Propranolol, Carvedilol and Rosuvastatin in the Prevention of Variceal Bleeding in Cirrhotic Portal Hypertension (Betastatin)

Propranolol, Carvedilol and Rosuvastatin in the Prevention of Recurrent Variceal Haemorrhage in Patients With Cirrhotic Portal Hypertension

Patients with hepatic cirrhosis and previous variceal bleeding will be randomly assigned to use propranolol or carvedilol. After 8 weeks, rosuvastatin or placebo will be blindly added to nonresponders (HVPG measurement > 12mmHg) for another 8 weeks and hemodynamic response will be assessed again.

Surrogate serum markers of portal hypertension will be evaluated and correlated to HVPG values and to its variations.

Study Overview

• Status: Unknown
• Conditions: Cirrhosis; Portal Hypertension; Variceal Hemorrhage
• Intervention / Treatment: Drug: Propranolol; Drug: Carvedilol; Drug: Rosuvastatin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil
    • Recruiting
    • Universidade Federal do Rio de Janeiro
    • Contact: Guilherme FM Rezende, MD, PhD; Phone Number: 55-21-999976292; Email: guimottarezende@gmail.com
    • Sub-Investigator: Andre Luiz M Torres, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Hepatic cirrhosis of any etiology
• Previous variceal bleeding
• Endoscopic variceal eradication at least 2 weeks before

Exclusion Criteria:

• Beta blocker or statin contraindications
• Model for End-Stage Liver Disease (MELD) score > 25
• Child-Pugh score > 13
• HVPG ≤ 12 mmHg
• Creatinine clearance < 50 mL/min
• Refractory ascites
• Hepatic encephalopathy stages 3 or 4
• Alcohol use in the last 6 months
• Hepatitis C treatment in the last 6 months
• Changing or initiating a new hepatitis B treatment in the last 6 months
• Malignant neoplasms from any origin except basal cell carcinoma
• HIV infection
• Pregnancy
• Anticoagulation
• Recent or complete portal vein thrombosis

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Phase 1: Propranolol (PPL); Hepatic venous pressure gradient (HVPG) will be measured before and after 120 minutes of a loading dose of Propranolol (PPL) 80 mg PO. Thereafter, patients will receive maintenance therapy with Propranolol (40 to 320 mg / day) adjusted according to blood pressure and heart rate. After 28 days of reaching the maximum tolerated dose, a new HVPG measurement will be performed.	Drug: Propranolol; 40mg to 320mg / day
Active Comparator: Phase 1: Carvedilol (CVD); HVPG will be measured before and after 120 minutes of a loading dose of Carvedilol (CVD) 12.5 mg PO. Thereafter, patients will receive maintenance therapy with Carvedilol (6.25 - 25 mg / day) adjusted according to blood pressure. After 28 days of reaching the maximum tolerated dose, a new HVPG measurement will be performed.	Drug: Carvedilol; 6.25mg to 25mg / day
Active Comparator: Phase 2: PPL non-responders/rosuvastatin; Patients treated with PROPRANOLOL (PPL) who do not reach HVPG fall below 12 mmHg will be randomized to receive the addition of ROSUVASTATIN 20 mg /day PO. HVPG will be measured again after 56 days.	Drug: Propranolol; 40mg to 320mg / day; Drug: Rosuvastatin; 20mg / day
Placebo Comparator: Phase 2: PPL non-responders/placebo; Patients treated with PROPRANOLOL (PPL) who do not reach HVPG fall below 12 mmHg will be randomized to receive the addition of PLACEBO 1 tablet PO. HVPG will be measured again after 56 days.	Drug: Propranolol; 40mg to 320mg / day; Drug: Placebo; Placebo of rosuvastatin
Active Comparator: Phase 2: CVD non-responders/rosuvastatin; Patients treated with CARVEDILOL (CVD) who do not reach HVPG fall below 12 mmHg will be randomized to receive the addition of ROSUVASTATIN 20 mg /day PO. HVPG will be measured again after 56 days.	Drug: Carvedilol; 6.25mg to 25mg / day; Drug: Rosuvastatin; 20mg / day
Placebo Comparator: Phase 2: CVD non-responders/placebo; Patients treated with CARVEDILOL (CVD) who do not reach HVPG fall below 12 mmHg will be randomized to receive the addition of PLACEBO 1 tablet PO. HVPG will be measured again after 56 days.	Drug: Carvedilol; 6.25mg to 25mg / day; Drug: Placebo; Placebo of rosuvastatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute hemodynamic response	A decrease in HVPG to 12 mmHg or lower	Two hours after a load dose of carvedilol or propranolol
Full hemodynamic response to beta blockers	A decrease in HVPG to 12 mmHg or lower	Eight weeks of carvedilol or propranolol
Full hemodynamic response to beta blockers plus rosuvastatin or placebo	A decrease in HVPG to 12 mmHg or lower	Eight weeks of beta blockers plus rosuvastatin or placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sufficient hemodynamic response to beta blockers plus rosuvastatin or placebo	A decrease in HVPG of at least 20% from baseline	Eight weeks of beta blockers plus rosuvastatin or placebo
Partial hemodynamic response to beta blockers plus rosuvastatin or placebo	A decrease in HVPG of at least 10% from baseline	Eight weeks of beta blockers plus rosuvastatin or placebo

Collaborators and Investigators

• Sponsor: Universidade Federal do Rio de Janeiro

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2019
• Primary Completion (Anticipated): December 20, 2020
• Study Completion (Anticipated): December 20, 2022

Study Registration Dates

• First Submitted: October 23, 2018
• First Submitted That Met QC Criteria: October 23, 2018
• First Posted (Actual): October 25, 2018

Study Record Updates

• Last Update Posted (Actual): May 14, 2019
• Last Update Submitted That Met QC Criteria: May 12, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Hypertension; Hemorrhage; Hypertension, Portal; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Antimetabolites; Protective Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Propranolol; Rosuvastatin Calcium; Carvedilol
• Other Study ID Numbers: 83211318.1.0000.5257

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

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