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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, 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, 177 patients will be recruited from 6 transplant centres across Canada and will be randomized to receive either the online prehabilitation program or usual care.
The primary outcome of physical function will be evaluated using the FTSST at baseline and 12 weeks (or last timepoint before transplant) assessed virtually or in-person. Secondary outcomes include liver specific physical frailty, aerobic fitness, health-related quality of life (QoL), participant experience and acceptability. Exploratory outcomes include other virtual and in-person physical function measures, covert hepatic encephalopathy (CHE), sarcopenia, malnutrition, adherence, behaviour factors, clinical and post-transplant outcomes. Results will be compared between the intervention and usual care groups.
This multi-centre randomized controlled trial (RCT) will be completed across the six 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 six participating 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 includes exercise, nutrition and psychological components that is accessed through the online digital web platform.
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.
Post-Transplant follow-up In the subgroup of patients who undergo LT, the same in-person and virtual testing will be carried out at 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.
Types of analyses
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 the results will be presented if substantial differences are found between this group and the intention-to-treat group.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prehabilitation Group | Experimental | 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. |
|
| Usual Care | No Intervention | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Prehabilitation Programming | Behavioral | 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. |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in liver frailty index from baseline | Liver frailty will be assessed with a cirrhosis-specific tool. The in-person LFI which includes grip strength, chair stand and balance testing, or the virtual TeLeFI which includes virtual FTSST, three stance balance test, and selected questions from validated surveys. 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. |
| 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 Completed at week 8 to account for the possibility of transplantation or loss-to-follow-up before the end of the 12 weeks. | Week 8 |
Inclusion Criteria:
≥18 years old with cirrhosis (confirmed with transient elastography by FibroScan, histology, or imaging-based assessment with compatible clinical picture), referred for transplant and are assessed to have a high likelihood of being listed according to a preliminary review by hepatologist or are already listed for LT, are pre-frail or frail on the liver frailty index (LFI) or (added August 30, 2024) pre-frail or frail on the TeLeFI (prefrail LFI 3.2-4.3 and frail LFI ≥4.4), have English or French language proficiency, and own an internet-connected device.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Puneeta Tandon | Contact | 780-492-9844 | ptandon@ualberta.ca | |
| Margaret McNeely | Contact | 780-248-1531 | margie.mcneely@ualberta.ca |
| Name | Affiliation | Role |
|---|---|---|
| Puneeta Tandon | University of Alberta | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Foothills Medical Centre | Recruiting | Calgary | Alberta | T2N 2T9 | Canada | |
| Kaye Edmonton Clinic |
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| ID | Term |
|---|---|
| D008103 | Liver Cirrhosis |
| D008107 | Liver Diseases |
| D000073496 | Frailty |
| D009043 | Motor Activity |
| D055948 | Sarcopenia |
| D044342 | Malnutrition |
| ID | Term |
|---|---|
| D004066 | Digestive System Diseases |
| D005355 | Fibrosis |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| Week 0 |
| Change in liver frailty index from baseline | Liver frailty will be assessed with a cirrhosis-specific tool. The in-person LFI which includes grip strength, chair stand and balance testing, or the virtual TeLeFI which includes virtual FTSST, three stance balance test, and selected questions from validated surveys. 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 |
| Changes in virtual physical function testing over time (2-min step test) | The 2-min step test is used to assess aerobic endurance and functional fitness. The subject marches in place for two minutes. The literature supports good correlation of this virtual measure when compared to in-person testing | Week 0 |
| Changes in virtual physical function testing over time (2-min step test) | The 2-min step test is used to assess aerobic endurance and functional fitness. The subject marches in place for two minutes. The literature supports good correlation of this virtual measure when compared to in-person testing | Week 12 |
| 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 (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 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 12 |
| Qualitative Acceptability Data | Inductive analysis of post-trial semi-structured interviews/focus groups with participants | Week 12 |
| Change in sarcopenia from baseline | Calf circumference is a simple measure for appendicular skeletal muscle and predicting sarcopenia | Week 0 |
| Change in sarcopenia from baseline | Calf circumference is a simple measure for appendicular skeletal muscle and predicting sarcopenia | 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. | 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 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 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 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 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 |
| 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 (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. | Post-transplant (12 weeks after transplant date) |
| Changes in virtual physical function testing over time (Single leg balance test) | The single leg balance test is used to assess static postural and balance control. The test assesses the length of time the subject can maintain their balance The literature supports good correlation of this virtual measure when compared to in-person testing | Week 0 |
| Changes in virtual physical function testing over time (Single leg balance test) | The single leg balance test is used to assess static postural and balance control. The test assesses the length of time the subject can maintain their balance The literature supports good correlation of this virtual measure when compared to in-person testing | Week 8 |
| Changes in virtual physical function testing over time (Single leg balance test) | The single leg balance test is used to assess static postural and balance control. The test assesses the length of time the subject can maintain their balance The literature supports good correlation of this virtual measure when compared to in-person testing | Week 12 |
| Changes in virtual physical function testing over time (Single leg balance test) | The single leg balance test is used to assess static postural and balance control. The test assesses the length of time the subject can maintain their balance The literature supports good correlation of this virtual measure when compared to in-person testing | Post-transplant (12 weeks after transplant date) |
| Changes in virtual physical function testing over time (2-min step test) | The 2-min step test is used to assess aerobic endurance and functional fitness. The subject marches in place for two minutes. The literature supports good correlation of this virtual measure when compared to in-person testing | Week 8 |
| Changes in virtual physical function testing over time (2-min step test) | The 2-min step test is used to assess aerobic endurance and functional fitness. The subject marches in place for two minutes. The literature supports good correlation of this virtual measure when compared to in-person testing | Post-transplant (12 weeks after transplant date) |
| Number of participants who died during the 12 week trial | Death will be collected through chart review | Week 12 |
| Number of hospitalizations and ambulatory clinic visits during the 12 week trial | Hospitalizations and ambulatory clinic visits will be collected through chart review | Week 12 |
| Number of participants who were transplanted during the 12 week trial | Data on transplantations occurring during the trial will be collected through chart review | Week 12 |
| Number of participants who died during the 2 years post-study completion | Death will be collected through chart review. Consent will be obtained to extend this to 2 years of extended follow-up for all participants and to link to administrative data-repositories for follow-on research. | 2 years post-study completion |
| Number of hospitalizations and ambulatory clinic visits during the 2 years post-study completion | Hospitalizations and ambulatory clinic visits will be collected through chart review. Consent will be obtained to extend this to 2 years of extended follow-up for all participants and to link to administrative data-repositories for follow-on research. | 2 years post-study completion |
| Number of participants who were transplanted during the 2 years post-study completion | Data on transplantations occurring during the trial will be collected through chart review. Consent will be obtained to extend this to 2 years of extended follow-up for all participants and to link to administrative data-repositories for follow-on research. | 2 years post-study completion |
| Economic Evaluation | Healthcare access and hospital usage will be collected through patient survey. | Week 12 |
| Total Length of stay at time of transplant | In participants transplanted within 3 months of the end of the trial data collection period, we will ascertain total length of stay at time of transplant | Post-transplant up to 3 months of the trial data collection period |
| Intensive care unit length of stay at time of post transplant | In participants transplanted within 3 months of the end of the trial data collection period, we will ascertain intensive care unit length of stay | Post-transplant up to 3 months of the trial data collection period |
| Days of mechanical ventilation at time of post transplant | In participants transplanted within 3 months of the end of the trial data collection period, we will ascertain days of mechanical ventilation | Post-transplant up to 3 months of the trial data collection period |
| Discharge location from hospital at time of transplant | In participants transplanted within 3 months of the end of the trial data collection period, we will ascertain discharge home from hospital (versus rehabilitation, nursing home or other institutional location) | Post-transplant up to 3 months of the trial data collection period |
| Readmissions within 30 days at time of transplant | In participants transplanted within 3 months of the end of the trial data collection period, we will ascertain any readmissions within 30 days. | Post-transplant up to 3 months of the trial data collection period |
| Malnutrition | The Patient-Generated Subjective Global Assessment (PG-SGA) is an instrument for assessment of nutrition status in patients with cancer and other diseases. It contains both a patient and a practitioner section. A higher score means worse outcomes. The numerical PG-SGA score provides professionals with clearer guidelines as to the level of medical nutrition therapy needed in a given case, while the A, B, or C rating provides an overall picture of a patient's current status. (A = well nourished, B = moderately malnourished or suspected malnutrition and C = severely malnourished). | Week 0 |
| Malnutrition | The Patient-Generated Subjective Global Assessment (PG-SGA) is an instrument for assessment of nutrition status in patients with cancer and other diseases. It contains both a patient and a practitioner section. A higher score means worse outcomes. The numerical PG-SGA score provides professionals with clearer guidelines as to the level of medical nutrition therapy needed in a given case, while the A, B, or C rating provides an overall picture of a patient's current status. (A = well nourished, B = moderately malnourished or suspected malnutrition and C = severely malnourished). | Week 12 |
| Adverse events | Major: death or hospitalization for an event occurring during or up to 3 h after exercise; cardiovascular events (stroke, myocardial infarction); permanent disability; angina, syncope, arrhythmia; variceal bleeding. Minor: hypoglycemia, hyper- or hypotension requiring medical attention, musculoskeletal injury or fall. | Week 12 |
| Changes in health care provider support from baseline | Chart review will record days of enteral or parenteral nutrition provided during hospitalization or as an outpatient and will also record exposure to the number of non-intervention digital platform based exercise sessions attended through to end of extended follow-up. | Week 0 |
| Changes in physical activity levels from baseline | Participants will be asked to journal about the amount of exercise they take part in over the course of the 12 week trial and for as long as possible into the extended follow-up period as they are willing to. | Week 0 |
| Changes in health care provider support from baseline | Chart review will record days of enteral or parenteral nutrition provided during hospitalization or as an outpatient and will also record exposure to the number of non-intervention digital platform based exercise sessions attended through to end of extended follow-up. | Week 4 |
| Changes in physical activity levels from baseline | Participants will be asked to journal about the amount of exercise they take part in over the course of the 12 week trial and for as long as possible into the extended follow-up period as they are willing to. | Week 4 |
| Changes in health care provider support from baseline | Chart review will record days of enteral or parenteral nutrition provided during hospitalization or as an outpatient and will also record exposure to the number of non-intervention digital platform based exercise sessions attended through to end of extended follow-up. | Week 8 |
| Changes in physical activity levels from baseline | Participants will be asked to journal about the amount of exercise they take part in over the course of the 12 week trial and for as long as possible into the extended follow-up period as they are willing to. | Week 8 |
| Changes in health care provider support from baseline | Chart review will record days of enteral or parenteral nutrition provided during hospitalization or as an outpatient and will also record exposure to the number of non-intervention digital platform based exercise sessions attended through to end of extended follow-up. | Week 12 |
| Changes in physical activity levels from baseline | Participants will be asked to journal about the amount of exercise they take part in over the course of the 12 week trial and for as long as possible into the extended follow-up period as they are willing to. | Week 12 |
| Changes in functional status from baseline | The TeLeFI assesses frailty and functional status virtually via phone and/or video capability without specialized equipment to identify patients who may be at risk of frailty as defined by the in-person LFI | Week 0 |
| Changes in functional status from baseline | The TeLeFI assesses frailty and functional status virtually via phone and/or video capability without specialized equipment to identify patients who may be at risk of frailty as defined by the in-person LFI | Week 8 |
| Changes in functional status from baseline | The TeLeFI assesses frailty and functional status virtually via phone and/or video capability without specialized equipment to identify patients who may be at risk of frailty as defined by the in-person LFI | Week 12 |
| Adherence to prehabilitation program goals | (i) 70% adherence to target protein intake and protein powder supplementation (assessed by dietary intake, nutrition check ins, platform metrics and monthly nutrition questionnaires), (ii) 70% adherence to exercise sessions (assessed by attendance, check ins, platform metrics) excluding study weeks with interruptions to programming due to health related issues (e.g. transplant dry runs, hospital admissions as these are common in patients awaiting LT) | Week 12 |
| Recruiting |
| Edmonton |
| Alberta |
| T6G1Z1 |
| Canada |
|
| Gordon and Leslie Diamond Health Care Centre | Recruiting | Vancouver | British Columbia | V5Z 1M9 | Canada |
| London Health Sciences Centre | Recruiting | London | Ontario | N6A 5W9 | Canada |
| Toronto General Hospital - Ajmera Transplant Centre | Recruiting | Toronto | Ontario | M5G 0A3 | Canada |
| McGill University Health Centre | Recruiting | Montreal | Quebec | H4A3J1 | Canada |
| D001519 | Behavior |
| D009133 | Muscular Atrophy |
| D020879 | Neuromuscular Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D001284 | Atrophy |
| D020763 | Pathological Conditions, Anatomical |
| D012816 | Signs and Symptoms |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |