Here is the design of a clinical trial:

Official Title: Cirrhosis Care Alberta (CCAB): A Pragmatic Type II Hybrid Effectiveness Implementation Trial Evaluating the Effectiveness of a Standardized Order Set

Included conditions:
- Cirrhosis, Liver

Study Armgroups:
- {'label': 'Control', 'type': 'NO_INTERVENTION', 'description': 'Current practice at baseline, routine cirrhosis care.'}
- {'label': 'Intervention', 'type': 'EXPERIMENTAL', 'description': 'Use of a standardized cirrhosis order set.', 'interventionNames': ['Other: Evidence-based standardized Cirrhosis order set']}
- {'label': 'Intervention + EMR', 'type': 'ACTIVE_COMPARATOR', 'description': 'Use of a standardized cirrhosis order set embedded within an electronic medical record.', 'interventionNames': ['Other: Evidence-based standardized Cirrhosis order set']}

Interventions:
- {'type': 'OTHER', 'name': 'Evidence-based standardized Cirrhosis order set', 'description': 'Standardized order sets for guidance in ascites, varices, hepatic encephalopathy, infections, and medication reconciliation (optimizing HE medication, medication prophylaxis, withdrawal of non-indicated proton pump inhibitors).', 'armGroupLabels': ['Intervention', 'Intervention + EMR']}

Primary Outcomes:
- {'measure': 'Cumulative hospital length of stay (LOS) per patient year', 'description': 'LOS', 'timeFrame': 'Baseline, 1 year, 2 year'}

Please estimate the sample size based on the assumption: 
The study assumes a significance level that provides >90% power to detect the effect in the three largest sites and the whole cohort, with a conservative estimate that 50% of eligible patients would receive the pathway. The analysis accounts for patient factors, observation clustering, and uses interrupted time series models with random intercepts for sites and an over-dispersed Poisson distribution.
Sample size, data collection and analysis
        
          Effectiveness outcomes - clinical outcomes, cost-utility
          
i.)Sample size


          Consistent with the type 1 hybrid trial design, the overarching sample size calculation is based on the cumulative 90-day hospital length of stay (LOS) [48]. Based on 2015/2016 AHS administrative data (4176 cirrhosis-attributed admissions for 2652 patients at study sites) [62] and CCAB implementation time per site, we estimate a pre-intervention cohort of 3975 patients and post-intervention cohort of 3975 patients (nâ=â7950). Our calculations tested our ability to detect a 3-day reduction in average 90-day cumulative LOS from our historically observed average of 13.7âdays. Computer simulations re-sampled historic LOS data to assess power to detect proposed effects for plausible scenarios using interrupted time series models with random intercepts for sites and an over-dispersed Poisson distribution. A scenario that assumed that 50% of eligible patients would receive the pathway (our most conservative estimate) and that there would be a rapid and sustained uptake of the pathway in the two years following implementation had >â90% power to detect an effect in the three largest sites and the whole cohort [63].
ii.)Data collection and analysis
          The index population will be identified at admission with a validated Canadian algorithm of ICD9 and ICD10 codes (overall accuracy 87%) [58]. We will analyze administrative data (nâ=â7950) using linear effect modeling that accounts for patient factors and observation clustering within sites [64]. We will use segmented regression analyses of interrupted time series to model 90-day cumulative LOS and hospitalization rate in each period [65], comparing post-intervention changes with pre-intervention secular trends [66]. We will evaluate and account for autocorrelation or other serial dependencies in data. Each of five geographic zones and eight hospital sites will serve as its own control, enabling us to identify effectiveness within each jurisdiction. We will also combine site series into generalized linear mixed effects models [64], with a random intercept for each site, fixed effects for time, and an indicator variable for pre-and post-intervention periods for each site.
          Cost-utility evaluation will estimate expected incremental cost per Quality Adjusted Life Year (QALY) gained by implementing CCAB, within the Net Benefit Regression framework [67]. Analysis will control for differences in relevant patient cohort characteristics. The evaluation will adopt a health system perspective and within-study analysis (only study cohort costs and outcomes), comparing resource use and health outcomes (health-related quality of life, mortality) for CCAB and usual care cohorts. These will be combined to calculate within-study expected QALY for each cohort. Methods for economic evaluation (e.g., discount rate choice, uncertainty characterization, results presentation) will adhere to recent reference case recommendations (Canadian Agency for Drugs & Technologies in Healthcare) [68]. Stochastic analysis will be implemented with non-parametric bootstraps. Results will be presented as Expected Net Health Benefit and Cost Effectiveness Acceptability Curve. We will also report Value of Information to characterize residual decision uncertainty on value to Alberta of CCAB spread and scale at study completion.
        
        
          Effectiveness outcome - quality of care measures
          
i.)Sample size


          We will randomly sample at least 50 charts per site. This will provide 95% confidence intervals with widths no greater than +/ââ10% for percentages of patients meeting quality measures (QMs) within each site.
ii.)Data collection and analysis
          Improvements in quality of care will be evaluated using QMs for each of the three CCAB order set domains [69] (see TableÂ 3). The majority of QMs will be obtained from administrative and chart review data audits from randomly selected charts and will take place quarterly during the study. The data from these audits will be used to promote change at each site. The central data collection team will record survey results in a secure AHS database for analysis. We will use inverse sampling weights to estimate the percent of patients attaining the QMs for the province. Administrative data will be analyzed for clinical outcomes, with additional analyses to compare change in QMs based on patient-reported outcomes, using linear mixed effects models that account for patient factors and observation clustering within sites [64].
Table 3Sample of Quality Measures (QMs)Cirrhosis Care Alberta Order Set DomainQuality Measure DefinitionManagement of Cirrhosis complicationsâAscites*Patients undergoing large volume paracentesis (>â5âl removed) should receive intravenous albumin (6â8âg per liter removed)âHepatic hydrothorax*Patients with ascites and/or hepatic hydrothorax should be managed with both sodium restriction and diuretics (unless there is a contraindication for diuretics)âSpontaneous bacterial peritonitis*Hospitalized patients with ascites, with an ascitic fluid polymorphonuclear count of â¥250 cells/mm3, should receive empiric antibiotics and albumin within 12âh of the test result. The first dose of albumin should be 1.5âg per kg body weight followed by a second infusion of 1.0âg/kg on day 3âSpontaneous bacterial pleuritis*Hospitalized patients with a pleural fluid polymorphonuclear count of â¥500 cells/mm3 (orââ¥â250 cells/mm3 with positive culture), should receive empiric antibiotics within 12âh of the test resultâRenal dysfunctionPatients with acute kidney injury should be given an intravenous albumin challenge of up to 100âgâÃâ2âdays.âHepatorenal syndromePatients with cirrhosis and hepatorenal syndrome who have a MAP of <â65âmmHg should receive a combination of vasoconstrictors and albumin therapyâVariceal bleed*Patients with cirrhosis who survive an episode of acute variceal hemorrhage should receive a combination of EVL (endoscopic variceal ligation) and Î² -blockersâHepatic encephalopathy*Patients who are discharged after an acute episode of hepatic encephalopathy should receive secondary prophylaxis with lactulose and/or rifaximinâAlcoholic hepatitisPatients with ETOH hepatitis and a MELD score of >â20 should be considered for prednisone therapy provided there are no contraindicationsManagement of Broader health needsâAdvance care planning and goals of carePatients admitted with cirrhosis should have goals of care documentedâAlcohol use disorder*Patients with cirrhosis should receive counseling or be referred to a substance abuse treatment program within 2âmonths of positive screeningâNutrition and physical activity optimizationPatients admitted with cirrhosis should be prescribed a high protein/high calorie (Â± as needed, a low sodium) dietPreparation for transition into the communityâStandardized cirrhosis education for patients/caregiversPatients with cirrhosis should receive cirrhosis education prior to dischargeâPost-discharge laboratory, diagnostic imaging and endoscopy appointmentsPatients with cirrhosis should receive information about when to have lab work done post dischargeâPost-discharge follow-up with primary and/or specialty care*Recently discharged patients with cirrhosis should have a clinic visit with a health care provider within 4âweeks of dischargeTable includes a sample of the Quality Measures (QM) that will be evaluated from each domain of the Cirrhosis Care Alberta (CCAB) order set. Additional QMs will also be evaluated. QMs were selected based on consensus by either: *Practice Metrics Committee of the American Association for the Study of Liver Diseases [70], or consensus between the CCAB study team members
        
        
          Effectiveness outcome - patient and caregiver experience with the intervention
          
i.)Sample size


          Purposeful maximum variation sampling will be used to ensure recruitment of a diverse group of patients and caregivers (rural, urban, socioeconomic status) to explore their experiences with the intervention. We estimate needing 40â50 participants to achieve saturation, typical for this methodological approach and appropriate given the variation in cirrhosis disease experiences [70]. This data will be supplemented by patient phone surveys done in the pre and post implementation periods where patients with cirrhosis admitted to study sites will be contacted 7â14âdays post-discharge and administered a health-related quality of life measure (EQ-5D) [71] and care transitions survey (CTM-15) [72] to assess their experience with care. For patient phone surveys, we will take a convenience sample of patients pre and post implementation of the intervention based on the capacity of units to identify patients.
ii.)Data collection and analysis
          The data collection will begin after 1â2âmonths post-implementation at each study site (to allow for intervention uptake). Patients and caregivers will be invited to participate in individual semi-structured qualitative interviews focusing on key areas such as self-management, self-efficacy for cirrhosis, and relationships with healthcare providers using qualitative description methods [70, 73, 74]. For comparable historical context, only patients with at least one hospital admission prior to implementation of the order set will be invited to participate. For participant convenience, interviews will be in-person or virtual, with these interviews being recorded and transcribed verbatim. Participant data will be coded into meaningful segments, then organized into areas of similar patterns or themes [75]. We will examine areas of commonality and difference in thematic analysis based on factors such as demographics, socioeconomic status and cirrhosis/hospitalization experiences [76, 77]. Data collection and analysis will be concurrent and iterative to enable refinement of the recruitment process and semi-structured interview guide [77].
        
        
          Implementation outcomes
          
i.)Sample size


          Over the course of the project we anticipate surveying approximately 280 service providers (physicians, nurses and other health professionals), estimates derived from the number of providers involved with the management of cirrhosis at the sites. The qualitative evaluation of implementation will use a similar sampling strategy with the evaluation of patientsâ experience described previously.
ii.)Data collection and analyses
          Implementation data will be collected from a variety of sources including AHS administrative database, chart reviews, provider surveys using validated questionnaires and interviews with physicians and nurses. The CCAB project repository and participant observations from throughout the project will be leveraged to obtain data on implementation context and processes. Implementation data will also be collected during monthly virtual learning session meetings and any on-site visits that occur during the study phases. The quantitative data will be analyzed descriptively to monitor reach, adoption and implementation fidelity following the PDSA cycles. Qualitative data will be analyzed using a framework analytic approach to evaluate the contextual factors impacting adoption, reach, implementation fidelity, implementation feasibility and maintenance of the CCAB order set rollout [78].