Evaluation of Albumin and Midodrine Versus Albumin Alone in Outcome of Refractory Ascites in Patients With Decompensated Cirrhosis.

Study Overview
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Brief Summary
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The project is about evaluation of albumin and midodrine versus albumin alone in outcome of refractory ascites in patients with decompensated cirrhosis. Cirrhosis is a leading cause of disability and mortality worldwide. Cirrhosis occurs in 50% of patients over 10 years. Decompensated cirrhosis carries a poor prognosis because the median survival time is about 2 years and it imposes a heavy burden on health care costs mainly due to the need for repeated hospital admission. The mortality is approximately 40% at 1 year and 50% at 2 years (12.7 per 100,000 population). A lot of times the prognosis is poor and the main factors leading to it are - AKI/HRS-NAKI, Hyponatremia, Grade of ascites-Refractory ascites, Sarcopenia, low Mean arterial pressure. Post review of the literature, it is realized that there are some gap areas - It is unknown whether combination of vasoconstrictor with albumin further decreases the need for paracentesis in patients of refractory ascites. There are no studies till date on using combination of vasoconstrictor with albumin for refractory ascites. There are no studies evaluating the prevalence and incidence of HRS-NAKI using the new definitions in patients with refractory ascites and impact of combining vasoconstrictor and albumin in improving renal outcomes in these patients.

Detailed Description
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Study population All patients with decompensated cirrhosis with refractory ascites who get admitted under the Department of Hepatology at Institute of Liver and Biliary Sciences, who fulfilthe inclusion criteria, exclusion criteria and provide informed consent Study design Single Centre Placebo Controlled an open level Randomised Controlled Trial Study period 1 year from ethics approval. Sample size Assuming that survival rate with albumin and midodrine is 80%, whereas with albumin alone is 60% ( ie. 20% absolute difference is observed with alpha of 5% power so we need to enroll 170 cases allotted in 2 groups further taking 10% as dropout rate. It was decided to enroll 200 cases allotted in 2 groups randomly by block randomization method taking block size as 10 Intervention Group A will be treated with SMT + Albumin + Midodrine (5mg thrice daily and will be increased every 3 days upto 15 mg thrice daily with target MAP (>75 mm and <90) and Group B with SMT + Albumin: 80grams/week for 2 weeks followed by 40gram/week + Placebo Stopping ruleAdverse reaction to Albumin Cardiopulmonary compromise Allergic reaction

Official Title
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Evaluation of Albumin and Midodrine Versus Albumin Alone in Outcome of Refractory Ascites in Patients With Decompensated Cirrhosis - A Double Blind Randomized Controlled Trial.

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Drug: Midodrine
* Biological: Albumin
* Other: Standard Medical Treatment
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Cirrhosis with refractory ascites Exclusion Criteria: - Recent Gastrointestinal bleeding within 7 days Systemic arterial hypertension (>160/90mmhg) Presence of hepatocellular carcinoma or portal vein thrombosis, Budd-chiari syndrome. Pregnancy No use of drugs affecting systemic hemodynamics 7 days prior to enrolment Patients with Cardiovascular disease (NYHA > II) or chronic obstructive pulmonary disease Refusal to participate Known or suspected hypersensitivity to albumin Prior TIPS Post liver or kidney transplantation Patients enrolled in other clinical trials Extrahepatic malignancy Patients on cardiac glycosides like digoxin, phenylephrine, ephedrine, thyroid hormones, ergot derivatives, salt retaining steroids like fludrocortisone, MAO inhibitors, alpha blockers metformin and ranitidine (known to have interactions with midodrine) Patients with intrinsic kidney disease, organ nephropathy and CKD stage 4 and MELD > 30 and extremely moribend patient

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midodrine + Albumin +Standard Medical Treatment<br>SMT + Albumin + Midodrine (5mg thrice daily and will be increased every 3 days upto 15 mg thrice daily with target MAP (>75 mm and <90). | Drug: Midodrine<br>* 5mg thrice daily and will be increased every 3 days upto 15 mg thrice daily with target MAP (>75 mm and <90)<br>Biological: Albumin<br>* 80grams/week for 2 weeks followed by 40gram/week<br>Other: Standard Medical Treatment<br>* Standard Medical Treatment<br>|
| Active Comparator: Albumin + Standard Medical Treatment+ Placebo<br>80grams/week for 2 weeks followed by 40gram/week + Placebo | Biological: Albumin<br>* 80grams/week for 2 weeks followed by 40gram/week<br>Other: Standard Medical Treatment<br>* Standard Medical Treatment<br>Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival free of transplant and TIPS |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of liver-related complications |  | 3 months | 
| Cumulative incidence of liver-related complications |  | 6 months | 
| Cumulative incidence of liver-related complications |  | 12 months | 
| Survival free of liver transplant in both groups |  | 1 year | 
| Survival free of TIPS in both groups |  | 1 year | 
| Incidence of HRS-AKD, in both groups at 1 year |  | 1 year | 
| Incidence of HRS-CKD in both groups at 1 year |  | 1 year | 
| Incidence of HRS AKI in both groups at 1 year |  | 1 year | 
| Cumulative frequency of large volume paracentesis |  | 3 months | 
| Cumulative frequency of large volume paracentesis |  | 6 months | 
| Cumulative frequency of large volume paracentesis |  | 12 months | 
| Improvement in fraility | AS PER MAYO FRAITITY INDEX , FRAITILY IS CLASSIFIED AS PRE FRAIL, FRAIL AND ROBUST. | 3 months | 
| Improvement in fraility | AS PER MAYO FRAITITY INDEX , FRAITILY IS CLASSIFIED AS PRE FRAIL, FRAIL AND ROBUST. | 6 months | 
| Improvement in fraility | AS PER MAYO FRAITITY INDEX , FRAITILY IS CLASSIFIED AS PRE FRAIL, FRAIL AND ROBUST. | 12 months | 
| Survival free of TIPS |  | 6 months | 
| Survival free of transplant at 6 months |  | 6 months |