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

NCT02173288 | Completed Phase 2 DMC

• 1 other identifier: Mido-tolvaptan 1
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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.

Conditions

Cirrhosis; Refractory/Recurrent Ascites

Outcome Measures

Primary Outcomes (1)

• Number of patients with control of ascites

  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 Outcomes (5)

• Number of patients with worsening of encephalopathy

  3 months

• Number of patients with impairment of liver function

  3 months

• Number of patients with variceal bleed

  3 months

• Number of patients developing hepatorenal syndrome

  3 months

• Number of patients with hypernatremia

  3 months

Study Arms (4)

Standard medical therapy

ACTIVE COMPARATOR

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

Drug: Standard medical therapy

Midodrine group

ACTIVE COMPARATOR

Standard medical therapy (n-15) with Midodrine 7.5 mg thrice a day

Drug: Standard medical therapy; Drug: Midodrine

Tolvaptan group

ACTIVE COMPARATOR

Standard medical therapy (n-15) with Tolvaptan 15 mg twice a day

Drug: Standard medical therapy; Drug: Tolvaptan

Tolvaptan plus midodrine arm

EXPERIMENTAL

Standard medical therapy (n-15) with Tolvaptan 15 mg twice a day and Midodrine 7.5 mg thrice a day

Drug: Standard medical therapy; Drug: Tolvaptan; Drug: Midodrine

Interventions

Standard medical therapy DRUG

Also known as: Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.

Midodrine group; Standard medical therapy; Tolvaptan group; Tolvaptan plus midodrine arm

Tolvaptan DRUG

Also known as: Tolvaptan 15 mg twice a day

Tolvaptan group; Tolvaptan plus midodrine arm

Midodrine DRUG

Also known as: Midodrine 7.5 mg thrice a day

Midodrine group; Tolvaptan plus midodrine arm

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead

Study Sites (1)

Dept. of Hepatology, PGIMER, Chandigarh

Chandigarh, 160012, India

Location

Related Publications (1)

• Rai N, Singh B, Singh A, Vijayvergiya R, Sharma N, Bhalla A, Singh V. Midodrine and tolvaptan in patients with cirrhosis and refractory or recurrent ascites: a randomised pilot study. Liver Int. 2017 Mar;37(3):406-414. doi: 10.1111/liv.13250. Epub 2016 Oct 2.

  PMID: 27614145 DERIVED

MeSH Terms

Conditions

Fibrosis; Ascites

Interventions

Furosemide; Tolvaptan; Midodrine

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfanilamides; Sulfonamides; Amides; Organic Chemicals; Aniline Compounds; Amines; Sulfones; Sulfur Compounds; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Ethanolamines; Amino Alcohols; Alcohols

Study Officials

• Virendra Singh

  PGIMER, Chandigarh

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Hepatology

Study Record Dates

• First Submitted: June 18, 2014
• First Posted: June 24, 2014
• Study Start: July 1, 2013
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: September 19, 2017

Record last verified: 2017-09

Locations

IN (1)