Cirrhosis, Liver, Portal Hypertension
Conditions
Keywords
Exercise program, Lactulose, Tai-Chi, Fall prevention, Dietary Protein
Brief summary
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 or liver transplant over 24 weeks. 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-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. As detailed below, an observational component that enrolls caregivers of the trial participants is being conducted. Upon completion, Participants listed in the record here only include trial participants; and the observational component was moved to a new registration for clarity, NCT07140120.
Detailed description
The Clinicaltrials.gov registration record was updated as requested by Patient-Centered Outcomes Research Institute (PCORI) based on protocol amendment version 3.0 after approval by the Institutional Review Board. These changes included: the additional aim for a supplemental observational study to assess social determinants of health, financial burdens, etc., and includes recruitment of the caregivers for this supplemental study along with the trial participants, as well as updated outcomes for the trial. After further discussion with PCORI, these changes were removed from this record and used to create a separate record for the supplemental study focused on caregivers (NCT07140120). The caregivers that are enrolled are not in the clinical trial. All clinical trial information is provided in this record, but upon completion of enrollment and consideration of transparent results reporting, it was decided to move all the items related to the observational supplemental study to its own record. To improve clarity in the record, the two arms representing stage 1 of the project were incorporated into the remaining four representing stage 2, so the remaining arms now represent both stage 1 and stage 2.
Interventions
BEHAVIORALEnhanced Usual Care
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.
DRUGLactulose
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.
BEHAVIORALInvestigator recommended exercise
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.
BEHAVIORALTeleTai-Chi (virtual)
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 and other device specific equipment to connect devices to televisions will be provided.
Sponsors
University of Michigan
Patient-Centered Outcomes Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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-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. The caregivers (of the trial participants) involved in the observational sub-study are not included in the trial in any fashion.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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(US) 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) * Recanalized umbilical vein (by US or cross-sectional imaging) * 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 total of lactulose * Took lactulose for non - HE reasons for \>28 days total in last 6 months * Took Rifaximin for \> 28 days total 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 lower body physical and/or occupational 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 Inclusion Criteria for the Caregivers of the participants: * Adult \> 18 years of age * Informal caregiver of a participant enrolled in LIVE-SMART * English speaking
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing a Hierarchical Composite of Events Over 24 Weeks: Injurious Falls, Non-injurious Falls, Incident Hepatic Encephalopathy, Liver Transplant, and Death/Transplant | Baseline to 24 weeks | Composite outcome is defined as any of the following: • Injurious Fall: Fracture, dislocation, cut, head injury, soft - tissue injury requiring medical intervention including: Hospitalization or overnight observation in the Emergency Room (ER); surgery, transfusion, stitches * Non - Injurious Fall: Inadvertently coming to rest on the floor or lower level * Include falls that result in minor injuries that are addressed with first aid (e.g., ice, bandage) * 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 * Liver transplant: Replacement of a diseased liver with the healthy liver from another person because of acute-on-chronic liver failure (using the EASL-CLIF-C definition consisting of an acute increase in the bilirubin and/or INR, acute kidney injury, overt HE, hypertension, and hypoxia). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Injurious Falls | Baseline to 24 weeks | Results reflect the number of participants who experienced at least one injurious fall. Injurious falls include: Fracture, dislocation, cut, head injury, soft - tissue injury requiring hospitalization. |
| Non-Injurious Falls | Baseline to 24 weeks | Results reflect the number of participants who experienced at least one non-injurious fall. Non- injurious falls include: Inadvertently coming to rest on the floor or lower level. |
| Incident Overt Hepatic Encephalopathy (HE) | Baseline to 24 weeks | Incident Overt HE includes: Acute disorientation requiring hospitalization or the initiation of HE - directed therapy, confirmed by a gastroenterologist or study investigator. |
| Death/Transplant for Acute-on-Chronic Liver Failure (ACLF) | Baseline to 24 weeks | Results reflect participants who died, or who received a liver transplant because of ACLF. |
| Incident of Liver Transplant for Non-ACLF Reason | Baseline to 24 weeks | Results reflect the number of participants who received replacement of a diseased liver with the healthy liver from another person for any reason other than ACLF. |
| Days-alive and Out-of-the-hospital | Approximately 26 Weeks | Days-alive and out-of-the-hospital is a continuous value, 1 for each day alive, 0 for days in hospital. Participants were queried and data was also abstracted from the Electronic Medical Record (EMR). Results reflect the average number of days participants were alive and out of the hospital. |
| Change in Cognitive Function Based on the Animal Naming Test (ANT) | Baseline to 24 weeks | 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 named (higher is better). Results reflect change from baseline. |
| Change in Visual Analog Scale (VAS) | Baseline to 24 weeks | This was a 1-item global rating of health scored 0-100. A score of 100 means the best health and 0 means the worst health imagined. Results reflect change from baseline. |
| Change in The Patient Reported Outcome Measurement Information System (PROMIS)-29+2 v2.1 Profile (PROPr) | Baseline to 24 weeks | PROPr is the combined score of the two scales in the PROMIS 29+2, a quality-of-life scale and a pain-rating scale, and is used to calculate a preference score. The scores from both scales provide an overall summary of health-related quality of life based on multiple domains summarizing a metric ranging from 0 (as bad as dead) to 1 (perfect or ideal health). Results reflect change from baseline. |
| Change in Depression Based on The Patient Reported Outcome Measurement Information System (PROMIS)-29+2 v2.1 | Baseline to 24 weeks | There were 4 questions that participants completed regarding depression. The scores were converted to t scores, which were normalized from the raw scores. The t score ranged from 0-100 with 0 denoting worst depression and 100 indicating no depression. Results reflect the change from baseline. |
| Change in Sleep Quality Based on the PROMIS-29+2 v2.1 | Baseline to 24 weeks | There were 4 questions that participants completed regarding sleep quality. The scores were converted to t scores, which were normalized from the raw scores. The t score ranged from 0-100 with 0 denoting worst sleep quality and 100 indicating best sleep quality. Results reflect change from baseline. |
| Physical Frailty Based on the Liver Frailty Index | Baseline to 24 weeks | Physical frailty was assessed with this index and was a composite of handgrip, timed chair-stands, and balance. The index ranged from -1.26 (robust) to 6.9 (frail), 50th percentile is 3.9. For individuals enrolled remotely, the study team assessed chair-stands. |
| Change in Physical Frailty Based on the Activities of Daily Living (ADLs) | Baseline to 24 weeks | Activities of daily living (ADLs), is a validated self-reported measure (disability is defined as \>1 ADL deficit) recommended by the American Society for Transplantation and AASLD. The score ranged from 0 to 6 (6 indicating full independence, 4 moderate impairment, and 2 or less severe functional impairment). Results reflect change from baseline. |
| Intervention Fidelity | 24 weeks | Evaluation of intervention fidelity was assessed at 50% and 100% of study completion. Results reflect participants who maintained fidelity by completing at least one of the following key intervention components: coordinator trainings, lactulose prescriptions ordered, enhanced usual care components delivered, Short Message Service (SMS) assessments sent, study visits completed, or exercise sessions completed. |
| Participant Adherence | 24 weeks | Adherence to lactulose, Tai-Chi, and nighttime protein supplementation was monitored. Results reflect the number of participants who discontinued their assigned intervention. |
| Participant Satisfaction With the Trial and Interventions Based on the Patient Global Impression of Change (PGIC) | 12 weeks and 24 weeks | Satisfaction with the trial was assessed using the 6-item Patient Global Impression of Change (PGIC). Participants selected from 1 (very much improved) to 7 (very much worse). Lower scores indicated higher satisfaction. |
| Change in Short Form (SF) - 8 | 24 weeks | The SF-8 is an abbreviated 8-item version of an original 36-item health survey (SF-36). It is a generic multipurpose quality of life instrument. It contains psychometrically based physical and mental health summary measures. The eight domains include general health, physical functioning, role physical, bodily pain, vitality, social functioning, mental health and role emotional. The scores were converted to t scores, which were normalized from the raw scores. The t score ranged from 0-100 with 0 denoting worst quality of life and 100 indicating best quality of life. Results reflect change from baseline. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORElliott Tapper, MD
University of Michigan
PRINCIPAL_INVESTIGATORMarina Serper, MD, MS
University of Pennsylvania
Participant flow
Pre-assignment details
3 consented individuals beyond the 230 shown below were determined to be ineligible, so their data was not included in any modules.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.9 years STANDARD_DEVIATION 11.1 |
| Cognitive Function Based on the Animal Naming Test (ANT) | 22.61 animals named STANDARD_DEVIATION 5.79 |
| Depression Based on The Patient Reported Outcome Measurement Information System (PROMIS)-29+2 v2.1 | 50.24 t score STANDARD_DEVIATION 9.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 212 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Physical Frailty Based on the Activities of Daily Living (ADLs) | 5.83 units on a scale STANDARD_DEVIATION 0.62 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 209 Participants |
| Region of Enrollment United States | 52 Participants |
| Sex: Female, Male Female | 138 Participants |
| Sex: Female, Male Male | 18 Participants |
| Short Form (SF) - 8 | 66.36 t score STANDARD_DEVIATION 20.79 |
| Sleep Quality Based on the PROMIS-29+2 v2.1 | 51.75 t score STANDARD_DEVIATION 6.26 |
| The Patient Reported Outcome Measurement Information System (PROMIS)-29+2 Profile (PROPr) | 0.46 units on a scale STANDARD_DEVIATION 0.24 |
| Visual Analog Scale (VAS) | 70.44 units on a scale STANDARD_DEVIATION 21.02 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 113 | 0 / 117 | 0 / 52 | 1 / 52 | 0 / 53 | 0 / 59 |
| other Total, other adverse events | 15 / 113 | 25 / 117 | 5 / 52 | 5 / 52 | 6 / 53 | 14 / 59 |
| serious Total, serious adverse events | 5 / 113 | 10 / 117 | 7 / 52 | 2 / 52 | 3 / 53 | 7 / 59 |
Outcome results
None listed