead to over 200,000 hospitalizations and 600,000 emergency department visits annually. Recent evidence indicates that responses to the commonly used Patient Health Questionnaire (PHQ9) can identify outpatients who are at risk of suicide attempt and suicide death and that specific psychotherapy or Care Management programs can prevent suicide attempts in high-risk patients. Motivated by these developments, the NIMH-funded Mental Health Research Network has undertaken a multisite trial of two outreach programs to prevent suicide attempts among outpatients identified by routinely administered PHQ9 questionnaires.Methods/designOutpatients who are at risk of suicide attempt are automatically identified using data from electronic health records (EHRs). Following a modified Zelen design, all those identified are assigned to continued usual care (i.e., no contact) or to be offered one of two population-based outreach programs. A Care Management intervention includes systematic outreach to assess suicide risk, EHR-based tools to implement risk-based care pathways, and care management to facilitate recommended follow-up. A Skills Training intervention includes interactive online training in Dialectical Behavior Therapy skills, supported by reminder and reinforcement messages from a skills coach. Each intervention supplements, rather than replaces, usual care; participants may receive any other services normally available. Interventions are delivered primarily by secure messaging through EHR patient portals. Suicide attempts and deaths following randomization are identified using state vital statistics data and health system EHR and insurance claim data. Primary evaluation will compare risk of suicide attempt or death over 18 months according to the initial assignment, regardless of intervention participation. Recruitment is underway in three health systems (Group Health Cooperative, HealthPartners, and Kaiser Permanente Colorado). Over 2500 participants have been randomized as of 1 March 2016, with enrollment averaging approximately 100 per week.DiscussionAssessing the effectiveness of population-based suicide prevention requires adherence to the principles of pragmatic trials: population-based enrollment, accepting variable treatment participation, assessing outcomes using health record data, and analyses based on intent-to-treat.Trial registrationClinicalTrials.gov registration #NCT02326883, registered on 23 December 2014.

Proposals to Conduct Randomized Controlled Trials Without Informed Consent: a Narrative Review.

Individual informed consent from all participants is required for most randomized clinical trials (RCTs). However, some exceptions-for example, emergency research-are widely accepted. The literature on various approaches to randomization without consent (RWOC) has never been systematically reviewed. Our goal was to provide a survey and narrative synthesis of published proposals for RWOC. We focused on proposals to randomize at least some participants in a study without first obtaining consent to randomization. This definition included studies that omitted informed consent entirely, omitted informed consent for selected patients (e.g., the control group), obtained informed consent to research but not to randomization, or only obtained informed consent to randomization after random assignment had already occurred. It omitted oral and staged consent processes that still obtain consent to randomization from all participants before randomization occurs. We identified ten different proposals for RWOC: two variants of cluster randomization, two variants of the Zelen design, consent to postponed information, two-stage randomized consent, cohort multiple RCT, emergency research, prompted optional randomization trials, and low-risk pragmatic RCTs without consent. Of all designs discussed here, only cluster randomized designs and emergency research are routinely used, with the justification that informed consent is infeasible in those settings. Other designs have raised concerns that they do not appropriately respect patient autonomy. Recent proposals have emphasized the importance for RWOC of demonstrating such respect through systematic patient engagement, transparency, and accountability, potentially in the context of learning health care systems.

A case management intervention targeted to reduce healthcare consumption for frequent Emergency Department visitors: results from an adaptive randomized trial.

A small group of frequent visitors to Emergency Departments accounts for a disproportionally large fraction of healthcare consumption including unplanned hospitalizations and overall healthcare costs. In response, several case and disease management programs aimed at reducing healthcare consumption in this group have been tested; however, results vary widely. To investigate whether a telephone-based, nurse-led case management intervention can reduce healthcare consumption for frequent Emergency Department visitors in a large-scale setup. A total of 12 181 frequent Emergency Department users in three counties in Sweden were randomized using Zelen's design or a traditional randomized design to receive either a nurse-led case management intervention or no intervention, and were followed for healthcare consumption for up to 2 years. The traditional design showed an overall 12% (95% confidence interval 4-19%) decreased rate of hospitalization, which was mostly driven by effects in the last year. Similar results were achieved in the Zelen studies, with a significant reduction in hospitalization in the last year, but mixed results in the early development of the project. Our study provides evidence that a carefully designed telephone-based intervention with accurate and systematic patient selection and appropriate staff training in a centralized setup can lead to significant decreases in healthcare consumption and costs. Further, our results also show that the effects are sensitive to the delivery model chosen.

Effect of rehabilitation in systemic sclerosis

Physical therapy could be of interest to reduce disability of systemic sclerosis (SSc) patients. To develop a physical therapy program for SSc and compare its efficacy with that of usual care. 12-month, parallel-group randomized controlled trial involving a modified Zelen design conducted between September 2005 and October 2011. Randomization was computer-generated with allocation concealment by fax to a central coordinating office. Investigators were not blinded, but participants in the control group were blinded to study hypothesis. Four tertiary-care hospitals. Patients were enrolled if they had a SSc diagnosis, a disability rating ≥ 0.5 on the Health Assessment Questionnaire Disability Index (HAQ-DI) or complaints of decreased mouth opening or limited range of motion of at least one joint. The experimental intervention was a 1-month personalized supervised physical therapy program provided by specifically trained care providers followed by home sessions. The comparator was usual care. The primary outcome was the HAQ-DI score at 12 months. In the intention-to-treat analysis, as compared with the usual care group ( n = 108), patients in the physical therapy group ( n = 110) showed reduced disability at 1 month (HAQ-DI between-group difference (0.14; 95% confidence interval [CI] –0.24 to –0.03; P = 0.01), at 6 months the HAQDI scores between-group difference was –0.12; 95% CI, –0.23 to 0.01; P = 0.054. There was no statistically significant difference at 12 months (between-group difference at 12 months, –0.01; 95% CI –0.15 to 0.13; P = 0.86). There was a statistically significant difference for hand mobility and function, and pain, at 1 month but no difference at 12 months. Microstomia was lower in the physical therapy group at 1, 6 and 12 months (between-group difference at 12 months, 1.62; 95% CI 0.32 to 2.93; P = 0.01). No differences in adverse effects were observed between the two treatment groups. A 1-month personalized supervised physical therapy program followed by home exercise sessions had short-term benefits for patients with SSc but did not reduce disability at 12 months. The program had long-term benefits for microstomia. NCT00318188 .

Transcutaneous auricular vagus nerve stimulation for pediatric epilepsy: study protocol for a randomized controlled trial.

BackgroundRecently, clinical observations reported the potential benefit of vagus nerve stimulation (VNS) for pediatric epilepsy. Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a newer non-invasive VNS, making it more accessible for treating pediatric epilepsy, yet there is limited clinical evidence for its effectiveness.Methods/DesignA three-center, randomized, parallel, controlled trial will be carried out to evaluate whether ta-VNS improves pediatric epilepsy. Pediatric patients aged 2 to 14 years with epilepsy will be recruited and randomly assigned to transcutaneous auricular vagus nerve stimulation (ta-VNS) group, transcutaneous auricular non-vagus nerve stimulation (tan-VNS) group, and control group with a 1:1: sqrt(2) allocation, as per a computer generated randomization schedule stratified by study center using permuted blocks of random sizes. We will use Zelen’s design, in which randomization occurs before informed consent. Patients in the stimulation groups will receive tan-VNS or ta-VNS three times a day for 6 months. Patients in the control group will not be provided with any stimulation during the 6 months. The guardians of the patients are required to keep a detailed diary to record the data. Outcome assessment including seizure frequency, electroencephalogram (EEG), heart rate variability (HRV) analysis, quality of life (QOL) and adverse events will be made at baseline and 2, 4 and 6 months after ta-VNS initiation. The seizure frequency and adverse events will be followed up at 1 year and 1.5 years after ta-VNS initiation.DiscussionResults of this trial will help clarify whether ta-VNS treatment is beneficial for pediatric patients, and will make clear whether the anticonvulsive effect of ta-VNS is correlated with the improvement of sympathovagal imbalance.Trial registrationClinical Trials Identifier: NCT02004340. Registration date: 13 November 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0906-8) contains supplementary material, which is available to authorized users.

The methodology flaws in Hinman's acupuncture clinical trial, Part II: Zelen design and effectiveness dilutions

In the October 2014 publication of JAMA, Dr. Hinman and colleagues published the study “Acupuncture for Chronic Knee Pain: A Randomized Clinical Trial,” which concluded that “in patients older than 50 years with moderate or severe chronic knee pain, neither laser nor needle acupuncture conferred benefit over sham for pain or function. Our findings do not support acupuncture for these patients”. As pointed out in my former article, Part I, there were serious flaws in the trial design and statistics, as well as in the interpretation of the results. This article attempts to address problems in the Zelen design used by Hinman et al. There are some advantages to using a Zelen design for a randomized controlled trial (RCT). First, a Zelen design has a post-randomization consent design, which means that consent is only sought for one treatment each time, without the uncertainty of randomization. Researchers can be more comfortable knowing that they have the participants’ consent each time they undergo a treatment. Patients can also be more comfortable with this design because they know which type of treatment they are receiving; unlike traditional RCTs, patients are not ignorant of whether they are receiving the placebo or experimental treatment. Effects such as resentful demoralization and what is known as the “Hawthorne effect” (altered behavior or performance resulting from awareness of being a part of an experimental study) become less of an issue as patients are not weary of being part of a new alternative group, only the “standard” therapy will applies to them. However, it does have some disadvantages, and therefore can cause biases, which will be discussed in detail below.