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.
Přehled studie
Postavení
Podmínky
Typ studie
Zápis (Očekávaný)
Fáze
- Fáze 2
Kontakty a umístění
Studijní kontakt
- Jméno: Virendra Singh, MD,DM,FASGE
- Telefonní číslo: 0172-275-6338
- E-mail: virendrasingh100@hotmail.com
Studijní záloha kontaktů
- Jméno: Rishav Aggarwal, MBBS
- Telefonní číslo: 9914032190
- E-mail: rishavaggarwal90@gmail.com
Studijní místa
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Chandigarh, Indie, 160012
- Nábor
- Dept of Hepatology, PGIMER
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Kontakt:
- Virendra Singh, MD, DM
- Telefonní číslo: +911722756338
- E-mail: virendrasingh100@hotmail.com
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
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
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: Randomizované
- Intervenční model: Paralelní přiřazení
- Maskování: Čtyřnásobek
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
|---|---|
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Aktivní komparátor: Group A (Dapaglifozin)
Group A will receive oral Dapaglifozin (10 mg/day) along with standard medical therapy for 6 months
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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
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Komparátor placeba: Group B (Placebo)
Group B will receive placebo of Dapaglifozin along with standard medical therapy for 6 months
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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.
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Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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control of ascites at 6-months
Časové okno: 6 months
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Control of ascites will be defined as follows-
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6 months
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Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Change in eGFR measured by MDRD-6 at 3 months and 6 months
Časové okno: 6 months
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eGFR will be measured by MDRD-6 formula
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6 months
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Change in urine output at 2-weeks, 3-months and 6-months
Časové okno: 6-months
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Change in 24-hour urine output (ml) at 6-months
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6-months
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Change in serum sodium (mEq/l) at 2-weeks, 3-months and 6 months
Časové okno: 6 months
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Change in serum sodium (mEq/l)
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6 months
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Change in 24-hours urinary sodium (mEq) at 2 weeks, 3 months and 6 months
Časové okno: 6 months
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Change in 24-hours urinary sodium (mEq)
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6 months
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Change in HbA1c at 3 and 6 months
Časové okno: 6 months
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Change in HbA1c
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6 months
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Change in Child-Turcotte-Pugh (CTP) score at 3 months and 6 months
Časové okno: 6 months
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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
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6 months
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Change in model for end stage liver disease (MELD) score at 3 months and 6 months
Časové okno: 6 months
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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
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6 months
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Incidence of spontaneous bacterial peritonitis (SBP), urinary tract infection (UTI) and other infections
Časové okno: 6 months
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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.
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6 months
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Incidence of overt hepatic encephalopathy over 6-months
Časové okno: 6 months
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Over hepatic encephalopathy (HE) will be defined as grade II or higher HE as per the West haven classification
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6 months
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Incidence of acute kidney injury over 6-months
Časové okno: 6 months
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Acute kidney injury will be defined as per the International Club of Ascites criteria
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6 months
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Incidence of Hyponatremia (serum sodium <130 meq/L), hypokalemia (Serum potassium < 3.5 meq/L), hyperkalemia (Serum potassium >6meq/L) over 6-months.
Časové okno: 6 months
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Hyponatremia: serum sodium <130 meq/L hypokalemia: serum potassium < 3.5 meq/L hyperkalemia: serum potassium >6meq/L)
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6 months
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Incidence of skeletal fractures over 6-months
Časové okno: 6 months
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Incidence of skeletal fractures over 6-months
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6 months
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Change in bone densitometry as assessed by DEXA at 6-months
Časové okno: 6 months
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Bone densitometry will be assessed by DEXA
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6 months
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Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months
Časové okno: 6 months
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Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months
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6 months
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Incidence of hepatocellular carcinoma over 6-months
Časové okno: 6 months
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Hepatocellular carcinoma will be diagnosed based on imaging findings and AFP
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6 months
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Changes in plasma renin activity and aldosterone levels at 6- months
Časové okno: 6 months
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Changes in plasma renin activity (ng/ml/hr) and aldosterone (ng/dL) levels at 6- months
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6 months
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Frequency and volume of LVP over 6-months.
Časové okno: 6 months
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Frequency and volume of ascitic fluid removed (in litres) over 6-months.
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6 months
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Survival at 6-months
Časové okno: Survival at 6-months
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Survival at 6-months after start of therapy
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Survival at 6-months
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Safety of dapaglifozin as assessed by adverse effects
Časové okno: 6 months
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Safety of dapaglifozin as assessed by adverse effects
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6 months
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Renal resistive index at 6 months
Časové okno: 6 months
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Renal resistive index will be measured using ultrasound doppler interrogation of intrarenal arteries using formula (peak systolic velocity - end-diastolic velocity) / peak systolic velocity
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6 months
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Spolupracovníci a vyšetřovatelé
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Aktuální)
Primární dokončení (Očekávaný)
Dokončení studie (Očekávaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Další relevantní podmínky MeSH
Další identifikační čísla studie
- Dapa recurrent ascites
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