Online Prehabilitation for Patients Awaiting Liver Transplantation

Study Overview
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Brief Summary
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Physical frailty is common in patients awaiting liver transplantation and has been associated with poor health outcomes. There is promising data from small studies showing that behavioural, nutrition and exercise therapy (prehabilitation) improves physical function in patients while they are waiting for a liver transplant. The proposed trial will assess if a 12-week online prehabilitation program improves physical function in patients listed for liver transplantation. Over 4 years, 221 patients will be recruited from 5 transplant centres across Canada and will be randomized to receive either the online prehabilitation program or usual care. The primary outcome will be the change in distance walked in 6 minutes between the beginning and end of the study. Secondary and exploratory outcomes include changes in the liver frailty intake, health-related quality of life, covert hepatic encephalopathy, and post-transplant health- related outcomes. Results will be compared between the intervention and usual care groups. If feasible, an economic evaluation will compare the costs and benefits of the prehabilitation program versus usual care.

Detailed Description
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This multi-centre randomized controlled trial (RCT) will be completed across the five major LT programs in Canada: Vancouver, Edmonton/Calgary, Toronto, London, and Montreal. Participants involved in this study will be LT transplant candidates with cirrhosis who are receiving care at one of the five participating LT programs. Participants involved in this study will be LT transplant candidates with cirrhosis who are receiving care at one of the five LT programs. Participants will be assessed for eligibility, provided informed signed consent, complete baseline testing and then be randomized to the prehabilitation arm or usual care. Participants will be randomized in a 2:1 ratio between groups. Prehabilitation Arm: The 12 week prehabilitation program include a 12 week nutrition and acceptance and commitment therapy program and a 10 week resistance exercise program that is accessed through the online digital platform. Participants will receive onboarding the platform during their initial nutrition assessment. The nutrition program includes a nutritional assessment, provision of a daily protein intake target (1.2-1.5 g/kg/day), online group sessions, and follow ups. Participants will also be provided with a clinically tested whey protein powder supplement with dosage based on their malnutrition scoring done at baseline. Follow ups will also be provided based on malnutrition scoring done at baseline. The exercise program includes an exercise assessment, follow along exercise videos, and weekly virtual exercise group sessions. The exercise specialist will advise one of three levels of exercise programming for each participant. Participants will be advised to complete 3 exercise sessions weekly from a combination of virtual group sessions and follow along videos and to participate in planned aerobic activity as much as possible. The weekly acceptance and commitment therapy based educational videos focus on reducing stress and anxiety and improving motivation and adherence. Control/Usual Care Arm: This group will receive standard care for LT candidates with cirrhosis and will be provided with standard online exercise, nutrition, and behavioural resources. Control participants will not receive access to the online digital platform. A short questionnaire will be sent to control participants every 4 weeks to track changes in physical activity. Extended Follow Up After the 12-week trial, all participants will have extended follow-up with virtual testing every 12 weeks, up to 6 months after completion of the 12-week trial. Until the time of transplant, death, delisting, or end of the extended follow-up period, intervention participants will have access to a maintenance version of the program on the platform. Post-Transplant follow-up In the subgroup of patients who undergo LT, the same in-person and virtual testing will be carried out at  6-12 weeks post-transplant (timing may vary due to site clinic flow) Data Collection Plan Sample size calculations are based on the primary outcome (the chair stand test: time to complete 5 sit-to-stands) using individual data from our local exercise study in cirrhosis (n=59), plus our sit-to-stand data from our study of 694 patients. After accounting for lack of trial completion, loss to follow up, the total sample size is 177, with 59 participants in the control and 118 in the intervention arm. Quantitative outcomes: Baseline and primary/secondary/exploratory outcome data will be collected with in-person and virtual visits at baseline and week 12 (end of trial). Post-trial, all participants will have extended follow-up with virtual visits every 12 weeks, up to 6 months after their trial completion. In the subgroup of patients undergoing LT, the same in-person and virtual assessment will be carried out at  6-12 weeks post-transplant (timing may vary due to site clinic flow). Charts will be reviewed for information on death, hospitalization, ambulatory care visits, medications and transplantation for up to 2 years after randomization in all participants. Dietary intake data (24-hour recall) may be collected using third party software. Qualitative data: Interviews/Focus groups will be conducted at the end of the study in a virtual format. Participation in the interviews/focus groups will be optional. Types of analyses Quantitative outcomes: Baseline demographic and clinical characteristics will be compared between groups to identify differences that exist despite randomization. Variables will be screened for assumptions of normality, and descriptive analyses presented for participant demographic, medical and outcome variables. Sex will be used in subgroup analysis of primary and secondary outcomes. It will also be a covariate for exploratory analysis in corresponding models. All analyses will adhere to the intention-to-treat principle. Qualitative data: Qualitative data will be analyzed inductively following a theoretical thematic approach. Data will be coded, with codes combined into larger categories and theme, with the goal of highlighting participant experiences and acceptability (barriers, facilitators) of the OPAL platform and intervention. Data collection and analysis will occur concurrently in order to enable refinement of interview/focus guide questions and deeper exploration of emerging themes. Primary outcome: The primary outcome (sit to stand test; time to do 5 sit-to-stands) will be analyzed by linear mixed models with random effects, adjusted for baseline score as a covariate. Sites will be entered as random effects. Secondary/exploratory outcomes: (1) Quantitative outcomes: Similar types of models will be used for continuous secondary/exploratory outcomes. To examine predictors of exercise and nutrition adherence (e.g. COM-B results), generalized linear models with binary outcome will be employed. To evaluate the potential effect of selected demographic variables on outcomes, as an exploratory analysis, models will be adjusted for clinically significant variables (e.g. sex, gender, digital technology proficiency). Results will be primarily descriptive. Exploratory per-protocol analysis will be performed and results presented if differences are substantial between this and the intention-to-treat group.

Official Title
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OPAL: Online Prehabilitation for Patients Awaiting Liver Transplantation - a Multicenter Randomized Controlled Trial to Reduce Physical Frailty and Improve Health Outcomes

Conditions
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Cirrhosis, Liver

Intervention / Treatment
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* Behavioral: Prehabilitation Programming


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥18 years old with cirrhosis (compatible fibroscan, histology or imaging based assessment + compatible clinical picture) Listed or being worked up with a high likelihood to be listed for LT Are pre-frail (liver frailty index (LFI) 3.2-4.3) or frail (LFI ≥4.4) Have English or French language proficiency Own an internet-connected device Exclusion Criteria: Listed for living related donor transplantation with expected time on the wait list <12 weeks, or model for end-stage liver disease (MELD-Na) Score >26 (Justification: time to transplant is very short) Robust status on frailty testing (LFI 0-3.1) (Justification: unlikely to see benefit) Unable to provide informed consent Presence of a clinical condition that makes the intervention unsafe or infeasible (e.g. unable to follow instruction) or unsafe environment for virtual participation Life expectancy less than 6 months, compassionate care (clinician judgment) (Justification: unlikely to see benefit) Recent variceal bleed or history of varices not on adequate prophylaxis (Justification: acute exercise increases portal pressure Transplant indication is cholangiocarcinoma.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prehabilitation Group<br>The prehabilitation group will be provided with access to the online digital web platform which contains the weekly acceptance and commitment therapy based education videos, nutrition intervention, and exercise intervention. | Behavioral: Prehabilitation Programming<br>* 12-weeks of online prehabilitation programming including: 1.12 weeks of nutrition programming focused on achieving a guideline- based protein intake of 1.2-1.5 g/kg/day. Participants will participate in a dietitian assessment and 0-2 dietitian follow-ups stratified by risk and 5 virtual group nutrition classes. Participants will be provided with a whey protein powder supplement - dosing stratified by risk. 2.10 weeks of exercise programming focused on completion of 3 full- body resistance/aerobic exercise sessions weekly (1 or 2 virtual group classes as per patient preference + 1 or 2 pre-recorded home exercise videos). 3.12 weeks of acceptance and commitment therapy based educational videos and online activities focused on reducing stress and anxiety and improving motivation and adherence.<br>|
| No Intervention: Usual Care<br>This group will receive standard care for LT candidates with cirrhosis and will be provided with standard online exercise, nutrition, and behavioural resources. Control participants will not receive access to the online digital platform. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in time to do 5-sit-to-stands from baseline | A time to complete 5 chair stands of >15 seconds predicts morbidity and mortality in patients with cirrhosis. This test shows promise as a frailty measure that could be evaluated over a virtual platform | Week 0 | 
| Change in time to do 5-sit-to-stands from baseline | A time to complete 5 chair stands of >15 seconds predicts morbidity and mortality in patients with cirrhosis. This test shows promise as a frailty measure that could be evaluated over a virtual platform | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in time to do 5-sit-to-stands from baseline | A time to complete 5 chair stands of >15 seconds predicts morbidity and mortality in patients with cirrhosis. This test shows promise as a frailty measure that could be evaluated over a virtual platform | Week 8 | 
| Change in distance in the 6 minute walk test from baseline | 6MWT distance correlates with waitlist mortality and QoL and is recommended by the American Society of Transplantation. It is associated with protein intake, activity level and physical function/ frailty. | Week 0 | 
| Change in distance in the 6 minute walk test from baseline | 6MWT distance correlates with waitlist mortality and QoL and is recommended by the American Society of Transplantation. It is associated with protein intake, activity level and physical function/ frailty. | Week 12 | 
| Change in distance in the 6 minute walk test from baseline | 6MWT distance correlates with waitlist mortality and QoL and is recommended by the American Society of Transplantation. It is associated with protein intake, activity level and physical function/ frailty. | Post-transplant ( 6-12 weeks after transplant date) | 
| Change in liver frailty index from baseline | Liver frailty will be assessed with a cirrhosis-specific tool: grip strength, chair stand and balance testing. The LFI is an independent predictor of waitlist mortality and hospitalization. The LFI score can be calculated using an online calculator (available at http://liverfrailtyindex.ucsf.edu), with patient physical frailty categorized as robust, prefrail, and frail according to their index (index < 3.2, robust; 3.2-4.5, prefrail; and >4.5, frail). Higher scores mean a worse outcome. | Week 0 | 
| Change in liver frailty index from baseline | Liver frailty will be assessed with a cirrhosis-specific tool: grip strength, chair stand and balance testing. The LFI is an independent predictor of waitlist mortality and hospitalization. The LFI score can be calculated using an online calculator (available at http://liverfrailtyindex.ucsf.edu), with patient physical frailty categorized as robust, prefrail, and frail according to their index (index < 3.2, robust; 3.2-4.5, prefrail; and >4.5, frail). Higher scores mean a worse outcome. | Week 12 | 
| Change in liver frailty index from baseline | Liver frailty will be assessed with a cirrhosis-specific tool: grip strength, chair stand and balance testing. The LFI is an independent predictor of waitlist mortality and hospitalization. The LFI score can be calculated using an online calculator (available at http://liverfrailtyindex.ucsf.edu), with patient physical frailty categorized as robust, prefrail, and frail according to their index (index < 3.2, robust; 3.2-4.5, prefrail; and >4.5, frail). Higher scores mean a worse outcome. | Post-transplant ( 6-12 weeks after transplant date) | 
| Change in covert hepatic encephalopathy from baseline | The EncephalApp Stroop (Stroop) test is a reliable, easy-to-use diagnostic test for CHE. It evaluates psychomotor speed and cognitive flexibility. | Week 0 | 
| Change in covert hepatic encephalopathy from baseline | The EncephalApp Stroop (Stroop) test is a reliable, easy-to-use diagnostic test for CHE. It evaluates psychomotor speed and cognitive flexibility. | Week 12 | 
| Change in covert hepatic encephalopathy from baseline | The EncephalApp Stroop (Stroop) test is a reliable, easy-to-use diagnostic test for CHE. It evaluates psychomotor speed and cognitive flexibility. | Post-transplant ( 6-12 weeks after transplant date) | 
| Change in health-related quality of life from baseline (CLDQ) | The disease-specific Chronic Liver Disease Questionnaire (CLDQ) is validated in cirrhosis. Overall CLDQ scores calculated for each domain range from 1 (most impaired) to 7, with higher scores indicating a minimum frequency of symptoms and hence a better HRQOL. | Week 0 | 
| Change in health-related quality of life from baseline (EQ5D5L and EQVAS) | The EuroQoL 5-D-5L and visual analog scale (EQ-VAS) are generic tools also validated in LT candidates and recipients. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. | Week 0 | 
| Change in health-related quality of life from baseline (CLDQ) | The disease-specific Chronic Liver Disease Questionnaire (CLDQ) is validated in cirrhosis. Overall CLDQ scores calculated for each domain range from 1 (most impaired) to 7, with higher scores indicating a minimum frequency of symptoms and hence a better HRQOL. | Week 8 | 
| Change in health-related quality of life from baseline (EQ5D5L and EQVAS) | The EuroQoL 5-D-5L and visual analog scale (EQ-VAS) are generic tools also validated in LT candidates and recipients. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems.This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. | Week 8 | 
| Change in health-related quality of life from baseline (CLDQ) | The disease-specific Chronic Liver Disease Questionnaire (CLDQ) is validated in cirrhosis. Overall CLDQ scores calculated for each domain range from 1 (most impaired) to 7, with higher scores indicating a minimum frequency of symptoms and hence a better HRQOL. | Week 12 | 
| Change in health-related quality of life from baseline (EQ5D5L and EQVAS) | The EuroQoL 5-D-5L and visual analog scale (EQ-VAS) are generic tools also validated in LT candidates and recipients. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems.This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. | Week 12 | 
| Change in health-related quality of life from baseline (CLDQ) | The disease-specific Chronic Liver Disease Questionnaire (CLDQ) is validated in cirrhosis. The EuroQoL 5-D-5L and visual analog scale (EQ-VAS) are generic tools also validated in LT candidates and recipients. Overall CLDQ scores calculated for each domain range from 1 (most impaired) to 7, with higher scores indicating a minimum frequency of symptoms and hence a better HRQOL. | Week 24 | 
| Change in health-related quality of life from baseline (EQ5D5L and EQVAS) | The EuroQoL 5-D-5L and visual analog scale (EQ-VAS) are generic tools also validated in LT candidates and recipients. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems.This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. | Week 24 | 
| Change in health-related quality of life from baseline (CLDQ) | The disease-specific Chronic Liver Disease Questionnaire (CLDQ) is validated in cirrhosis. Overall CLDQ scores calculated for each domain range from 1 (most impaired) to 7, with higher scores indicating a minimum frequency of symptoms and hence a better HRQOL. | Week 36 | 
| Change in health-related quality of life from baseline (EQ5D5L and EQVAS) | The EuroQoL 5-D-5L and visual analog scale (EQ-VAS) are generic tools also validated in LT candidates and recipients. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. | Week 36 | 
| Change in health-related quality of life from baseline (CLDQ) | The disease-specific Chronic Liver Disease Questionnaire (CLDQ) is validated in cirrhosis. Overall CLDQ scores calculated for each domain range from 1 (most impaired) to 7, with higher scores indicating a minimum frequency of symptoms and hence a better HRQOL. | Post-transplant ( 6-12 weeks after transplant date) | 
| Change in health-related quality of life from baseline (EQ5D5L and EQVAS) | The EuroQoL 5-D-5L and visual analog scale (EQ-VAS) are generic tools also validated in LT candidates and recipients. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. | Post-transplant ( 6-12 weeks after transplant date) | 
| Change in 6-item COM-B scale over time during intervention | Perceived capability, opportunity, and motivation will be assessed over the trial period to understand how the COM-B impacts adherence. Each item is scaled (0 [strongly disagree] to 7 [strongly agree]) and 3 subscores are computed. A higher score means higher perceived capability, opportunity, and motivation | Week 4 | 
| Change in 6-item COM-B scale over time during intervention | Perceived capability, opportunity, and motivation will be assessed over the trial period to understand how the COM-B impacts adherence. Each item is scaled (0 [strongly disagree] to 7 [strongly agree]) and 3 subscores are computed. A higher score means higher perceived capability, opportunity, and motivation | Week 8 | 
| Change in 6-item COM-B scale over time during intervention | Perceived capability, opportunity, and motivation will be assessed over the trial period to understand how the COM-B impacts adherence. Each item is scaled (0 [strongly disagree] to 7 [strongly agree]) and 3 subscores are computed. A higher score means higher perceived capability, opportunity, and motivation. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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frailty, transplant, nutrition, exercise, ehealth, application, wellness, prehabilitation, sarcopenia, malnutrition, physical function