Midodrine and Albumin in Patients With Refractory Ascites

Sponsor

Postgraduate Institute of Medical Education and Research (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04621617

Collaborator

(none)

114

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Refractory ascites is seen in 5-10% of patients with cirrhosis.Decompensated cirrhosis with refractory ascites has a mortality rate of around 40% in a year and a median survival of 6 months.Portal hypertension and splanchnic vasodilation are major factors in the development of ascites.The treatment of refractory ascites involves salt restriction, diuretics, large volume paracentesis (LVP), transjugular Intrahepatic Portosystemic shunt (TIPS) and Liver Transplantation (LT). Currently the only curative treatment is LT. However, LT is limited due to organ shortage and high cost.

Long-term human albumin (HA) administration in patients with uncomplicated and refractory ascites, has shown to improve survival or delay the complications of cirrhosis. Midodrine, an oral α1- adrenergic agonist has been used in refractory ascites with variable results. However, there is no study on the use of long term Midodrine and HA in patients with refractory ascites. Therefore, we plan to study the effect of long term midodrine and HA in patients with refractory ascites.

Condition or Disease	Intervention/Treatment	Phase
Refractory Ascites	Drug: Albumin Drug: Midodrine Drug: Standard medical therapy (SMT)	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

114 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Midodrine and Albumin in Patients With Refractory Ascites. A Randomised Controlled Trial.

Anticipated Study Start Date :

Nov 1, 2020

Anticipated Primary Completion Date :

Dec 1, 2021

Anticipated Study Completion Date :

Apr 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Albumin + Midodrine + SMT Human albumin plus oral midodrine	Drug: Albumin Human albumin will be administered by intravenous infusion at a dose of 1.5 gm/kg/week for 2 weeks followed by HA 40 grams every 7days Drug: Midodrine Oral Midodrine will be given at a dose of 7.5 mg three times in a day Drug: Standard medical therapy (SMT) SMT will include nutritional support, rifaximin, lactulose or lactitol, diuretics, SBP prophylaxis with norfloxacin, restriction of sodium, multivitamins, and other supportive measures as deemed necessary. LVP will be done as needed. Patients on non-selective beta blockers will continue to do so with dose modifications/withdrawal as per Baveno VI guidelines.
Active Comparator: Albumin + SMT Human albumin plus placebo of midodrine	Drug: Albumin Human albumin will be administered by intravenous infusion at a dose of 1.5 gm/kg/week for 2 weeks followed by HA 40 grams every 7days Drug: Standard medical therapy (SMT) SMT will include nutritional support, rifaximin, lactulose or lactitol, diuretics, SBP prophylaxis with norfloxacin, restriction of sodium, multivitamins, and other supportive measures as deemed necessary. LVP will be done as needed. Patients on non-selective beta blockers will continue to do so with dose modifications/withdrawal as per Baveno VI guidelines.
Placebo Comparator: SMT standard medical therapy plus placebo of midodrine	Drug: Standard medical therapy (SMT) SMT will include nutritional support, rifaximin, lactulose or lactitol, diuretics, SBP prophylaxis with norfloxacin, restriction of sodium, multivitamins, and other supportive measures as deemed necessary. LVP will be done as needed. Patients on non-selective beta blockers will continue to do so with dose modifications/withdrawal as per Baveno VI guidelines.

Arm

Intervention/Treatment

Active Comparator: Albumin + Midodrine + SMT

Human albumin plus oral midodrine

Drug: Albumin

Human albumin will be administered by intravenous infusion at a dose of 1.5 gm/kg/week for 2 weeks followed by HA 40 grams every 7days

Drug: Midodrine

Oral Midodrine will be given at a dose of 7.5 mg three times in a day

Drug: Standard medical therapy (SMT)

SMT will include nutritional support, rifaximin, lactulose or lactitol, diuretics, SBP prophylaxis with norfloxacin, restriction of sodium, multivitamins, and other supportive measures as deemed necessary. LVP will be done as needed. Patients on non-selective beta blockers will continue to do so with dose modifications/withdrawal as per Baveno VI guidelines.

Active Comparator: Albumin + SMT

Human albumin plus placebo of midodrine

Drug: Albumin

Human albumin will be administered by intravenous infusion at a dose of 1.5 gm/kg/week for 2 weeks followed by HA 40 grams every 7days

Drug: Standard medical therapy (SMT)

Placebo Comparator: SMT

standard medical therapy plus placebo of midodrine

Drug: Standard medical therapy (SMT)

Outcome Measures

Primary Outcome Measures

Number of patients with control of ascites at 1 year [1 year]
Control of ascites will be defined as- Complete response will be total absence of ascites. Partial response as presence of ascites not requiring paracentesis Non response will be defined as persistence of severe ascites requiring paracentesis.

Secondary Outcome Measures

Change in estimated glomerular filtration rate (eGFR) measured by modified diet in renal disease 6 (MDRD6) formula at 3 months intervals [1 year]
eGFR will be measured using MDRD6 formula
Changes in concentration of albumin at 3 months intervals [1 year]
Change in concentration of serum albumin (g/dl)
Change in model for end stage liver disease (MELD) score [1 year]
Change in MELD score. The MELD score incorporates the variables of serum bilirubin, creatinine and Internation Normalised Ratio (INR). Higher MELD score indicates worse prognosis
Change in mean arterial pressure at 3 months interval [1 year]
Change in mean arterial pressure (mm of Hg) will be noted
Changes in serum and 24- hour urine sodium [1 year]
Serum and urine sodium concentration will be measured in meq/L
Incidence of spontaneous bacterial peritonitis (SBP) and other infections [1 year]
The diagnosis of SBP will be based on neutrophil count in ascitic ﬂuid of >250/mm3 as determined by microscopy and positive ascitic fluid culture or >250 /mm3 with negative culture called as culture negative neutrocytic ascites.20 Other infections will be diagnosed as per CDC criteria.
Number of patients who develop paracentesis induced circulatory dysfunction (PICD) [1 year]
PICD will be defined as an increase in plasma renin activity (PRA) of >50% of the pre-treatment value to a level > 4ng/ml/hr on 6th day after paracentesis
Number of patients who develop hyponatremia [1 year]
Hyponatremia will be defined using serum sodium concentrations of <130meq/L.
Change in Child-Turcotte-Pugh (CTP) score [1 year]
Change in CTP score. The CTP score incorporates the variables of serum bilirubin, albumin, prothrombin time-INR, grade of ascites and hepatic encephalopathy. The score ranges from 5-15 and a higher score portends a worse prognosis
Number of patients who develop hypokalemia [1 year]
Hypokalemia will be defined using serum potassium levels <3 meq/L
Number of patients who develop hyperkalemia [1 year]
hyperkalemia will be defined using serum potassium levels >6 meq/L

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age between 18 and 80 years
Refractory ascites in cirrhosis of any etiology

Exclusion Criteria:

Mixed ascites: cirrhosis plus another cause of ascites
Gastrointestinal bleed within 7 days of enrolment.
Presence of hepatorenal syndrome
Hepatic encephalopathy grade 2 or higher
Infection within 1 month preceding the study
Cardiovascular disease (ejection fraction < 35% or abnormal ECG) or arterial hypertension (BP > 140/90 mm of Hg)
Abnormal urine analysis with proteinuria > 500 mg/24 hour or 50 red blood cells/high power field, or granular casts or ultrasonographic evidence of intrinsic renal disease
Presence of hepatocellular carcinoma or portal vein thrombosis
Treatment with drug with known effects on systemic and renal hemodynamics within 7 days of inclusion excepting beta-blockers
Patient not willing for study.
Patient opting for liver transplantation/ transjugular intrahepatic portosystemic shunt

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Postgraduate Institute of Medical Education and Research

Investigators

Principal Investigator: Virendra Singh, MD, DM, PGIMER, Chandigarh

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Dr.Virendra Singh, Professor and Head, Department of Hepatology, Postgraduate Institute of Medical Education and Research

ClinicalTrials.gov Identifier:

NCT04621617

Other Study ID Numbers:

IEC-06/2020-1691

First Posted:

Nov 9, 2020

Last Update Posted:

Nov 9, 2020

Last Verified:

Nov 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Ascites

Midodrine

Study Results

No Results Posted as of Nov 9, 2020