Norepinephrine and Vasopressin for Rescue Versus Early Vasopressin for Vasopressor Dependent Sepsis (NoVa)

Norepinephrine and Vasopressin for Rescue Versus Early Vasopressin for Vasopressor Dependent Sepsis: An Open-label, Multicenter, Randomized, Controlled Trial: NoVa

The norepinephrine and vasopressin for rescue versus early vasopressin for vasopressor dependent sepsis (NoVa) is a phase 3, multicenter, open-label, randomized controlled trial comparing an early vasopressin initiation strategy versus norepinephrine plus vasopressin initiation only as a rescue strategy for hemodynamic management of critically ill patients with vasopressor dependent sepsis.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Early Vasopressin; Drug: Norepinephrine and Vasopressin for Rescue

Detailed Description

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated body response to infection. Its most severe form, septic shock, occurs when underlying circulatory and cellular metabolic abnormalities are pronounced, indicating greater severity and higher mortality. Vasopressor use is a cornerstone aspect in the treatment of critically ill patients with sepsis-associated hemodynamic dysfunction, with norepinephrine, a catecholamine, being the vasopressor of choice.

Vasopressin is an endogenous peptide hormone with potential advantages over norepinephrine in a catecholamine-sparing strategy for treating sepsis-associated hemodynamic dysfunction.

This is a phase 3, multicenter, open-label, randomized controlled trial. Adult patients with sepsis-associated hemodynamic dysfunction in the ICU may be eligible to participate. We aim to enroll 2,800 patients.

• Study Type: Interventional
• Enrollment (Estimated): 2800
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bruno M Tomazini, MD; Phone Number: +5511982839173; Email: btomazini@hcor.com.br
• Study Contact Backup: Name: Alexandre Biasi Cavalcanti, PhD; Phone Number: +551130536611; Email: abiasi@hcor.com.br

Study Locations

• Brazil
  • Rio Grande do Sul
    • Caxias do Sul, Rio Grande do Sul, Brazil
      • Recruiting
      • Hospital Geral de Caxias do Sul
      • Contact: Emerson Silva
  • S
    • São Paulo, S, Brazil
      • Not yet recruiting
      • Hospital SEPACO
      • Contact: Flávio Freitas
  • Santa Catarina
    • Florianópolis, Santa Catarina, Brazil
      • Recruiting
      • Hospital Nereu Ramos
      • Contact: Israel Maia, PhD; Email: israels.maia@gmail.com ;
  • São Paulo
    • Barretos, São Paulo, Brazil
      • Not yet recruiting
      • Hospital de Amor - Unidade Barretos (Fundação PIO XII)
      • Contact: Cristina Amendola
    • São Paulo, São Paulo, Brazil, 05435000
      • Recruiting
      • Hospital do Coracao
      • Contact: Marcelo Romano, MD
      • Contact: Luzia Taniguchi, MSc
    • São Paulo, São Paulo, Brazil
      • Not yet recruiting
      • BP-A Beneficiência Portuguesa de São Paulo
      • Contact: Viviane Veiga; Email: dveiga@uol.com.br
    • São Paulo, São Paulo, Brazil
      • Not yet recruiting
      • Hospital Alemao Oswaldo Cruz
      • Contact: Mino Cestari, MD
    • São Paulo, São Paulo, Brazil
      • Recruiting
      • Hospital São Paulo - UNIFESP
      • Contact: Flavia Machado; Email: frmachado@unifesp.br;

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with vasopressor dependent sepsis, defined by infection suspicion and antibiotic administration or laboratory confirmed viral infection, plus hypotension with the need of vasopressors for at least one hour;
• Admitted or expected to be admitted to the ICU in the next 12 hours
• Adequate volume resuscitation in the opinion of the attending physician
• Use of norepinephrine > 0.05μg/Kg/min and ≤ 0.25μg/Kg/min for at least 1 hour and at most 24 hours at the time of inclusion

Exclusion Criteria:

• Use of norepinephrine > 0.25μg/Kg/min in the last 24 hours, except when administered transiently in the context of sedation for a procedure or the initial phase of volume resuscitation for a period of less than one hour
• Dialysis-dependent chronic kidney disease or acute kidney injury that received renal replacement therapy during current hospitalization or are expected to receive renal replacement therapy in the next 24 hours
• Use of other vasopressors (except norepinephrine) at the moment of inclusion
• Use of vasopressors for sepsis in the last 7 days
• Suspected or confirmed acute mesenteric ischemia
• Anaphylaxis or known hypersensitivity to the study drug
• Expect to die in the next 24 hours
• Medical team not committed to full support at the time of inclusion
• Previous inclusion in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early Vasopressin; After randomization, vasopressin will be initiated and titrated up to 0.04U/min to maintain the target mean arterial pressure (MAP). Concurrently, norepinephrine will be reduced, with the goal of using the maximum dose of vasopressin and minimizing or eliminating the use of norepinephrine, while still maintaining the target MAP.	Drug: Early Vasopressin; Early Vasopressin group: Vasopressin up to 0.04U/min initiated after randomization.
Active Comparator: Norepinephrine plus vasopressin for rescue; After randomization, norepinephrine will be titrated to maintain the target MAP. Vasopressin will be introduced as a rescue strategy only if the norepinephrine dose exceeds 0.5 μg/kg/min. Once vasopressin is initiated, it can be titrated up to 0.04U/min to help maintain the target MAP if the norepinephrine dose remains above 0.5 μg/kg/min.	Drug: Norepinephrine and Vasopressin for Rescue; Norepinephrine and Vasopressin for Rescue group: Vasopressin up to 0.04U/min initiated only if norepinephrine dose exceeds 0.5 μg/kg/min.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality or renal replacement therapy	Composite of all-cause mortality or renal replacement therapy within 28 days after randomization.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	All-cause mortality within 28 days after randomization	28 days
Renal replacement-therapy	Need of renal replacement therapy within 28 days after randomization.	28 days
Renal replacement-free days	Renal-replacement free days are defined by the number of days a patient is alive and free of renal replacement support between randomization and day 28. Non-survivors will be considered to have zero renal replacement-free days.	28 days
ICU-free days	Number of days a patient is alive and outside the ICU between randomization and day 28. Non-survivors will be considered to have zero ICU-free days.	28 days
Hospital-free days	Number of days a patient is alive and outside the hospital between randomization and day 28. Non-survivors will be considered to have zero hospital-free days.	28 days
Organ support-free days and its components	The definition of organ support involves three components: renal replacement therapy, invasive mechanical ventilation, and vasopressor use. Organ support-free days are defined by the number of days a patient is alive and free of all three organ support therapies between randomization and day 28. Non-survivors will be considered to have zero organ support-free days.	28 days
Cardiac arrhythmias	Occurrence of cardiac arrhythmias between randomization and day 28	28 days
Ischemic events	Occurrence of mesenteric ischemia, ischemic stroke, digital ischemia and acute coronary syndrome between randomization and day 28	28 days

Collaborators and Investigators

• Sponsor: Hospital do Coracao
• Collaborators: Brazilian Research in Intensive Care Network (BRICNet); National Institute of Science and Technology (INCT) in Precision Intensive Care Medicine
• Investigators: Principal Investigator: Bruno M Tomazini, MD, Hcor Research Institute; Study Chair: Machado R Flavia, PhD, Universidade Federal de Sao Paulo

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2024
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: June 11, 2024
• First Submitted That Met QC Criteria: June 13, 2024
• First Posted (Actual): June 18, 2024

Study Record Updates

• Last Update Posted (Actual): January 30, 2026
• Last Update Submitted That Met QC Criteria: January 28, 2026
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Septic shock; Norepinephrine; Vasopressin; Critically ill; Vasopressor dependent sepsis
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pituitary Diseases; Shock; Pathological Conditions, Signs and Symptoms; Critical Illness; Shock, Septic; Diabetes Insipidus; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amines; Catechols; Phenols; Benzene Derivatives; Alcohols; Amino Alcohols; Ethanolamines; Biogenic Monoamines; Biogenic Amines; Catecholamines; Pituitary Hormones, Posterior; Pituitary Hormones; Norepinephrine; Vasopressins
• Other Study ID Numbers: ip_hcor_nova

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Submission of a statistical analysis plan for the purposed analyses for the Steering Committee evaluation. Compliance with Brazilian data privacy law.
• IPD Sharing Time Frame: 1 year after study publication
• IPD Sharing Access Criteria: Submission of a statistical analysis plan for the purposed analyses for the Steering Committee evaluation. Compliance with Brazilian data privacy law.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No