CirrhosisNCT01331785
Mechanism and the Effect of Midodrine on Portal Pressures in Patients With Cirrhosis
A study testing Midodrine in people with Cirrhosis and End Stage Liver Disease, run by The Cleveland Clinic at 1 site in United States.
Trial summary
Ascites is a frequent complication of patients with portal hypertension. As portal hypertension progresses, a percentage of these patients develop refractory ascites. Management options at that point include either TIPS or intermittent large volume paracentesis (LVP), with its attendant risks, Portal hypertension is… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Cirrhosis, End Stage Liver Disease, Ascites
- What is being tested?
- Midodrine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2011to Jul 2012
- Phase
- Interventional
- 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 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 to 70 years old
- Evidence of ESLD and ascites
- Ascites requiring periodic large volume paracentesis (1+ / month) of more than 3 months duration
- Systolic BP < 100 mmHg
Who cannot join
- Prior liver transplant
- Evaluated for multiple organ transplant
- Malignancies
- Non cirrhotic causes of ascites
- Prior TIPS usage (transjugular intrahepatic porto-systemic shunt)
- Primary renal diseases
Show all 12Show fewer
- Chronic kidney disease (CKD) >=4
- Grade 3 or 4 encephalopathy
- Child C cirrhosis or model for end stage liver disease (MELD) > 20
- Patients requiring large volume paracentesis for more than 12 months
- Frequency of paracentesis less than 6 in the preceding 3 months
- Active recreational drug and alcohol usage
Trial locations and contacts
1 site in 1 country.
About this study
Ascites is a frequent complication of patients with portal hypertension. As portal hypertension progresses, a percentage of these patients develop refractory ascites. Management options at that point include either TIPS or intermittent large volume paracentesis (LVP), with its attendant risks, Portal hypertension is accompanied by systemic circulatory dysfunction (decreased systemic vascular resistance and systolic BP), which is exacerbated by large volume paracentesis, with resultant renal and cardiac dysfunction. There are limited options for managing patients with acute decompensation, such as hepatorenal syndrome, although midodrine and other vasoconstrictors have been used in such patients. Midodrine has not been used as a possible therapeutic for ascites. Midodrine however, has been found to change the hemodynamics related to portal hypertension and ascites. There has been also change in mediators related to renal and circulation in studies of short duration (7 days) but not found in studies of 1 month duration, however the clinical effects of midodrine is found for longer duration in other similar conditions.
The purpose of the study is to assess the utility of midodrine in patients with obvious systemic circulatory dysfunction (hypotension) in improving the outcome of patients with refractory ascites and change in hemodynamic parameters and its mediators.
Read more
Specific endpoints include:
- an objective reduction of the volume/rate of accumulation of ascites and 2) a decrease in the frequency of LVP.
Read the detailed description
The pathophysiology of ascites is complex and various mechanisms have been proposed. Splanchnic and systemic vasodilation related to excess nitric oxide has been associated with systemic hypotension and increased portal flow.(8-10) This is associated with hemodynamic compensatory mechanisms, including activation of the renin-angiotension aldosterone system (RAAS), sympathetic nervous system (SNS), and non osmotic release of anti-diuretic hormones (ADH).(11, 12) These ultimately result in renal dysfunction, associated with sodium and fluid retention.(13) Several studies have shown reversal of HRS and decreased circulatory dysfunction when vasoconstrictors are administered. Various vasoconstrictors (noradrenaline, teleperessin, octreotide and midodrine) have been used in the management of hepato renal syndrome (HRS). (14-17) Midodrine appears to have some advantages, including the benefit of being an oral medication. (18) The beneficial effects have been noted as early as 6 hours after the use of midodrine in patients with ascites with or without HRS (2) with decreased plasma renin activity (PRA), antidiuretic hormone (ADH), nitrite and nitrate activity (NOx), increased renal plasma flow (RPF), glomerular filtration rate (GFR), increased urine sodium concentration (UNa) and volume, increased mean atrial pressure (MAP), decreased heart rate (HR) and cardiac output (CO). There was also decreased aldosterone in non-azotemic cirrhotic patients with or without ascites in patients studied for 7 days. (3) The renal function improvement was not substantiated in other studies. In patients treated for a month along with octreotide there was no significant improvement of renal function but marginal reversible liver dysfunction with decreased body weight (paracentesis adjusted weight),(19) A similar significant weight reduction was also noted in another study.(7) Midodrine has been shown to be safe and effective in patients when used to prevent dialysis induced hypotension, and has improved systolic pressure, without a significantly increased volume of fluid filtered by dialysis and no change in body weight in patients studied.(20, 21) The beneficial effects have been attributed to its modulating effects on autonomic function and increasing peripheral vessel resistances.(22) The drug has been found to effective and safe in acute and chronic use (21, 23) with minimal side effects.(24)
Vasoconstrictors in patients with ascites and hydrothorax In non azotemic cirrhotic patients with ascites, the addition of octreotide improved diuresis and decreased renin, increased MAP, decreased CO and improved renal function by increasing GFR, increased urine sodium and volume excretion.(25) In patient with massive hydrothorax with mild ascites and no azotemia, addition of midodrine to octreotide improves MAP, increases GFR, RPF and urine sodium and volume; and prevents recurrence of hydrothorax. Vasoconstrictors have been recommended as treatment for hydrothorax (4-6)and has been found beneficial in refractory ascites.(26)
Significance Vasoconstrictors like midodrine have been shown to be beneficial, with improvement of circulatory dysfunction in various groups of patients including patients with HRS type 1, type 2, non azotemic patients and in patients requiring hemodialysis. There are suggestions of decreased body weight in some of these patients. In patients with hydrothorax, addition of vasoconstrictors has helped in relieving the symptoms. The investigators suggest that midodrine could also benefit patients with refractory ascites. By decreasing the rate of ascitic fluid accumulation, it may be possible to decrease the volume of ascites drained or lengthen the interval between paracentesis, giving comfort to the patients. The beneficial effect on portal pressures and ascites could be due to other mechanisms (such as autonomic function) rather than their effect on renal hemodynamics as they are not sustained. There are no studies where this has been systematically analyzed.
- Conditions
- Cirrhosis, End Stage Liver Disease, Ascites, Hypotension
- Being tested
- Midodrine
- Keywords
- paracentesis, ascites, hypotension
- Medical subject headings
- Fibrosis, End Stage Liver Disease, Ascites, Hypotension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MidodrineDrug
Midodrine 2.5 mg to 10 mg three times a day to increase systolic BP above 100 mmHgor by 10 mmHg
| Study group | Role | What they receive |
|---|---|---|
| Midodrine | Experimental | Not described Receives: Drug: Midodrine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Volume and frequency of paracentesis and quality of life
To quantify the volume and rate of production of ascites (as estimated by the frequency of paracentesis) in patients with refractory ascites and hypotension requiring intermittent LVP and comparing these values before and after use of midodrine.
Measured: 3 months of study drug
Secondary outcomes (1)
Renal and cardiovascular hemodynamic changes
- To determine the effect of midodrine on the hemodynamics in these patients as well us its effect on circulatory (blood pressure), renal parameters (BUN, creatinine, serum and urine sodium), and the hormones and mediators (plasma renin, anti diuretic hormone, angiotension, aldosterone, nitrite and nitrate activity) known to be associated with cirrhosis.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Apr 2011 (estimated)
- Study startApr 2011
- Primary completionJul 2012
- Study completionJul 2012
Why it stopped: Lack of enrollment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for CirrhosisStudies of the same condition, open and under way.
- More trials run by The Cleveland ClinicThe 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 N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Cleveland Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- American College of Gastroenterology
- Responsible party
- Sponsor
- Investigators
- Achuthan Sourianarayanane, Principal investigator, The Cleveland Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01331785
- Sponsor's protocol ID
- ACG-CR-026-2010
- Status last verified
- Apr 2011
- First submitted
- 7 Apr 2011
- Last updated
- 31 Jul 2013
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 31 Jul 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanism and the Effect of Midodrine on Portal Pressures in Patients With Cirrhosis
- ClinicalTrials.gov ID
- NCT01331785
- Acronym / sponsor ID
- ACG-CR-026-2010
- Conditions
- Cirrhosis, End Stage Liver Disease, Ascites, Hypotension
- Keywords
- paracentesis, ascites, hypotension
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Lack of enrollment
- Enrolment
- 0 participants (actual)
- Lead sponsor
- The Cleveland ClinicUniversity, hospital or other
- Collaborators
- American College of Gastroenterology
- Study start
- Apr 2011
- Primary completion
- Jul 2012 (actual)
- Study completion
- Jul 2012 (actual)
- First posted
- 8 Apr 2011 (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.
Ascites is a frequent complication of patients with portal hypertension. As portal hypertension progresses, a percentage of these patients develop refractory ascites. Management options at that point include either TIPS or intermittent large volume paracentesis (LVP), with its attendant risks, Portal hypertension is accompanied by systemic circulatory dysfunction (decreased systemic vascular resistance and systolic BP), which is exacerbated by large volume paracentesis, with resultant renal and cardiac dysfunction. There are limited options for managing patients with acute decompensation, such as hepatorenal syndrome, although midodrine and other vasoconstrictors have been used in such patients. Midodrine has not been used as a possible therapeutic for ascites. Midodrine however, has been found to change the hemodynamics related to portal hypertension and ascites. There has been also change in mediators related to renal and circulation in studies of short duration (7 days) but not found in studies of 1 month duration, however the clinical effects of midodrine is found for longer duration in other similar conditions.
The purpose of the study is to assess the utility of midodrine in patients with obvious systemic circulatory dysfunction (hypotension) in improving the outcome of patients with refractory ascites and change in hemodynamic parameters and its mediators.
Specific endpoints include:
- an objective reduction of the volume/rate of accumulation of ascites and 2) a decrease in the frequency of LVP.
Detailed description
The pathophysiology of ascites is complex and various mechanisms have been proposed. Splanchnic and systemic vasodilation related to excess nitric oxide has been associated with systemic hypotension and increased portal flow.(8-10) This is associated with hemodynamic compensatory mechanisms, including activation of the renin-angiotension aldosterone system (RAAS), sympathetic nervous system (SNS), and non osmotic release of anti-diuretic hormones (ADH).(11, 12) These ultimately result in renal dysfunction, associated with sodium and fluid retention.(13) Several studies have shown reversal of HRS and decreased circulatory dysfunction when vasoconstrictors are administered. Various vasoconstrictors (noradrenaline, teleperessin, octreotide and midodrine) have been used in the management of hepato renal syndrome (HRS). (14-17) Midodrine appears to have some advantages, including the benefit of being an oral medication. (18) The beneficial effects have been noted as early as 6 hours after the use of midodrine in patients with ascites with or without HRS (2) with decreased plasma renin activity (PRA), antidiuretic hormone (ADH), nitrite and nitrate activity (NOx), increased renal plasma flow (RPF), glomerular filtration rate (GFR), increased urine sodium concentration (UNa) and volume, increased mean atrial pressure (MAP), decreased heart rate (HR) and cardiac output (CO). There was also decreased aldosterone in non-azotemic cirrhotic patients with or without ascites in patients studied for 7 days. (3) The renal function improvement was not substantiated in other studies. In patients treated for a month along with octreotide there was no significant improvement of renal function but marginal reversible liver dysfunction with decreased body weight (paracentesis adjusted weight),(19) A similar significant weight reduction was also noted in another study.(7) Midodrine has been shown to be safe and effective in patients when used to prevent dialysis induced hypotension, and has improved systolic pressure, without a significantly increased volume of fluid filtered by dialysis and no change in body weight in patients studied.(20, 21) The beneficial effects have been attributed to its modulating effects on autonomic function and increasing peripheral vessel resistances.(22) The drug has been found to effective and safe in acute and chronic use (21, 23) with minimal side effects.(24)
Vasoconstrictors in patients with ascites and hydrothorax In non azotemic cirrhotic patients with ascites, the addition of octreotide improved diuresis and decreased renin, increased MAP, decreased CO and improved renal function by increasing GFR, increased urine sodium and volume excretion.(25) In patient with massive hydrothorax with mild ascites and no azotemia, addition of midodrine to octreotide improves MAP, increases GFR, RPF and urine sodium and volume; and prevents recurrence of hydrothorax. Vasoconstrictors have been recommended as treatment for hydrothorax (4-6)and has been found beneficial in refractory ascites.(26)
Significance Vasoconstrictors like midodrine have been shown to be beneficial, with improvement of circulatory dysfunction in various groups of patients including patients with HRS type 1, type 2, non azotemic patients and in patients requiring hemodialysis. There are suggestions of decreased body weight in some of these patients. In patients with hydrothorax, addition of vasoconstrictors has helped in relieving the symptoms. The investigators suggest that midodrine could also benefit patients with refractory ascites. By decreasing the rate of ascitic fluid accumulation, it may be possible to decrease the volume of ascites drained or lengthen the interval between paracentesis, giving comfort to the patients. The beneficial effect on portal pressures and ascites could be due to other mechanisms (such as autonomic function) rather than their effect on renal hemodynamics as they are not sustained. There are no studies where this has been systematically analyzed.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Midodrine | Experimental | Drug: Midodrine |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age 18 to 70 years old
- Evidence of ESLD and ascites
- Ascites requiring periodic large volume paracentesis (1+ / month) of more than 3 months duration
- Systolic BP < 100 mmHg
Key exclusion criteria (12 listed)
- Prior liver transplant
- Evaluated for multiple organ transplant
- Malignancies
- Non cirrhotic causes of ascites
- Prior TIPS usage (transjugular intrahepatic porto-systemic shunt)
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 |
|---|---|---|
| MidodrineMidodrine 2.5 mg to 10 mg three times a day to increase systolic BP above 100 mmHgor by 10 mmHg | Drug | Midodrine |
Primary outcome
Volume and frequency of paracentesis and quality of life
Time frame: 3 months of study drug
To quantify the volume and rate of production of ascites (as estimated by the frequency of paracentesis) in patients with refractory ascites and hypotension requiring intermittent LVP and comparing these values before and after use of midodrine.
1 secondary outcome
Renal and cardiovascular hemodynamic changes
Time frame: 3 months
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jul 2013.
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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.
Achuthan Sourianarayanane principal investigator
The Cleveland Clinic
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Midodrine in people with Cirrhosis and End Stage Liver Disease, run by The Cleveland Clinic at 1 site in United States.
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 4 inclusion and 12 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: withdrawn, as of the sponsor's last update on 31 Jul 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
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?
Volume and frequency of paracentesis and quality of life (time frame: 3 months of study drug). 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 31 Jul 2013.