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

3. september 2021 oppdatert av: Dr.Virendra Singh, Postgraduate Institute of Medical Education and Research

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.

Studieoversikt

Status

Rekruttering

Forhold

Intervensjon / Behandling

Studietype

Intervensjonell

Registrering (Forventet)

44

Fase

  • Fase 2

Kontakter og plasseringer

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Studiekontakt

Studer Kontakt Backup

Studiesteder

  • India
      • Chandigarh, India, 160012
        • Rekruttering
        • Dept of Hepatology, PGIMER
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Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år til 70 år (Voksen, Eldre voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

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

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Firemannsrom

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Aktiv komparator: Group A (Dapaglifozin)
Group A will receive oral Dapaglifozin (10 mg/day) along with standard medical therapy for 6 months
Legemiddel: Dapagliflozin (10Mg Tab) along with standard medical therapy
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 komparator: Group B (Placebo)
Group B will receive placebo of Dapaglifozin along with standard medical therapy for 6 months
Legemiddel: Placebo of dapaglifozin along with standard medical therapy
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.

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
control of ascites at 6-months
Tidsramme: 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

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Change in eGFR measured by MDRD-6 at 3 months and 6 months
Tidsramme: 6 months
eGFR will be measured by MDRD-6 formula
6 months
Change in urine output at 2-weeks, 3-months and 6-months
Tidsramme: 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
Tidsramme: 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
Tidsramme: 6 months
Change in 24-hours urinary sodium (mEq)
6 months
Change in HbA1c at 3 and 6 months
Tidsramme: 6 months
Change in HbA1c
6 months
Change in Child-Turcotte-Pugh (CTP) score at 3 months and 6 months
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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.
Tidsramme: 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
Tidsramme: 6 months
Incidence of skeletal fractures over 6-months
6 months
Change in bone densitometry as assessed by DEXA at 6-months
Tidsramme: 6 months
Bone densitometry will be assessed by DEXA
6 months
Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months
Tidsramme: 6 months
Incidence of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma over 6-months
6 months
Incidence of hepatocellular carcinoma over 6-months
Tidsramme: 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
Tidsramme: 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.
Tidsramme: 6 months
Frequency and volume of ascitic fluid removed (in litres) over 6-months.
6 months
Survival at 6-months
Tidsramme: Survival at 6-months
Survival at 6-months after start of therapy
Survival at 6-months
Safety of dapaglifozin as assessed by adverse effects
Tidsramme: 6 months
Safety of dapaglifozin as assessed by adverse effects
6 months
Renal resistive index at 6 months
Tidsramme: 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

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Sponsor

Postgraduate Institute of Medical Education and Research

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Faktiske)

3. september 2021

Primær fullføring (Forventet)

19. mai 2022

Studiet fullført (Forventet)

19. mai 2022

Datoer for studieregistrering

Først innsendt

14. august 2021

Først innsendt som oppfylte QC-kriteriene

14. august 2021

Først lagt ut (Faktiske)

20. august 2021

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

5. september 2021

Siste oppdatering sendt inn som oppfylte QC-kriteriene

3. september 2021

Sist bekreftet

1. september 2021

Mer informasjon

Begreper knyttet til denne studien

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • Dapa recurrent ascites

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Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

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