The Application of Lifestyle Enhancing Validated Integrative Therapies for Everyday Pain in Cirrhosis

The Application of Lifestyle Enhancing Validated Integrative Therapies for Everyday Pain in Cirrhosis (ALLEVIATE-C) is a multicenter, individual-level, parallel-arm, 1:1 randomized superiority trial with a 4-week run-in period followed by 48 weeks of intervention and follow-up. The study will compare effectiveness of a high-touch vs low-touch self-management program to treat chronic pain among patients with cirrhosis.

Participants in the high-touch arm receive tailored digital self-management program, individualized pain coaching, and a structured walking or meditation curriculum selected through Active Choice as the primary behavioral focus for 48 weeks. The high-touch arm also includes on-demand coaching for low-pain self-efficacy and optional group coaching sessions.

Participants in the low-touch arm receive access to the self-guided digital self-management platform with automated educational content and behavioral nudges for 48 weeks.

Remote or in-person follow up study visits will occur at 12, 24, 36, and 48 weeks.

Endpoints include:

* Primary: Change from baseline in pain interference over 48 weeks (measured using the Pain, Enjoyment of Life, and General Activity (PEG) scale).
* Secondary: Health-related quality of life, cognitive function, average daily step count, pain-related disability, nociplastic pain, cumulative exposure to potentially risky medications, days alive and out of the hospital, pain management strategies, intervention engagement, and care partner burden.
* Implementation: Acceptability, feasibility, intervention fidelity, and barriers and facilitators to implementation.

• High-touch self-management program (Behavioral): Tailored digital self-management program, individualized pain coaching, and a structured walking or meditation curriculum selected through Active Choice as the primary behavioral focus for 48 weeks. On-demand coaching for low-pain self-efficacy and optional group coaching sessions.
• Low-touch self-management program (Behavioral): Access to the self-guided digital self-management platform with automated educational content and behavioral nudges for 48 weeks.

Primary outcomes

• Pain Interference [48 weeks]: Change from baseline in pain interference over 48 weeks, measured by repeated assessments using the Pain, Enjoyment of life, and General activity (P.E.G.) scale at 12, 24, 36, and 48 weeks, and compared between the two groups. The PEG is a three-item scale with a minimum value of 0 and a maximum value of 10 for each question. A higher score indicates a worse outcome.

Secondary outcomes

• Health-related quality of life [48 weeks]: Change from baseline in health-related quality of life over 48 weeks, assessed using the PROMIS-29+2 Profile v2.1 (PROPr) domain T-scores (physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities, and pain interference) as well as the multidomain PROPr summary score. Most domains of the PROPr are ranked on a scale with a minimum of 1 and a maximum of 5. Scores for domains are assessed differently. For fatigue, anxiety, depression, sleep disturbance, and pain interference, a higher score indicates a worse outcome. For physical function, cognitive function, and ability to participate in social roles, a higher score indicates a better outcome. Pain intensity is separately ranked on a scale of 0 to 10, with a higher score indicating a worse outcome.
• Average daily step count [48 weeks]: Change from baseline in average daily step count over 48 weeks, captured via wearable fitness trackers (Fitbit).
• Pain-related disability [48 weeks]: Change from baseline in pain-related disability at 48 weeks, measured by the Pain Disability Index (PDI) total score. The PDI is a 7-item scale with a minimum value of 0 and a maximum value of 10 for each question. A higher score indicates a worse outcome.
• Severity of nociplastic pain [52 weeks]: Change from baseline in severity of nociplastic pain over 52 weeks, assessed using the Fibromyalgia Severity Score (FSS).
• Cumulative exposure to potentially risky medications [48 weeks]: Change from baseline in cumulative exposure to potentially risky medications over 48 weeks, quantified using the Opioid Total Standardized Dose (TSD) across medication classes relevant to cirrhosis.
• Days alive and out of the hospital [48 weeks]: Days alive and out of the hospital (DAOH) over 48 weeks, incorporating hospitalizations, emergency room (ER) visits, and death.
• Animal Naming Test [48 weeks]: Change in cognitive function, measured by the Animal Naming Test (ANT), over 48 weeks.
• Patient-reported use and perceived effectiveness of pharmacologic and non-pharmacologic pain management strategies [52 weeks]: Change from baseline in patient-reported use and perceived effectiveness of pharmacologic and non-pharmacologic pain management strategies at 52 weeks, assessed using a structured study-specific pain management inventory.
• Caregiver burden [48 weeks]: Change from baseline in care partner caregiver burden, measured by the 12-item Zarit Burden Interview (ZBI-12), over 48 weeks.

Sex: All, ages: 18 Years to any

Patient Inclusion Criteria:

1. Age > 18 years of age.
2. Clinical diagnosis of cirrhosis established by any one of the following:

   1. Liver biopsy consistent with cirrhosis.
   2. Noninvasive evidence of cirrhosis, defined as ≥2 of the following criteria:

      * Imaging (Ultrasound (US), Computed Tomography (CT) or Magnetic Resonance Imaging (MRI)) demonstrating cirrhosis liver morphology (e.g., 'cirrhosis', cirrhotic appearing', 'nodular') with supportive findings (e.g., splenomegaly or recanalized umbilical vein).
      * Transient elastography (TE) (FibroScan) liver stiffness > 12.5 kilopascal (kPa) with IQR/Median <30% or Magnetic resonance elastography > 5.0 kPa
      * Laboratory evidence including AST/platelet ratio index (APRI) >2.0, FIB-4 >2.67 or Platelet count <150 x 10⁹/L.
      * CT, MRI, or Esophagogastroduodenoscopy (EGD) showing the presence of esophageal varices
   3. History of at least one cirrhosis complication, including variceal hemorrhage, hepatocellular carcinoma (HCC), ascites, or hepatic encephalopathy.
3. Liver transplant recipients are eligible if the transplanted cirrhotic allograft meets the above criteria.
4. Chronic pain, defined as a Pain, Enjoyment of Life, and General Activity (PEG) scale score > 4, assessed during screening prior to consent.
5. Ability to ambulate (walk), either independently or with the use of assistive devices.
6. Reliable access to Wi-Fi or cellular data.
7. Ownership of, or reliable access to, a smartphone with the ability and willingness to receive study-related text messages.
8. Ability to speak and read English or Spanish.

Patient Exclusion Criteria:

1. Acute pain due to injury (e.g., surgery, fracture, trauma, burn) within 28 days.
2. Diagnosed or suspected noncirrhotic portal hypertension.
3. Episode of overt hepatic encephalopathy (HE) within 28 days prior to consent.

   a. Overt HE is defined as acute disorientation requiring hospitalization or initiation of HE-directed therapy (e.g., lactulose, fluids, rifaximin) with diagnosis made by a gastroenterologist, hepatologist, or study investigator and resolution following therapy.
4. Model for End-Stage Liver Disease - Na (MELD-Na) score > 25 calculated using the UNOS algorithm.

   a. Participants with MELD-Na > 25 due to clinically stable end-stage renal disease (ESRD) may be eligible if total bilirubin < 5 mg/dL.
5. Advanced hepatocellular carcinoma (HCC) defined as Barcelona Clinic Liver Cancer (BCLC) stage > C, or current treatment with systemic therapy for HCC (e.g., sorafenib, atezolizumab/bevacizumab, durvalumab/tremelimumab, regorafenib, cabozantinib).
6. > 2 paracenteses within 56 days prior to consent.
7. Fontan-associated liver disease without cirrhosis on biopsy.
8. Inpatient hospital admission lasting > 24 hours within 28 days prior to consent.
9. Active metastatic solid malignancy or acute leukemia within 3 years prior to consent.
10. Estimated life expectancy < 1 year, as determined by the study investigator.
11. Planned living donor liver transplantation within 12 weeks of enrollment.
12. Routine meditation practice, defined as meditation occurring weekly or more frequently.
13. Inability to participate in study procedures, including inability to read study materials, cognitive impairment, or psychiatric illness that would preclude participation in the opinion of the investigator.
14. Concurrent enrollment in another nonpharmacologic pain management study or formal pain management program utilizing nonpharmacologic approaches.
15. Deemed unsuitable for participation by the study investigator.
16. Prisoners.

Care Partner Inclusion Criteria

1. Age > 18 years of age.
2. Informal caregiver of a participant enrolled in ALLEVIATE-C
3. Ability to speak and read English or Spanish.

Care Partner Exclusion Criteria

1. Inability to participate in study procedures, including inability to read study materials, cognitive impairment, or psychiatric illness that would preclude participation in the opinion of the investigator.
2. Deemed unsuitable for participation by the study investigator.