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.

Patient Inclusion Criteria:

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

• Liver biopsy consistent with cirrhosis.
• 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
• History of at least one cirrhosis complication, including variceal hemorrhage, hepatocellular carcinoma (HCC), ascites, or hepatic encephalopathy.
• Liver transplant recipients are eligible if the transplanted cirrhotic allograft meets the above criteria.
• Chronic pain, defined as a Pain, Enjoyment of Life, and General Activity (PEG) scale score > 4, assessed during screening prior to consent.
• Ability to ambulate (walk), either independently or with the use of assistive devices.
• Reliable access to Wi-Fi or cellular data.
• Ownership of, or reliable access to, a smartphone with the ability and willingness to receive study-related text messages.
• Ability to speak and read English or Spanish.

Patient Exclusion Criteria:

• Acute pain due to injury (e.g., surgery, fracture, trauma, burn) within 28 days.
• Diagnosed or suspected noncirrhotic portal hypertension.
• 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.

• 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.

• 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).
• > 2 paracenteses within 56 days prior to consent.
• Fontan-associated liver disease without cirrhosis on biopsy.
• Inpatient hospital admission lasting > 24 hours within 28 days prior to consent.
• Active metastatic solid malignancy or acute leukemia within 3 years prior to consent.
• Estimated life expectancy < 1 year, as determined by the study investigator.
• Planned living donor liver transplantation within 12 weeks of enrollment.
• Routine meditation practice, defined as meditation occurring weekly or more frequently.
• 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.
• Concurrent enrollment in another nonpharmacologic pain management study or formal pain management program utilizing nonpharmacologic approaches.
• Deemed unsuitable for participation by the study investigator.
• Prisoners.

Care Partner Inclusion Criteria

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

Care Partner Exclusion Criteria

• 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.
• Deemed unsuitable for participation by the study investigator.