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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
300
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).
Hospital Universitari Vall d'Hebron
Barcelona, Spain
RECRUITINGValues 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).
Time frame: 24 months
Time-dependent composite clinical endpoint
Time to occurrence of the composite endpoint of only clinical events until study termination.
Time frame: End of Follow-up
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.
Time frame: 24 months
Evaluate if the administration of zinc decreases the risk of CSPH estimated by the ANTICIPATE model.
Odds Ratio
Time frame: 24 months
Evaluate if the administration of zinc reduces the risk of hepatocellular carcinoma.
Odds Ratio
Time frame: 24 months
Evaluate if the administration of zinc reduces the risk of bacterial infections.
Odds Ratio
Time frame: 24 months
Evaluate if the administration of zinc improves overall transplant-free survival and the risk of liver-related death.
Odds Ratio
Time frame: 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)
Time frame: 24 months
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