Efficacy of Early Terlipressin Plus Albumin Therapy in Comparison to Standard Treatment for HRS-AKI in Acute-on-chronic Liver Failure.

Sponsor

Institute of Liver and Biliary Sciences, India (Other)

Overall Status

Recruiting

CT.gov ID

NCT04416282

Collaborator

(none)

140

Enrollment

Location

Arms

23.6

Anticipated Duration (Months)

5.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Acute on chronic liver failure (ACLF) is a distinct entity where, because of severe acute hepatic injury, a rapid loss of liver function develops in a patient with previous chronic liver disease(4). These patients have severe hepatic dysfunction, and outcome is defined by functional hepatic reserve and extent of extra-hepatic organ failures(5). Renal failure is a frequent extra-hepatic organ failure, and its presence is an independent prognostic marker for mortality(12). The pathophysiological basis of renal dysfunction in patients with ACLF is different compared to those with decompensated cirrhosis (DC)(6). Systemic inflammation is the hallmark of ACLF, characterized by a cytokine storm wherein there is an increase in both pro- and anti-inflammatory cytokines, such as interleukin (IL)-6, IL-8, IL-1β, and IL-10, leading to circulatory dysfunction and organ failure(3). These patients therefore have a higher incidence and progression of acute kidney injury (AKI). Diagnosis of HRS-AKI in ACLF currently requires 48 h of volume repletion with albumin and diuretic withdrawal. Therefore waiting for 48 hours to start treatment with terlipressin can be associated with worsening of AKI stage, worsening of ACLF stage and thereby suboptimal treatment response and high mortality despite treatment response. Therefore early initiation of terlipressin as continuous infusion after volume repletion with IV albumin in ACLF-AKI is safe and prevents AKI progression by splanchnic vasoconstriction and improved renal perfusion.

Condition or Disease	Intervention/Treatment	Phase
Acute-On-Chronic Liver Failure Hepatorenal Syndrome Acute Kidney Injury	Drug: Terlipressin Biological: Albumin	N/A

Detailed Description

Aim To compare the effect of Early initiation of Terlipressin (ET arm) to albumin at 12 hour in ACLF patients with non-volume responsive AKI versus standard Terlipressin (ST arm) at 48 hours.

Primary Objective Efficacy of early terlipressin infusion in comparison to Standard treatment for resolution of AKI at day 7.

Secondary Objectives

Full and partial AKI response at 48 and 72 h and 96 hours
Mortality at Day 28, Day 90
Baseline organ failure(s), MELD, CLIF-SOFA score and ACLF score
New onset organ failures
Urine Output
Progression or resolution of OFs at day 7
Change in MELD, CLIF-SOFA score and ACLF score at day 7
Change in NGAL, FENa, FE-Urea at day 7
Treatment related adverse effects and their grades

Methodology:

Study population:

All patients admitted to the Institute of Liver and Biliary Sciences (ILBS) with ACLF with AKI- HRS will be evaluated for inclusion. ACLF will be defined by the APASL criteria.

Study Design A prospective, randomized, single center open label study

Study Period:Two year

Intervention & monitoring:

Clinical Protocol An informed consent will be taken from ACLF patients with AKI within 24-hours of admission. No alteration in the treatment or investigative procedures of the included patients will be done. All included patients will be followed from admission till death or discharge. All discharged patients will then be followed till 30-days.

Preliminary work up

At admission:

(A) Complete history and physical examination

Recent Diuretics use
Loose stools
Recurrent vomiting
Fever, signs of sepsis (SIRS)
H/s/o LRTI, SSTI, SBP
Recent contrast use (< 7 days)
Use of nephrotoxins including NSAIDs
Prior renal dysfunction, known CKD, HD
History of HTN, Diabetes
History of renal stones
History s/o hypotensive episodes (shock)

Pre-randomization interventions:

(B) Intervention during 0-12 hours (Before randomization) -

Withdrawal of diuretics
Withdrawal of lactulose (in patients with loose stools)
Urine output monitoring (catheterize and monitor hourly or 12 h cumulative)
2 hourly MAP, Pulse rate
Empirical IV antibiotics to be given in case of suspected/proven sepsis (Avoid nephrotoxic drugs e.g Amikacin, Colistin, Amphotericin etc as possible)
IV hydration with albumin at 12 hours preferably 40 g (20 %) + 500 ml crystalloids)

Labs and follow-up:

Baseline (at admission) - Blood : KFT, LFT, CBC, INR, Blood c/s, pro-BNP Imaging : USG abdomen, USG KUB, Renal doppler, C-X-ray, 2D ECHO Urine : Urine R/E and cultures, Urine Na, Urea, NGAL, Creatinine, FENa, FE Urea A/F analysis - for SBP
At 12 hours (Before randomization) - Blood - KFT
At D1, D2, D3, D5, D7, D14, D28 post randomization Blood : KFT Urine : Urine Na, Urea, NGAL, Creatinine, FENa, FE Urea (At Day 3 and 7) Imaging : Renal doppler (Day 3)

Clinical evaluation:

Etiology of cirrhosis (Baseline)
Severity of liver disease (Baseline, D3, D7) MELD score, CLIF-SOFA score, MELD-Na score, AARC score
Stage of ACLF (Baseline,D3, D7) AARC grade, CLIF ACLF grade
Complications / Organ failures (Baseline,D3, D7) HE, Bleed, AKI stage, SBP, Infection (specify site and severity) Respiratory and circulatory failure

Follow up duration Duration of admission till discharge or death will be noted. Patients will be followed up to 28-days for re-admission(s) and survival.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Efficacy of Early Terlipressin Plus Albumin Therapy in Comparison to Standard Treatment for HRS-AKI in Acute-on-chronic Liver Failure- A Randomized Open Label Study.

Actual Study Start Date :

Jun 22, 2020

Anticipated Primary Completion Date :

Jun 10, 2022

Anticipated Study Completion Date :

Jun 10, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Terlipressin + Albumin Injection terlipressin 2 mg/24 hours infusion + i/v albumin 1g/Kg/day	Drug: Terlipressin Injection terlipressin 2 mg/24 hours infusion Biological: Albumin i/v albumin 1g/Kg/day
Active Comparator: Albumin i/v albumin 1g/Kg/day for next 36 hours f/b inj terlipressin 2mg/24 hours	Biological: Albumin i/v albumin 1g/Kg/day

Arm

Intervention/Treatment

Experimental: Terlipressin + Albumin

Injection terlipressin 2 mg/24 hours infusion + i/v albumin 1g/Kg/day

Drug: Terlipressin

Injection terlipressin 2 mg/24 hours infusion

Biological: Albumin

i/v albumin 1g/Kg/day

Active Comparator: Albumin

i/v albumin 1g/Kg/day for next 36 hours f/b inj terlipressin 2mg/24 hours

Biological: Albumin

i/v albumin 1g/Kg/day

Outcome Measures

Primary Outcome Measures

Acute Kidney Injury reversal by day 7 in both groups [Day 7]

Secondary Outcome Measures

Mortality in both groups [Day 28]
Mortality in both groups [Day 90]
Progression or resolution of Organ failures [Day 90]
Adverse Events in both groups [Day 90]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18-65 years
ACLF as per APASL criteria
AKI at admission as defined by ICA-AKI criteria
AKI stage 2/3 at 12 hour of admission

Exclusion Criteria:

At Admission:

Age <18 years
Patients on renal replacement therapy (RRT)
Post renal or liver transplantation
History of CAD, ischemic cardiomyopathy, PVD, ventricular arrhythmia
Decompensated cirrhosis not fulfilling ACLF criteria
Cirrhotics with AKI managed as outpatients
Grade III/IV HE or Shock requiring inotropes or patients on mechanical ventilator at time of randomization
In-hospital new AKI
Active urinary sediments - 2+ albumin or above, dysmorphic RBCs
Known CKD, obstructive uropathy
Lack of informed consent
Prior intolerance or S/E to Terlipressin or albumin