Acute Bleeding Esophageal VaricesPhase 3PorthosNCT01618890
Hepatic Venous Pressure Gradient-guided Versus Standard Beta-blocker Therapy in Primary Prevention of Variceal Bleeding
A Phase 3 study testing Hepatic venous pressure gradient measurement in people with Acute Bleeding Esophageal Varices and Liver Cirrhosis, run by Leiden University Medical Center at 6 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Acute Bleeding Esophageal Varices, Liver Cirrhosis
- What is being tested?
- Hepatic venous pressure gradient measurement
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 78 participants
- Where
- 6 sitesin 2 countries
- Study dates
- Sep 2012to Dec 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with liver cirrhosis Large (≥5 mm) esophageal varices
Who cannot join
- 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)
Trial locations and contacts
6 sites in 2 countries.
6 sites in 2 countries
Netherlands4 sites, 4 recruiting
- Recruiting
Academisch Medisch Centrum
Amsterdam
Ulrich Beuers, Prof.dr.
- Recruiting
Free University Medical Centre
Amsterdam
Karin van Nieuwkerk, Dr.
- Recruiting
Leiden University Medical Centre
Leiden, 2333 ZA
Minneke Coenraad, Dr., +31-71-5269111 ext. 99127, m.j.coenraad@lumc.nl
- Recruiting
Haga Hospital
The Hague
Jan Nicolaï, Dr.
Belgium2 sites, 2 recruiting
- Recruiting
Universitair Ziekenhuis Antwerpen
Antwerp, B-2650
Thomas Vanwolleghem
- Recruiting
Universitaire Ziekenhuizen Leuven
Leuven
Frederik Nevens, Prof. dr.
About this study
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 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.
Read more
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
Read the 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
- Conditions
- Acute Bleeding Esophageal Varices, Liver Cirrhosis
- Being tested
- Hepatic venous pressure gradient measurement
- Keywords
- Prevention, Esophageal variceal bleeding, Hepatic Venous Pressure Gradient, Betablocker therapy
- Medical subject headings
- Liver Cirrhosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hepatic venous pressure gradient measurementProcedure or surgery
Also called Hepatic venous pressure measurement, Endoscopic variceal band ligation, Propranolol
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.
| Study group | Role | What they receive |
|---|---|---|
| HVPG-propranolol arm | Experimental | 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. Receives: Procedure: Hepatic venous pressure gradient measurement |
| Propranolol arm | No intervention | 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
First variceal bleeding episodes
First variceal bleeding episodes
Measured: two years of follow-up
Secondary outcomes (4)
Mortality
Mortality
Measured: two years
Occurrence of other cirrhosis-related complications
ascites spontaneous bacterial peritonitis hepatic encephalopathy hepatorenal syndrome hepatocellular carcinoma
Measured: two years
Costs of treatments
Costs of treatments
Measured: two years
Adverse effects
Adverse effects associated with NSBB therapy, endoscopic band ligation, hepatic venous pressure gradient
Measured: two years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jun 2012 (estimated)
- Study startSep 2012
- Primary completionDec 2020 (estimated)
- Study completionDec 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Bleeding Esophageal VaricesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 78 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Universitair Ziekenhuis Brussel, Haga Hospital, Universitaire Ziekenhuizen KU Leuven, Ziekenhuis Netwerk Antwerpen (ZNA)
- Responsible party
- Principal investigator, Dr. M.J.Coenraad, Leiden University Medical Center
- Investigators
- Minneke Coenraad, Dr., Principal investigator, Leiden University Medical Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01618890
- Sponsor's protocol ID
- LUMC-40226
- Acronym
- Porthos
- Status last verified
- Sep 2019
- First submitted
- 11 Jun 2012
- Last updated
- 30 Sep 2019
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 30 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01618890
- Acronym / sponsor ID
- Porthos / LUMC-40226
- Conditions
- Acute Bleeding Esophageal Varices, Liver Cirrhosis
- Keywords
- Prevention, Esophageal variceal bleeding, Hepatic Venous Pressure Gradient, Betablocker therapy
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 78 participants (estimated)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Collaborators
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Universitair Ziekenhuis Brussel, Haga Hospital, Universitaire Ziekenhuizen KU Leuven, Ziekenhuis Netwerk Antwerpen (ZNA)
- Study start
- Sep 2012 (actual)
- Primary completion
- Dec 2020 (estimated)
- Study completion
- Dec 2022 (estimated)
- First posted
- 13 Jun 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| HVPG-propranolol arm | Experimental | Procedure: Hepatic venous pressure gradient measurementA 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 arm | No intervention | –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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Patients with liver cirrhosis Large (≥5 mm) esophageal varices
Key exclusion criteria (8 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Hepatic venous pressure gradient measurementAlso: Hepatic venous pressure measurement, Endoscopic variceal band ligation, PropranololPerform 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. | Procedure or surgery | HVPG-propranolol arm |
Primary outcome
First variceal bleeding episodes
Time frame: two years of follow-up
First variceal bleeding episodes
4 secondary outcomes
Mortality
Time frame: two years
Occurrence of other cirrhosis-related complications
Time frame: two years
Costs of treatments
Time frame: two years
Adverse effects
Time frame: two years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Sep 2019.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Minneke Coenraad, Dr. principal investigator
Leiden University Medical Centre
6 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Hepatic venous pressure gradient measurement in people with Acute Bleeding Esophageal Varices and Liver Cirrhosis, run by Leiden University Medical Center at 6 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 30 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Minneke Coenraad, Dr. (+31-71-5269111 ext. *9127, m.j.coenraad@lumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
First variceal bleeding episodes (time frame: two years of follow-up). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Sep 2019.