To Assess the Efficacy of Midodrine in Prevention of Cirrhosis Related Complications in Children Awaiting Liver Transplantation.

To Assess the Efficacy of Midodrine in Prevention of Cirrhosis Related Complications in Children Awaiting Liver Transplantation

Children with cirrhosis awaiting transplantation are more proned to develop various complications. The pathogenesis of cirrhotic complications (ascites, hyponatremia, acute kidney injury) includes release of vasodilatory molecules like nitric oxide, damage associated molecular pathogens (DAMPs) and pattern associated molecular pathogens (PAMPs) secondary to bacterial translocation, which causes splanchnic bed vasodilation resulting in activation of renin-angiotensin and aldosterone axis(RAAS) causing sodium and water retention and renal vasoconstriction [1].

The development of complications in these children may result in death or may preclude them from reaching upto liver transplantation [2].

Midodrine is an α1 adrenergic receptor agonist, which increases vascular tone causing rise in the blood pressure, thereby improving renal perfusion and causes RAAS deactivation. The effects of midodrine is documented in reduction of refractory ascites, hepatorenal syndrome and hyponatremia[2-4].

One group will receive only standard medical therapy and other group will receive midodrine and standard medical therapy for 6 months. Mean arterial pressure will be monitored at every OPD visit. At the end of 12 weeks, and 24 weeks, plasma renin activity, incidence of complications related to cirrhosis like new onset ascites, increase in grade of ascites, hyponatremia, acute kidney injury and spontaneous bacterial peritonitis will be assessed. Also the transplant free survival and need for albumin transfusion will be compared between the two groups.

In case of liver transplantation or death before 6 months, midodrine will be stopped

Study Overview

• Status: Completed
• Conditions: Cirrhosis, Liver
• Intervention / Treatment: Drug: Midodrine Oral Tablet; Other: Standard Medical Treatment

Detailed Description

Aim: To determine the efficacy of midodrine in preventing development of complications in children with cirrhosis awaiting liver transplantation

Primary Objective:

1) To compare incidence of complications (Acute kidney injury, New onset ascites or increase in grade of ascites, Spontaneous bacterial peritonitis, Hyponatremia, Hepatic encephalopathy) of cirrhosis in patients receiving midodrine (at a dose of 0.25 - 0.5mg/kg/day) and standard medical therapy versus standard medical therapy alone for 6 months

Secondary Objectives:

• Frequency of development of new onset ascites or increase in grade of ascites by 6 months
• Change in serum sodium from baseline to 6 months
• Change in Mean arterial pressure (MAP) at 1 week and then 2 weekly till the end of the study
• Plasma renin activity at baseline, at 12 weeks and 24 weeks
• Frequency of development of SBP over 6 months
• Change in eGFR from baseline to 6 months
• Frequency of developing AKI by 6 months
• Frequency of development of Hepatic encephalopathy by 6 months
• Proportion of patients developing hypertension at 6 months
• Frequency of development of drug related adverse effects by 6 months
• Requirement of albumin infusion in 2 groups
• Transplant free survival

Methodology:

• Study population :Children and Adolescents of age group upto 18 years with cirrhosis and PELD/ MELDNa score more than 14, on waitlist for liver transplantation following up in the Pediatric Hepatology Department
• Study design: Open label RCT (computer based randomization - block randomization with block size of 4)
• Study period: 6 months weeks for each patient; The study will be conducted between January 2022 and July 2023
• Sample size:
• Pilot study - 10 patients in each group

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • New Delhi, India, 110070
    • Institute of Liver and Biliary Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 week to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Children and Adolescents of age group upto 18 years with cirrhosis and PELD/ MELDNa score more than 14, on waitlist for liver transplantation following up in the Pediatric Hepatology Department, ILBS will be prospectively included in this study after informed consent

Exclusion Criteria:

Presence of Portal vein thrombosis Renal or cardiovascular disease or arterial hypertension Presence of HCC

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; Midodrine starting at 0.25mg/kg/day in 2-3 divided doses, increased to 0.5mg/kg/day after 7 days if MAP does not increase by >10% ; Midodrine dosage will be decreased by 25% in case of arterial hypertension (>95th centile BP for the age). Also Standard medical therapy as per departmental protocol will be continued	Drug: Midodrine Oral Tablet; Midodrine starting at 0.25mg/kg/day in 2-3 divided doses, increased to 0.5mg/kg/day after 7 days if MAP does not increase by >10% ; Midodrine dosage will be decreased by 25% in case of arterial hypertension (>95th centile BP for the age). Also Standard medical therapy as per departmental protocol will be continued; Other: Standard Medical Treatment; Albumin infusion 1g/kg/day - maximum 20gm/day and repeat till serum albumin reaches 2.8g/dl If serum albumin is < 2.8g/dl SBP - Day 1 and Day 3 For Ascites : Restriction of sodium to < 2meq/kg/day A combination of a distal-acting diuretic (spironolactone, 3-6 mg/ kg/day) and loop-acting diuretic (furosemide,0.5- 2 mg/kg per day) was given with dose escalation by one step at a time if there is no decrease in weight (by ≥ 0.5 %/day) after 5-7 days Therapeutic paracentesis (>50ml/kg) with infusion of albumin (8 g/L) performed for tense, symptomatic ascites For Spontaneous Bacterial Peritonitis : IV antibiotics for 7 days Albumin Infusion on Day 1 and Day 3
Active Comparator: Standard medical therapy; Standard medical therapy as per departmental protocol	Other: Standard Medical Treatment; Albumin infusion 1g/kg/day - maximum 20gm/day and repeat till serum albumin reaches 2.8g/dl If serum albumin is < 2.8g/dl SBP - Day 1 and Day 3 For Ascites : Restriction of sodium to < 2meq/kg/day A combination of a distal-acting diuretic (spironolactone, 3-6 mg/ kg/day) and loop-acting diuretic (furosemide,0.5- 2 mg/kg per day) was given with dose escalation by one step at a time if there is no decrease in weight (by ≥ 0.5 %/day) after 5-7 days Therapeutic paracentesis (>50ml/kg) with infusion of albumin (8 g/L) performed for tense, symptomatic ascites For Spontaneous Bacterial Peritonitis : IV antibiotics for 7 days Albumin Infusion on Day 1 and Day 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complications between the two groups	• To compare incidence of complications (Acute kidney injury, New onset ascites or increase in grade of ascites, Spontaneous bacterial peritonitis, Hyponatremia, Hepatic encephalopathy) of cirrhosis in patients receiving midodrine (at a dose of 0.25 - 0.5mg/kg/day) and standard medical therapy versus standard medical therapy alone for 6 months	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Transplant free survival	6 months
• Frequency of development of new onset ascites or increase in grade of ascites by 6 months	6 months
Change in serum sodium from baseline to 6 months	6 months
Change in Mean arterial pressure (MAP) at 1 week and then 2 weekly till the end of the study	6 months
Plasma renin activity at baseline, at 12 weeks and 24 weeks	6 months
Frequency of development of SBP over 6 months	6 months
Change in eGFR from baseline to 6 months	6 months
Frequency of developing AKI by 6 months	6 months
Frequency of development of Hepatic encephalopathy by 6 months	6 months
Proportion of patients developing hypertension at 6 months	6 months
Frequency of development of drug related adverse effects by 6 months	6 months
Requirement of albumin infusion in 2 groups	6 months

Collaborators and Investigators

• Sponsor: Institute of Liver and Biliary Sciences, India
• Investigators: Study Director: Prof. Seema Alam, MD, ILBS

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Actual): May 30, 2023
• Study Completion (Actual): May 30, 2023

Study Registration Dates

• First Submitted: March 11, 2022
• First Submitted That Met QC Criteria: March 11, 2022
• First Posted (Actual): March 18, 2022

Study Record Updates

• Last Update Posted (Estimated): October 9, 2023
• Last Update Submitted That Met QC Criteria: October 6, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis; 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: ILBS-Cirrhosis-49

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