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

Cirrhosis, Liver Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05287100
• Other study ID #: ILBS-Cirrhosis-49
• Status: Completed
• Phase: N/A
• Start date: January 1, 2022
• Est. completion date: May 30, 2023

Study information

• Verified date: October 2023
• Source: Institute of Liver and Biliary Sciences, India
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: May 30, 2023
• Est. primary completion date: May 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Days to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Cirrhosis, Liver
• Fibrosis
• Liver Cirrhosis

Intervention

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

Locations

Country	Name	City	State
India	Institute of liver and biliary sciences	New Delhi

Sponsors (1)

Lead Sponsor	Collaborator
Institute of Liver and Biliary Sciences, India

Country where clinical trial is conducted

India, 

Outcome

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