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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05014594
Other study ID # Dapa recurrent ascites
Secondary ID
Status Recruiting
Phase Phase 2
First received
Last updated
Start date September 3, 2021
Est. completion date May 19, 2022

Study information

Verified date September 2021
Source Postgraduate Institute of Medical Education and Research
Contact Virendra Singh, MD,DM,FASGE
Phone 0172-275-6338
Email virendrasingh100@hotmail.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The development of ascites is a landmark event in the natural history of cirrhosis and signifies a grim prognosis. Portal hypertension and splanchnic arterial vasodilatation are the major contributors in the development of ascites. Vasodilatation with the consequential decrease in effective circulating volume leads to the activation of sympathetic nervous system and renin angiotensin aldosterone system (RAAS), leading to antinatriuretic effects and retention of sodium and water. This results in the formation of ascites. Management of ascites primarily consists of salt restrictrion and diuretics. Liver transplant is the ultimate panacea. Dapaglifozin, a Sodium glucose linked transporter-2(SGLT-2) inhibitor, is a part of the routine armamentarium for treatment of patients with Diabetes Mellitus type-2. Its safety is well established in non-diabetic patients too where it has been shown to improve cardiovascular outcomes. The risk of hypoglycemia is negligible as its action is independent of insulin. By virtue of its natriuretic effect, it has been shown to reduce hospitalisations in patients with heart failure irrespective of the presence of diabetes. We hypothesise that a similar natriuretic effect may help in suppressing the renin-angiotensin axis with improved mobilization of ascites in patients with cirrhosis. Pharmacokinetic data on the use of Dapaglifozin suggest that there is no need for dose modification in cirrhosis. The AUC and Cmax for Dapaglifozin in Child Pugh C cirrhosis is 67% and 40%, respectively. In a recent small case series, SGLT-2 inhibitors including dapaglifozin led to improvement in fluid retention and serum sodium, without acute kidney injury or encephalopathy, in patients with cirrhosis. However, SGLT-2 inhibitors have not been evaluated in randomized controlled trials. In this pilot study, we plan to evaluate the efficacy and safety of dapaglifozin in cirrhotics patients with recurrent ascites.


Recruitment information / eligibility

Status Recruiting
Enrollment 44
Est. completion date May 19, 2022
Est. primary completion date May 19, 2022
Accepts healthy volunteers No
Gender All
Age group 18 Years to 70 Years
Eligibility Inclusion Criteria: 1. Age 18-70 years 2. Cirrhosis as determined by clinical findings, hemogram and liver function tests, endoscopic findings and imaging 3. Recurrent ascites: Recurrent ascites will be defined as tense ascites recurring at least thrice within the last 1-year despite optimal standard medical treatment including large volume paracentesis and diuretics Exclusion Criteria: 1. Presence of chronic kidney disease as defined by an estimated glomerular filtration rate of <60 ml/min for more than 3 months. The MDRD-6 equation will be used for estimating GFR. 2. Portal vein thrombosis 3. Hepatocellular carcinoma. 4. Gastrointestinal bleed in the preceding 2-weeks 5. Overt hepatic encephalopathy in the preceding 1-month 6. Documented hypoglycemia in the preceding 1-month 7. Serum sodium < 125 meq/l 8. History of skeletal fracture in the preceding year or any past history of fragility fracture 9. History of peripheral vascular disease 10. Acute kidney injury as defined by the International Club of Ascites criteria 11. Infection within 1-month preceding the study 12. Anatomic urologic defects that predispose to urinary tract infection 13. Mixed ascites (additional etiology of ascites apart from portal hypertension) 14. Any severe extra hepatic condition including respiratory and cardiac failure 15. Acute-on-chronic liver failure as per the APASL or CANONIC criteria 16. Treatment with drug with known effects on systemic and renal hemodynamics within 7 days of inclusion excepting beta-blockers 17. Patients opting for liver transplant or TIPS 18. Refusal to give consent

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Dapagliflozin (10Mg Tab) along with standard medical therapy
Oral Dapaglifozin (10 mg/day) along with standard medical therapy will be given to Group A while a placebo of dapaglifozin along with standard medical therapy will be used in Group B
Placebo of dapaglifozin along with standard medical therapy
Standard medical therapy will include dietary restriction of sodium, treatment with diuretics, repeated LVP as needed and other supportive care. Patients on non-selective beta blockers will continue to do so with dose modifications/withdrawal as per Baveno VI guidelines.

Locations

Country Name City State
India Dept of Hepatology, PGIMER Chandigarh

Sponsors (1)

Lead Sponsor Collaborator
Postgraduate Institute of Medical Education and Research

Country where clinical trial is conducted

India, 

Outcome

Type Measure Description Time frame Safety issue
Primary control of ascites at 6-months Control of ascites will be defined as follows-
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.
6 months
Secondary Change in eGFR measured by MDRD-6 at 3 months and 6 months eGFR will be measured by MDRD-6 formula 6 months
Secondary Change in urine output at 2-weeks, 3-months and 6-months Change in 24-hour urine output (ml) at 6-months 6-months
Secondary Change in serum sodium (mEq/l) at 2-weeks, 3-months and 6 months Change in serum sodium (mEq/l) 6 months
Secondary Change in 24-hours urinary sodium (mEq) at 2 weeks, 3 months and 6 months Change in 24-hours urinary sodium (mEq) 6 months
Secondary Change in HbA1c at 3 and 6 months Change in HbA1c 6 months
Secondary Change in Child-Turcotte-Pugh (CTP) score at 3 months and 6 months 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 6 months
Secondary Change in model for end stage liver disease (MELD) score at 3 months and 6 months 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 6 months
Secondary Incidence of spontaneous bacterial peritonitis (SBP), urinary tract infection (UTI) and other infections The diagnosis of SBP will be based on neutrophil count in ascitic ?uid of >250/mm3 as determined by microscopy and positive ascitic fluid culture or >250 /mm3 with negative culture called as culture negative neutrocytic ascites.Other infections will be diagnosed as per CDC criteria. 6 months
Secondary Incidence of overt hepatic encephalopathy over 6-months Over hepatic encephalopathy (HE) will be defined as grade II or higher HE as per the West haven classification 6 months
Secondary Incidence of acute kidney injury over 6-months Acute kidney injury will be defined as per the International Club of Ascites criteria 6 months
Secondary Incidence of Hyponatremia (serum sodium <130 meq/L), hypokalemia (Serum potassium < 3.5 meq/L), hyperkalemia (Serum potassium >6meq/L) over 6-months. Hyponatremia: serum sodium <130 meq/L hypokalemia: serum potassium < 3.5 meq/L hyperkalemia: serum potassium >6meq/L) 6 months
Secondary Incidence of skeletal fractures over 6-months Incidence of skeletal fractures over 6-months 6 months
Secondary Change in bone densitometry as assessed by DEXA at 6-months Bone densitometry will be assessed by DEXA 6 months
Secondary Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months 6 months
Secondary Incidence of hepatocellular carcinoma over 6-months Hepatocellular carcinoma will be diagnosed based on imaging findings and AFP 6 months
Secondary Changes in plasma renin activity and aldosterone levels at 6- months Changes in plasma renin activity (ng/ml/hr) and aldosterone (ng/dL) levels at 6- months 6 months
Secondary Frequency and volume of LVP over 6-months. Frequency and volume of ascitic fluid removed (in litres) over 6-months. 6 months
Secondary Survival at 6-months Survival at 6-months after start of therapy Survival at 6-months
Secondary Safety of dapaglifozin as assessed by adverse effects Safety of dapaglifozin as assessed by adverse effects 6 months
Secondary Renal resistive index at 6 months Renal resistive index will be measured using ultrasound doppler interrogation of intrarenal arteries using formula (peak systolic velocity - end-diastolic velocity) / peak systolic velocity 6 months
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