Clinical trial NCT05899231: Online Prehabilitation for Patients Awaiting Liver Transplantation
Official title: OPAL: Online Prehabilitation for Patients Awaiting Liver Transplantation - a Multicenter Randomized Controlled Trial to Reduce Physical Frailty and Improve Health Outcomes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cirrhosis, Liver
Keywords: frailty
transplant
nutrition
exercise
ehealth
application
wellness
prehabilitation
sarcopenia
malnutrition
physical function
Lead sponsor: University of Alberta
Sponsor class: OTHER
First posted: 2023-06-12
Enrollment: 177
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

1. 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.
2. 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

1. 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.
2. 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in time to do 5-sit-to-stands from baseline
timeFrame: Week 0
measure: Change in time to do 5-sit-to-stands from baseline
timeFrame: Week 12
Secondary outcomes:
measure: Change in time to do 5-sit-to-stands from baseline
timeFrame: Week 8
measure: Change in distance in the 6 minute walk test from baseline
timeFrame: Week 0
measure: Change in distance in the 6 minute walk test from baseline
timeFrame: Week 12
measure: Change in distance in the 6 minute walk test from baseline
timeFrame: Post-transplant (~6-12 weeks after transplant date)
measure: Change in liver frailty index from baseline
timeFrame: Week 0
measure: Change in liver frailty index from baseline
timeFrame: Week 12
measure: Change in liver frailty index from baseline
timeFrame: Post-transplant (~6-12 weeks after transplant date)
measure: Change in covert hepatic encephalopathy from baseline
timeFrame: Week 0
measure: Change in covert hepatic encephalopathy from baseline
timeFrame: Week 12
measure: Change in covert hepatic encephalopathy from baseline
timeFrame: Post-transplant (~6-12 weeks after transplant date)
measure: Change in health-related quality of life from baseline (CLDQ)
timeFrame: Week 0
measure: Change in health-related quality of life from baseline (EQ5D5L and EQVAS)
timeFrame: Week 0
measure: Change in health-related quality of life from baseline (CLDQ)
timeFrame: Week 8
measure: Change in health-related quality of life from baseline (EQ5D5L and EQVAS)
timeFrame: Week 8
measure: Change in health-related quality of life from baseline (CLDQ)
timeFrame: Week 12
measure: Change in health-related quality of life from baseline (EQ5D5L and EQVAS)
timeFrame: Week 12
measure: Change in health-related quality of life from baseline (CLDQ)
timeFrame: Week 24
measure: Change in health-related quality of life from baseline (EQ5D5L and EQVAS)
timeFrame: Week 24
measure: Change in health-related quality of life from baseline (CLDQ)
timeFrame: Week 36
measure: Change in health-related quality of life from baseline (EQ5D5L and EQVAS)
timeFrame: Week 36
measure: Change in health-related quality of life from baseline (CLDQ)
timeFrame: Post-transplant (~6-12 weeks after transplant date)
measure: Change in health-related quality of life from baseline (EQ5D5L and EQVAS)
timeFrame: Post-transplant (~6-12 weeks after transplant date)
measure: Change in 6-item COM-B scale over time during intervention
timeFrame: Week 4
measure: Change in 6-item COM-B scale over time during intervention
timeFrame: Week 8
measure: Change in 6-item COM-B scale over time during intervention
timeFrame: Week 12
Other outcomes:
measure: Change in sarcopenia from baseline
timeFrame: Week 0
measure: Change in sarcopenia from baseline
timeFrame: Week 12
measure: Change in sarcopenia from baseline
timeFrame: Post-transplant (~6-12 weeks after transplant date)
measure: Changes in virtual physical function testing over time (30 sec chair sit to stand)
timeFrame: Baseline (Week ~1-2)
measure: Changes in virtual physical function testing over time (Single leg balance test)
timeFrame: Baseline (Week ~1-2)
measure: Changes in virtual physical function testing over time (2-min step test)
timeFrame: Baseline (Week ~1-2)
measure: Changes in virtual physical function testing over time (30 sec chair sit to stand)
timeFrame: Week 8
measure: Changes in virtual physical function testing over time (Single leg balance test)
timeFrame: Week 8
measure: Changes in virtual physical function testing over time (2-min step test)
timeFrame: Week 8
measure: Changes in virtual physical function testing over time (30 sec chair sit to stand)
timeFrame: Week 12
measure: Changes in virtual physical function testing over time (Single leg balance test)
timeFrame: Week 12
measure: Changes in virtual physical function testing over time (2-min step test)
timeFrame: Week 12
measure: Changes in virtual physical function testing over time (30 sec chair sit to stand)
timeFrame: Week 24
measure: Changes in virtual physical function testing over time (Single leg balance test)
timeFrame: Week 24
measure: Changes in virtual physical function testing over time (2-min step test)
timeFrame: Week 24
measure: Changes in virtual physical function testing over time (30 sec chair sit to stand)
timeFrame: Week 36
measure: Changes in virtual physical function testing over time (Single leg balance test)
timeFrame: Week 36
measure: Changes in virtual physical function testing over time (2-min step test)
timeFrame: Week 36
measure: Changes in virtual physical function testing over time (30 sec chair sit to stand)
timeFrame: Post-transplant (~6-12 weeks after transplant date)
measure: Changes in virtual physical function testing over time (Single leg balance test)
timeFrame: Post-transplant (~6-12 weeks after transplant date)
measure: Changes in virtual physical function testing over time (2-min step test)
timeFrame: Post-transplant (~6-12 weeks after transplant date)
measure: Number of participants who died during the 12 week trial
timeFrame: Week 12
measure: Number of hospitalizations and ambulatory clinic visits during the 12 week trial
timeFrame: Week 12
measure: Number of participants who were transplanted during the 12 week trial
timeFrame: Week 12
measure: Number of participants who died during the 2 years post-study completion
timeFrame: 2 years post-study completion
measure: Number of hospitalizations and ambulatory clinic visits during the 2 years post-study completion
timeFrame: 2 years post-study completion
measure: Number of participants who were transplanted during the 2 years post-study completion
timeFrame: 2 years post-study completion
measure: Economic Evaluation
timeFrame: Week 12
measure: Total Length of stay at time of transplant
timeFrame: Post-transplant up to 3 months of the trial data collection period
measure: Intensive care unit length of stay at time of post transplant
timeFrame: Post-transplant up to 3 months of the trial data collection period
measure: Days of mechanical ventilation at time of post transplant
timeFrame: Post-transplant up to 3 months of the trial data collection period
measure: Discharge location from hospital at time of transplant
timeFrame: Post-transplant up to 3 months of the trial data collection period
measure: Readmissions within 30 days at time of transplant
timeFrame: Post-transplant up to 3 months of the trial data collection period
measure: Malnutrition
timeFrame: Week 0
measure: Adverse events
timeFrame: Week 12
measure: Changes in health care provider support from baseline
timeFrame: Week 0
measure: Changes in physical activity levels from baseline
timeFrame: Week 0
measure: Changes in health care provider support from baseline
timeFrame: Week 4
measure: Changes in physical activity levels from baseline
timeFrame: Week 4
measure: Changes in health care provider support from baseline
timeFrame: Week 8
measure: Changes in physical activity levels from baseline
timeFrame: Week 8
measure: Changes in health care provider support from baseline
timeFrame: Week 12
measure: Changes in physical activity levels from baseline
timeFrame: Week 12
measure: Changes in health care provider support from baseline
timeFrame: Week 24
measure: Changes in physical activity levels from baseline
timeFrame: Week 24
measure: Changes in health care provider support from baseline
timeFrame: Week 36
measure: Changes in physical activity levels from baseline
timeFrame: Week 36
measure: Qualitative Acceptability Data
timeFrame: Week 12
measure: Changes in functional status from baseline
timeFrame: Week 0
measure: Changes in functional status from baseline
timeFrame: Week 8
measure: Changes in functional status from baseline
timeFrame: Week 12
Locations:
city: Edmonton
country: Canada
facility: Kaye Edmonton Clinic
state: Alberta
Study officials:
affiliation: University of Alberta
name: Puneeta Tandon
role: PRINCIPAL_INVESTIGATOR
References: