Sodium-glucose Linked Transporter 2 (SGLT-2) Inhibitors in Recurrent Ascites: a Pilot RCT
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 44
- 试验地点
- 1
- 主要终点
- control of ascites at 6-months
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Group A (Dapaglifozin)
Group A will receive oral Dapaglifozin (10 mg/day) along with standard medical therapy for 6 months
干预措施: Dapagliflozin (10Mg Tab) along with standard medical therapy (Drug)
Group B (Placebo)
Group B will receive placebo of Dapaglifozin along with standard medical therapy for 6 months
干预措施: Placebo of dapaglifozin along with standard medical therapy (Drug)
结局指标
主要结局
control of ascites at 6-months
时间窗: 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.
次要结局
- Change in eGFR measured by MDRD-6 at 3 months and 6 months(6 months)
- Change in urine output at 2-weeks, 3-months and 6-months(6-months)
- Change in serum sodium (mEq/l) at 2-weeks, 3-months and 6 months(6 months)
- Change in Child-Turcotte-Pugh (CTP) score at 3 months and 6 months(6 months)
- Change in 24-hours urinary sodium (mEq) at 2 weeks, 3 months and 6 months(6 months)
- Change in HbA1c at 3 and 6 months(6 months)
- Change in model for end stage liver disease (MELD) score at 3 months and 6 months(6 months)
- Incidence of spontaneous bacterial peritonitis (SBP), urinary tract infection (UTI) and other infections(6 months)
- Incidence of overt hepatic encephalopathy over 6-months(6 months)
- Incidence of acute kidney injury over 6-months(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.(6 months)
- Incidence of skeletal fractures over 6-months(6 months)
- Incidence of hepatocellular carcinoma over 6-months(6 months)
- Changes in plasma renin activity and aldosterone levels at 6- months(6 months)
- Frequency and volume of LVP over 6-months.(6 months)
- Change in bone densitometry as assessed by DEXA at 6-months(6 months)
- Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months(6 months)
- Survival at 6-months(Survival at 6-months)
- Safety of dapaglifozin as assessed by adverse effects(6 months)
- Renal resistive index at 6 months(6 months)
研究者
Dr.Virendra Singh
Professor and Head, Department of Hepatology
Post Graduate Institute of Medical Education and Research, Chandigarh