Randomized Control Study in REsuscitation of SEpsis Trial

Official title

Randomized Control Study on Normal Saline vs Plasmalite vs Plasma in REsuscitation of SEpsis Trial (RESET) - A Feasibility and Comparative Study

Overview

Crystalloids vs. Synthetic Plasma for Fluid Resuscitation in Children with Sepsis - REsuscitation of SEpsis Trial (RESET): A Comparative and Feasibility Study This research study, called the REsuscitation of SEpsis Trial (RESET), is a randomized clinical trial comparing crystalloids and synthetic plasma for fluid resuscitation in children with sepsis. Below, we explain some key aspects you should be aware of. What is a Clinical Trial? A clinical trial is a type of medical research designed to gather more information on how our bodies respond to medications or other treatments. Most new medical treatments must be evaluated in clinical trials before they can be approved by government agencies. These agencies ensure that new treatments are not only safe but also beneficial for patients-what medicine refers to as being "safe and effective." If a new treatment has not yet been approved, it is considered "experimental." Researchers analyze the results of multiple clinical trials to determine which medications work best and how they function. The advancement of medical science requires the participation of many people in numerous studies worldwide. What is the Purpose of This Study? This study evaluates whether Octaplas LG helps children and adolescents with sepsis and whether it improves the function of blood vessels inflamed due to infection. Sepsis occurs when an infection severely affects a person's health. Octaplas LG is a medication approved for use in Colombia. It is known as pharmaceutical plasma and is obtained from voluntary donors worldwide. It undergoes an ultra-detailed sterilization process using the most advanced techniques for processing blood derivatives. In medicine, fresh frozen plasma (FFP) is typically used, which is the equivalent of Octaplas LG but with far fewer industrial sterilization processes. These additional processes in Octaplas LG significantly reduce the risk of transmitting infections. Although Octaplas LG is approved by INVIMA, its use for fluid resuscitation has not yet been approved. This study will compare Octaplas LG with normal saline solution and Ringer's lactate, which are commonly used for rehydrating patients. All three treatments will be administered in the same manner. Why is My Child Being Asked to Participate? Your child is being invited to participate in this clinical study because: They are receiving care in the pediatric intensive care unit (PICU). They are between one month and 18 years old. They have been diagnosed with sepsis and require fluid resuscitation. Your child's participation is voluntary. If you decide not to participate, your child will not lose any medical benefits. Your child's doctor has determined that they may be a good candidate for this study. You are free to discuss participation with your family, friends, or another physician. Some members of your child's healthcare team may also be involved in this research. They are dedicated to your child's care as well as the objectives of this study. However, you are not obligated to participate. If you choose to enroll your child, you will be asked to sign an informed consent form. How Will My Child Be Assigned to a Treatment Group? Upon admission to the pediatric intensive care unit (PICU), if your child has a confirmed sepsis diagnosis and requires intravenous fluids or plasma to support heart function, they will be randomly assigned to one of the three treatment groups. Randomization is a research method used in clinical trials to assign patients to study groups in an unbiased way-similar to drawing numbers from a hat. Neither you, your child's doctor, nor the researchers will choose which group your child is placed in. Instead, a computer will randomly assign them to a group. Treatment Groups: Group 1: Normal Saline (0.9% Sodium Chloride) Your child will receive the standard treatment for sepsis, including antibiotics, intravenous fluids, heart function monitoring, mechanical ventilation if needed, and blood pressure medications (vasopressors) if necessary. Group 2: Ringer's Lactate In addition to standard sepsis management, your child will receive Ringer's lactate, another commonly used resuscitation fluid in pediatric sepsis. Group 3: Octaplas LG In addition to standard sepsis management, your child will receive pharmaceutical synthetic plasma, which contains proteins and essential blood components that have undergone advanced processing to eliminate the risk of infectious disease transmission. How Many Children Will Participate in This Study? At Fundación Cardioinfantil-Instituto de Cardiología, we are seeking the participation of approximately 150 children in this study. How Long Will My Child Be in the Study? Your child will remain in their assigned treatment group for up to 28 days from PICU admission or until they no longer require intensive care hospitalization.

Detailed description

Protocol Title: Randomized Clinical Trial Comparing Crystalloids vs. Synthetic Plasma for Fluid Resuscitation in Children with Sepsis - REsuscitation of Sepsis Trial (RESET): Feasibility and Comparative Study

Development Phase: Phase IV Study

Sponsor:

Fundación Cardioinfantil - Instituto de Cardiología Children's Hospital of Pittsburgh - Center for Trauma and Transfusion Medicine Research, University of Pittsburgh, Pittsburgh, USA

Medical Sponsor and International Coordinator Dr. Jaime Fernández - Pediatric Intensivist, Head of the Pediatric Intensive Care Unit, Fundación Cardioinfantil, Bogotá, Colombia Dr. Phillip Spinella, MD, FCCM - Pediatric Intensivist, Department of Surgery and Anesthesia, Children's Hospital of Pittsburgh; Emeritus Professor, Department of Surgery and Critical Care, University of Pittsburgh; Director, Center for Trauma and Transfusion Medicine Research, University of Pittsburgh, Pittsburgh, USA

Drug Manufacturer: Octapharma

Study Center: Fundación Cardioinfantil - Bogotá, Colombia

Study Objectives

Primary Objective:

To evaluate the feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock. Feasibility study.

Secondary Objectives:

1. Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups. 2. Assess intravascular volume via echocardiography at 6 ± 2, 24 ± 8, and 48 ± 8 hours across groups. 3. Compare the total volume of normal saline, lactate, or plasma administered for resuscitation within the first 6, 24, and 48 hours. 4. Evaluate net fluid balance at 24 and 48 hours. 5. Compare oxygenation parameters (S/F ratio, P/F ratio, oxygenation index) between the two groups at 0, 6, 24, and 48 hours in ventilated children. 6. Assess organ dysfunction scores (PELOD, pSOFA, and NP-MODS) daily for 48 hours. 7. Compare peak inotropic scores daily over 48 hours. 8. Evaluate endothelial injury markers and hemostatic parameters. 9. Assess inflammatory markers and coagulation activation measures. 10. Monitor transfusion-related reactions. 11. Compare healthcare-associated infections. 12. Assess 28-day mortality and cause of death.

Study Design A prospective, randomized, open-label, feasibility-controlled trial.

Investigational Medicinal Product

Patients diagnosed with septic shock who meet the inclusion criteria will be randomly assigned to one of three intervention arms:

* Group A: Bolus dose of 10 mL/kg normal saline (NS) (max. 500 mL) administered over \<15 minutes. * Group B: Bolus dose of 10 mL/kg Ringer's lactate (max. 500 mL) administered over \<15 minutes. * Group C: Pharmaceutical fresh frozen plasma (OCTAPLAS LG®), bolus dose of 10 mL/kg (max. 500 mL) administered over \<15 minutes.

The commercial product OCTAPLAS LG® has been registered with INVIMA in Colombia for five years and is used as a plasma replacement in cardiac surgery, hematologic diseases, or intensive care settings where blood bank plasma is unavailable.

Study Population Children aged 1 month to 18 years diagnosed with sepsis, admitted to the Pediatric Intensive Care Unit (PICU) at Fundación Cardioinfantil over a 12-month period, and meeting eligibility criteria.

Interventions

• Biological Pharmaceutical fresh frozen plasma
  OCTAPLAS LG® has been registered with INVIMA in Colombia for five years and is used as a plasma replacement in cardiac surgery, hematologic diseases, or intensive care settings where blood bank plasma is unavailable
• Drug Normal Saline
  Bolus dose of 10 mL/kg normal saline (NS) (max. 500 mL) administered over \<15 minutes.
• Drug Ringer lactate (RL)
  Bolus dose of 10 mL/kg Ringer's lactate (max. 500 mL) administered over \<15 minutes.

Primary outcome measures

• Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Rate of Signed Informed Consent [Time frame: Within the first 2 hours after presentation to the PICU. Percentage (%)]
• Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Time to Plasma Administration [Time frame: Within the first 24 hours after admission. Minutes (min)]
• Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Follow-up Rate [Time frame: From PICU admission until day 28 or PICU discharge. Percentage (%)]
• Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Ability to Obtain and Process Biological Samples [Time frame: During the first 24 hours post-intervention. Percentage (%)]
• Feasibility in terms of efficacy and safety of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock: Incidence of Clinical Outcomes [Time frame: Up to 28 days post-intervention or until PICU discharge. Number of events (n), Percentage (%)]
• Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Oxygenation as Assessed by PaO₂/FiO₂ Ratio [Time frame: Within the first 24 hours of intervention. Ratio (unitless)]
• Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Oxygenation Index (OI) [Time frame: Within the first 24 hours of intervention. Unitless value]
• Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Intravascular Volume Status [Time frame: Within the first 24 hours of intervention. Categorized as improved / no change / worsened (qualitative)]
• Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Inotropic Score [Time frame: Maximum value during the first 24 hours post-intervention. Inotropic score (numeric)]
• Efficacy of crystalloids versus synthetic fresh plasma as the initial resuscitation fluid in children presenting with septic shock in clinical variables and supports: Endothelial Injury Markers [Time frame: Baseline and within 24 hours post-intervention. ng/mL]

Secondary outcome measures (12)

• Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Systemic Vascular Resistance (SVR) [Time frame: During the 24-hour intervention period. dyn·s/cm⁵]
• Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Cardiac Output (CO) [Time frame: During the 24-hour intervention period. Liters per minute (L/min)]
• Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Cardiac Index (CI) [Time frame: During the 24-hour intervention period. Liters per minute per square meter (L/min/m²)]
• Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Stroke Volume Variability (SVV) [Time frame: During the 24-hour intervention period. Percentage (%)]
• Compare hemodynamic parameters using continuous non-invasive cardiac output monitoring (iCON®) between groups: Pulse Pressure Variation (PPV) [Time frame: During the 24-hour intervention period. Percentage (%)]
• Total Volume of Resuscitation Fluid Administered Within the First 6, 24, and 48 Hours [Time frame: At 6, 24, and 48 hours after admission. Milliliters (mL)]
• Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of IL-1 at 0, 6, and 24 Hours [Time frame: 0, 6, and 24 hours after fluid administration. pg/mL]
• Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of IL-6 at 0, 6, and 24 Hours [Time frame: 0, 6, and 24 hours. pg/mL]
• Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of IL-10 at 0, 6, and 24 Hours [Time frame: 0, 6, and 24 hours. pg/mL]
• Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of TNF-alpha at 0, 6, and 24 Hours [Time frame: 0, 6, and 24 hours. pg/mL]
• Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of Syndecan-1 at 0, 6, and 24 Hours [Time frame: 0, 6, and 24 hours. ng/mL]
• Evaluate endothelial injury markers and hemostatic parameters, and assess inflammatory markers and coagulation activation measures: Plasma Concentration of Soluble E-selectin (sE-selectin) [Time frame: 0, 6, and 24 hours. ng/mL]

Eligibility criteria

Inclusion criteria

• Age: ≥1 month (corrected gestational age) to 18 years.
• Diagnosis of sepsis with at least one of the following conditions:
• Signs of poor perfusion: prolonged capillary refill ≥2 sec, weak peripheral pulses, unexplained metabolic acidosis (base deficit > (-)5.0 mEq/L), altered. mental status, lactate ≥2 mmol/L (sample drawn without tourniquet use. (Appendix 2). OR
• Systolic blood pressure (SBP) below the 5th percentile for age.
• Signed informed consent from the patient's legal guardian.

Exclusion criteria

• Receipt of ≥2 boluses of NS 0.9% or balanced solution in the last 24 hours for the current sepsis episode (bolus defined as ≥10 mL/kg (max. 500 mL) of NS/RL given in <30 min).
• Known allergic reaction to plasma-derived products.
• Known IgA deficiency.
• Suspected or confirmed congestive heart failure.
• Nephrotic syndrome.
• Known chronic kidney disease with fluid overload or congestive heart failure.
• Diagnosed hemorrhagic dengue fever confirmed by antigen or serology (NS1 or IgM positive).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Colombia · 1 center

• Fundacion CardioInfantil - Instituto de Cardiología — Bogotá

Publications

• Iba T, Maier CL, Helms J, Ferrer R, Thachil J, Levy JH. Managing sepsis and septic shock in an endothelial glycocalyx-friendly way: from the viewpoint of surviving sepsis campaign guidelines. Ann Intensive Care. 2024 Apr 24;14(1):64. doi: 10.1186/s13613-024-01301-6. PMID 38658435
• Obonyo NG, Sela DP, Raman S, Rachakonda R, Schneider B, Hoe LES, Fanning JP, Bassi GL, Maitland K, Suen JY, Fraser JF. Resuscitation-associated endotheliopathy (RAsE): a conceptual framework based on a systematic review and meta-analysis. Syst Rev. 2023 Nov 22;12(1):221. doi: 10.1186/s13643-023-02385-0. PMID 37990333
• Torres LN, Chung KK, Salgado CL, Dubick MA, Torres Filho IP. Low-volume resuscitation with normal saline is associated with microvascular endothelial dysfunction after hemorrhage in rats, compared to colloids and balanced crystalloids. Crit Care. 2017 Jun 29;21(1):160. doi: 10.1186/s13054-017-1745-7. PMID 28659186

Identifiers

NCT: NCT07035509 · CEIC-456-2024

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗