Midodrine and Albumin in Patients With Refractory Ascites

Phase 3

• Conditions: Refractory Ascites
• Interventions: Drug: Albumin; Drug: Standard medical therapy (SMT); Drug: Midodrine

• Registration Number: NCT04621617
• Lead Sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh

Brief Summary

Refractory ascites is seen in 5-10% of patients with cirrhosis.Decompensated cirrhosis with refractory ascites has a mortality rate of around 40% in a year and a median survival of 6 months.Portal hypertension and splanchnic vasodilation are major factors in the development of ascites.The treatment of refractory ascites involves salt restriction, diuretics, large volume paracentesis (LVP), transjugular Intrahepatic Portosystemic shunt (TIPS) and Liver Transplantation (LT). Currently the only curative treatment is LT. However, LT is limited due to organ shortage and high cost.

Long-term human albumin (HA) administration in patients with uncomplicated and refractory ascites, has shown to improve survival or delay the complications of cirrhosis. Midodrine, an oral α1- adrenergic agonist has been used in refractory ascites with variable results. However, there is no study on the use of long term Midodrine and HA in patients with refractory ascites. Therefore, we plan to study the effect of long term midodrine and HA in patients with refractory ascites.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-10-27
• Status Verified: 2020-11
• Study Start: 2020-11
• Study First Submitted QC: 2020-11-03
• Last Update Submitted: 2020-11-03
• Study First Posted: 2020-11-09
• Last Update Posted: 2020-11-09
• Primary Completion: 2021-12
• Study Completion: 2022-04

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 114

Inclusion Criteria

1. Age between 18 and 80 years
2. Refractory ascites in cirrhosis of any etiology

Exclusion Criteria

1. Mixed ascites: cirrhosis plus another cause of ascites
2. Gastrointestinal bleed within 7 days of enrolment.
3. Presence of hepatorenal syndrome
4. Hepatic encephalopathy grade 2 or higher
5. Infection within 1 month preceding the study
6. Cardiovascular disease (ejection fraction < 35% or abnormal ECG) or arterial hypertension (BP > 140/90 mm of Hg)
7. Abnormal urine analysis with proteinuria > 500 mg/24 hour or 50 red blood cells/high power field, or granular casts or ultrasonographic evidence of intrinsic renal disease
8. Presence of hepatocellular carcinoma or portal vein thrombosis
9. Treatment with drug with known effects on systemic and renal hemodynamics within 7 days of inclusion excepting beta-blockers
10. Patient not willing for study.
11. Patient opting for liver transplantation/ transjugular intrahepatic portosystemic shunt

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Albumin + SMT	Standard medical therapy (SMT)	Human albumin plus placebo of midodrine
Albumin + Midodrine + SMT	Midodrine	Human albumin plus oral midodrine
Albumin + Midodrine + SMT	Standard medical therapy (SMT)	Human albumin plus oral midodrine
Albumin + SMT	Albumin	Human albumin plus placebo of midodrine
Albumin + Midodrine + SMT	Albumin	Human albumin plus oral midodrine
SMT	Standard medical therapy (SMT)	standard medical therapy plus placebo of midodrine

Primary Outcome Measures

Name	Time	Method
Number of patients with control of ascites at 1 year	1 year	Control of ascites will be defined as-; * Complete response will be total absence of ascites.; * Partial response as presence of ascites not requiring paracentesis; * Non response will be defined as persistence of severe ascites requiring paracentesis.

Secondary Outcome Measures

Name	Time	Method
Change in mean arterial pressure at 3 months interval	1 year	Change in mean arterial pressure (mm of Hg) will be noted
Number of patients who develop hyponatremia	1 year	Hyponatremia will be defined using serum sodium concentrations of \<130meq/L.
Changes in concentration of albumin at 3 months intervals	1 year	Change in concentration of serum albumin (g/dl)
Change in Child-Turcotte-Pugh (CTP) score	1 year	Change in CTP score. The CTP score incorporates the variables of serum bilirubin, albumin, prothrombin time-INR, grade of ascites and hepatic encephalopathy. The score ranges from 5-15 and a higher score portends a worse prognosis
Change in estimated glomerular filtration rate (eGFR) measured by modified diet in renal disease 6 (MDRD6) formula at 3 months intervals	1 year	eGFR will be measured using MDRD6 formula
Change in model for end stage liver disease (MELD) score	1 year	Change in MELD score. The MELD score incorporates the variables of serum bilirubin, creatinine and Internation Normalised Ratio (INR). Higher MELD score indicates worse prognosis
Changes in serum and 24- hour urine sodium	1 year	Serum and urine sodium concentration will be measured in meq/L
Incidence of spontaneous bacterial peritonitis (SBP) and other infections	1 year	The diagnosis of SBP will be based on neutrophil count in ascitic fluid of \>250/mm3 as determined by microscopy and positive ascitic fluid culture or \>250 /mm3 with negative culture called as culture negative neutrocytic ascites.20 Other infections will be diagnosed as per CDC criteria.
Number of patients who develop hypokalemia	1 year	Hypokalemia will be defined using serum potassium levels \<3 meq/L
Number of patients who develop hyperkalemia	1 year	hyperkalemia will be defined using serum potassium levels \>6 meq/L
Number of patients who develop paracentesis induced circulatory dysfunction (PICD)	1 year	PICD will be defined as an increase in plasma renin activity (PRA) of \>50% of the pre-treatment value to a level \> 4ng/ml/hr on 6th day after paracentesis