Efficacy and Safety of Midodrine in Refractory or Recurrent Ascites in Children With Cirrhosis.

NCT05084534 | Withdrawn DMC

• 1 other identifier: ILBS-Cirrhosis-47
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Refractory ascites is seen in 17% of cirrhotic patients with the 1year mortality rate being high, upto 20-50% \[1\]. The pathogenesis of cirrhotic ascites 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 causing sodium and water retention. The standard medical therapy for the treatment of ascites includes sodium restriction to 2mEq/kg/day with diuretics (Spirinolactone 3-6mg/kg/day and furosemide 0.5-2 mg/kg/day) and therapeutic paracentesis (\>50ml/kg/day) with albumin replacement at 8g/L of ascitic fluid tapped. Refractory ascites is defined as ascites that cannot be mobilized by sodium - restricted diet (maximum upto 2mEq/kg/day- 88meq=2gm of salt) and high-dose diuretic treatment (6 mg/kg/day of spironolactone and 2 mg/kg/day of furosemide) or optimum doses of diuretics cannot be given due to development of diuretic-induced complications (Sodium \<130mEq, AKI as per KDIGO, hypovolemia, hypo (\<3.5meq)/hyperkalemia (\>5meq); new onset HE) and recurrent ascites as ascites that has recurred within a 12 weeks period despite standard treatment. All the children and adolescents upto 18 years of age with refractory or recurrent ascites will be included in the study and randomized into 2 groups. One group will receive only standard medical therapy and other group will receive midodrine and standard medical therapy for 12 weeks. Mean arterial pressure will be monitored at every OPD visit. At the end of 12 weeks, plasma renin activity, number of therapeutic paracentesis done, change in serum sodium, estimated glomerular filtration rate and complications will be assessed. If there is complete resolution of ascites, liver transplantation or death before 12 weeks, midodrine will be stopped.

Conditions

Refractory Ascites in Children With Cirrhosis

Outcome Measures

Primary Outcomes (1)

• • To compare the proportion of patients who will achieve partial or complete control of ascites at 12 weeks after therapy between the two groups

  12 weeks

Secondary Outcomes (13)

• • Comparison of total number of therapeutic paracentesis (>50ml/kg) procedures between the groups by the end of 12 weeks

  12 weeks

• • Frequency of complete response (elimination of ascites) by 12 weeks

  12 weeks

• • Time taken to achieve complete response

  12 weeks

• • Frequency of partial response (persistent ascites not requiring therapeutic paracentesis) by 12 weeks

  12 weeks

• • To compare change in plasma renin activity from baseline to 12 weeks

  12 weeks

Study Arms (2)

Midodrine hydrochloride plus standard medical treatment

EXPERIMENTAL

* Standard Medical Treatment will be continued in all, which includes, * To continue restriction of sodium to \< 2meq/kg/day * To continue maximum tolerable dose of diuretics * Repeat LVP with infusion of albumin (8 g/L) performed for tense, symptomatic ascites * Albumin infusion for serum albumin \<2.5g/dl - dose 1g/kg/day (maximum 20g/day) * Midodrine starting at 0.25mg/kg/day in divided doses, increased to 0.5mg/kg/day after 7 days if MAP does not increase by \>10% (maximum dose - 15mg/day) * Midodrine dosage will be decreased by 25% in case of arterial hypertension (\>95th centile BP for the age)

Drug: Midodrine; Other: Standard medical treatment

Standard medical treatment

OTHER

* Standard Medical Treatment will be continued in all, which includes, * To continue restriction of sodium to \< 2meq/kg/day * To continue maximum tolerable dose of diuretics * Repeat LVP with infusion of albumin (8 g/L) performed for tense, symptomatic ascites * Albumin infusion for serum albumin \<2.5g/dl - dose 1g/kg/day (maximum 20g/day)

Other: Standard medical treatment

Interventions

Midodrine DRUG

Midodrine starting at 0.25mg/kg/day in divided doses, increased to 0.5mg/kg/day after 7 days if MAP does not increase by \>10% (maximum dose - 15mg/day) • Midodrine dosage will be decreased by 25% in case of arterial hypertension (\>95th centile BP for the age)

Midodrine hydrochloride plus standard medical treatment

Standard medical treatment OTHER

Standard Medical Treatment will be continued in all, which includes, * To continue restriction of sodium to \< 2meq/kg/day * To continue maximum tolerable dose of diuretics * Repeat LVP with infusion of albumin (8 g/L) performed for tense, symptomatic ascites * Albumin infusion for serum albumin \<2.5g/dl - dose 1g/kg/day (maximum 20g/day)

Midodrine hydrochloride plus standard medical treatment; Standard medical treatment

Eligibility Criteria

• Age: 6 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Children and Adolescents of age group upto 18 years with cirrhosis and refractory Ascites that cannot be mobilized by sodium - restricted diet (maximum upto 2mEq/kg/day- 88meq=2gm of salt) and high-dose diuretic treatment (6 mg/kg/day of spironolactone and 2 mg/kg/day of furosemide) or optimum doses of diuretics cannot be given due to development of diuretic-induced complications (Sodium \<130mEq, AKI as per KDIGO, hypovolemia, hypokalemia (\<3.5meq)/hyperkalemia (\>5meq); new onset HE) or ascites that recurs within 4 weeks of mobilization) or recurrent ascites ( Ascites that has recurred 3 times within 12 months despite standard medical treatment) with stable renal function (age appropriate creatinine level in last 2 weeks) attending the Pediatric Hepatology Department, ILBS will be prospectively included in this study after informed consent.

You may not qualify if:

• GIT bleeding in last 1 month
• SBP in last 1 month
• HE grade 3 or higher
• Septic shock
• Hepatorenal syndrome
• Presence of PVT
• Renal or cardiovascular disease or arterial hypertension
• Presence of HCC

Sponsors & Collaborators

• Institute of Liver and Biliary Sciences, India: lead

Study Sites (1)

ILBS

New Delhi, 110070, India

Location

MeSH Terms

Interventions

Midodrine

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 18, 2021
• First Posted: October 19, 2021
• Study Start: November 1, 2021
• Primary Completion: February 1, 2023
• Study Completion: March 1, 2023
• Last Updated: May 7, 2024

Record last verified: 2021-10

Locations

IN (1)