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

Septic Shock Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05207280
• Other study ID #: CONTENTSS
• Status: Recruiting
• Phase: Phase 3
• Start date: October 11, 2022
• Est. completion date: November 2024

Study information

• Verified date: April 2023
• Source: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Contact: Clara Rosso Fernández
• Phone: 955012144
• Email: claram.rosso.sspa[@]juntadeandalucia.es
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 152
• Est. completion date: November 2024
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic

Intervention

Combination Product:
• Noradrenaline plus Terlipressin
Comparison Norepinephrine plus placebo versus Terlipressin plus Norepinephrine for the Treatment of Septic Shock

Locations

Country	Name	City	State
Spain	Hospital San Juan de Dios del Aljarafe	Bormujos	Sevilla
Spain	Hospital Puerta del mar	Cádiz
Spain	Hospital Universitario Reina Sofía	Córdoba
Spain	Hospital Universitario Clínico San Cecilio	Granada
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Complejo Hospitalario de Jaén	Jaén
Spain	Hospital Universitario Jerez de la Frontera	Jerez De La Frontera	Cádiz
Spain	Hospital Universitario Regional de Málaga	Málaga
Spain	Hospital Universitario Virgen del Rocío	Seville
Spain	Hospital Universitario Virgen Macarena	Seville

Sponsors (1)

Lead Sponsor	Collaborator
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Organ failure	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
Primary	Days of life free of stay in the Intensive Care Unit	Number of the days of life free of stay in the Intensive Care Unit measured after the administration of terlipressin / placebo	28 days
Secondary	Lactate clearance	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
Secondary	Vasopressor-free days of life	Measure of vasopressor-free days of life	28 days
Secondary	Need of renal replacement therapies	Assessment of the change in the need of renal replacement therapies	28 days
Secondary	Mechanical ventilation-free days of life	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
Secondary	vasopressor index	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
Secondary	Mortality	Evaluation of the number of patients who die from the signing of the informed consent until day 28	28 days
Secondary	Mortality	Evaluation of the number of patients who die from the signing of the informed consent until day 90	90 days
Secondary	Adverse effects related to the administration of vasopressors	Measure of the adverse effects related to the administration of vasopressors until the end of study	90 days
Secondary	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	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
Secondary	Relation between the appearance of adverse effects and genetic variants of the receptor 1a and LNPEP.	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
Secondary	Relation of the mortality with genetic variants of the receptor 1a and LNPEP.	Measure of the relation between the mortality with genetic variants of the vasopressin receptor 1a and LNPEP	90 days