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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Septic Shock

Intervention / Treatment
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* Combination Product: Noradrenaline plus Terlipressin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (18 years or older). Patients with septic shock 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: Pregnant or lactating patients. Pathologies in which terlipressin is clinically indicated: gastrointestinal bleeding due to esophageal-gastric varices, hepatorenal syndrome. Patients diagnosed with unstable acute coronary syndrome. Patients with acute or chronic mesenteric ischemia. Patients with Raynaud's Phenomenon, or vasospastic disease. Patients participating in another intervention clinical trial. Patients with active bleeding. Patients with renal replacement technique at the time of randomization. Patients with some limitation of life support treatment Previous use of terlipressin during your stay in the intensive Care Unit

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, parallel, multicenter, double-blind clinical trial with two treatment arms
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Noradrenaline plus Terlipressin<br>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<br>* Comparison Norepinephrine plus placebo versus Terlipressin plus Norepinephrine for the Treatment of Septic Shock<br>* Other names: Noradrenaline plus placebo;|
| Placebo Comparator: Noradrenaline plus placebo<br>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<br>* Comparison Norepinephrine plus placebo versus Terlipressin plus Norepinephrine for the Treatment of Septic Shock<br>* Other names: Noradrenaline plus placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Vasopressor-free days of life | Measure of vasopressor-free days of life | 28 days | 
| Need of renal replacement therapies | Assessment of the change in the need of renal replacement therapies | 28 days | 
| 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 | 
| 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 | 
| Mortality | Evaluation of the number of patients who die from the signing of the informed consent until day 28 | 28 days | 
| Mortality | 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 | 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 | 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. | 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. | Measure of the relation between the mortality with genetic variants of the vasopressin receptor 1a and LNPEP | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic Shock