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

3 septembre 2021 mis à jour par: 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.

Aperçu de l'étude

Statut

Recrutement

Les conditions

Intervention / Traitement

Type d'étude

Interventionnel

Inscription (Anticipé)

44

Phase

  • Phase 2

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Coordonnées de l'étude

Sauvegarde des contacts de l'étude

Lieux d'étude

  • Inde
      • Chandigarh, Inde, 160012
        • Recrutement
        • Dept of Hepatology, PGIMER
        • Contact:

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans à 70 ans (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

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

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation parallèle
  • Masquage: Quadruple

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Comparateur actif: Group A (Dapaglifozin)
Group A will receive oral Dapaglifozin (10 mg/day) along with standard medical therapy for 6 months
Médicament: 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
Comparateur placebo: Group B (Placebo)
Group B will receive placebo of Dapaglifozin along with standard medical therapy for 6 months
Médicament: 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.

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
control of ascites at 6-months
Délai: 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

Mesures de résultats secondaires

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

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Postgraduate Institute of Medical Education and Research

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude (Réel)

3 septembre 2021

Achèvement primaire (Anticipé)

19 mai 2022

Achèvement de l'étude (Anticipé)

19 mai 2022

Dates d'inscription aux études

Première soumission

14 août 2021

Première soumission répondant aux critères de contrôle qualité

14 août 2021

Première publication (Réel)

20 août 2021

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

5 septembre 2021

Dernière mise à jour soumise répondant aux critères de contrôle qualité

3 septembre 2021

Dernière vérification

1 septembre 2021

Plus d'information

Termes liés à cette étude

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • Dapa recurrent ascites

Informations sur les médicaments et les dispositifs, documents d'étude

Étudie un produit pharmaceutique réglementé par la FDA américaine

Non

Étudie un produit d'appareil réglementé par la FDA américaine

Non

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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