Sodium-glucose Linked Transporter 2 (SGLT-2) Inhibitors in Recurrent Ascites: a Pilot RCT

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.

Study Overview

• Status: Recruiting
• Conditions: Cirrhosis; Ascites Hepatic
• Intervention / Treatment: Drug: Dapagliflozin (10Mg Tab) along with standard medical therapy; Drug: Placebo of dapaglifozin along with standard medical therapy

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Virendra Singh, MD,DM,FASGE; Phone Number: 0172-275-6338; Email: virendrasingh100@hotmail.com
• Study Contact Backup: Name: Rishav Aggarwal, MBBS; Phone Number: 9914032190; Email: rishavaggarwal90@gmail.com

Study Locations

• India
  • Chandigarh, India, 160012
    • Recruiting
    • Dept of Hepatology, PGIMER
    • Contact: Virendra Singh, MD, DM; Phone Number: +911722756338; Email: virendrasingh100@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A (Dapaglifozin); Group A will receive oral Dapaglifozin (10 mg/day) along with standard medical therapy for 6 months	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 Comparator: Group B (Placebo); Group B will receive placebo of Dapaglifozin along with standard medical therapy for 6 months	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in eGFR measured by MDRD-6 at 3 months and 6 months	eGFR will be measured by MDRD-6 formula	6 months
Change in urine output at 2-weeks, 3-months and 6-months	Change in 24-hour urine output (ml) at 6-months	6-months
Change in serum sodium (mEq/l) at 2-weeks, 3-months and 6 months	Change in serum sodium (mEq/l)	6 months
Change in 24-hours urinary sodium (mEq) at 2 weeks, 3 months and 6 months	Change in 24-hours urinary sodium (mEq)	6 months
Change in HbA1c at 3 and 6 months	Change in HbA1c	6 months
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
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
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 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.Other infections will be diagnosed as per CDC criteria.	6 months
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
Incidence of acute kidney injury over 6-months	Acute kidney injury will be defined as per the International Club of Ascites criteria	6 months
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
Incidence of skeletal fractures over 6-months	Incidence of skeletal fractures over 6-months	6 months
Change in bone densitometry as assessed by DEXA at 6-months	Bone densitometry will be assessed by DEXA	6 months
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
Incidence of hepatocellular carcinoma over 6-months	Hepatocellular carcinoma will be diagnosed based on imaging findings and AFP	6 months
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
Frequency and volume of LVP over 6-months.	Frequency and volume of ascitic fluid removed (in litres) over 6-months.	6 months
Survival at 6-months	Survival at 6-months after start of therapy	Survival at 6-months
Safety of dapaglifozin as assessed by adverse effects	Safety of dapaglifozin as assessed by adverse effects	6 months
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

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2021
• Primary Completion (Anticipated): May 19, 2022
• Study Completion (Anticipated): May 19, 2022

Study Registration Dates

• First Submitted: August 14, 2021
• First Submitted That Met QC Criteria: August 14, 2021
• First Posted (Actual): August 20, 2021

Study Record Updates

• Last Update Posted (Actual): September 5, 2021
• Last Update Submitted That Met QC Criteria: September 3, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Ascites; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: Dapa recurrent ascites

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No