Midodrine and Albumin in Patients With Refractory Ascites

Study Overview
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Brief Summary
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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.

Official Title
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Midodrine and Albumin in Patients With Refractory Ascites. A Randomised Controlled Trial.

Conditions
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Refractory Ascites

Intervention / Treatment
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* Drug: Albumin
* Drug: Midodrine
* Drug: Standard medical therapy (SMT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 80 years Refractory ascites in cirrhosis of any etiology Exclusion Criteria: Mixed ascites: cirrhosis plus another cause of ascites Gastrointestinal bleed within 7 days of enrolment. Presence of hepatorenal syndrome Hepatic encephalopathy grade 2 or higher Infection within 1 month preceding the study Cardiovascular disease (ejection fraction < 35% or abnormal ECG) or arterial hypertension (BP > 140/90 mm of Hg) 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 Presence of hepatocellular carcinoma or portal vein thrombosis Treatment with drug with known effects on systemic and renal hemodynamics within 7 days of inclusion excepting beta-blockers Patient not willing for study. Patient opting for liver transplantation/ transjugular intrahepatic portosystemic shunt

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Albumin + Midodrine + SMT<br>Human albumin plus oral midodrine | Drug: Albumin<br>* Human albumin will be administered by intravenous infusion at a dose of 1.5 gm/kg/week for 2 weeks followed by HA 40 grams every 7days<br>Drug: Midodrine<br>* Oral Midodrine will be given at a dose of 7.5 mg three times in a day<br>Drug: Standard medical therapy (SMT)<br>* SMT will include nutritional support, rifaximin, lactulose or lactitol, diuretics, SBP prophylaxis with norfloxacin, restriction of sodium, multivitamins, and other supportive measures as deemed necessary. LVP will be done as needed. Patients on non-selective beta blockers will continue to do so with dose modifications/withdrawal as per Baveno VI guidelines.<br>|
| Active Comparator: Albumin + SMT<br>Human albumin plus placebo of midodrine | Drug: Albumin<br>* Human albumin will be administered by intravenous infusion at a dose of 1.5 gm/kg/week for 2 weeks followed by HA 40 grams every 7days<br>Drug: Standard medical therapy (SMT)<br>* SMT will include nutritional support, rifaximin, lactulose or lactitol, diuretics, SBP prophylaxis with norfloxacin, restriction of sodium, multivitamins, and other supportive measures as deemed necessary. LVP will be done as needed. Patients on non-selective beta blockers will continue to do so with dose modifications/withdrawal as per Baveno VI guidelines.<br>|
| Placebo Comparator: SMT<br>standard medical therapy plus placebo of midodrine | Drug: Standard medical therapy (SMT)<br>* SMT will include nutritional support, rifaximin, lactulose or lactitol, diuretics, SBP prophylaxis with norfloxacin, restriction of sodium, multivitamins, and other supportive measures as deemed necessary. LVP will be done as needed. Patients on non-selective beta blockers will continue to do so with dose modifications/withdrawal as per Baveno VI guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with control of ascites at 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in estimated glomerular filtration rate (eGFR) measured by modified diet in renal disease 6 (MDRD6) formula at 3 months intervals | eGFR will be measured using MDRD6 formula | 1 year | 
| Changes in concentration of albumin at 3 months intervals | Change in concentration of serum albumin (g/dl) | 1 year | 
| Change in model for end stage liver disease (MELD) score | 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 | 1 year | 
| Change in mean arterial pressure at 3 months interval | Change in mean arterial pressure (mm of Hg) will be noted | 1 year | 
| Changes in serum and 24- hour urine sodium | Serum and urine sodium concentration will be measured in meq/L | 1 year | 
| Incidence of spontaneous bacterial peritonitis (SBP) and other infections | 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. | 1 year | 
| Number of patients who develop paracentesis induced circulatory dysfunction (PICD) | 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 | 1 year | 
| Number of patients who develop hyponatremia | Hyponatremia will be defined using serum sodium concentrations of <130meq/L. | 1 year | 
| Change in Child-Turcotte-Pugh (CTP) score | 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 | 1 year | 
| Number of patients who develop hypokalemia | Hypokalemia will be defined using serum potassium levels <3 meq/L | 1 year | 
| Number of patients who develop hyperkalemia | hyperkalemia will be defined using serum potassium levels >6 meq/L | 1 year |