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Hepatic Venous Pressure Gradient-guided Versus Standard Beta-blocker Therapy in Primary Prevention of Variceal Bleeding (Porthos)

Primary Purpose

Acute Bleeding Esophageal Varices, Liver Cirrhosis

Status
Unknown status
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Hepatic venous pressure gradient measurement
Sponsored by
Leiden University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Bleeding Esophageal Varices focused on measuring Prevention, Esophageal variceal bleeding, Hepatic Venous Pressure Gradient, Betablocker therapy

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with liver cirrhosis Large (≥5 mm) esophageal varices

Exclusion Criteria:

  • History of esophageal variceal hemorrhage
  • Pregnancy
  • Contraindications to beta-blocker therapy
  • Esophageal varices in the absence of liver cirrhosis
  • Intermediate, advanced or terminal stage hepatocellular carcinoma (BCLC stage B, C or D)
  • Refractory ascites
  • Hepatorenal syndrome
  • Prior treatment or prophylaxis for esophageal varices or varices bleeding (propranolol use, TIPS, endoscopic banding ligation, endoscopic sclerotherapy)

Sites / Locations

  • Universitair Ziekenhuis AntwerpenRecruiting
  • Universitaire Ziekenhuizen LeuvenRecruiting
  • Academisch Medisch CentrumRecruiting
  • Free University Medical CentreRecruiting
  • Leiden University Medical CentreRecruiting
  • Haga HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

HVPG-propranolol arm

Propranolol arm

Arm Description

A baseline hepatic venous pressure gradient measurement (HVPG measurement) is performed in day-care setting. After this procedure propranolol is started at 20 mg BID. with dose escalation as described in the propranolol arm. A second HVPG measurement is performed at 4 weeks after adequate propranolol therapy. In patients who reach target HVPG reduction (responders), propranolol is continued at the same dose without routine control endoscopy. In patients who do not reach target HVPG reduction (nonresponders), endoscopic band ligation is performed in day-care setting with intervals of 2-4 weeks until complete obliteration of varices. Follow-up endoscopy with 6 months interval is performed to detect and treat recurrent large varices.

Propranolol start 20 mg BID. orally with dose escalation based on heart frequency (HF) with 3-days interval to the maximum tolerated dose. No routine control endoscopy is required.

Outcomes

Primary Outcome Measures

First variceal bleeding episodes
First variceal bleeding episodes

Secondary Outcome Measures

Mortality
Mortality
Occurrence of other cirrhosis-related complications
ascites spontaneous bacterial peritonitis hepatic encephalopathy hepatorenal syndrome hepatocellular carcinoma
Costs of treatments
Costs of treatments
Adverse effects
Adverse effects associated with NSBB therapy, endoscopic band ligation, hepatic venous pressure gradient

Full Information

First Posted
June 11, 2012
Last Updated
September 27, 2019
Sponsor
Leiden University Medical Center
Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Free University Medical Center, Haga Hospital, Universitaire Ziekenhuizen KU Leuven, Ziekenhuis Netwerk Antwerpen (ZNA)
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1. Study Identification

Unique Protocol Identification Number
NCT01618890
Brief Title
Hepatic Venous Pressure Gradient-guided Versus Standard Beta-blocker Therapy in Primary Prevention of Variceal Bleeding
Acronym
Porthos
Official Title
A Multi-center Randomized Controlled Study of Primary Prevention of Esophageal Variceal Bleeding in Cirrhotic Patients Treated With HVPG-guided Beta- Blocker Therapy or Standard Heart Rate-guided Beta-blocker Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
September 2019
Overall Recruitment Status
Unknown status
Study Start Date
September 2012 (Actual)
Primary Completion Date
December 2020 (Anticipated)
Study Completion Date
December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Leiden University Medical Center
Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Free University Medical Center, Haga Hospital, Universitaire Ziekenhuizen KU Leuven, Ziekenhuis Netwerk Antwerpen (ZNA)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Study hypothesis: Hepatic venous pressure gradient (HVPG)-directed primary prophylaxis with nonselective beta-blocker therapy (NSBB) leads to a reduction in first variceal bleeding episodes and is cost-effective in the long term. Study design: A multi-center randomized controlled study comparing nonselective beta-blocker therapy guided by the hemodynamic response as determined by the difference in HVPG before and after starting oral NSBB therapy, to standard heart rate-guided NSBB therapy in patients with esophageal varices due to liver cirrhosis without a history of esophageal variceal hemorrhage. Primary study parameters/outcome of the study: First variceal bleeding episodes occurring within the first two years. Secondary study parameters/outcome of the study: Mortality Occurrence of other cirrhosis-related complications Occurrence of hepatocellular carcinoma Costs of treatments Adverse effects
Detailed Description
Background of the study: About 50% of cirrhotic patients who use nonselective beta-blockers (NSBB) for primary prevention of variceal bleeding do not reach target hemodynamic response, defined as HVPG < 12 mmHg or a > 20% decrease in HVPG from baseline. These so-called hemodynamic nonresponding patients have significantly higher rate of first esophageal variceal hemorrhage as compared to patients who do respond to NSBB. International institutions that publish guidelines differ in their recommendations concerning HVPG monitoring. As a result, practice currently varies widely. The investigators hypothesize that HVPG-directed primary prophylaxis leads to a reduction in first variceal bleeding episodes and is cost-effective in the long term. Objective of the study: To determine cost-effectiveness of hepatic venous pressure gradient (HVPG)-guided nonselective beta-blocker therapy as compared to standard heart rate-guided beta-blocker therapy in the primary prevention of esophageal variceal bleeding in cirrhotic patients. Study design: A multi-center randomized controlled study comparing nonselective beta-blocker therapy guided by the hemodynamic response as determined by the difference in HVPG before and after starting oral nonselective beta-blockers, to standard heart rate-guided nonselective beta-blocker therapy in patients with esophageal varices due to liver cirrhosis. Study population: Patients with liver cirrhosis and large (>5 mm) esophageal varices without a history of esophageal variceal hemorrhage. Intervention: -In HVPG-group: Perform baseline HVPG measurement, then start propranolol 20 mg orally twice daily (BID), increase the dose stepwise with 3 days interval to decrease the heart rate to maximum tolerated dose. After 4 weeks a second HVPG is performed. In hemodynamic responders (who reach target decrease in HVPG) NSBB are continued until end of follow-up. In hemodynamic nonresponders (who do not reach target decrease in HVPG), NSBB are continued and repeated endoscopic band ligation is performed with 2-4 weeks interval until complete obliteration of large varices. -In control group: Start propranolol 20 mg BID, increase the dose stepwise with 3 days interval to maximum heart rate-guided tolerated dose. Primary study parameters/outcome of the study: First variceal bleeding episodes occurring within the first two years. Secondary study parameters/outcome of the study: Mortality Occurrence of other cirrhosis-related complications Occurrence of hepatocellular carcinoma Costs of treatments Adverse effects

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Bleeding Esophageal Varices, Liver Cirrhosis
Keywords
Prevention, Esophageal variceal bleeding, Hepatic Venous Pressure Gradient, Betablocker therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
78 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
HVPG-propranolol arm
Arm Type
Experimental
Arm Description
A baseline hepatic venous pressure gradient measurement (HVPG measurement) is performed in day-care setting. After this procedure propranolol is started at 20 mg BID. with dose escalation as described in the propranolol arm. A second HVPG measurement is performed at 4 weeks after adequate propranolol therapy. In patients who reach target HVPG reduction (responders), propranolol is continued at the same dose without routine control endoscopy. In patients who do not reach target HVPG reduction (nonresponders), endoscopic band ligation is performed in day-care setting with intervals of 2-4 weeks until complete obliteration of varices. Follow-up endoscopy with 6 months interval is performed to detect and treat recurrent large varices.
Arm Title
Propranolol arm
Arm Type
No Intervention
Arm Description
Propranolol start 20 mg BID. orally with dose escalation based on heart frequency (HF) with 3-days interval to the maximum tolerated dose. No routine control endoscopy is required.
Intervention Type
Procedure
Intervention Name(s)
Hepatic venous pressure gradient measurement
Other Intervention Name(s)
Hepatic venous pressure measurement, Endoscopic variceal band ligation, Propranolol
Intervention Description
Perform baseline HVPG measurement, then start propranolol 20 mg orally twice daily (BID), increase the dose stepwise to maximum tolerated dose. After 4 weeks a second HVPG is performed. In hemodynamic nonresponders from the study arm, repeated endoscopic band ligation is performed in daycare setting with intervals of 2-4 weeks. In hemodynamic responders (HVPG second measurement< 12 mmHg or >20% reduction in HVPG compared to baseline) beta-blockers are continued until end of follow-up.
Primary Outcome Measure Information:
Title
First variceal bleeding episodes
Description
First variceal bleeding episodes
Time Frame
two years of follow-up
Secondary Outcome Measure Information:
Title
Mortality
Description
Mortality
Time Frame
two years
Title
Occurrence of other cirrhosis-related complications
Description
ascites spontaneous bacterial peritonitis hepatic encephalopathy hepatorenal syndrome hepatocellular carcinoma
Time Frame
two years
Title
Costs of treatments
Description
Costs of treatments
Time Frame
two years
Title
Adverse effects
Description
Adverse effects associated with NSBB therapy, endoscopic band ligation, hepatic venous pressure gradient
Time Frame
two years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with liver cirrhosis Large (≥5 mm) esophageal varices Exclusion Criteria: History of esophageal variceal hemorrhage Pregnancy Contraindications to beta-blocker therapy Esophageal varices in the absence of liver cirrhosis Intermediate, advanced or terminal stage hepatocellular carcinoma (BCLC stage B, C or D) Refractory ascites Hepatorenal syndrome Prior treatment or prophylaxis for esophageal varices or varices bleeding (propranolol use, TIPS, endoscopic banding ligation, endoscopic sclerotherapy)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Minneke Coenraad, Dr.
Phone
+31-71-5269111
Ext
*9127
Email
m.j.coenraad@lumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Minneke Coenraad, Dr.
Organizational Affiliation
Leiden University Medical Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universitair Ziekenhuis Antwerpen
City
Antwerpen
ZIP/Postal Code
B-2650
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Thomas Vanwolleghem
Facility Name
Universitaire Ziekenhuizen Leuven
City
Leuven
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Frederik Nevens, Prof. dr.
Facility Name
Academisch Medisch Centrum
City
Amsterdam
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ulrich Beuers, Prof.dr.
Facility Name
Free University Medical Centre
City
Amsterdam
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Karin van Nieuwkerk, Dr.
Facility Name
Leiden University Medical Centre
City
Leiden
ZIP/Postal Code
2333 ZA
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Minneke Coenraad, Dr.
Phone
+31-71-5269111
Ext
99127
Email
m.j.coenraad@lumc.nl
Facility Name
Haga Hospital
City
The Hague
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jan Nicolaï, Dr.

12. IPD Sharing Statement

Learn more about this trial

Hepatic Venous Pressure Gradient-guided Versus Standard Beta-blocker Therapy in Primary Prevention of Variceal Bleeding

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