Efficacy and Safety of Early Initiation of Midodrine for Control and Prevention of Ascites and Its Related Complications in Acute-on-chronic Liver Failure.

Efficacy and Safety of Early Initiation of Midodrine for Control and Prevention of Ascites and Its Related Complications in Acute-on-chronic Liver Failure: A Randomized Controlled Trial.

Ascites is a cardinal and debilitating complication in patients with acute-on-chronic liver failure (ACLF), significantly correlating with disease severity and poor prognosis. The underlying pathophysiology is driven by severe splanchnic arterial vasodilation, which reduces effective arterial blood volume and triggers compensatory neurohumoral activation. This cascade leads to profound sodium retention, renal vasoconstriction, and circulatory instability. Consequently, patients with ACLF frequently experience diuretic intolerance and are at elevated risk for severe complications, including electrolyte disturbances, acute kidney injury (AKI), and hepatorenal syndrome (HRS).

Current management strategies rely heavily on diuretics and albumin; however, the efficacy of diuretics is often limited by systemic hypotension and pre-existing renal impairment, leading to frequent treatment failure or diuretic-induced complications. Existing clinical guidelines lack definitive recommendations regarding the preemptive use of vasoconstrictors to stabilize hemodynamics before ascites becomes refractory. Midodrine, an oral alpha-1 adrenergic agonist, targets this circulatory dysfunction by increasing systemic vascular resistance and improving renal perfusion. This randomized controlled trial aims to evaluate the efficacy and safety of the early initiation of midodrine in achieving better control of ascites and preventing the progression to renal complications in patients with acute-on-chronic liver failure.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute on Chronic Liver Failure
• Intervention / Treatment: Drug: Midodrine; Other: Standard Medical Treatment

• Study Type: Interventional
• Enrollment (Estimated): 113
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dr Chunnee Zangmu Bhutia, MD; Phone Number: 01146300000; Email: czb.cr7@gmail.com
• Study Contact Backup: Name: Dr Ankur S Jindal, DM; Phone Number: 01146300000; Email: ankur.jindal3@gmail.com

Study Locations

• India
  • National Capital Territory of Delhi
    • New Delhi, National Capital Territory of Delhi, India, 110070
      • Institute of Liver and Biliary Sciences
      • Contact: Dr Chunnee Zangmu Bhutia; Phone Number: 01146300000; Email: czb.cr7@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years.
2. ACLF
3. Ascites (Grade II/III).
4. Willing/able for salt restriction, labs, urine collections, and follow-ups; consent obtained.

Exclusion Criteria:

1. SCr ≥ 1.5 mg/dL OR ongoing AKI >stage I
2. Persistent or uncorrectable severe hyponatremia (Na ≤120 mEq/L), hyperkalemia (>6.0 mEq/L) or any other critical electrolyte imbalance.
3. Refractory ascites
4. Spontaneous bacterial peritonitis
5. Hepatic encephalopathy grade II-III.
6. Shock, need for IV vasopressors, SBP <90 mmHg or MAP <65 despite fluids/albumin.
7. Active GI bleed, uncontrolled infection/sepsis, or SBP at screening.
8. Severe cardiomyopathy, critical valvular disease, arrhythmias contraindicating α-agonists.
9. ACLF patients on Mechanical ventilation/ICU/ionotropes/High flow oxygen
10. Pregnancy, lactation.
11. Hypersensitivity/intolerance to midodrine.
12. Significant LUTS.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Midodrine+SMT; Sodium restriction to ≤5 g/day.; Combination of spironolactone 50 mg + furosemide 20 mg daily as a fixed dose.a) Stepwise titration every 3 days if tolerated, with careful monitoring for AKI, hyponatremia, encephalopathy. Dose reduction or discontinuation if diuretic-related complications develop.; Other supportive measures: as per the clinicianLactulose ± rifaximin for hepatic encephalopathy prophylaxis/management.IV albumin during LVPAntibiotic prophylaxis/treatment as indicated for SBP or systemic infections.Correction of electrolytes and renal support as needed.Management of precipitating factors (alcohol, infection, flare of hepatitis, GI bleed, etc.).; Midodrine: Start with 5 mg TDS. Increase 2.5 mg every day with target MAP increase of 10 mmHg, maximum upto 15 mg TDS.	Drug: Midodrine; Start with 5 mg TDS. Increase 2.5 mg every day with target MAP increase of 10 mmHg, maximum upto 15 mg TDS.; Other: Standard Medical Treatment; Sodium restriction to ≤5 g/day.; Combination of spironolactone 50 mg + furosemide 20 mg daily as a fixed dose.a) Stepwise titration every 3 days if tolerated, with careful monitoring for AKI, hyponatremia, encephalopathy. Dose reduction or discontinuation if diuretic-related complications develop.; Other supportive measures: as per the clinicianLactulose ± rifaximin for hepatic encephalopathy prophylaxis/management.IV albumin during LVPAntibiotic prophylaxis/treatment as indicated for SBP or systemic infections.Correction of electrolytes and renal support as needed.Management of precipitating factors (alcohol, infection, flare of hepatitis, GI bleed, etc.).
Active Comparator: Placebo+SMT; Sodium restriction to ≤5 g/day.; Combination of spironolactone 50 mg + furosemide 20 mg daily as a fixed dose.a) Stepwise titration every 3 days if tolerated, with careful monitoring for AKI, hyponatremia, encephalopathy. Dose reduction or discontinuation if diuretic-related complications develop.; Other supportive measures: as per the clinicianLactulose ± rifaximin for hepatic encephalopathy prophylaxis/management.IV albumin during LVPAntibiotic prophylaxis/treatment as indicated for SBP or systemic infections.Correction of electrolytes and renal support as needed.Management of precipitating factors (alcohol, infection, flare of hepatitis, GI bleed, etc.).; Placebo	Other: Standard Medical Treatment; Sodium restriction to ≤5 g/day.; Combination of spironolactone 50 mg + furosemide 20 mg daily as a fixed dose.a) Stepwise titration every 3 days if tolerated, with careful monitoring for AKI, hyponatremia, encephalopathy. Dose reduction or discontinuation if diuretic-related complications develop.; Other supportive measures: as per the clinicianLactulose ± rifaximin for hepatic encephalopathy prophylaxis/management.IV albumin during LVPAntibiotic prophylaxis/treatment as indicated for SBP or systemic infections.Correction of electrolytes and renal support as needed.Management of precipitating factors (alcohol, infection, flare of hepatitis, GI bleed, etc.).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients with no ascites between the two groups at day 28.	Day 28

Secondary Outcome Measures

Outcome Measure	Time Frame
Mortality	day 28
Percentage of patients with no ascites	Day 7 & 14
Partial ascites response	7,14,28 days
Absent response or worsening of ascites	28 day
Large Volume Paracentesis requirement in two groups	day 7 and 28
Cumulative dose of diuretics/Albumin/midodrine/carvedilol	day 28
Change in Intra Abdominal pressure measured by manometer between both groups	Day 7
Change in MAP between both groups.	7 days, then day 14 and 28
Change in Weight change between both groups.	7 days, then day 14 and 28
Change in urine output daily between both groups	7 days, then day 14 and 28
Change in HR between both groups	7 days, then day 14 and 28
Change in urine Na	day 3, 7 and 28 from baseline
Change in MELD score between both groups.	day 4, 7 and 28
Change in AARC score between both groups.	day 4, 7 and 28
Reduction in Hepatic Venous Pressure Gradient between both groups.	14 and 28 days.
New onset AKI between both groups.	day 28
New onset SBP between both groups	day 28
New onset AKI, SBP, HE, Hyponatremia, shock and need for MV	day 28
New onset HE between both groups	day 28
New onset Hyponatremia between both groups.	day 28
New onset shock between both groups.	day 28
New onset need for MV between both groups	day 28
Treatment related adverse effects	day 28

Collaborators and Investigators

• Sponsor: Institute of Liver and Biliary Sciences, India

Study record dates

Study Major Dates

• Study Start (Estimated): February 5, 2026
• Primary Completion (Estimated): August 30, 2027
• Study Completion (Estimated): August 30, 2027

Study Registration Dates

• First Submitted: January 29, 2026
• First Submitted That Met QC Criteria: February 13, 2026
• First Posted (Actual): February 20, 2026

Study Record Updates

• Last Update Posted (Actual): February 20, 2026
• Last Update Submitted That Met QC Criteria: February 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Liver Failure, Acute; Acute-On-Chronic Liver Failure; Organic Chemicals; Amines; Alcohols; Amino Alcohols; Ethanolamines; Midodrine
• Other Study ID Numbers: ILBS-ACLF-26

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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