Zinc Supplementation to Improve Prognosis in Patients With Compensated Advanced Chronic Liver Disease.

Zinc Supplementation to Improve Prognosis in Patients With Compensated Advanced Chronic Liver Disease: A Multicenter, Randomized, Double-blind, Placebo Controlled Clinical Trial

Zinc homeostasis could play a role in advanced chronic liver disease (cACLD) and its supplementation has been linked with improvement in liver function, decrease of hepatic complications and reduction in hepatocellular carcinoma (HCC) incidence. cACLD encompasses a heterogeneous group of patients with a variable risk of clinically significant portal hypertension (CSPH) and clinical events. The ANTICIPATE model is a validated model for stratifying these risks. Our aim is to demonstrate that the administration of zinc can reduce the rate and risk of presenting clinical events (first decompensation, HCC, death and liver transplantation). This study protocol describes an ongoing phase III, national, multicentre, randomized, double-blind clinical trial that will enroll 300 patients to receive either the trial treatment (zinc acexamate) or placebo. An inclusion period of 42 months is planned, with a minimal duration of follow up of 2 years. Our principal hypothesis is that zinc could modify the natural history of cACLD patients, with an overall improvement in prognosis

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma; Portal Hypertension; Advanced Chronic Liver Disease
• Intervention / Treatment: Drug: Zinc Acexamate

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Joan Genescá, MD, PhD; Phone Number: 934 89 30 00; Email: joan.genesca@vallhebron.cat

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall d'Hebron
    • Contact: Joan Genescá, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients of both sexes with diagnosed compensated advanced chronic liver disease (cACLD) determined by hepatic stiffness on transient elastography >15 kPa.
• Age between 18 and 80 years, inclusive.
• Absence of prior or current decompensation.
• For women of childbearing age, a possible pregnancy will be ruled out by a pregnancy test prior to the start of the study. Following the test, the woman must use an effective contraceptive method during sexual intercourse (see Appendix I) in the days leading up to the start of treatment, and continue to use it throughout the treatment period, as well as for several days after its completion.
• Signing of informed consent.

Exclusion Criteria:

• History or current presence of hepatocellular carcinoma.
• Concomitant systemic disease with a short-term poor prognosis.
• Pregnancy, breastfeeding, or refusal to use contraceptive measures during participation in the study.
• Patients with compensated advanced chronic liver disease (cACLD) due to hepatitis B virus (HBV) under antiviral treatment, and those with cACLD due to hepatitis C virus (HCV) cured with antiviral treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zinc Acexamate; The experimental group will receive ACZ at a daily dose of 600 mg, equivalent to 100mg of elemental zinc (one hard gelatin capsule of 300 mg of ACZ twice a day). Treatment will be stopped when the patient presents any of the events that define the main endpoint of the study.	Drug: Zinc Acexamate; The experimental group will receive ACZ at a daily dose of 600 mg, equivalent to 100mg of elemental zinc (one hard gelatin capsule of 300 mg of ACZ twice a day). Treatment will be stopped when the patient presents any of the events that define the main endpoint of the study. The control group will receive twice a day orally hard gelatin capsules, identical to those of ACZ, in color, weight and nature, but containing an inert preparation (isomaltose).; Other Names: Placebo
Placebo Comparator: Placebo; The control group will receive twice a day orally hard gelatin capsules, identical to those of ACZ, in color, weight and nature, but containing an inert preparation (isomaltose).	Drug: Zinc Acexamate; The experimental group will receive ACZ at a daily dose of 600 mg, equivalent to 100mg of elemental zinc (one hard gelatin capsule of 300 mg of ACZ twice a day). Treatment will be stopped when the patient presents any of the events that define the main endpoint of the study. The control group will receive twice a day orally hard gelatin capsules, identical to those of ACZ, in color, weight and nature, but containing an inert preparation (isomaltose).; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Values 1-6. Ordinal scale to assess efficacy of the intervention.	Ordinal scale to assess efficacy of the intervention, with expected distribution of patients on each study arm at the 2-year mark, based on an effect size of an OR of 0.55.The most severe category (Value 6) will be the development of clinical events:First decompensation,hepatocellular carcinoma, liver related-death (non-liver-related deaths as competing events), and liver transplantation.Those patients free of a liver-related event at 2 years,will be classified according to the risk of CSPH (ANTICIPATE model value), distributing patients in the ordinal scale with ascending hierarchy of CSPH risk: Level 1,<0.30 risk;Level 2,0.30-0.45 risk;Level 3, 0.45-0.60 risk;Level 4, 0.60-0.85 risk;and Level 5, >0.85 risk. Expected clinical events at 2 years of follow-up (PREDESCI study and others on natural history of liver cirrhosis) with added effect of decompensation, HCC and death:20% of clinical events at 2 years (16% decompensations,2% hepatocellular carcinomas and 2% deaths).	24 months
Time-dependent composite clinical endpoint	Time to occurrence of the composite endpoint of only clinical events until study termination.	End of Follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate if the administration of zinc decreases the risk of having the first decompensation and what type.	Number of descompensations: First descompensation, hepatocellular carcinoma, liver related-death, liver transplantation.	24 months
Evaluate if the administration of zinc decreases the risk of CSPH estimated by the ANTICIPATE model.	Odds Ratio	24 months
Evaluate if the administration of zinc reduces the risk of hepatocellular carcinoma.	Odds Ratio	24 months
Evaluate if the administration of zinc reduces the risk of bacterial infections.	Odds Ratio	24 months
Evaluate if the administration of zinc improves overall transplant-free survival and the risk of liver-related death.	Odds Ratio	24 months
Evaluate if the administration of zinc improves liver function as measured by Child-Pugh and End-stage Liver Disease (MELD) score.	Child-Pugh: 5 (better outcome) to 15 (worse outcome). Child- Pugh has not an unabbreviated title. MELD: 6 (better outcome) to 40 (worse outcome)	24 months

Collaborators and Investigators

• Sponsor: Hospital Universitari Vall d'Hebron Research Institute
• Collaborators: Hospital General Universitario Gregorio Marañon; Hospital Clinic of Barcelona; Germans Trias i Pujol Hospital; Hospital del Mar; Hospital Universitari de Bellvitge; Hospital Vall d'Hebron; Hospital Universitario Central de Asturias; Hospital Miguel Servet; Hospital Universitario Marqués de Valdecilla; University Hospital of Girona Dr.Josep Trueta; Complejo Hospitalario de Toledo; Hospital de la Santa creu i Sant Pau - Barcelona; Parc Taulí Hospital Universitari; Hospital Universitario Puerta del Hierro

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2022
• Primary Completion (Estimated): March 2, 2026
• Study Completion (Estimated): March 2, 2026

Study Registration Dates

• First Submitted: April 30, 2024
• First Submitted That Met QC Criteria: May 23, 2024
• First Posted (Actual): May 30, 2024

Study Record Updates

• Last Update Posted (Actual): June 4, 2024
• Last Update Submitted That Met QC Criteria: June 3, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Hypertension, Portal; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; 6-acetylaminocaproic acid
• Other Study ID Numbers: IC/LV/ACZ/PCHC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No