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

Study Overview
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Brief Summary
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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

Detailed Description
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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

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

Conditions
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Cirrhosis, Liver

Intervention / Treatment
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* Drug: Midodrine Oral Tablet
* Other: Standard Medical Treatment


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 10 Days
Maximum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midodrine<br>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<br>* 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<br>Other: Standard Medical Treatment<br>* 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<br>|
| Active Comparator: Standard medical therapy<br>Standard medical therapy as per departmental protocol | Other: Standard Medical Treatment<br>* 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<br>|

What is the study measuring?
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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 | Measure Description | Time Frame |
| --- | --- | --- |
| • 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 | 
| Transplant free survival |  | 6 months |