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

Phase 2

• Conditions: Cirrhosis; Portal Hypertension; Variceal Hemorrhage
• Interventions: Drug: Propranolol; Drug: Carvedilol; Drug: Rosuvastatin; Drug: Placebo

• Registration Number: NCT03720067
• Lead Sponsor: Universidade Federal do Rio de Janeiro

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-10-23
• Study First Submitted QC: 2018-10-23
• Study First Posted: 2018-10-25
• Study Start: 2019-01-25
• Status Verified: 2019-05
• Last Update Submitted: 2019-05-12
• Last Update Posted: 2019-05-14
• Primary Completion: 2020-12-20
• Study Completion: 2022-12-20

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 80

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 2: PPL non-responders/rosuvastatin	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.
Phase 2: PPL non-responders/placebo	Propranolol	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.
Phase 2: PPL non-responders/placebo	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.
Phase 2: CVD non-responders/placebo	Carvedilol	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.
Phase 2: CVD non-responders/placebo	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.
Phase 1: Carvedilol (CVD)	Carvedilol	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.
Phase 1: Propranolol (PPL)	Propranolol	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.
Phase 2: PPL non-responders/rosuvastatin	Propranolol	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.
Phase 2: CVD non-responders/rosuvastatin	Carvedilol	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.
Phase 2: CVD non-responders/rosuvastatin	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Universidade Federal do Rio de Janeiro; 🇧🇷 Rio de Janeiro, Brazil