Clinical trial NCT05207280: Clinical Trial Comparing Noradrenaline (NA) Plus Placebo Versus Noradrenaline Plus Terlipressin (TP) in Septic Shock
Official title: Randomized Clinical Trial Comparing Noradrenaline Plus Placebo Versus Terlipressin Plus Noradrenaline for the Treatment of Septic Shock
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Septic Shock
Keywords: Septic Shock
Lead sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Sponsor class: OTHER
First posted: 2022-01-26
Enrollment: 152
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, parallel, multicenter, double-blind clinical trial with two treatment arms
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Organ failure
timeFrame: 72 hours
measure: Days of life free of stay in the Intensive Care Unit
timeFrame: 28 days
Secondary outcomes:
measure: Lactate clearance
timeFrame: 6, 12, 24 and 72 hours
measure: Vasopressor-free days of life
timeFrame: 28 days
measure: Need of renal replacement therapies
timeFrame: 28 days
measure: Mechanical ventilation-free days of life
timeFrame: 28 days
measure: vasopressor index
timeFrame: 28 days
measure: Mortality
timeFrame: 28 days
measure: Mortality
timeFrame: 90 days
measure: Adverse effects related to the administration of vasopressors
timeFrame: 90 days
measure: 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
timeFrame: 90 days
measure: Relation between the appearance of adverse effects and genetic variants of the receptor 1a and LNPEP.
timeFrame: 90 days
measure: Relation of the mortality with genetic variants of the receptor 1a and LNPEP.
timeFrame: 90 days
Other outcomes:
Locations:
city: Jerez De La Frontera
country: Spain
facility: Hospital Universitario Jerez de la Frontera
state: Cádiz
city: Bormujos
country: Spain
facility: Hospital San Juan de Dios del Aljarafe
state: Sevilla
city: Cádiz
country: Spain
facility: Hospital Puerta del mar
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Granada
country: Spain
facility: Hospital Universitario Clínico San Cecilio
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaén
city: Málaga
country: Spain
facility: Hospital Universitario Regional de Málaga
city: Seville
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Seville
country: Spain
facility: Hospital Universitario Virgen del Rocío
Study officials:
affiliation: Hospital Universitario Virgen Macarena
name: José Garnacho Montero
role: PRINCIPAL_INVESTIGATOR
References: