Overview

This trial is active, not recruiting.

Conditions cirrhosis, refractory/recurrent ascites
Treatments standard medical therapy, tolvaptan, midodrine
Phase phase 2/phase 3
Sponsor Postgraduate Institute of Medical Education and Research
Start date July 2013
End date March 2016
Trial size 50 participants
Trial identifier NCT02173288, Mido-tolvaptan 1

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Active Comparator)
Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
standard medical therapy Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
(Active Comparator)
Standard medical therapy (n-15) with Midodrine 7.5 mg thrice a day
standard medical therapy Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
midodrine Midodrine 7.5 mg thrice a day
(Active Comparator)
Standard medical therapy (n-15) with Tolvaptan 15 mg twice a day
standard medical therapy Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
tolvaptan Tolvaptan 15 mg twice a day
(Experimental)
Standard medical therapy (n-15) with Tolvaptan 15 mg twice a day and Midodrine 7.5 mg thrice a day
standard medical therapy Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
tolvaptan Tolvaptan 15 mg twice a day
midodrine Midodrine 7.5 mg thrice a day

Primary Outcomes

Measure
Number of patients with control of ascites
time frame: 3 months

Secondary Outcomes

Measure
Number of patients with worsening of encephalopathy
time frame: 3 months
Number of patients with impairment of liver function
time frame: 3 months
Number of patients with variceal bleed
time frame: 3 months
Number of patients developing hepatorenal syndrome
time frame: 3 months
Number of patients with hypernatremia
time frame: 3 months

Eligibility Criteria

Male or female participants from 18 years up to 70 years old.

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 .

Additional Information

Official title Role of Midodrine and Tolvaptan in Patients With Cirrhosis With Refractory or Recurrent Ascites
Trial information was received from ClinicalTrials.gov and was last updated in March 2016.
Information provided to ClinicalTrials.gov by Postgraduate Institute of Medical Education and Research.