Clinical Trial Comparing Noradrenaline (NA) Plus Placebo Versus Noradrenaline Plus Terlipressin (TP) in Septic Shock

April 25, 2023 updated by: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Randomized Clinical Trial Comparing Noradrenaline Plus Placebo Versus Terlipressin Plus Noradrenaline for the Treatment of Septic Shock

Septic shock is a major health problem. In the clinical practice guidelines of the Surviving Sepsis Campaign is recommended to add vasopressin (VP) or epinephrine in case of not reaching the goal of mean arterial pressure (MAP) although with a low level of evidence.

This is a clinical trial with the purpose of comparing the efficacy and safety of norepinephrine (NE) plus placebo versus NE plus terlipressin (TP) in adult patients with septic shock and with a Sepsis related Organ Failure Assessment score (SOFA)> 4 points. The primary objective will be a combined end-point: reduction of organic dysfunction measured at 72 h by SOFA score and by the increase in ICU (Intensive care unit) -free days measured at 28 days.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Introduction: Septic shock is a major health problem. The clinical practice guidelines of the Surviving Sepsis Campaign establish the use of NE if after resuscitation with fluids a MAP> 65 mm Hg is not achieved. In these guidelines, it is recommended to add VP or epinephrine in case of not reaching the goal of MAP although with a low level of evidence.

TP is a synthetic analogue of VP with a long half-life. Preliminary studies on the use of TP associated with NE have not shown a decrease in mortality, although a reduction in organic dysfunction at 72 h, with discordant data regarding the rate of adverse events.

Material and Methods: Randomized, parallel, double-blind and multicenter clinical trial with the purpose of comparing the efficacy and safety of NE plus placebo versus NE plus TP in adult patients with septic shock and with a SOFA score> 4 points. The threshold dose of NE> 0.2 µg / kg / min is chosen to associate the second vasopressor (TP or placebo). The primary objective will be a combined end-point: reduction of organic dysfunction measured at 72 h by SOFA score and by the increase in ICU -free days measured at 28 days. The secondary objectives will be: mortality at 28 and 90 days, the need of renal replacement therapies, mechanical ventilation-free days, vasopressor-free days, and adverse reactions. Sample size of 152 patients (76 per arm), stratified by center and severity of illness. In addition, 6 single nucleotide polymorphisms of the vasopressin V1a receptor and a polymorphism of leucyl / cystinyl aminopeptidase or vasopressinase will be determined to establish its association with mortality in septic shock and with the efficacy and the occurrence of adverse effects due to the use of TP.

Study Type

Interventional

Enrollment (Anticipated)

152

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Spain
      • Cádiz, Spain, 11009
      • Córdoba, Spain, 14004
      • Granada, Spain, 18014
        • Recruiting
        • Hospital Universitario Virgen de las Nieves
        • Contact:
        • Principal Investigator:
          • María del Mar Jiménez Quintana
      • Granada, Spain, 18016
      • Jaén, Spain, 23007
        • Recruiting
        • Complejo Hospitalario de Jaén
        • Contact:
        • Principal Investigator:
          • Ricardo Rivera Fernández
      • Málaga, Spain, 29010
        • Recruiting
        • Hospital Universitario Regional de Malaga
        • Contact:
        • Principal Investigator:
          • Manuel Herrera Gutiérrez
      • Seville, Spain, 41013
        • Recruiting
        • Hospital Universitario Virgen del Rocio
        • Contact:
        • Principal Investigator:
          • Rosario Amaya Villar
      • Seville, Spain, 41009
        • Recruiting
        • Hospital Universitario Virgen Macarena
        • Contact:
        • Principal Investigator:
          • José Garnacho Montero
    • Cádiz
      • Jerez De La Frontera, Cádiz, Spain, 11407
        • Recruiting
        • Hospital Universitario Jerez de la Frontera
        • Contact:
    • Sevilla
      • Bormujos, Sevilla, Spain, 41930

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Adult patients (18 years or older).
  2. Patients with septic shock
  3. Patients with a SOFA > 4 points.

5. Oxygen saturation in the central venous system > 70% 5. Central venous pressure> 8 mmHg. 6. Signature of the informed consent by the patient or her legal representative.

Exclusion Criteria:

  1. Pregnant or lactating patients.
  2. Pathologies in which terlipressin is clinically indicated: gastrointestinal bleeding due to esophageal-gastric varices, hepatorenal syndrome.
  3. Patients diagnosed with unstable acute coronary syndrome.
  4. Patients with acute or chronic mesenteric ischemia.
  5. Patients with Raynaud's Phenomenon, or vasospastic disease.
  6. Patients participating in another intervention clinical trial.
  7. Patients with active bleeding.
  8. Patients with renal replacement technique at the time of randomization.
  9. Patients with some limitation of life support treatment
  10. Previous use of terlipressin during your stay in the intensive Care Unit

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Noradrenaline plus Terlipressin
Patients enrolled in this arm, will receive noradrenaline with dose equal to or greater than 0.2 μg / Kg / min for at least 3 hours. Solution for infusion (Intravenous). And: Terlipressin with dose 1 mg every 6 hours diluted in a 50 mL serum to pass in 15-30 minutesin injectable solution. Intravenous (diluted in a 50 mL serum to pass in 15-30 minutes)
Combination product: Noradrenaline plus Terlipressin
Comparison Norepinephrine plus placebo versus Terlipressin plus Norepinephrine for the Treatment of Septic Shock
Other Names:
  • Noradrenaline plus placebo
Placebo Comparator: Noradrenaline plus placebo
Patients enrolled in this arm, will receive noradrenaline with dose equal to or greater than 0.2 μg / Kg / min for at least 3 hours in solution for infusion (Intravenous), and placebo with solution in vial with the same external appearance as terlipressin. 1 mg every 6 hours, diluted in a 50 mL serum to pass in 15-30 minutes in injectable solution Route of administration: Intravenous, diluted in a 50 mL serum to pass in 15-30 minutes
Combination product: Noradrenaline plus Terlipressin
Comparison Norepinephrine plus placebo versus Terlipressin plus Norepinephrine for the Treatment of Septic Shock
Other Names:
  • Noradrenaline plus placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Organ failure
Time Frame: 72 hours
Number of organ failures related sepsis. Assessment Sepsis related Organ Failure Assessmen scale (SOFA scale) after administration of terlipressin / placebo. These scale assesses organ dysfunction. In patients with infection, a SOFA score ≥ 2 points (in patients with chronic organ dysfunction, a 2 point increase from baseline score) is diagnostic of sepsis.
72 hours
Days of life free of stay in the Intensive Care Unit
Time Frame: 28 days
Number of the days of life free of stay in the Intensive Care Unit measured after the administration of terlipressin / placebo
28 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Lactate clearance
Time Frame: 6, 12, 24 and 72 hours
Measure of the difference between lactate in arterial blood measured at the beginning of vasopressor treatment and that measured at 6, 12, 24 and 72 hours.
6, 12, 24 and 72 hours
Vasopressor-free days of life
Time Frame: 28 days
Measure of vasopressor-free days of life
28 days
Need of renal replacement therapies
Time Frame: 28 days
Assessment of the change in the need of renal replacement therapies
28 days
Mechanical ventilation-free days of life
Time Frame: 28 days
Measure of days free of mechanical ventilation, by means of the difference between 28 and the sum of the days the patient is under invasive mechanical ventilation or has died.
28 days
vasopressor index
Time Frame: 28 days
Calculation of the vasopressor index, defined as dose of dopamine + dose of dobutamine + dose of epinephrine (x100) + dose of phenylephrine (x100) + dose of terlipressin / placebo.
28 days
Mortality
Time Frame: 28 days
Evaluation of the number of patients who die from the signing of the informed consent until day 28
28 days
Mortality
Time Frame: 90 days
Evaluation of the number of patients who die from the signing of the informed consent until day 90
90 days
Adverse effects related to the administration of vasopressors
Time Frame: 90 days
Measure of the adverse effects related to the administration of vasopressors until the end of study
90 days
Relation between organ failure and days of life free of stay in the Intensive Care Unit with the genetic variants of the receptor 1a and LNPEP
Time Frame: 90 days
Measure of the relation between number of organ failures related sepsis and number of the days of life free of stay in the Intensive Care Unit with the genetic variants of the vasopressin receptor 1a and LNPEP
90 days
Relation between the appearance of adverse effects and genetic variants of the receptor 1a and LNPEP.
Time Frame: 90 days
Measure of the relation between adverse effects due to the use of terlipressin and genetic variants of the vasopressin receptor 1a and LNPEP
90 days
Relation of the mortality with genetic variants of the receptor 1a and LNPEP.
Time Frame: 90 days
Measure of the relation between the mortality with genetic variants of the vasopressin receptor 1a and LNPEP
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Investigators

  • Principal Investigator: José Garnacho Montero, Hospital Universitario Virgen Macarena

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 11, 2022

Primary Completion (Anticipated)

November 1, 2024

Study Completion (Anticipated)

November 1, 2024

Study Registration Dates

First Submitted

November 18, 2021

First Submitted That Met QC Criteria

January 13, 2022

First Posted (Actual)

January 26, 2022

Study Record Updates

Last Update Posted (Actual)

April 27, 2023

Last Update Submitted That Met QC Criteria

April 25, 2023

Last Verified

April 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CONTENTSS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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