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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02173288
Recruitment Status : Completed
First Posted : June 24, 2014
Last Update Posted : September 19, 2017
Sponsor:
Information provided by (Responsible Party):
Dr.Virendra Singh, Postgraduate Institute of Medical Education and Research

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Cirrhosis Refractory/Recurrent Ascites Drug: Standard medical therapy Drug: Tolvaptan Drug: Midodrine Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Role of Midodrine and Tolvaptan in Patients With Cirrhosis With Refractory or Recurrent Ascites
Study Start Date : July 2013
Actual Primary Completion Date : March 2016
Actual Study Completion Date : March 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cirrhosis

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 Name: 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: Standard medical therapy
Other Name: Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.

Drug: Midodrine
Other Name: Midodrine 7.5 mg thrice a day

Active Comparator: Tolvaptan group
Standard medical therapy (n-15) with Tolvaptan 15 mg twice a day
Drug: Standard medical therapy
Other Name: Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.

Drug: Tolvaptan
Other Name: Tolvaptan 15 mg twice a day

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: Standard medical therapy
Other Name: Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.

Drug: Tolvaptan
Other Name: Tolvaptan 15 mg twice a day

Drug: Midodrine
Other Name: Midodrine 7.5 mg thrice a day




Primary Outcome Measures :
  1. 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



Secondary Outcome Measures :
  1. Number of patients with worsening of encephalopathy [ Time Frame: 3 months ]
  2. Number of patients with impairment of liver function [ Time Frame: 3 months ]
  3. Number of patients with variceal bleed [ Time Frame: 3 months ]
  4. Number of patients developing hepatorenal syndrome [ Time Frame: 3 months ]
  5. Number of patients with hypernatremia [ Time Frame: 3 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 .

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02173288


Locations
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India
Dept. of Hepatology, PGIMER, Chandigarh
Chandigarh, India, 160012
Sponsors and Collaborators
Postgraduate Institute of Medical Education and Research
Investigators
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Study Chair: Virendra Singh PGIMER, Chandigarh

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Dr.Virendra Singh, Professor of Hepatology, Postgraduate Institute of Medical Education and Research
ClinicalTrials.gov Identifier: NCT02173288    
Other Study ID Numbers: Mido-tolvaptan 1
First Posted: June 24, 2014    Key Record Dates
Last Update Posted: September 19, 2017
Last Verified: September 2017
Additional relevant MeSH terms:
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Liver Cirrhosis
Fibrosis
Ascites
Pathologic Processes
Liver Diseases
Digestive System Diseases
Furosemide
Spironolactone
Tolvaptan
Midodrine
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Diuretics, Potassium Sparing
Antidiuretic Hormone Receptor Antagonists
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents
Adrenergic alpha-1 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents