Prehab and Creatine/Whey Supplementation in Frailty Among Patients With Cirrhosis

• HEAL-ME digital app (Behavioral), also known as exercise, nutrition: HEAL-ME is a digital prehabilitation app that provides semi-guided nutrition/exercise prehabilitation
• Creatine supplementation (Dietary supplement), also known as Creatine: Patients will take 5g creatine supplementation daily for 13 weeks
• Whey protein supplementation (Dietary supplement), also known as Whey: Patients will take 35g whey protein supplementation daily
• Placebo (Dietary supplement): Patients will be administered daily placebo supplementation.

Primary outcomes

• Frailty [From enrollment to end of study at 12 weeks]: Frailty will be used to assess muscle quality. The liver frailty index (LFI) includes the measurement of grip strength, chair stands, and balance. The Liver Fraity Index typically ranges from 1.0 to 5.0 with the following cut-offs: Robust is Liver Frailty Index <3.2, Pre-frail is Liver Frailty Index between 3.2 and 4.4, and Frail is Liver frailty Index ≥4.4. We will use the previously identified cut-off of ≥4.4 (frail) vs. <4.4 (not frail) to identify frailty in this study.

Secondary outcomes

• Feasibility: Completion Rate [From study enrollment to end of study at 12 weeks]: Completion rate will be assessed by study coordinators. Study coordinators will identify patients who do or do not complete the study during check-ins. Reasons for dropping out of the study will be recorded by study coordinators.
• Health-related quality of life (HRQOL) [From enrollment to end of study at 12 weeks]: The Patient Reported Outcomes Measurement Information System (PROMIS)-29 v 2.0 is a NIH-supported effort to develop and disseminate patient-reported measures of HRQOL that has built-in normative reference to the US general population. The PROMIS-29 v2.0 will be used to assess HRQOL. A score ≤25 has been used to define the 25th percentile value for the general population and has previously been used in our studies to be considered poor HRQOL.
• Self-Reported Physical Activity [From enrollment to end of study at 12 weeks]: The Duke Activity Status Index (DASI) will be used to measure self-reported physical activity. The DASI questionnaire provides a score from 0 to 58.2 with higher scores indicating better functional status and lower score indicating worse functional status. DASI will be measured as a continuous variable
• Sarcopenia [From enrollment to end of study at 12 weeks]: Sarcopenia will be measured by abdominal computed tomography (CT) scan measured CT-quantified skeletal muscle index (skeletal muscle index (SMI) <50 cm2/m2 for men and <39 cm2/m2 for women). We have previously demonstrated that CT-quantified sarcopenia is associated with worse outcomes in patients with cirrhosis.
• Feasibility: Adherence Rate [From study enrollment to end of study at 12 weeks]: Adherence rate will be assessed by study coordinators at each check-in. Adherence rate will include total adherence to the study protocol, adherence to supplement/placebo, and adherence to HEAL-ME activities.
• Feasibility: Patient Satisfaction [From study enrollment to end of study at 12 weeks]: Patient satisfaction will be assessed by study coordinators at the end of the study. Patient satisfaction will be reported as a scalar variable from 0 to 5.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Confirmed diagnosis of cirrhosis by ICD-10 code, liver biopsy, abdominal imaging, or transient elastography
* Access to digital device and internet at home
* Ability to provide written informed consent before any study-related activities
* Ability to remain in study for at least 3 months

Exclusion Criteria:

* Allergy to milk protein
* On hemodialysis
* No English language proficiency
* Presence of condition or abnormality that in opinion of the Investigator will compromise safety of the patient or quality of the data
* Concomitant severe underlying systemic illness that in the opinion of the Investigator would interfere with completion of study
* Pregnant, breastfeeding, or intention of becoming pregnant during study time frame

• Results publication: Wang M, Kent D, Pariani K, Elia J, Seetharaman S, Lee C, Mansour J, Mak C, Tandon P, Lai J. Strength training intervention with creatine/whey protein supplementation vs placebo on frailty in older adults with cirrhosis (STRIVE): A Randomized Controlled Trial. Res Sq [Preprint]. 2026 Sep 19:rs.3.rs-10695023. doi: 10.21203/rs.3.rs-10695023/v1. PMID 42780265

• Jennifer Lai, MD, MBA, Principal investigator, University of California, San Francisco