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.
調査の概要
状態
研究の種類
入学 (予想される)
段階
- フェーズ2
連絡先と場所
研究連絡先
- 名前：Virendra Singh, MD,DM,FASGE
- 電話番号：0172-275-6338
- メール：virendrasingh100@hotmail.com
研究連絡先のバックアップ
- 名前：Rishav Aggarwal, MBBS
- 電話番号：9914032190
- メール：rishavaggarwal90@gmail.com
研究場所
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Chandigarh、インド、160012
- 募集
- Dept of Hepatology, PGIMER
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コンタクト：
- Virendra Singh, MD, DM
- 電話番号：+911722756338
- メール：virendrasingh100@hotmail.com
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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アクティブコンパレータ：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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プラセボコンパレーター：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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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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control of ascites at 6-months
時間枠：6 months
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Control of ascites will be defined as follows-
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6 months
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Change in eGFR measured by MDRD-6 at 3 months and 6 months
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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.
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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.
時間枠：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
時間枠：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
時間枠：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
時間枠：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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協力者と研究者
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (予想される)
研究の完了 (予想される)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
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