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

Study Overview
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Brief Summary
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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.

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

Conditions
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Cirrhosis, Ascites Hepatic

Intervention / Treatment
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* Drug: Dapagliflozin (10Mg Tab) along with standard medical therapy
* Drug: Placebo of dapaglifozin along with standard medical therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 years Cirrhosis as determined by clinical findings, hemogram and liver function tests, endoscopic findings and imaging 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: 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. Portal vein thrombosis Hepatocellular carcinoma. Gastrointestinal bleed in the preceding 2-weeks Overt hepatic encephalopathy in the preceding 1-month Documented hypoglycemia in the preceding 1-month Serum sodium < 125 meq/l History of skeletal fracture in the preceding year or any past history of fragility fracture History of peripheral vascular disease Acute kidney injury as defined by the International Club of Ascites criteria Infection within 1-month preceding the study Anatomic urologic defects that predispose to urinary tract infection Mixed ascites (additional etiology of ascites apart from portal hypertension) Any severe extra hepatic condition including respiratory and cardiac failure Acute-on-chronic liver failure as per the APASL or CANONIC criteria Treatment with drug with known effects on systemic and renal hemodynamics within 7 days of inclusion excepting beta-blockers Patients opting for liver transplant or TIPS Refusal to give consent

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A (Dapaglifozin)<br>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<br>* 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<br>|
| Placebo Comparator: Group B (Placebo)<br>Group B will receive placebo of Dapaglifozin along with standard medical therapy for 6 months | Drug: Placebo of dapaglifozin along with standard medical therapy<br>* 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.<br>|

What is the study measuring?
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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 |