Supporting ColoREctal Equitable Navigation (SCREEN): a protocol for a stepped-wedge cluster randomized trial for patient navigation in primary care.

BACKGROUND: Black individuals in the United States (US) have a higher incidence of and mortality from colorectal cancer (CRC) compared to other racial groups, and CRC is the second leading cause of death among Hispanic/Latino populations in the US. Patient navigation is an evidence-based approach to narrow inequities in cancer screening among Black and Hispanic/Latino patients. Despite this, limited healthcare systems have implemented patient navigation for screening at scale. METHODS: We are conducting a stepped-wedge cluster randomized trial of 15 primary care clinics with six steps of six-month duration to scale a patient navigation program to improve screening rates among Black and Hispanic/Latino patients. After six months of baseline data collection with no intervention we will randomize clinics, whereby three clinics will join the intervention arm every six months until all clinics cross over to intervention. During the intervention roll out we will conduct training and education for clinics, change infrastructure in the electronic health record, create stakeholder relationships, assess readiness, and deliver iterative feedback. Framed by the Practical, Robust Implementation Sustainment Model (PRISM) we will focus on effectiveness, reach, provider adoption, and implementation. We will document adaptations to both the patient navigation intervention and to implementation strategies. To address health equity, we will engage multilevel stakeholder voices through interviews and a community advisory board to plan, deliver, adapt, measure, and disseminate study progress. Provider-level feedback will include updates on disparities in screening orders and completions. DISCUSSION: Primary care clinics are poised to close disparity gaps in CRC screening completion but may lack an understanding of the magnitude of these gaps and how to address them. We aim to understand how to tailor a patient navigation program for CRC screening to patients and providers across diverse clinics with wide variation in baseline screening rates, payor mix, proximity to specialty care, and patient volume. Findings from this study will inform other primary care practices and health systems on effective and sustainable strategies to deliver patient navigation for CRC screening among racial and ethnic minorities. TRIAL REGISTRATION: NCT06401174.

Minimisation of dialysis risk in hospital patients with chronic kidney disease (MinDial): study protocol for a multicentre, stepped-wedge, cluster-randomised controlled trial.

BACKGROUND: Early identification of patients with chronic kidney disease (CKD) and advancing kidney insufficiency, followed by specialist care, can decelerate the progression of the disease. However, awareness of the importance and possible consequences of kidney insufficiency is low among doctors and patients. Since kidney insufficiency can be asymptomatic even in higher stages, it is often not even known to those belonging to risk groups. This study aims to clarify whether, for hospitalised patients with advanced chronic kidney disease, a risk-based appointment with a nephrology specialist reduces disease progression. METHODS: The target population of the study is hospitalised CKD patients with an increased risk of end-stage renal disease (ESRD), more specifically with an ESRD risk of at least 9% in the next 5 years. This risk is estimated by the internationally validated Kidney Failure Risk Equation (KFRE). The intervention consists of a specific appointment with a nephrology specialist after the hospital stay, while control patients are discharged from the hospital as usual. Eight medical centres include participants according to a stepped-wedge design, with randomised sequential centre-wise crossover from recruiting patients into the control group to recruitment to the intervention. The estimated glomerular filtration rate (eGFR) is measured for each patient during the hospital stay and after 12 months within the regular care by the general practitioner. The difference in the change of the eGFR over this period is compared between the intervention and control groups and considered the primary endpoint. DISCUSSION: This study is designed to evaluate the effect of risk-based appointments with nephrology specialists for hospitalised CKD patients with an increased risk of end-stage renal disease. If the intervention is proven to be beneficial, it may be implemented in routine care. Limitations will be examined and discussed. The evaluation will include further endpoints such as non-guideline-compliant medication, economic considerations and interviews with contributing physicians to assess the acceptance and feasibility of the intervention. TRIAL REGISTRATION: German Clinical Trials Register DRKS00029691 . Registered on 12 September 2022.

HPV Multilevel Intervention Strategies Targeting Immunization in Community Settings (HPV MISTICS): Study protocol for a hybrid 1 stepped-wedge cluster randomized trial.

BACKGROUND: This protocol paper describes the overall design for HPV MISTICS, a multilevel intervention to increase human papillomavirus (HPV) vaccination initiation and completion rates among adolescents aged 11-17. METHODS: We will conduct a hybrid type 1 implementation-effectiveness trial using a stepped-wedge cluster randomized trial in eight federally qualified health centers (FQHCs) in Florida. Intervention components target three levels: system, providers, and parents. Outcomes will be assessed using quantitative (e.g., vaccination data, survey data) and qualitative methods (e.g., staff and parent interviews). We expect to quantify changes in HPV vaccine series initiation and completion rates for adolescents ages 11-17 in the eight FQHCs. We have hypothesized a 20-percentage point increase in HPV vaccine series initiation and a 10-percentage point increase in series completion. We also anticipate being able to explore factors at the system, provider, and patient levels as potential covariates. Implementation outcomes, barriers, and facilitators identified in the study will help characterize the implementation process and inform potential future intervention scale-up. RESULTS: The project is ongoing; effectiveness and implementation outcomes will be determined following project completion. CONCLUSIONS: Findings will provide evidence of an equity-informed research design and implementation procedures that could help improve HPV vaccination rates in similar health systems. CLINICAL TRIALS IDENTIFIER: NCT05677360 (date registered: 2022-12-22); https://clinicaltrials.gov/study/NCT05677360?lead=Moffitt%20Cancer%20Center%20&aggFilters=status:rec&page=2&rank=17.

Reconsidering stepped wedge cluster randomized trial designs with implementation periods: Fewer sequences or the parallel-group design with baseline and implementation periods are potentially more efficient.

BACKGROUND/AIMS: When designing a cluster randomized trial, advantages and disadvantages of tentative designs must be weighed. The stepped wedge design is popular for multiple reasons, including its potential to increase power via improved efficiency relative to a parallel-group design. In many realistic settings, it will take time for clusters to fully implement the intervention. When designing the HEALing (Helping to End Addiction Long-termSM) Communities Study, implementation time was a major consideration, and we examined the efficiency and practicality of three designs. Specifically, a three-sequence stepped wedge design with implementation periods, a corresponding two-sequence modified design that is created by removing the middle sequence, and a parallel-group design with baseline and implementation periods. In this article, we study the relative efficiencies of these specific designs. More generally, we study the relative efficiencies of modified designs when the stepped wedge design with implementation periods has three or more sequences. We also consider different correlation structures. METHODS: We compare efficiencies of stepped wedge designs with implementation periods consisting of three to nine sequences with a variety of corresponding designs. The three-sequence design is compared to the two-sequence modified design and to the parallel-group design with baseline and implementation periods analysed via analysis of covariance. Stepped wedge designs with implementation periods consisting of four or more sequences are compared to modified designs that remove all or a subset of 'middle' sequences. Efficiencies are based on the use of linear mixed effects models. RESULTS: In the studied settings, the modified design is more efficient than the three-sequence stepped wedge design with implementation periods. The parallel-group design with baseline and implementation periods with analysis of covariance-based analysis is often more efficient than the three-sequence design. With respect to stepped wedge designs with implementation periods that are comprised of more sequences, there are often corresponding modified designs that improve efficiency. However, use of only the first and last sequences has the potential to be either relatively efficient or inefficient. Relative efficiency is impacted by the strength of the statistical correlation among outcomes from the same cluster; for example, the relative efficiencies of modified designs tend to be greater for smaller cluster auto-correlation values. CONCLUSION: If a three-sequence stepped wedge design with implementation periods is being considered for a future cluster randomized trial, then a corresponding modified design using only the first and last sequences should be considered if sole focus is on efficiency. However, a parallel-group design with baseline and implementation periods and analysis of covariance-based analysis can be a practical, efficient alternative. For stepped wedge designs with implementation periods and a larger number of sequences, modified versions that remove 'middle' sequences should be considered. Due to the potential sensitivity of design efficiencies, statistical correlation should be carefully considered.

A stepped-wedge randomised controlled trial to assess efficacy and cost-effectiveness of a care-bundle to prevent falls in older hospitalised patients.

BACKGROUND: Patient accidental falls in a hospital environment are a serious problem for patient safety, and for the additional costs due to associated medical interventions. OBJECTIVE: The endpoints of this study were the assessment of the fall incidence in the hospital before and after the implementation of a multidisciplinary care-bundle, along with a cost-effectiveness evaluation. DESIGN: A stepped-wedge trial was conducted between April 2015 and December 2016 in Bologna University Hospital. METHODS: Incidence rates (IRs) of falls in both the control and intervention periods were calculated. A multilevel mixed-effects generalised linear model with logit link function, adjusted for age, sex, cluster cross-over timing and patients' clinical severity was used to estimate odds ratios (OR) of fall risk of patients of the intervention group respect to the controls.Intervention costs associated with the introduction of the care-bundle intervention were spread between patients per cluster-period-group of exposure. Incremental cost-effectiveness ratio was evaluated using total costs in the intervention and control groups. RESULTS: IRs of falls in control and intervention periods were respectively 3.15 and 2.58 for 1,000 bed-days. After adjustment, the subjects receiving the intervention had a statistically significant reduced risk of falling with respect to those who did not (OR = 0.71, 95% confidence interval: 0.60-0.84). According to the cost-effectiveness analysis, the incremental cost per fall prevented was €873.92 considering all costs, and €1644.45 excluding costs related falls. CONCLUSIONS: Care-bundle had a protective effect on patients, with a statistically significant reduction of the fall risk. This type of intervention appears cost-effective compared to routine practices.

Do glycaemic treatment targets affect the perinatal mental health status of women with gestational diabetes? - Data from the TARGET Trial.

BACKGROUND: Gestational diabetes mellitus is associated with perinatal mental disorders. Effective management may reduce this risk, but there is little evidence on effects of different glycaemic treatment targets. We assessed whether tight glycaemic treatment targets compared with less-tight targets reduce the risk of poor mental health outcomes in women with gestational diabetes. METHODS: This was a secondary analysis of data from women who consented to complete perinatal mental health questionnaires as participants in the TARGET Trial, a stepped-wedge cluster randomized trial in 10 hospitals in New Zealand. All hospitals initially used less tight glycaemic targets for management of gestational diabetes and were sequentially randomized, in clusters of two at 4-monthly intervals, to using tighter glycaemic targets. Data were collected from 414 participants on anxiety (6-item Spielberger State Anxiety scale), depression (Edinburgh Postnatal Depression Scale), and health-related quality of life (36-Item Short-Form General Health Survey) at the time of diagnosis (baseline), 36 weeks of gestation, and 6 months postpartum. The primary outcome was composite poor mental health (any of anxiety, vulnerability to depression, or poor mental health-related quality of life). Generalized linear mixed models were used to determine the main treatment effect with 95% confidence intervals using an intention-to-treat approach. RESULTS: We found no differences between randomised glycaemic target groups in the primary outcome at 36 weeks' (relative risk (RR): 1.07; 95% confidence interval 0.58, 1.95) and 6 months postpartum (RR: 1.03; 0.58, 1.81). There were similarly no differences in the components of the primary outcome at 36 weeks' [anxiety (RR: 0.85; 0.44, 1.62), vulnerability to depression (RR: 1.10; 0.43, 2.83), or poor mental health-related quality of life (RR: 1.05; 0.50, 2.20)] or at 6 months postpartum [anxiety (RR:1.21; 0.59, 2.48), vulnerability to depression (RR:1.41; 0.53, 3.79), poor mental health-related quality of life (RR: 1.11; 0.59, 2.08)]. CONCLUSION: We found no evidence that adoption of tighter glycaemic treatment targets in women with gestational diabetes alters their mental health status at 36 weeks' gestation and at 6 months postpartum. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12615000282583 (ANZCTR-Registration). Date of registration: 25 March 2015.

Protocol for a pragmatic stepped wedge cluster randomized clinical trial testing behavioral economic implementation strategies to increase supplemental breast MRI screening among patients with extremely dense breasts.

BACKGROUND: Increased breast density augments breast cancer risk and reduces mammography sensitivity. Supplemental breast MRI screening can significantly increase cancer detection among women with dense breasts. However, few women undergo this exam, and screening is consistently lower among racially minoritized populations. Implementation strategies informed by behavioral economics ("nudges") can promote evidence-based practices by improving clinician decision-making under conditions of uncertainty. Nudges directed toward clinicians and patients may facilitate the implementation of supplemental breast MRI. METHODS: Approximately 1600 patients identified as having extremely dense breasts after non-actionable mammograms, along with about 1100 clinicians involved with their care at 32 primary care or OB/GYN clinics across a racially diverse academically based health system, will be enrolled. A 2 × 2 randomized pragmatic trial will test nudges to patients, clinicians, both, or neither to promote supplemental breast MRI screening. Before implementation, rapid cycle approaches informed by clinician and patient experiences and behavioral economics and health equity frameworks guided nudge design. Clinicians will be clustered into clinic groups based on existing administrative departments and care patterns, and these clinic groups will be randomized to have the nudge activated at different times per a stepped wedge design. Clinicians will receive nudges integrated into the routine mammographic report or sent through electronic health record (EHR) in-basket messaging once their clinic group (i.e., wedge) is randomized to receive the intervention. Independently, patients will be randomized to receive text message nudges or not. The primary outcome will be defined as ordering or scheduling supplemental breast MRI. Secondary outcomes include MRI completion, cancer detection rates, and false-positive rates. Patient sociodemographic information and clinic-level variables will be examined as moderators of nudge effectiveness. Qualitative interviews conducted at the trial's conclusion will examine barriers and facilitators to implementation. DISCUSSION: This study will add to the growing literature on the effectiveness of behavioral economics-informed implementation strategies to promote evidence-based interventions. The design will facilitate testing the relative effects of nudges to patients and clinicians and the effects of moderators of nudge effectiveness, including key indicators of health disparities. The results may inform the introduction of low-cost, scalable implementation strategies to promote early breast cancer detection. TRIAL REGISTRATION: ClinicalTrials.gov NCT05787249. Registered on March 28, 2023.

mHealth Intervention for Vietnamese Living With Diabetes: Protocol for a Stepped Wedge Pilot Study.

BACKGROUND: Evidence indicates participation in a diabetes self-management education and support program improves self-care behaviors and hemoglobin A1c. Language and cultural differences may be barriers to program participation resulting in ineffective self-management, but these factors can be addressed with appropriate interventions. Given the high health care costs associated with diabetes complications, we developed a multicomponent, culturally tailored Self-Management Mobile Health Intervention for US Vietnamese With Diabetes (SMart-D). OBJECTIVE: This study aims to evaluate the SMart-D intervention's feasibility, acceptability, and effectiveness with intentions to scale up the intervention in the future. This mixed methods study incorporates the Reach, Effectiveness, Adoption, Implementation, Maintenance framework to evaluate the intervention. METHODS: This stepped wedge randomized controlled pilot study will be conducted over 2 years in collaboration with primary care clinics. Eligible participants are patients with type 2 diabetes who are receiving health care from participating clinics. Clinics will be randomly assigned to an implementation date and will begin with patients enrolling in the control period while receiving standard care, then cross over to the intervention period where patients receive standard care plus the SMart-D intervention for over 12 weeks. Focus groups or interviews will be conducted with clinicians and patients after study completion. Qualitative data will be analyzed using NVivo. Outcomes on self-care behavior changes will be measured with the Summary of Diabetes Self-Care Activities scale and clinical changes will be measured using laboratory tests. A generalized linear mixed-effect model will be used to compute time effect, clustering effect, and the interaction of the control and intervention periods using SAS (version 9.4; SAS Institute). RESULTS: We hypothesize that (1) at least 50% (n=5) of eligible clinics and 50% (n=40) of eligible patients who are invited will participate, and at least 70% (n=56) of patients will complete the program, and (2) patients who receive the intervention will have improved self-care behaviors and clinical test results with at least 75% (n=60) of the patients maintaining improved outcomes at follow-up visits compared with baseline, and participants will verbalize that the intervention is feasible and acceptable. As of August 2023, we enrolled 10 clinics and 60 patients. Baseline data results will be available by the end of 2023 and outcome data will be published in 2025. CONCLUSIONS: This is the first Vietnamese diabetes self-management education and support intervention that leverages mobile health technology to address the barriers of language and culture differences through collaboration with primary care clinics. This study will provide a better understanding of the implementation process, demonstrate the potential effectiveness of the intervention, accelerate the pace of moving evidence-based interventions to practice among the US Vietnamese population, and potentially provide a replicable implementation model that can be culturally adapted to other non-English speaking ethnic minorities. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48585.

Trusted residents and housing assistance to decrease violence exposure in New Haven (TRUE HAVEN): a strengths-based and community-driven stepped-wedge intervention to reduce gun violence.

BACKGROUND: We describe the rationale and study design for "TRUsted rEsidents and Housing Assistance to decrease Violence Exposure in New Haven (TRUE HAVEN)," a prospective type 1 hybrid effectiveness/implementation study of a multi-level intervention using a stepped wedge design. TRUE HAVEN aims to lower rates of community gun violence by fostering the stability, wealth, and well-being of individuals and families directly impacted by incarceration through the provision of stable housing and by breaking the cycle of trauma. DESIGN: TRUE HAVEN is an ongoing, multi-level intervention with three primary components: financial education paired with housing support (individual level), trauma-informed counseling (neighborhood level), and policy changes to address structural racism (city/state level). Six neighborhoods with among the highest rates of gun violence in New Haven, Connecticut, will receive the individual and neighborhood level intervention components sequentially beginning at staggered 6-month steps. Residents of these neighborhoods will be eligible to participate in the housing stability and financial education component if they were recently incarcerated or are family members of currently incarcerated people; participants will receive intense financial education and follow-up for six months and be eligible for special down payment and rental assistance programs. In addition, trusted community members and organization leaders within each target neighborhood will participate in trauma-informed care training sessions to then be able to recognize when their peers are suffering from trauma symptoms, to support these affected peers, and to destigmatize accessing professional mental health services and connect them to these services when needed. Finally, a multi-stakeholder coalition will be convened to address policies that act as barriers to housing stability or accessing mental healthcare. Interventions will be delivered through existing partnerships with community-based organizations and networks. The primary outcome is neighborhood rate of incident gun violence. To inform future implementation and optimize the intervention package as the study progresses, we will use the Learn As You Go approach to optimize and assess the effectiveness of the intervention package on the primary study outcome. DISCUSSION: Results from this protocol will yield novel evidence for whether and how addressing structural racism citywide leads to a reduction in gun violence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05723614. Registration date: February 01, 2023. Please refer to https://clinicaltrials.gov/ct2/show/NCT05723614 for public and scientific inquiries.

A semi-Markov multistate cure model for estimating intervention effects in stepped wedge design trials.

Multistate models are useful for studying exposures that affect transitions among a set of health states. However, they can be challenging to apply when exposures are time-varying. We develop a multistate model and a method of likelihood construction that allows application of the model to data in which interventions or other exposures can be time-varying and an individual may to be exposed to multiple intervention conditions while progressing through states. The model includes cure proportions, reflecting the possibility that some individuals will never leave certain states. We apply the approach to analyze patient vaccination data from a stepped wedge design trial evaluating two interventions to increase uptake of human papillomavirus vaccination. The states are defined as the number of vaccine doses the patient has received. We model state transitions as a semi-Markov process and include cure proportions to account for individuals who will never leave a given state (e.g. never receive their next dose). Multistate models typically quantify intervention effects as hazard ratios contrasting the intensities of transitions between states in intervention versus control conditions. For multistate processes, another clinically meaningful outcome is the change in the percentage of the study population that has achieved a specific state (e.g. completion of all required doses) by a specific point in time due to an intervention. We present a method for quantifying intervention effects in this manner. We apply the model to both simulated and real-world data and also explore some conditions under which such models may give biased results.

Evidence of secular trends during the COVID-19 pandemic in a stepped wedge cluster randomized trial examining sexual and reproductive health outcomes among Indigenous youth.

BACKGROUND: Nen UnkUmbi/EdaHiYedo ("We Are Here Now," or NE) is an intervention to prevent STIs, HIV, HCV, and teen pregnancy among Assiniboine and Sioux youth of the Fort Peck Reservation in the state of Montana in the USA. A cluster-randomized stepped-wedge design (SWD) trial is used to evaluate NE, where clusters are schools. The purpose of this study is to evaluate whether there is evidence of a secular trend associated with the COVID-19 pandemic. METHODS: The original study design is a cluster-randomized stepped-wedge design (SWD), in which five schools that youth from Fort Peck attend are the clusters to be randomized into the intervention one at a time, with all schools eventually being randomized to the intervention across three steps. N/E is a 5-year study involving 456 15- to 18-year-old youth. For this study, we use a mixed quantitative and qualitative methods approach to understand how the COVID-19 pandemic may have been associated with the study's primary outcome variables. Data were drawn from the first cluster exposed to the intervention and one control cluster that did not yet receive the intervention during the period in which COVID-19 mitigation efforts were being implemented. A pre-post COVID questionnaire was added to core measures administered, and semistructured qualitative interviews were conducted with youths regarding their perceptions of how the pandemic altered their sexual behaviors. RESULTS: One hundred eighteen youth responded to the questionnaire and 31 youth participated in semistructured qualitative interviews. Youth reporting having sex with less people due to COVID-19 reported more sex acts (incident rate ratio (IRR)=3.6, 95% CI 1.6-8.1) in comparison to those who did not report having sex with less people, and youth who reported having sex with the same amount of people due to COVID-19 reported less sex acts (IRR=0.31, 95% CI 0.14-0.7) in comparison to those who did not report having sex with the same amount of people. Youth reporting having sex less times due to COVID-19 experienced a greater number of sex acts in comparison to those who did not report having sex less times (IRR=2.7, 1.2-6.4). Results suggest that more sexually active individuals reported perceiving having sex with less people and less frequent engagement in sex during the pandemic. It is possible that the COVID-19 pandemic period was associated with a truncation in the distribution of sexual activity that would bias an estimate of the intervention's effect. CONCLUSION: Findings suggest evidence of a secular trend. This trend must be accounted for at trial end, and sensitivity analyses are recommended. Documenting and reporting on these findings encourages transparent reporting during the implementation of a SWD trial during a global pandemic, and informs endline analyses. TRIAL REGISTRATION: This trial is registered with the Clinical trials registry of the US National Library of Medicine at the National Institutes of Health (NIH). It was registered on October 1, 2018. The study presented in this manuscript is funded by NIH National Institute on Minority Health and Health Disparities (NIMHD), Award # R01MD012761-01, Elizabeth Rink (Principal Investigator). The study's ClinicalTrials.gov number is NCT03694418.

Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT): A stepped wedge hybrid type 1 effectiveness-implementation study.

BACKGROUND: Extended-release injectable naltrexone (XR-NTX) is an effective treatment for opioid use disorder (OUD), but initiation remains a barrier to implementation. Standard practice requires a 10- to 15-day inpatient admission prior to XR-NTX initiation and involves a methadone or buprenorphine taper followed by a 7- to 10-day washout, as recommended in the Prescribing Information for XR-NTX. A 5- to 7-day rapid induction approach was developed that utilizes low-dose oral naltrexone and non-opioid medications. METHODS: The CTN-0097 Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT) study was a hybrid type I effectiveness-implementation trial that compared the effectiveness of the standard procedure (SP) to the rapid procedure (RP) for XR-NTX initiation across six community inpatient addiction treatment units, and evaluated the implementation process. Sites were randomized to RP every 14 weeks in an optimized stepped wedge design. Participants (target recruitment = 450) received the procedure (SP or RP) that the site was implementing at time of admission. The hypothesis was RP will be non-inferior to SP on proportion of inpatients who receive XR-NTX, with a shorter admission time for RP. Superiority testing of RP was planned if the null hypothesis of inferiority of RP to SP was rejected. DISCUSSION: If RP for XR-NTX initiation is shown to be effective, the shorter inpatient stay could make XR-NTX more feasible and have an important public health impact expanding access to OUD pharmacotherapy. Further, a better understanding of facilitators and barriers to RP implementation can help with future translatability and uptake to other community programs. TRIAL REGISTRATION: NCT04762537 Registered February 21, 2021.

Comparison of analysis methods and design choices for treatment-by-period interaction in unidirectional switch designs: a simulation study.

BACKGROUND: Due to identifiability problems, statistical inference about treatment-by-period interactions has not been discussed for stepped wedge designs in the literature thus far. Unidirectional switch designs (USDs) generalize the stepped wedge designs and allow for estimation and testing of treatment-by-period interaction in its many flexible design forms. METHODS: Under different forms of the USDs, we simulated binary data at both aggregated and individual levels and studied the performances of the generalized linear mixed model (GLMM) and the marginal model with generalized estimation equations (GEE) for estimating and testing treatment-by-period interactions. RESULTS: The parallel group design had the highest power for detecting the treatment-by-period interactions. While there was no substantial difference between aggregated-level and individual-level analysis, the GLMM had better point estimates than the marginal model with GEE. Furthermore, the optimal USD for estimating the average treatment effect was not efficient for treatment-by-period interaction and the marginal model with GEE required a substantial number of clusters to yield unbiased estimates of the interaction parameters when the correlation structure is autoregressive of order 1 (AR1). On the other hand, marginal model with GEE had better coverages than GLMM under the AR1 correlation structure. CONCLUSION: From the designs and methods evaluated, in general, parallel group design with a GLMM is, preferred for estimation and testing of treatment-by-period interaction in a clustered randomized controlled trial for a binary outcome.

Co-creation using crowdsourcing to promote PrEP adherence in China: study protocol for a stepped-wedge randomized controlled trial.

BACKGROUND: Adherent pre-exposure prophylaxis (PrEP) uptake can prevent HIV infections. Despite the high HIV incidence, Chinese key populations have low PrEP uptake and adherence. New interventions are needed to increase PrEP adherence among key populations in China. Co-creation methods are helpful to solicit ideas from the community to solve public health problems. The study protocol aims to describe the design of a stepped-wedge trial and to evaluate the efficacy of co-created interventions to facilitate PrEP adherence among key populations in China. METHODS: The study will develop intervention packages to facilitate PrEP adherence among Chinese key populations using co-creation methods. The study will then evaluate the efficacy of the co-created intervention packages using a stepped-wedge randomized controlled trial. This four-phased closed cohort stepped-wedge design will have four clusters. Each cluster will start intervention at three-month intervals. Seven hundred participants who initiated PrEP will be recruited. Participants will be randomized to the clusters using block randomization. The intervention condition includes receiving co-created interventions in addition to standard of care. The control condition is the standard of care that includes routine clinical assessment every 3 months. All participants will also receive an online follow-up survey every 3 months to record medication adherence and will be encouraged to use a WeChat mini-app for sexual and mental health education throughout the study. The primary outcomes are PrEP adherence and retention in PrEP care throughout the study period. We will examine a hypothesis that a co-created intervention can facilitate PrEP adherence. Generalized linear mixed models will be used for the primary outcome analysis. DISCUSSION: Developing PrEP adherence interventions in China faces barriers including suboptimal PrEP uptake among key populations, the lack of effective PrEP service delivery models, and insufficient community engagement in PrEP initiatives. Our study design addresses these obstacles by using co-creation to generate social media-based intervention materials and embedding the study design in the local healthcare system. The study outcomes may have implications for policy and intervention practices among CBOs and the medical system to facilitate PrEP adherence among key populations. TRIAL REGISTRATION: The study is registered in Clinical Trial databases in China (ChiCTR2100048981, July 19, 2021) and the US (NCT04754139, February 11, 2021).

Rationale, Design, and Methods for Nen Unkumbi/Edahiyedo ("We Are Here Now"): A Multi-Level Randomized Controlled Trial to Improve Sexual and Reproductive Health Outcomes in a Northern Plains American Indian Reservation Community.

American Indian (AI) youth in the United States experience disproportionate sexual and reproductive health (SRH) disparities relative to their non-Indigenous, white counterparts, including increased rates of sexually transmitted infections (STIs), earlier sexual debut, increased rates of teen birth, and reduced access to SRH services. Past research shows that to improve SRH outcomes for AI youth in reservation communities, interventions must address complex factors and multiple levels of community that influence sexual risk behaviors. Here, we describe development of a multi-level, multi-component randomized controlled trial (RCT) to intervene upon SRH outcomes in a Northern Plains American Indian reservation community. Our intervention is rooted in a community based participatory research framework and is evaluated with a stepped wedge design that integrates 5 reservation high schools into a 5-year, cluster-randomized RCT. Ecological Systems Theory was used to design the intervention that includes (1) an individual level component of culturally specific SRH curriculum in school, (2) a parental component of education to improve parent-child communication about SRH and healthy relationships, (3) a community component of cultural mentorship, and (4) a systems-level component to improve delivery of SRH services from reservation healthcare agencies. In this article we present the rationale and details of our research design, instrumentation, data collection protocol, analytical methods, and community participation in the intervention. Our intervention builds upon existing community strengths and integrates traditional Indigenous knowledge and values with current public health knowledge to reduce SRH disparities.

Topical sirolimus solution for lingual microcystic lymphatic malformations in children and adults (TOPGUN): study protocol for a multicenter, randomized, assessor-blinded, controlled, stepped-wedge clinical trial.

BACKGROUND: Lingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations presenting as clusters of cysts filled with lymph fluid or blood. Even small well-limited lesions can be responsible for a heavy burden, inducing pain, aesthetic prejudice, or oozing, bleeding, infections. The natural history of LMLMs is progressive worsening punctuated by acute flares. Therapeutic options include surgery, laser excision, and radiofrequency ablation but all are potentially detrimental and expose to local relapse. Therefore, the management frequently relies on a "watchful waiting" approach. In complicated LMLMs, treatment with oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is often used. Topical applications of sirolimus on the buccal mucosae have been reported in other oral diseases with good tolerance and none to slight detectable blood sirolimus concentrations. We aim to evaluate the efficacy and safety of a 1 mg/mL sirolimus solution applied once daily on LMLM of any stage in children and adults after 4, 8, 12, 16, 20, and 24 weeks of treatment compared to usual care (no treatment). METHODS: This is a randomized, multicentric study using an individually randomized stepped-wedge design over 24 weeks to evaluate topical application of a 1 mg/mL sirolimus solution once daily, on LMLM, versus usual care (no treatment), the control condition. Participants begin with an observational period and later switch to the intervention at a randomized time (week 0, 4, 8, or 12). Visits occur every 4 weeks, either in the study center or by teleconsulting. The primary outcome will be the evaluation of global severity of the LMLM on monthly standardized photographs by 3 independent blinded experts using the physical global assessment (PGA) 0 to 5 scale. Secondary outcomes will include lesion size measurement and quality of life assessment, investigator, and patient-assessed global disease and specific symptoms (oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain, and global discomfort) assessment. A biological monitoring will be performed including residual blood sirolimus concentration and usual laboratory parameters. DISCUSSION: Given the disappointing state of current treatment options in LMLMs, topical sirolimus could become firstline therapy in treating LMLMs if its efficacy and safety were to be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04128722 . Registered on 24 September 2019. EudraCT: EUCTR2019-001530-33-FR Sponsor (University Hospital Center of Tours - CHRU Tours): DR190041-TOPGUN French regulatory authorities: ID RCB: 2019-001530-33.

Sample size calculators for planning stepped-wedge cluster randomized trials: a review and comparison.

Recent years have seen a surge of interest in stepped-wedge cluster randomized trials (SW-CRTs). SW-CRTs include several design variations and methodology is rapidly developing. Accordingly, a variety of power and sample size calculation software for SW-CRTs has been developed. However, each calculator may support only a selected set of design features and may not be appropriate for all scenarios. Currently, there is no resource to assist researchers in selecting the most appropriate calculator for planning their trials. In this paper, we review and classify 18 existing calculators that can be implemented in major platforms, such as R, SAS, Stata, Microsoft Excel, PASS and nQuery. After reviewing the main sample size considerations for SW-CRTs, we summarize the features supported by the available calculators, including the types of designs, outcomes, correlation structures and treatment effects; whether incomplete designs, cluster-size variation or secular trends are accommodated; and the analytical approach used. We then discuss in more detail four main calculators and identify their strengths and limitations. We illustrate how to use these four calculators to compute power for two real SW-CRTs with a continuous and binary outcome and compare the results. We show that the choice of calculator can make a substantial difference in the calculated power and explain these differences. Finally, we make recommendations for implementing sample size or power calculations using the available calculators. An R Shiny app is available for users to select the calculator that meets their requirements (https://douyang.shinyapps.io/swcrtcalculator/).

Stepped Wedge Cluster Randomized Trials: A Methodological Overview.

BACKGROUND: Stepped wedge cluster randomized trials enable rigorous evaluations of health intervention programs in pragmatic settings. In the present study, we aimed to update neurosurgeon scientists on the design of stepped wedge randomized trials. METHODS: We have presented an overview of recent methodological developments for stepped wedge designs and included an update on the newer associated methodological tools to aid with future study designs. RESULTS: We defined the stepped wedge trial design and reviewed the indications for the design in depth. In addition, key considerations, including mainstream methods of analysis and sample size determination, were discussed. CONCLUSIONS: Stepped wedge designs can be attractive for study intervention programs aiming to improve the delivery of patient care, especially when examining a small number of heterogeneous clusters.

A Quality Improvement Emergency Department Surge Management Platform (SurgeCon): Protocol for a Stepped Wedge Cluster Randomized Trial.

BACKGROUND: Despite many efforts, long wait times and overcrowding in emergency departments (EDs) have remained a significant health service issue in Canada. For several years, Canada has had one of the longest wait times among the Organisation for Economic Co-operation and Development countries. From a patient's perspective, this challenge has been described as "patients wait in pain or discomfort for hours before being seen at EDs." To overcome the challenge of increased wait times, we developed an innovative ED management platform called SurgeCon that was designed based on continuous quality improvement principles to maintain patient flow and mitigate the impact of patient surge on ED efficiency. The SurgeCon quality improvement intervention includes a protocol-driven software platform, restructures ED organization and workflow, and aims to establish a more patient-centric environment. We piloted SurgeCon at an ED in Carbonear, Newfoundland and Labrador, and found that there was a 32% reduction in ED wait times. OBJECTIVE: The primary objective of this trial is to determine the effects of SurgeCon on ED performance by assessing its impact on length of stay, the time to a physician's initial assessment, and the number of patients leaving the ED without being seen by a physician. The secondary objectives of this study are to evaluate SurgeCon's effects on patient satisfaction and patient-reported experiences with ED wait times and its ability to create better-value care by reducing the per-patient cost of delivering ED services. METHODS: The implementation of the intervention will be assessed using a comparative effectiveness-implementation hybrid design. This type of hybrid design is known to shorten the amount of time associated with transitioning interventions from being the focus of research to being used for practice and health care services. All EDs with 24/7 on-site physician support (category A hospitals) will be enrolled in a 31-month, pragmatic, stepped wedge cluster randomized trial. All clusters (hospitals) will start with a baseline period of usual care and will be randomized to determine the order and timing of transitioning to intervention care until all hospitals are using the intervention to manage and operationalize their EDs. RESULTS: Data collection for this study is continuing. As of February 2022, a total of 570 randomly selected patients have participated in telephone interviews concerning patient-reported experiences and patient satisfaction with ED wait times. The first of the 4 EDs was randomly selected, and it is currently using SurgeCon's eHealth platform and applying efficiency principles that have been learned through training since September 2021. The second randomly selected site will begin intervention implementation in winter 2022. CONCLUSIONS: By assessing the impact of SurgeCon on ED services, we hope to be able to improve wait times and create better-value ED care in this health care context. TRIAL REGISTRATION: ClinicalTrials.gov NCT04789902; https://clinicaltrials.gov/ct2/show/NCT04789902. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30454.

Study protocol for the Respond to Prevent Study: a multi-state randomized controlled trial to improve provision of naloxone, buprenorphine and nonprescription syringes in community pharmacies.

Access to the opioid antidote naloxone is a critical component of addressing the opioid crisis. Naloxone is a population-level prevention intervention associated with substantial reductions in overdose mortality and reduction of nonfatal overdose. Pharmacies' pivotal role in dispensing medications like buprenorphine for the treatment of opioid use disorder and selling nonprescription syringes places them at the crossroads of opioid access and risk mitigation methods like naloxone provision. Testing ways to optimize pharmacy-based naloxone provision will be key as the country expands the implementation of naloxone through the medical system. In the Respond to Prevent Study, we conducted a large, practical study of a pharmacy-focused intervention in a sample of Washington, Oregon, Massachusetts and New Hampshire community chain pharmacies to increase naloxone dispensing and improve opioid safety. The intervention integrated two evidence-based educational toolkits and streamlined materials to enhance the focus on naloxone policy, stigma reduction, and patient communications around naloxone, nonprescription syringes and buprenorphine access. The real-world study implemented a stepped wedge, clustered randomized trial design across 175 community chain pharmacies to evaluate the effectiveness of the Respond to Prevent intervention in increasing: (a) pharmacy based naloxone distribution rates, naloxone-related patient engagement, and pharmacist and technicians' attitudes, knowledge, perceived behavioral control and self-efficacy toward naloxone; and (b) pharmacy nonprescription syringe sales, and pharmacist and technicians' attitudes, knowledge, perceived behavioral control and self-efficacy toward dispensing buprenorphine for opioid use disorder (secondary outcomes). This commentary provides a brief narrative about the study and presents insights on the design and adaptations to our study protocol, including those adopted during the unprecedented COVID-19 pandemic further compounded by Western wildfires in 2020.