Clinical trial NCT05014594: Sodium-glucose Linked Transporter 2 (SGLT-2) Inhibitors in Recurrent Ascites: a Pilot RCT
Official title: Sodium-glucose Linked Transporter 2 (SGLT-2) Inhibitors in Recurrent Ascites: a Pilot RCT
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Cirrhosis
Ascites Hepatic
Lead sponsor: PGIMER
Sponsor class: UNKNOWN
First posted: 2021-08-20
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: control of ascites at 6-months
timeFrame: 6 months
Secondary outcomes:
measure: Change in eGFR measured by MDRD-6 at 3 months and 6 months
timeFrame: 6 months
measure: Change in urine output at 2-weeks, 3-months and 6-months
timeFrame: 6-months
measure: Change in serum sodium (mEq/l) at 2-weeks, 3-months and 6 months
timeFrame: 6 months
measure: Change in 24-hours urinary sodium (mEq) at 2 weeks, 3 months and 6 months
timeFrame: 6 months
measure: Change in HbA1c at 3 and 6 months
timeFrame: 6 months
measure: Change in Child-Turcotte-Pugh (CTP) score at 3 months and 6 months
timeFrame: 6 months
measure: Change in model for end stage liver disease (MELD) score at 3 months and 6 months
timeFrame: 6 months
measure: Incidence of spontaneous bacterial peritonitis (SBP), urinary tract infection (UTI) and other infections
timeFrame: 6 months
measure: Incidence of overt hepatic encephalopathy over 6-months
timeFrame: 6 months
measure: Incidence of acute kidney injury over 6-months
timeFrame: 6 months
measure: Incidence of Hyponatremia (serum sodium <130 meq/L), hypokalemia (Serum potassium < 3.5 meq/L), hyperkalemia (Serum potassium >6meq/L) over 6-months.
timeFrame: 6 months
measure: Incidence of skeletal fractures over 6-months
timeFrame: 6 months
measure: Change in bone densitometry as assessed by DEXA at 6-months
timeFrame: 6 months
measure: Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months
timeFrame: 6 months
measure: Incidence of hepatocellular carcinoma over 6-months
timeFrame: 6 months
measure: Changes in plasma renin activity and aldosterone levels at 6- months
timeFrame: 6 months
measure: Frequency and volume of LVP over 6-months.
timeFrame: 6 months
measure: Survival at 6-months
timeFrame: Survival at 6-months
measure: Safety of dapaglifozin as assessed by adverse effects
timeFrame: 6 months
measure: Renal resistive index at 6 months
timeFrame: 6 months
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: Dept of Hepatology, PGIMER
Study officials:
References: