LiveSMART Trial to Prevent Falls in Patients With Cirrhosis

Study Overview
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Brief Summary
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This multicenter trial is being conducted to determine if sequential lactulose and Tele (virtual) Tai-Chi reduces the rate of injurious fall, non-injurious falls, incident overt Hepatic Encephalopathy (HE), and death. Participants that are enrolled will be randomized to stage one of this project for approximately 12 weeks. After completing stage one, participants will be re-evaluated and if eligible will be re-randomized to stage 2 of the project that will last approximately 12 more weeks. The study hypothesizes that sequential lactulose/TeleTai-Chi will reduce falls, incident overt HE, death and physical frailty and will improve cognitive function, and Health Related Quality of Life (HRQOL) over 24 weeks compared to other treatment combinations.

Official Title
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LiveSMART: A Sequential, Multiple Assignment Randomized Trial to Prevent Falls in Patients With Cirrhosis

Conditions
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Cirrhosis, Liver, Portal Hypertension

Intervention / Treatment
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* Behavioral: Enhanced Usual Care
* Drug: Lactulose
* Behavioral: Investigator recommended exercise
* Behavioral: TeleTai-Chi (virtual)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of cirrhosis based on histology and/or imaging specified in the protocol. Evidence of portal hypertension - must meet at least one of the following criteria: Ascites (present or within past 2 years) Varices (seen by Esophagogastroduodenoscopy or by Ultrasound or cross-sectional imaging) Fibroscan Liver stiffness measurement (LSM) >25 kilopascals (kPa) (if no other factors present) Magnetic resonance elastography (MRE) LSM > 5 kPa (if no other factors present) Acoustic radiation force impulse LSM > 17kpa (if no other factors present) Hepatic vein pressure gradient > 10 millimetres of mercury (mmHg) Portal hypertensive gastropathy seen on Esophagogastroduodenoscopy Platelet count < 80/ units per liter (uL) Access to Wireless Fidelity (Wi-Fi) at home Owns or access to a smartphone, tablet or computer English or Spanish speaking Willing to participate in exercise program Exclusion Criteria: Overt hepatic encephalopathy (HE) within 6 months, requiring >28 days of lactulose Took lactulose for non - HE reasons for >28 days in last 6 months Model for End Stage Liver Disease (MELD) > 25 (Exception: MELD > 25 with clinically stable End-Stage Renal Disease (ESRD) for whom the bilirubin is < 5 g/dL) Barcelona Clinic Liver Cancer (BCLC) > C Hepatocellular Carcinoma (HCC) Currently taking Sorafenib, Atezolizumab/Bevacizumab, Regorafinib, or Cabozatinib Greater than (>) 3 paracentesis/month in last 2 months Active Metastatic solid malignancy or acute leukemia within last 3 years Severe cognitive, vision, or hearing impairment (without use of corrective lenses or hearing assist devices) or psychiatric illness precluding study participation Currently participates in Tai-Chi or performs >150 min/week vigorous physical activity Currently receiving physical therapy Living in an assisted living facility Hemoglobin A1C > 12 (within past 12 months) Requires a low galactose diet Deemed unsuitable by the study investigator

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: Sequential Assignment
Interventional Model Description: Participants will be randomized in stage 1 to enhanced usual care or enhanced usual care plus lactulose. After 12 weeks participants will be re-evaluated to continue into stage 2 will be re-randomized to TeleTai-Chi (at-home, via Zoom, supervised by a study team instructor) vs. continued enhanced usual care. The participants that took lactulose in Stage 1 will continue to take lactulose through Stage 2 until their participation is complete.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enhanced usual care group<br>Participants will be in stage 1 for approximately 12 weeks and then be re-evaluated. Participation will end the study if not qualified for 2nd stage. | Behavioral: Enhanced Usual Care<br>* Patients will be provided and counseled on two methods which will enhance care. The first is a handout on nutrition recommendations and protein supplementation. This will include the recommendation of both high protein snacks during the daytime (e.g., protein bars) and a high-protein night-time snack (e.g., peanut butter and crackers). The second will be to counsel participants on falls prevention methods that can be enacted in day-to-day life. All participants will be provided with a standard hand-out of Centers for Disease Control and Prevention (CDC)-endorsed fall-risk reduction measures.<br>|
| Experimental: Treatment (Lactulose) group plus enhanced usual care<br>Participants will be in stage 1 for approximately 12 weeks and then be re-evaluated. Participation will end the study if not qualified for 2nd stage. | Behavioral: Enhanced Usual Care<br>* Patients will be provided and counseled on two methods which will enhance care. The first is a handout on nutrition recommendations and protein supplementation. This will include the recommendation of both high protein snacks during the daytime (e.g., protein bars) and a high-protein night-time snack (e.g., peanut butter and crackers). The second will be to counsel participants on falls prevention methods that can be enacted in day-to-day life. All participants will be provided with a standard hand-out of Centers for Disease Control and Prevention (CDC)-endorsed fall-risk reduction measures.<br>Drug: Lactulose<br>* Patients will be prescribed lactulose and will also receive enhanced usual care. Lactulose will be taken on a specific schedule based on the average number of bowel movements on average per day. It will be started at 15 milliliter (mL) dose and will be instructed to slowly increase the lactulose dose over the course of the first week of Stage 1 participation. The prescribed maximum dose will be 30 mL (20g) twice daily. The dose will slowly increase toward the maximum or until participants reach 2-3 soft bowel movements daily. Participants that receive Lactulose during stage 1 will continue this in stage 2 (if re-randomized).<br>|
| Active Comparator: Enhanced usual care group followed by investigator recommended exercise<br>This is considered stage 2 for 12 weeks (for eligible re-randomized participants). | Behavioral: Enhanced Usual Care<br>* Patients will be provided and counseled on two methods which will enhance care. The first is a handout on nutrition recommendations and protein supplementation. This will include the recommendation of both high protein snacks during the daytime (e.g., protein bars) and a high-protein night-time snack (e.g., peanut butter and crackers). The second will be to counsel participants on falls prevention methods that can be enacted in day-to-day life. All participants will be provided with a standard hand-out of Centers for Disease Control and Prevention (CDC)-endorsed fall-risk reduction measures.<br>Behavioral: Investigator recommended exercise<br>* Participants randomized to enhanced usual care will be reminded of standard fall precautions outlined in the Fall Prevention Primer that were provided in Stage 1 and will receive exercise recommendations.<br>|
| Experimental: Treatment (Lactulose) plus enhanced usual care then TeleTai-Chi exercise classes<br>This is considered stage 2 for 12 weeks (for eligible re-randomized participants) | Behavioral: Enhanced Usual Care<br>* Patients will be provided and counseled on two methods which will enhance care. The first is a handout on nutrition recommendations and protein supplementation. This will include the recommendation of both high protein snacks during the daytime (e.g., protein bars) and a high-protein night-time snack (e.g., peanut butter and crackers). The second will be to counsel participants on falls prevention methods that can be enacted in day-to-day life. All participants will be provided with a standard hand-out of Centers for Disease Control and Prevention (CDC)-endorsed fall-risk reduction measures.<br>Drug: Lactulose<br>* Patients will be prescribed lactulose and will also receive enhanced usual care. Lactulose will be taken on a specific schedule based on the average number of bowel movements on average per day. It will be started at 15 milliliter (mL) dose and will be instructed to slowly increase the lactulose dose over the course of the first week of Stage 1 participation. The prescribed maximum dose will be 30 mL (20g) twice daily. The dose will slowly increase toward the maximum or until participants reach 2-3 soft bowel movements daily. Participants that receive Lactulose during stage 1 will continue this in stage 2 (if re-randomized).<br>Behavioral: TeleTai-Chi (virtual)<br>* TeleTai-Chi will be taught remotely via live Zoom classes of up to 15 patients by a certified TeleTai-Chi instructor three times per week (for approximately 12 weeks). Classes will be conducted via a HIPAA-compliant Zoom server through the University of Michigan. Participants will be instructed to use Zoom by smartphone, tablet, or computer. High-Definition Multimedia Interface (HDMI) cables to connect devices to televisions will be provided.<br>|
| Experimental: Enhanced usual care group followed by Tele-Tai Chi exercise classes<br>This is considered stage 2 for 12 weeks (for eligible re-randomized participants) | Behavioral: Enhanced Usual Care<br>* Patients will be provided and counseled on two methods which will enhance care. The first is a handout on nutrition recommendations and protein supplementation. This will include the recommendation of both high protein snacks during the daytime (e.g., protein bars) and a high-protein night-time snack (e.g., peanut butter and crackers). The second will be to counsel participants on falls prevention methods that can be enacted in day-to-day life. All participants will be provided with a standard hand-out of Centers for Disease Control and Prevention (CDC)-endorsed fall-risk reduction measures.<br>Behavioral: TeleTai-Chi (virtual)<br>* TeleTai-Chi will be taught remotely via live Zoom classes of up to 15 patients by a certified TeleTai-Chi instructor three times per week (for approximately 12 weeks). Classes will be conducted via a HIPAA-compliant Zoom server through the University of Michigan. Participants will be instructed to use Zoom by smartphone, tablet, or computer. High-Definition Multimedia Interface (HDMI) cables to connect devices to televisions will be provided.<br>|
| Experimental: Treatment (Lactulose) plus enhanced usual care then recommended exercise<br>This is considered stage 2 for 12 weeks (for eligible re-randomized participants) | Behavioral: Enhanced Usual Care<br>* Patients will be provided and counseled on two methods which will enhance care. The first is a handout on nutrition recommendations and protein supplementation. This will include the recommendation of both high protein snacks during the daytime (e.g., protein bars) and a high-protein night-time snack (e.g., peanut butter and crackers). The second will be to counsel participants on falls prevention methods that can be enacted in day-to-day life. All participants will be provided with a standard hand-out of Centers for Disease Control and Prevention (CDC)-endorsed fall-risk reduction measures.<br>Drug: Lactulose<br>* Patients will be prescribed lactulose and will also receive enhanced usual care. Lactulose will be taken on a specific schedule based on the average number of bowel movements on average per day. It will be started at 15 milliliter (mL) dose and will be instructed to slowly increase the lactulose dose over the course of the first week of Stage 1 participation. The prescribed maximum dose will be 30 mL (20g) twice daily. The dose will slowly increase toward the maximum or until participants reach 2-3 soft bowel movements daily. Participants that receive Lactulose during stage 1 will continue this in stage 2 (if re-randomized).<br>Behavioral: Investigator recommended exercise<br>* Participants randomized to enhanced usual care will be reminded of standard fall precautions outlined in the Fall Prevention Primer that were provided in Stage 1 and will receive exercise recommendations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A hierarchical composite of events over 24 weeks: injurious falls, non-injurious falls, incident Hepatic Encephalopathy, and death/transplant | Composite outcome is defined as any of the following: Injurious Fall: Fracture, dislocation, cut, head injury, soft - tissue injury requiring hospitalization Non - Injurious Fall: Inadvertently coming to rest on the floor or lower level Incident Overt HE: Acute disorientation requiring hospitalization or the initiation of HE - directed therapy, confirmed by a gastroenterologist or study investigator Death: Mortality with any cause | Baseline to 24 weeks (following stage 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Function based on the Animal Naming Test (ANT) | The animal naming test assesses cognitive function. It is a timed test that that consists of participants listing as many unique animals as possible in 60 seconds. This is a validated test used for the assessment of hepatic encephalopathy. The score is the number of unique animals stated (higher is better). | Baseline to 24 weeks (following stage 2) | 
| Days-alive and out-of-the-hospital | Days-alive and out-of-the-hospital is a continuous value, 1 for each day alive, 0 for days in hospital. Participants will be queried and data will also be abstracted from the Electronic Medical Record (EMR). | Baseline to 24 weeks (following stage 2) | 
| Injurious Falls | Falls include: Fracture, dislocation, cut, head injury, soft - tissue injury requiring hospitalization. | Baseline to 24 weeks (following stage 2) | 
| Non-Injurious Falls | Non- Injurious Falls include: Inadvertently coming to rest on the floor or lower level | Baseline to 24 weeks (following stage 2) | 
| Incident Overt hepatic encephalopathy (HE) | Incident Overt HE includes: Acute disorientation requiring hospitalization or the initiation of HE - directed therapy, confirmed by a gastroenterologist or study investigator. | Baseline to 24 weeks (following stage 2) | 
| Death/transplant | Mortality with any cause or liver transplantation | Baseline to 24 weeks (following stage 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise program, Lactulose, Tai-Chi, Fall prevention, Dietary Protein