To Compare the Safety and Efficacy of Dapagliflozin Plus Metformin Versus Sitagliptin Plus Metformin for Treatment of Diabetes in Patients With Compensated and Stable Decompensated Cirrhosis

Study Overview
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Brief Summary
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Diabetes prevalence is increasing among cirrhotics and use of OAD in cirrhotics is limited because of risk of hypoglycaemia and other adverse effects, therefore in this study we would be using OAD in the form of Sitagliptin or Dapagliflozin to look for glycemic response as well as to look for other benefits such as weight reduction and improvement in lipid parameters.

Detailed Description
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Hypothesis In patients with cirrhosis and T2DM with poor glycemic control on metformin requiring dual therapy, Dapagliflozin is safe and superior to Sitagliptin in achieving glycemic control. Moreover, Dapagliflozin use leads to improvement in parameters of metabolic dysfunction, clinical decompensation and cardio-renal protection. Aim compare the safety and efficacy of metformin plus sitagliptin compared to metformin plus dapagliflozin in effective glycemic control and improvement in parameters of metabolic dysfunction, cirrhosis complications and organ dysfunction at 24 weeks. Study population:Patients with compensated and stable decompensated cirrhosis and age 18-70 years with CTP 5-8 Study design: A prospective, randomized, single center open label study The study will be conducted on the consecutive patients with liver cirrhosis and type 2 diabetes mellitus seen at the outpatient clinics of Department of Hepatology, ILBS Sample size: 200 Assuming that 40% people had HbA1c <7 in Dapagliflozin and 25% in sitagliptin.Alpha = 5%,Power = 80%,Need to enroll total 200 cases(100 in each arm), Drop rate = 10%,Total enrollment = 100 cases (80 each arm). Randomization by block randomization method taking block size as 10 Intervention: This RCT will be conducted at ILBS New Delhi Monitoring and assessment: Monitoring will be done for all the parameters of the objective. Documentation will be done for any adverse effects which will happen. Adverse effects: to be monitored

Official Title
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An Open Label Randomized Control Trial to Compare the Safety and Efficacy of Dapagliflozin Plus Metformin Versus Sitagliptin Plus Metformin for Treatment of Diabetes in Patients With Compensated and Stable Decompensated Cirrhosis

Conditions
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Compensated Cirrhosis, Decompensated Cirrhosis

Intervention / Treatment
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* Drug: Metformin
* Drug: Sitagliptin
* Drug: Dapagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 years Child A/B Liver cirrhosis in outpatient setting T2DM patients who have not used any glucose-lowering agents within 8 weeks before consenting, or those who have only used metformin, in addition to diet and exercise HbA1c level of 7.1% or higher but no more than 9.0% BMI of 23 kg/m2 or higher patients who can be monitored closely for medication compliance patients who provide written informed consent. Exclusion Criteria: Age <18 years Post renal or liver transplantation CTP C / ACLF Intrinsic/structural kidney disease, obstructive uropathy, ADPKD, Anatomic urologic defects that predispose to urinary tract infection Active sepsis / SBP at enrollment Grade II/III/IV HE Pregnancy or Lactating mother Known CKD, obstructive uropathy Patient on MV, NIV, systemic sepsis and shock Lack of informed consent Prior intolerance or S/E to SGLT-2i or DPP4i patients with type 1 diabetes or secondary diabetes patients with medical history of diabetic ketoacidosis patients with medical history of myocardial infarction, cerebral infarction, or stroke within 12 weeks before consent to the study estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m2 unstable hypertension or dyslipidemia within 12 weeks before consent to the study HB <9 g/L, patients with haemoglobinopathy, acute hemolysisStudy period: one year after ethical approval.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin with Sitagliptin<br>Metformin: 1.5g/d CTPA,1g/d CTPB Sitagliptin: Assess HbA1c/HBSG at 8 weeks, increase sitagliptin to 100 mg if HbA1c>7% | Drug: Metformin<br>* Metformin: 1.5g/d CTPA,1g/d CTPB<br>Drug: Sitagliptin<br>* Sitagliptin: Assess HbA1c/HBSG at 8 weeks, increase sitagliptin to 100 mg if HbA1c>7%<br>|
| Experimental: Metformin with Dapagliflozin<br>Metformin: 1.5g/d CTPA,1g/d CTPB Dapagliflozin: Assess HbA1c/HBSG at 8 weeks, increase dapagliflozin to 10 mg if HbA1c>7% | Drug: Metformin<br>* Metformin: 1.5g/d CTPA,1g/d CTPB<br>Drug: Dapagliflozin<br>* Assess HbA1c/HBSG at 8 weeks, increase Dapagliflozin to 10 mg if HbA1c>7%<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with glycemic control at 24 weeks (HBA1c <7.0 %) |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with glycemic control at 8 and 16 weeks (HBA1c <7.0 %) |  | 8 and 16 weeks | 
| Ideal body weight loss of ≥3% relative to baseline at 24 week |  | 24 weeks | 
| Incidence and frequency of hypoglycemia (BS <54 mg/dl) episodes |  | 8 weeks | 
| Incidence and frequency of hypoglycemia (BS <54 mg/dl) episodes |  | 16 weeks | 
| Incidence and frequency of hypoglycemia (BS <54 mg/dl) episodes |  | 24 weeks | 
| Changes in HbA1c at 24 week relative to baseline |  | 24 weeks | 
| Changes in BMI at 24 week relative to baseline |  | 24 weeks | 
| changes in Blood insulin at 24 week |  | 24 weeks | 
| changes in lipid profile at 24 week |  | 24 weeks | 
| Change in ALT at 8, 16 and 24 week |  | 8, 16 and 24 week | 
| Change in HVPG at 24 week compared to baseline |  | 24 weeks | 
| Change in LSM at 24 week compared to baseline |  | 24 weeks | 
| Change in SSM at 24 week compared to baseline |  | 24 weeks | 
| Incidence of urinary protein excretion at 8, 16 and 24 weeks |  | 8, 16 and 24 weeks | 
| Incidence of serum creatinine at 8, 16 and 24 weeks |  | 8, 16 and 24 weeks | 
| Number of patients with Complications of cirrhosis (ascites, HE, Bleed, AKI, Infection) at 24 week |  | 24 weeks | 
| Medicine adherence rate in both groups |  | 24 weeks | 
| Adverse effects to study drugs in both groups |  | 24 weeks | 
| Number of patients with Mortality/ Liver transplantation in both groups |  | 24 weeks |