Role of Midodrine and Tolvaptan in Patients With Cirrhosis With Refractory or Recurrent Ascites

September 18, 2017 updated by: Dr.Virendra Singh, Postgraduate Institute of Medical Education and Research
The development of ascites in the natural history of cirrhosis heralds a worsening of the prognosis to 50% survival at 2 years, and this deteriorates to 30-50% at 1 year when the ascites becomes refractory to medical therapy. Hemodynamic alterations and their relation to neurohumoral systems are essential in pathophysiology of ascites formation. The theory that best explain the ascites formation and sodium retention in cirrhotics is portal hypertension leading to splanchnic arterial vasodilatation leading to underfilling of arterial circulation which is sensed by the arterial and the cardiopulmonary receptors leading to sympathetic nervous system activation and activation of the anti-natriuretic factors (RAAS and arginine vasopressin), resulting in sodium and water retention. The therapeutic options available for patients with refractory ascites are serial therapeutic paracentesis, liver transplantation and transjugular intrahepatic portosystemic shunts.Vasopressin V2 receptor antagonists antagonize the antidiuretic effects of vasopressin at the V2 receptor located in the renal collecting duct, they increase free water clearance, and thus may be helpful in mobilizing excess water in conditions associated with water retention including cirrhosis. The use of V2 receptor antagonists in cirrhosis with ascites has been shown to be safe and efficacious. Midodrine, an alpha adreno receptor agonist by causing splanchnic vasoconstriction has been used in hepatorenal syndrome (HRS) and for control of ascites in patients with refractory or recurrent ascites. It is possible that vasoconstrictors and aquaretics (V2 receptor antagonists) by acting at different sites in combination may reverse some of the pathogenic events that results in refractory or recurrent ascites.There are no reports on the use of combination of midodrine and tolvaptan in the patients with cirrhosis with ascites. Therefore, we plan to study the role of midodrine, tolvaptan and their combination on systemic hemodynamics, renal functions and control of ascites in patients with cirrhosis and refractory or recurrent ascites.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

50

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • India
      • Chandigarh, India, 160012
        • Dept. of Hepatology, PGIMER, Chandigarh

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:60 consecutive patients with cirrhosis and refractory or recurrent ascites with stable renal function ( creatinine level <1.5mg/dl for at least 7 days ).

Exclusion Criteria:

  • Presence of gastrointestinal bleeding, HRS, hepatic encephalopathy of grade 2 or higher or infection within 1 month preceding the study or during the study, presence of diabetes, intrinsic renal or cardiovascular disease or arterial hypertension on history and physical examination, abnormal urine analysis, chest radiograph or electrocardiogram, presence of hepatocellular carcinoma or portal vein thrombosis or treatment with drugs with known effects on systemic and renal hemodynamics within 7 days of inclusion .

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Standard medical therapy
Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
Drug: Standard medical therapy
Other Names:
  • Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
ACTIVE_COMPARATOR: Midodrine group
Standard medical therapy (n-15) with Midodrine 7.5 mg thrice a day
Drug: Midodrine
Other Names:
  • Midodrine 7.5 mg thrice a day
Drug: Standard medical therapy
Other Names:
  • Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
ACTIVE_COMPARATOR: Tolvaptan group
Standard medical therapy (n-15) with Tolvaptan 15 mg twice a day
Drug: Tolvaptan
Other Names:
  • Tolvaptan 15 mg twice a day
Drug: Standard medical therapy
Other Names:
  • Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
EXPERIMENTAL: Tolvaptan plus midodrine arm
Standard medical therapy (n-15) with Tolvaptan 15 mg twice a day and Midodrine 7.5 mg thrice a day
Drug: Tolvaptan
Other Names:
  • Tolvaptan 15 mg twice a day
Drug: Midodrine
Other Names:
  • Midodrine 7.5 mg thrice a day
Drug: Standard medical therapy
Other Names:
  • Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with control of ascites
Time Frame: 3 months

Control of ascites will be defined as:

Complete: defined as the elimination of ascites Partial: presence of ascites not requiring paracentesis Failure: defined as persistence of ascites requiring paracentesis
3 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Number of patients with worsening of encephalopathy
Time Frame: 3 months
3 months
Number of patients with impairment of liver function
Time Frame: 3 months
3 months
Number of patients with variceal bleed
Time Frame: 3 months
3 months
Number of patients developing hepatorenal syndrome
Time Frame: 3 months
3 months
Number of patients with hypernatremia
Time Frame: 3 months
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Postgraduate Institute of Medical Education and Research

Investigators

  • Study Chair: Virendra Singh, PGIMER, Chandigarh

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2013

Primary Completion (ACTUAL)

March 1, 2016

Study Completion (ACTUAL)

March 1, 2016

Study Registration Dates

First Submitted

June 18, 2014

First Submitted That Met QC Criteria

June 20, 2014

First Posted (ESTIMATE)

June 24, 2014

Study Record Updates

Last Update Posted (ACTUAL)

September 19, 2017

Last Update Submitted That Met QC Criteria

September 18, 2017

Last Verified

September 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Mido-tolvaptan 1

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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