Esophageal and Gastric VaricesPhase 3NCT00006398
Prevention of Esophageal Varices by Beta-Adrenergic Blockers
A Phase 3 study testing Timolol Maleate in people with Esophageal and Gastric Varices and Liver Cirrhosis, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 5 sites in 3 countries.
Trial summary
The purpose of this study is to learn whether timolol is useful in preventing or delaying the appearance of gastroesophageal varices, a complication that may develop in the future as a consequence of liver disease. Cirrhosis causes an increased resistance of blood flowing through the liver. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Esophageal and Gastric Varices, Liver Cirrhosis, Portal Hypertension
- What is being tested?
- Timolol Maleate
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 213 participants
- Where
- 5 sitesin 3 countries
- Study dates
- Aug 1993to Sep 2002
- 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
- Liver biopsy compatible with cirrhosis.
- Absence of gastroesophageal varices.
- An increased hepatic venous pressure gradient (HVPG) (6mmHg).
- Age over 18 and below 76 years.
- Informed, written consent.
- Absence of exclusion criteria.
Who cannot join
- Presence of ascites that requires specific treatment (diuretics, paracentesis, peritoneo-venous shunt, etc).
- Proven hepatocellular carcinoma by radiological or histological criteria.
- Splenic or portal vein thrombosis by Doppler-ultrasound.
- Presence of any concurrent disease that is expected to decrease life expectancy to less than one year.
- Patients taking diuretics, beta-blockers, clonidine, prazosin, nitrates, molsidomine and any drug which may have an effect on splanchnic hemodynamics/portal pressure.
- Patients participating in other pharmacological randomized clinical trials.
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- Patients with primary biliary cirrhosis and primary sclerosing cholangitis will also be excluded since these entities have a slower progression of the disease, are usually enrolled in other clinical trials and are transplanted at an earlier stage.
- Contraindications to beta-blockers: asthma, COPD with positive broncoconstrictive test, heart failure, A-V block, aortic valve stenosis, organic psychosis, insulin-dependent diabetes, hypersensitivity to beta-blockers.
- Women who are pregnant, nursing or of childbearing potential and who are not using oral or mechanical contraception.
Trial locations and contacts
5 sites in 3 countries.
5 sites in 3 countries
United States3 sites
The Faulkner Hospital
Boston, Massachusetts, 02130
Yale University Sch. of Medicine
New Haven, Connecticut, 06520
VA CT Healthcare System
West Haven, Connecticut, 06516
About this study
Official title: Randomized, Double-Blind Study of Timolol (A Nonselective Beta-Adrenergic Blocker) vs Placebo to Prevent Complications of Hepatic Portal Hypertension in Patients With Cirrhosis
The purpose of this study is to learn whether timolol is useful in preventing or delaying the appearance of gastroesophageal varices, a complication that may develop in the future as a consequence of liver disease. Cirrhosis causes an increased resistance of blood flowing through the liver. This leads to an increased pressure in the portal vein (the vein that takes blood to your liver). High portal pressure is responsible for the appearance of complications of chronic liver disease such as varices and variceal bleeding (bleeding from veins in your esophagus). Timolol belongs to a group of medications called beta-blockers. Beta-blockers decrease high portal pressure and previous studies have shown that beta-blocker pills are useful in preventing bleeding from varices in patients who already have varices. A more desirable effect would be if these pills could prevent not only bleeding from varices but the appearance of varices (and therefore of bleeding).
- Being tested
- Timolol Maleate, Placebo
- Keywords
- cirrhosis, esophageal varices, variceal hemorrhage, beta-adrenergic blocker
- Medical subject headings
- Esophageal and Gastric Varices, Liver Cirrhosis, Hypertension, Portal, Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Timolol MaleateDrug
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Timolol Maleate | Experimental | Dose titrated from 5 mg per day to up to 80 mg per day depending on heart rate Receives: Drug: Timolol Maleate |
| Placebo | Placebo comparator | Timelol placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Varices
Development of varices
Measured: 6 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Oct 2000 (estimated)
- Study startAug 1993
- Primary completionSep 2002
- Study completionSep 2002
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Esophageal and Gastric VaricesStudies of the same condition, open and under way.
- More trials run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)The sponsor's other registered studies.
- 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
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 213 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Collaborators
- Yale University
- Responsible party
- Sponsor
- Investigators
- Roberto J Groszmann, M.D., Principal investigator, Yale University School of Med.Norman Grace, M.D., Tufts UniversityJaime Bosch, M.D., University of BarcelonaAndrew Burroughs, M.D., University of LondonGuadalupe Garcia-Tsao, M.D., Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00006398
- Sponsor's protocol ID
- Timolol (completed)
- Other IDs
- R01DK046580, YALESM 6618
- Status last verified
- May 2017
- First submitted
- 5 Oct 2000
- Last updated
- 1 Jun 2017
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Sarin SK, Groszmann RJ, Mosca PG, Rojkind M, Stadecker MJ, Bhatnagar R, Reuben A, Dayal Y. Propranolol ameliorates the development of portal-systemic shunting in a chronic murine schistosomiasis model of portal hypertension. J Clin Invest. 1991 Mar;87(3):1032-6. doi: 10.1172/JCI115062.
PubMed 1900306Escorsell A, Ferayorni L, Bosch J, Garcia-Pagan JC, Garcia-Tsao G, Grace ND, Rodes J, Groszmann RJ. The portal pressure response to beta-blockade is greater in cirrhotic patients without varices than in those with varices. Gastroenterology. 1997 Jun;112(6):2012-6. doi: 10.1053/gast.1997.v112.pm9178694.
PubMed 9178694Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, Escorsell A, Garcia-Pagan JC, Patch D, Matloff DS, Gao H, Makuch R; Portal Hypertension Collaborative Group. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005 Nov 24;353(21):2254-61. doi: 10.1056/NEJMoa044456.
PubMed 16306522Ripoll C, Groszmann RJ, Garcia-Tsao G, Bosch J, Grace N, Burroughs A, Planas R, Escorsell A, Garcia-Pagan JC, Makuch R, Patch D, Matloff DS; Portal Hypertension Collaborative Group. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol. 2009 May;50(5):923-8. doi: 10.1016/j.jhep.2009.01.014. Epub 2009 Mar 5.
PubMed 19303163
Study at a glance
From the registry record, last updated by the sponsor on 1 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized, Double-Blind Study of Timolol (A Nonselective Beta-Adrenergic Blocker) vs Placebo to Prevent Complications of Hepatic Portal Hypertension in Patients With Cirrhosis
- ClinicalTrials.gov ID
- NCT00006398
- Acronym / sponsor ID
- Timolol (completed)
- Keywords
- cirrhosis, esophageal varices, variceal hemorrhage, beta-adrenergic blocker
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 213 participants (actual)
- Lead sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)US National Institutes of Health
- Collaborators
- Yale University
- Study start
- Aug 1993 (actual)
- Primary completion
- Sep 2002 (actual)
- Study completion
- Sep 2002 (actual)
- First posted
- 6 Oct 2000 (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.
The purpose of this study is to learn whether timolol is useful in preventing or delaying the appearance of gastroesophageal varices, a complication that may develop in the future as a consequence of liver disease. Cirrhosis causes an increased resistance of blood flowing through the liver. This leads to an increased pressure in the portal vein (the vein that takes blood to your liver). High portal pressure is responsible for the appearance of complications of chronic liver disease such as varices and variceal bleeding (bleeding from veins in your esophagus). Timolol belongs to a group of medications called beta-blockers. Beta-blockers decrease high portal pressure and previous studies have shown that beta-blocker pills are useful in preventing bleeding from varices in patients who already have varices. A more desirable effect would be if these pills could prevent not only bleeding from varices but the appearance of varices (and therefore of bleeding).
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Timolol Maleate | Experimental | Drug: Timolol MaleateDose titrated from 5 mg per day to up to 80 mg per day depending on heart rate |
| Placebo | Placebo comparator | Drug: PlaceboTimelol placebo |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Liver biopsy compatible with cirrhosis.
- Absence of gastroesophageal varices.
- An increased hepatic venous pressure gradient (HVPG) (6mmHg).
- Age over 18 and below 76 years.
- Informed, written consent.
Key exclusion criteria (9 listed)
- Presence of ascites that requires specific treatment (diuretics, paracentesis, peritoneo-venous shunt, etc).
- Proven hepatocellular carcinoma by radiological or histological criteria.
- Splenic or portal vein thrombosis by Doppler-ultrasound.
- Presence of any concurrent disease that is expected to decrease life expectancy to less than one year.
- Patients taking diuretics, beta-blockers, clonidine, prazosin, nitrates, molsidomine and any drug which may have an effect on splanchnic hemodynamics/portal pressure.
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 |
|---|---|---|
| Timolol Maleate | Drug | Timolol Maleate |
| Placebo | Drug | Placebo |
Primary outcome
Varices
Time frame: 6 years
Development of varices
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jun 2017.
- Background: PubMed 1900306Sarin SK, Groszmann RJ, Mosca PG, Rojkind M, Stadecker MJ, Bhatnagar R, Reuben A, Dayal Y. Propranolol ameliorates the development of portal-systemic shunting in a chronic murine schistosomiasis model of portal hypertension. J Clin Invest. 1991 Mar;87(3):1032-6. doi: 10.1172/JCI115062.
- Background: PubMed 9178694Escorsell A, Ferayorni L, Bosch J, Garcia-Pagan JC, Garcia-Tsao G, Grace ND, Rodes J, Groszmann RJ. The portal pressure response to beta-blockade is greater in cirrhotic patients without varices than in those with varices. Gastroenterology. 1997 Jun;112(6):2012-6. doi: 10.1053/gast.1997.v112.pm9178694.
- Results publication: PubMed 16306522Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, Escorsell A, Garcia-Pagan JC, Patch D, Matloff DS, Gao H, Makuch R; Portal Hypertension Collaborative Group. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005 Nov 24;353(21):2254-61. doi: 10.1056/NEJMoa044456.
- Derived from this study: PubMed 19303163Ripoll C, Groszmann RJ, Garcia-Tsao G, Bosch J, Grace N, Burroughs A, Planas R, Escorsell A, Garcia-Pagan JC, Makuch R, Patch D, Matloff DS; Portal Hypertension Collaborative Group. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol. 2009 May;50(5):923-8. doi: 10.1016/j.jhep.2009.01.014. Epub 2009 Mar 5.
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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.
Roberto J Groszmann, M.D. principal investigator
Yale University School of Med.
Norman Grace, M.D.
Tufts University
Jaime Bosch, M.D.
University of Barcelona
5 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Timolol Maleate in people with Esophageal and Gastric Varices and Liver Cirrhosis, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 5 sites in 3 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 6 inclusion and 9 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: finished, as of the sponsor's last update on 1 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States, Spain, United Kingdom. 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. Some participants in this study may receive a placebo. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Varices (time frame: 6 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00006398, which also lists 4 linked publications.
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 1 Jun 2017.