Midodrine and Albumin in Patients With Refractory Ascites

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

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.

Study Overview

• Status: Unknown
• Conditions: Refractory Ascites
• Intervention / Treatment: Drug: Albumin; Drug: Midodrine; Drug: Standard medical therapy (SMT)

• Study Type: Interventional
• Enrollment (Anticipated): 114
• Phase: Phase 3

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Albumin + Midodrine + SMT; Human albumin plus oral midodrine	Drug: Albumin; 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; Drug: Midodrine; Oral Midodrine will be given at a dose of 7.5 mg three times in a day; Drug: Standard medical therapy (SMT); 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.
Active Comparator: Albumin + SMT; Human albumin plus placebo of midodrine	Drug: Albumin; 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; Drug: Standard medical therapy (SMT); 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.
Placebo Comparator: SMT; standard medical therapy plus placebo of midodrine	Drug: Standard medical therapy (SMT); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Principal Investigator: Virendra Singh, MD, DM, PGIMER, Chandigarh

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2020
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): April 1, 2022

Study Registration Dates

• First Submitted: October 27, 2020
• First Submitted That Met QC Criteria: November 3, 2020
• First Posted (Actual): November 9, 2020

Study Record Updates

• Last Update Posted (Actual): November 9, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Ascites; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Vasoconstrictor Agents; Adrenergic alpha-1 Receptor Agonists; Midodrine
• Other Study ID Numbers: IEC-06/2020-1691

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No