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.
Studie Overzicht
Toestand
Conditie
Studietype
Inschrijving (Verwacht)
Fase
- Fase 2
Contacten en locaties
Studiecontact
- Naam: Virendra Singh, MD,DM,FASGE
- Telefoonnummer: 0172-275-6338
- E-mail: virendrasingh100@hotmail.com
Studie Contact Back-up
- Naam: Rishav Aggarwal, MBBS
- Telefoonnummer: 9914032190
- E-mail: rishavaggarwal90@gmail.com
Studie Locaties
-
-
-
Chandigarh, Indië, 160012
- Werving
- Dept of Hepatology, PGIMER
-
Contact:
- Virendra Singh, MD, DM
- Telefoonnummer: +911722756338
- E-mail: virendrasingh100@hotmail.com
-
-
Deelname Criteria
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
Accepteert gezonde vrijwilligers
Geslachten die in aanmerking komen voor studie
Beschrijving
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
Studie plan
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Behandeling
- Toewijzing: Gerandomiseerd
- Interventioneel model: Parallelle opdracht
- Masker: Verviervoudigen
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
|---|---|
|
Actieve vergelijker: Group A (Dapaglifozin)
Group A will receive oral Dapaglifozin (10 mg/day) along with standard medical therapy for 6 months
|
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-vergelijker: Group B (Placebo)
Group B will receive placebo of Dapaglifozin along with standard medical therapy for 6 months
|
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.
|
Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
|
control of ascites at 6-months
Tijdsspanne: 6 months
|
Control of ascites will be defined as follows-
|
6 months
|
Secundaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
|
Change in eGFR measured by MDRD-6 at 3 months and 6 months
Tijdsspanne: 6 months
|
eGFR will be measured by MDRD-6 formula
|
6 months
|
|
Change in urine output at 2-weeks, 3-months and 6-months
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 6 months
|
Change in 24-hours urinary sodium (mEq)
|
6 months
|
|
Change in HbA1c at 3 and 6 months
Tijdsspanne: 6 months
|
Change in HbA1c
|
6 months
|
|
Change in Child-Turcotte-Pugh (CTP) score at 3 months and 6 months
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 6 months
|
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
Tijdsspanne: 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
Tijdsspanne: 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.
Tijdsspanne: 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
Tijdsspanne: 6 months
|
Incidence of skeletal fractures over 6-months
|
6 months
|
|
Change in bone densitometry as assessed by DEXA at 6-months
Tijdsspanne: 6 months
|
Bone densitometry will be assessed by DEXA
|
6 months
|
|
Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months
Tijdsspanne: 6 months
|
Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months
|
6 months
|
|
Incidence of hepatocellular carcinoma over 6-months
Tijdsspanne: 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
Tijdsspanne: 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.
Tijdsspanne: 6 months
|
Frequency and volume of ascitic fluid removed (in litres) over 6-months.
|
6 months
|
|
Survival at 6-months
Tijdsspanne: Survival at 6-months
|
Survival at 6-months after start of therapy
|
Survival at 6-months
|
|
Safety of dapaglifozin as assessed by adverse effects
Tijdsspanne: 6 months
|
Safety of dapaglifozin as assessed by adverse effects
|
6 months
|
|
Renal resistive index at 6 months
Tijdsspanne: 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
|
Medewerkers en onderzoekers
Studie record data
Bestudeer belangrijke data
Studie start (Werkelijk)
Primaire voltooiing (Verwacht)
Studie voltooiing (Verwacht)
Studieregistratiedata
Eerst ingediend
Eerst ingediend dat voldeed aan de QC-criteria
Eerst geplaatst (Werkelijk)
Updates van studierecords
Laatste update geplaatst (Werkelijk)
Laatste update ingediend die voldeed aan QC-criteria
Laatst geverifieerd
Meer informatie
Termen gerelateerd aan deze studie
Aanvullende relevante MeSH-voorwaarden
Andere studie-ID-nummers
- Dapa recurrent ascites
Informatie over medicijnen en apparaten, studiedocumenten
Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel
Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct
Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .