<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/NCT03822091</url>
  </required_header>
  <id_info>
    <org_study_id>TERLI AND NORAD IN HRS</org_study_id>
    <nct_id>NCT03822091</nct_id>
  </id_info>
  <brief_title>Terlipressin Infusion Alone Vs Terlipressin With Noradrenaline Infusion In The Treatment of Hepatorenal Syndrome Type 1</brief_title>
  <official_title>Comparison of The Effectiveness of Terlipressin Infusion Alone Vs Terlipressin With Noradrenaline Infusion In The Treatment of Hepatorenal Syndrome Type 1</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Postgraduate Institute of Medical Education and Research</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Postgraduate Institute of Medical Education and Research</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Hepatorenal syndrome (HRS) is defined as a functional renal failure in a patient with chronic&#xD;
      liver disease, or liver cirrhosis.The splanchnic circulation undergoes severe vasodilation,&#xD;
      as a result of portal hypertension, causing an underfilling of systemic arteries.This results&#xD;
      in intense renal vasoconstriction and functional renal failure. The best treatment options&#xD;
      for HRS I would be a drug which has renal vasodilator property and additional splanchnic&#xD;
      vasoconstriction. An increase in circulating blood volume would be of additional benefit.&#xD;
      Currently Terlipressin is considered superior to other drugs in the management of HRS I.&#xD;
      Other drugs in use are Noradrenaline and Midodrine. Albumin is added to these drugs in order&#xD;
      to expand plasma volume. Terlipressin, a Vasopressin analog, has agonistic activity at V1&#xD;
      receptors. Noradrenaline acts as an agonist at α-adrenergic receptors with mild β-agonistic&#xD;
      activity. The two major drugs used in the management of HRS act at different receptors and&#xD;
      have completely varied mechanisms of action. Thus, a combination therapy would improve the&#xD;
      rate of response considerably. There have been multiple studies, measuring the efficacy,&#xD;
      safety and dosing of both drugs, but none combining both Terlipressin and Noradrenaline.&#xD;
      Hence our study would be a pioneer in formulating a new and possibly more efficacious&#xD;
      treatment protocol for patients of Type I HRS, in whom the treatment options are otherwise&#xD;
      very limited. If successful, this would open new horizons of therapy for Terlipressin&#xD;
      refractory HRS, which, otherwise is an ominous condition.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 28, 2019</start_date>
  <completion_date type="Actual">January 30, 2020</completion_date>
  <primary_completion_date type="Actual">January 30, 2020</primary_completion_date>
  <phase>Phase 3</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>Number of patients responding to treatment.</measure>
    <time_frame>15 days</time_frame>
    <description>Complete response defined as serum creatinine &lt;1.5 mg/dl</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients who will develop adverse events due to drugs used for treatment</measure>
    <time_frame>15 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients surviving without transplant.</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Type 1 HEPATO RENAL SYNDROME(HRS)</condition>
  <arm_group>
    <arm_group_label>TERLIPRESSIN GROUP</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>TERLIPRESSIN WITH NORADRENALINE GROUP</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Terlipressin</intervention_name>
    <description>Patients with Type 1 HRS will be given Terlipressin at the dose of 2mg/24 hrs as infusion. After 48 hours of initial monitoring, patients who do not respond to the initial dose of Terlipressin, and randomised into group A and B. Group A patients will receive further higher doses of Terlipressin. The dose of Terlipressin will be increased by 1mg after 24 hrs if:&#xD;
the creatinine values decrease by &lt;12.5%&#xD;
MAP increase of &lt;10 mmHg&#xD;
urine output of &lt;200 ml in 4 hours.&#xD;
Maximum terlipressin dose will be given upto 12 mg/day.Albumin will be administered in both arms according to standard protocol at the following dose :&#xD;
1st day - Albumin at 1 gram/kg - a maximum dose of 100grams can be given.&#xD;
A dose of 20gram/day to 60gram/day in the following days.</description>
    <arm_group_label>TERLIPRESSIN GROUP</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Terlipressin and Noradrenaline</intervention_name>
    <description>Patients with Type 1 HRS will be given Terlipressin at the dose of 2mg/24 hrs as infusion. After 48 hours of initial monitoring, patients who do not respond to the initial dose of Terlipressin, will be randomised into group A and B. Group B patients will be treated with&#xD;
Terlipressin(2mg/24hr infusion- fixed dose) and Noradrenaline, which would be given as a continuous infusion at a starting dose of 0.5 mg/hr. The dose od noradrenaline will be increased every 24 hours in steps of 0.5 mg/hr, the maximum dose being 3 mg/hr IF:&#xD;
the creatinine values decrease by &lt;12.5%&#xD;
MAP increase of &lt;10 mmHg&#xD;
urine output of &lt;200 ml in 4 hours.</description>
    <arm_group_label>TERLIPRESSIN WITH NORADRENALINE GROUP</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. age&gt;18 years and &lt;80 yrs;&#xD;
&#xD;
          2. Cirrhosis as diagnosed by clinical findings, endoscopy or USG examination or by liver&#xD;
             biopsy.&#xD;
&#xD;
          3. HRS I as defined by the following features:&#xD;
&#xD;
               1. The patient should have Cirrhosis and also ascites&#xD;
&#xD;
               2. Renal failure of rapid onset -Initial value of sCr, doubling to reach a level of&#xD;
                  more than 226mmol/L (2.5 mg/dL) in less than two weeks&#xD;
&#xD;
               3. There should be absence of shock.&#xD;
&#xD;
               4. sCr value does not reduce to less than 1.5 mg/dl even after 2 days of stopping&#xD;
                  diuretics and giving Inj.Albumin for plasma volume expansion (1g/kg ) upto&#xD;
                  100g/day.&#xD;
&#xD;
               5. No H/O being treated currently or recently with drugs having nephrotoxicity.&#xD;
&#xD;
               6. Absence of parenchymal renal disease:&#xD;
&#xD;
                    -  Proteinuria &lt; 0.5g/day&#xD;
&#xD;
                    -  Absence of microhaematuria (&lt;50 red cells/high powered field)&#xD;
&#xD;
                    -  Normal renal ultrasonography&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. AKI improved after plasma volume expansion&#xD;
&#xD;
          2. Any history of coronary artery disease, peripheral vascular disease, arrhythmias, and&#xD;
             cardiomyopathy.&#xD;
&#xD;
          3. Hepatocellular Carcinoma&#xD;
&#xD;
          4. Septic shock&#xD;
&#xD;
          5. Any severe extra-hepatic condition including respiratory and cardiac failure.&#xD;
&#xD;
          6. Any contraindication which precludes the use of Noradrenaline and Terlipressin&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Post Graduate Institute of Medical Education and Research</name>
      <address>
        <city>Chandigarh</city>
        <zip>160012</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 28, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 30, 2019</study_first_posted>
  <last_update_submitted>May 7, 2023</last_update_submitted>
  <last_update_submitted_qc>May 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 9, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Postgraduate Institute of Medical Education and Research</investigator_affiliation>
    <investigator_full_name>Dr.Virendra Singh</investigator_full_name>
    <investigator_title>Professor of Hepatology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatorenal Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Terlipressin</mesh_term>
    <mesh_term>Norepinephrine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03822091
org study id: TERLI AND NORAD IN HRS
nct id: NCT03822091
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Hepatorenal syndrome (HRS) is defined as a functional renal failure in a patient with chronic
      liver disease, or liver cirrhosis.The splanchnic circulation undergoes severe vasodilation,
      as a result of portal hypertension, causing an underfilling of systemic arteries.This results
      in intense renal vasoconstriction and functional renal failure. The best treatment options
      for HRS I would be a drug which has renal vasodilator property and additional splanchnic
      vasoconstriction. An increase in circulating blood volume would be of additional benefit.
      Currently Terlipressin is considered superior to other drugs in the management of HRS I.
      Other drugs in use are Noradrenaline and Midodrine. Albumin is added to these drugs in order
      to expand plasma volume. Terlipressin, a Vasopressin analog, has agonistic activity at V1
      receptors. Noradrenaline acts as an agonist at α-adrenergic receptors with mild β-agonistic
      activity. The two major drugs used in the management of HRS act at different receptors and
      have completely varied mechanisms of action. Thus, a combination therapy would improve the
      rate of response considerably. There have been multiple studies, measuring the efficacy,
      safety and dosing of both drugs, but none combining both Terlipressin and Noradrenaline.
      Hence our study would be a pioneer in formulating a new and possibly more efficacious
      treatment protocol for patients of Type I HRS, in whom the treatment options are otherwise
      very limited. If successful, this would open new horizons of therapy for Terlipressin
      refractory HRS, which, otherwise is an ominous condition.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients responding to treatment.
time frame: 15 days
description: Complete response defined as serum creatinine <1.5 mg/dl
measure: Number of patients who will develop adverse events due to drugs used for treatment
time frame: 15 days
measure: Number of patients surviving without transplant.
time frame: 90 days
arm group label: TERLIPRESSIN GROUP
arm group type: Active Comparator
arm group label: TERLIPRESSIN WITH NORADRENALINE GROUP
arm group type: Experimental
intervention type: Drug
intervention name: Terlipressin
description: Patients with Type 1 HRS will be given Terlipressin at the dose of 2mg/24 hrs as infusion. After 48 hours of initial monitoring, patients who do not respond to the initial dose of Terlipressin, and randomised into group A and B. Group A patients will receive further higher doses of Terlipressin. The dose of Terlipressin will be increased by 1mg after 24 hrs if:
the creatinine values decrease by <12.5%
MAP increase of <10 mmHg
urine output of <200 ml in 4 hours.
Maximum terlipressin dose will be given upto 12 mg/day.Albumin will be administered in both arms according to standard protocol at the following dose :
1st day - Albumin at 1 gram/kg - a maximum dose of 100grams can be given.
A dose of 20gram/day to 60gram/day in the following days.
arm group label: TERLIPRESSIN GROUP
intervention type: Drug
intervention name: Terlipressin and Noradrenaline
description: Patients with Type 1 HRS will be given Terlipressin at the dose of 2mg/24 hrs as infusion. After 48 hours of initial monitoring, patients who do not respond to the initial dose of Terlipressin, will be randomised into group A and B. Group B patients will be treated with
Terlipressin(2mg/24hr infusion- fixed dose) and Noradrenaline, which would be given as a continuous infusion at a starting dose of 0.5 mg/hr. The dose od noradrenaline will be increased every 24 hours in steps of 0.5 mg/hr, the maximum dose being 3 mg/hr IF:
the creatinine values decrease by <12.5%
MAP increase of <10 mmHg
urine output of <200 ml in 4 hours.
arm group label: TERLIPRESSIN WITH NORADRENALINE GROUP
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
facility: 
country: India
responsible party type: Principal Investigator
investigator affiliation: Postgraduate Institute of Medical Education and Research
investigator full name: Dr.Virendra Singh
investigator title: Professor of Hepatology
mesh term: Hepatorenal Syndrome
mesh term: Syndrome
mesh term: Terlipressin
mesh term: Norepinephrine
sharing ipd: No