<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04416282</url>
  </required_header>
  <id_info>
    <org_study_id>ILBS-ACLF-04</org_study_id>
    <nct_id>NCT04416282</nct_id>
  </id_info>
  <brief_title>Efficacy of Early Terlipressin Plus Albumin Therapy in Comparison to Standard Treatment for HRS-AKI in Acute-on-chronic Liver Failure.</brief_title>
  <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.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institute of Liver and Biliary Sciences, India</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institute of Liver and Biliary Sciences, India</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Acute on chronic liver failure (ACLF) is a distinct entity where, because of severe acute&#xD;
      hepatic injury, a rapid loss of liver function develops in a patient with previous chronic&#xD;
      liver disease(4). These patients have severe hepatic dysfunction, and outcome is defined by&#xD;
      functional hepatic reserve and extent of extra-hepatic organ failures(5). Renal failure is a&#xD;
      frequent extra-hepatic organ failure, and its presence is an independent prognostic marker&#xD;
      for mortality(12). The pathophysiological basis of renal dysfunction in patients with ACLF is&#xD;
      different compared to those with decompensated cirrhosis (DC)(6). Systemic inflammation is&#xD;
      the hallmark of ACLF, characterized by a cytokine storm wherein there is an increase in both&#xD;
      pro- and anti-inflammatory cytokines, such as interleukin (IL)-6, IL-8, IL-1β, and IL-10,&#xD;
      leading to circulatory dysfunction and organ failure(3). These patients therefore have a&#xD;
      higher incidence and progression of acute kidney injury (AKI). Diagnosis of HRS-AKI in ACLF&#xD;
      currently requires 48 h of volume repletion with albumin and diuretic withdrawal. Therefore&#xD;
      waiting for 48 hours to start treatment with terlipressin can be associated with worsening of&#xD;
      AKI stage, worsening of ACLF stage and thereby suboptimal treatment response and high&#xD;
      mortality despite treatment response. Therefore early initiation of terlipressin as&#xD;
      continuous infusion after volume repletion with IV albumin in ACLF-AKI is safe and prevents&#xD;
      AKI progression by splanchnic vasoconstriction and improved renal perfusion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aim To compare the effect of Early initiation of Terlipressin (ET arm) to albumin at 12 hour&#xD;
      in ACLF patients with non-volume responsive AKI versus standard Terlipressin (ST arm) at 48&#xD;
      hours.&#xD;
&#xD;
      Primary Objective Efficacy of early terlipressin infusion in comparison to Standard treatment&#xD;
      for resolution of AKI at day 7.&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
        -  Full and partial AKI response at 48 and 72 h and 96 hours&#xD;
&#xD;
        -  Mortality at Day 28, Day 90&#xD;
&#xD;
        -  Baseline organ failure(s), MELD, CLIF-SOFA score and ACLF score&#xD;
&#xD;
        -  New onset organ failures&#xD;
&#xD;
        -  Urine Output&#xD;
&#xD;
        -  Progression or resolution of OFs at day 7&#xD;
&#xD;
        -  Change in MELD, CLIF-SOFA score and ACLF score at day 7&#xD;
&#xD;
        -  Change in NGAL, FENa, FE-Urea at day 7&#xD;
&#xD;
        -  Treatment related adverse effects and their grades&#xD;
&#xD;
      Methodology:&#xD;
&#xD;
      Study population:&#xD;
&#xD;
      All patients admitted to the Institute of Liver and Biliary Sciences (ILBS) with ACLF with&#xD;
      AKI- HRS will be evaluated for inclusion. ACLF will be defined by the APASL criteria.&#xD;
&#xD;
      Study Design A prospective, randomized, single center open label study&#xD;
&#xD;
      Study Period:Two year&#xD;
&#xD;
      Intervention &amp; monitoring:&#xD;
&#xD;
      Clinical Protocol An informed consent will be taken from ACLF patients with AKI within&#xD;
      24-hours of admission. No alteration in the treatment or investigative procedures of the&#xD;
      included patients will be done. All included patients will be followed from admission till&#xD;
      death or discharge. All discharged patients will then be followed till 30-days.&#xD;
&#xD;
      Preliminary work up&#xD;
&#xD;
      At admission:&#xD;
&#xD;
      (A) Complete history and physical examination&#xD;
&#xD;
        -  Recent Diuretics use&#xD;
&#xD;
        -  Loose stools&#xD;
&#xD;
        -  Recurrent vomiting&#xD;
&#xD;
        -  Fever, signs of sepsis (SIRS)&#xD;
&#xD;
        -  H/s/o LRTI, SSTI, SBP&#xD;
&#xD;
        -  Recent contrast use (&lt; 7 days)&#xD;
&#xD;
        -  Use of nephrotoxins including NSAIDs&#xD;
&#xD;
        -  Prior renal dysfunction, known CKD, HD&#xD;
&#xD;
        -  History of HTN, Diabetes&#xD;
&#xD;
        -  History of renal stones&#xD;
&#xD;
        -  History s/o hypotensive episodes (shock)&#xD;
&#xD;
      Pre-randomization interventions:&#xD;
&#xD;
      (B) Intervention during 0-12 hours (Before randomization) -&#xD;
&#xD;
        -  Withdrawal of diuretics&#xD;
&#xD;
        -  Withdrawal of lactulose (in patients with loose stools)&#xD;
&#xD;
        -  Urine output monitoring (catheterize and monitor hourly or 12 h cumulative)&#xD;
&#xD;
        -  2 hourly MAP, Pulse rate&#xD;
&#xD;
        -  Empirical IV antibiotics to be given in case of suspected/proven sepsis (Avoid&#xD;
           nephrotoxic drugs e.g Amikacin, Colistin, Amphotericin etc as possible)&#xD;
&#xD;
        -  IV hydration with albumin at 12 hours preferably 40 g (20 %) + 500 ml crystalloids)&#xD;
&#xD;
      Labs and follow-up:&#xD;
&#xD;
        -  Baseline (at admission) - Blood : KFT, LFT, CBC, INR, Blood c/s, pro-BNP Imaging : USG&#xD;
           abdomen, USG KUB, Renal doppler, C-X-ray, 2D ECHO Urine : Urine R/E and cultures, Urine&#xD;
           Na, Urea, NGAL, Creatinine, FENa, FE Urea A/F analysis - for SBP&#xD;
&#xD;
        -  At 12 hours (Before randomization) - Blood - KFT&#xD;
&#xD;
        -  At D1, D2, D3, D5, D7, D14, D28 post randomization Blood : KFT Urine : Urine Na, Urea,&#xD;
           NGAL, Creatinine, FENa, FE Urea (At Day 3 and 7) Imaging : Renal doppler (Day 3)&#xD;
&#xD;
      Clinical evaluation:&#xD;
&#xD;
        -  Etiology of cirrhosis (Baseline)&#xD;
&#xD;
        -  Severity of liver disease (Baseline, D3, D7) MELD score, CLIF-SOFA score, MELD-Na score,&#xD;
           AARC score&#xD;
&#xD;
        -  Stage of ACLF (Baseline,D3, D7) AARC grade, CLIF ACLF grade&#xD;
&#xD;
        -  Complications / Organ failures (Baseline,D3, D7) HE, Bleed, AKI stage, SBP, Infection&#xD;
           (specify site and severity) Respiratory and circulatory failure&#xD;
&#xD;
      Follow up duration Duration of admission till discharge or death will be noted. Patients will&#xD;
      be followed up to 28-days for re-admission(s) and survival.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 22, 2020</start_date>
  <completion_date type="Actual">June 10, 2022</completion_date>
  <primary_completion_date type="Actual">June 10, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Acute Kidney Injury reversal by day 7 in both groups</measure>
    <time_frame>Day 7</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mortality in both groups</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality in both groups</measure>
    <time_frame>Day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression or resolution of Organ failures</measure>
    <time_frame>Day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events in both groups</measure>
    <time_frame>Day 90</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">70</enrollment>
  <condition>Acute-On-Chronic Liver Failure</condition>
  <condition>Hepatorenal Syndrome</condition>
  <condition>Acute Kidney Injury</condition>
  <arm_group>
    <arm_group_label>Terlipressin + Albumin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Injection terlipressin 2 mg/24 hours infusion + i/v albumin 1g/Kg/day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Albumin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>i/v albumin 1g/Kg/day for next 36 hours f/b inj terlipressin 2mg/24 hours</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Terlipressin</intervention_name>
    <description>Injection terlipressin 2 mg/24 hours infusion</description>
    <arm_group_label>Terlipressin + Albumin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Albumin</intervention_name>
    <description>i/v albumin 1g/Kg/day</description>
    <arm_group_label>Albumin</arm_group_label>
    <arm_group_label>Terlipressin + Albumin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 18-65 years&#xD;
&#xD;
          2. ACLF as per APASL criteria&#xD;
&#xD;
          3. AKI at admission as defined by ICA-AKI criteria&#xD;
&#xD;
          4. AKI stage 2/3 at 12 hour of admission&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        -&#xD;
&#xD;
        At Admission:&#xD;
&#xD;
          -  Age &lt;18 years&#xD;
&#xD;
          -  Patients on renal replacement therapy (RRT)&#xD;
&#xD;
          -  Post renal or liver transplantation&#xD;
&#xD;
          -  History of CAD, ischemic cardiomyopathy, PVD, ventricular arrhythmia&#xD;
&#xD;
          -  Decompensated cirrhosis not fulfilling ACLF criteria&#xD;
&#xD;
          -  Cirrhotics with AKI managed as outpatients&#xD;
&#xD;
          -  Grade III/IV HE or Shock requiring inotropes or patients on mechanical ventilator at&#xD;
             time of randomization&#xD;
&#xD;
          -  In-hospital new AKI&#xD;
&#xD;
          -  Active urinary sediments - 2+ albumin or above, dysmorphic RBCs&#xD;
&#xD;
          -  Known CKD, obstructive uropathy&#xD;
&#xD;
          -  Lack of informed consent&#xD;
&#xD;
          -  Prior intolerance or S/E to Terlipressin or albumin&#xD;
&#xD;
        At 12 Hour before randomization:&#xD;
&#xD;
        • Regression of AKI (&gt;0.3 mg/dl) above baseline after IV albumin (20% 40 gm) + IV&#xD;
        Crystalloids 500 ml therapy for 12 hours&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Institute of Liver &amp; Biliary Sciences</name>
      <address>
        <city>New Delhi</city>
        <state>Delhi</state>
        <zip>110070</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>June 1, 2020</study_first_submitted>
  <study_first_submitted_qc>June 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>April 5, 2023</last_update_submitted>
  <last_update_submitted_qc>April 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Failure</mesh_term>
    <mesh_term>Hepatic Insufficiency</mesh_term>
    <mesh_term>End Stage Liver Disease</mesh_term>
    <mesh_term>Acute-On-Chronic Liver Failure</mesh_term>
    <mesh_term>Hepatorenal Syndrome</mesh_term>
    <mesh_term>Acute Kidney Injury</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Terlipressin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04416282
org study id: ILBS-ACLF-04
nct id: NCT04416282
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Acute Kidney Injury reversal by day 7 in both groups
time frame: Day 7
measure: Mortality in both groups
time frame: Day 28
measure: Mortality in both groups
time frame: Day 90
measure: Progression or resolution of Organ failures
time frame: Day 90
measure: Adverse Events in both groups
time frame: Day 90
arm group label: Terlipressin + Albumin
arm group type: Experimental
description: Injection terlipressin 2 mg/24 hours infusion + i/v albumin 1g/Kg/day
arm group label: Albumin
arm group type: Active Comparator
description: i/v albumin 1g/Kg/day for next 36 hours f/b inj terlipressin 2mg/24 hours
intervention type: Drug
intervention name: Terlipressin
description: Injection terlipressin 2 mg/24 hours infusion
arm group label: Terlipressin + Albumin
intervention type: Biological
intervention name: Albumin
description: i/v albumin 1g/Kg/day
arm group label: Albumin
arm group label: Terlipressin + Albumin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
facility: 
country: India
responsible party type: Sponsor
mesh term: Liver Failure
mesh term: Hepatic Insufficiency
mesh term: End Stage Liver Disease
mesh term: Acute-On-Chronic Liver Failure
mesh term: Hepatorenal Syndrome
mesh term: Acute Kidney Injury
mesh term: Terlipressin
sharing ipd: Undecided