Fludrocortisone Dose Response Relationship in Septic Shock - FluDReSS (FluDReSS)

A Phase II Open Label Randomised Controlled Clinical Trial of Different Dosing Regimens of Fludrocortisone in Septic Shock With Assessment of Temporal Changes in Hormonal, Inflammatory, and Genetic Markers of Vascular Responsiveness

The purpose of this study is to determine the most suitable dose of Fludrocortisone in reversal of sepsis and shock associated with sepsis in patients who are admitted to the ICU.

The investigators will be looking to see whether patients receiving Fludrocortisone at different doses recover quicker and spend less time in hospital and in ICU, and to understand the reasons why this happens at certain doses.

Sepsis is caused by toxic substances (toxins) from bacteria and other organism entering the bloodstream from a site of infection. In some people, the infection can progress to sepsis and septic shock where the functions of organs in the body are affected. Patients suffering from sepsis and septic shock are commonly managed in the intensive care unit (ICU) where they are prescribed antibiotics as standard therapy, as well as other therapies to support the functions of the body.

Fludrocortisone is a steroid that has previously shown to be beneficial to help in shock in patients in ICU, but more information is required about the exact dose that is required to achieve this. This has been shown by previous research.

However, the exact role of Fludrocortisone and the best dose has not been studied adequately to date as well as the ways in how it works within the body. The study aims to look tat the dose and the way it works.

Study Overview

• Status: Completed
• Conditions: Septic Shock; Critically Ill
• Intervention / Treatment: Drug: Fludrocortisone Acetate; Drug: Fludrocortisone Acetate; Drug: Fludrocortisone Acetate; Other: Standard Therapy

Detailed Description

Aim:

1. To conduct a multi-centre randomised controlled trial to assess the effect of 3 different dose regimens of fludrocortisone on shock reversal in septic shock patients treated with hydrocortisone.
2. To assess the temporal changes in endocrine inflammatory and gene expression markers in septic shock patients.

Hypotheses:

In patients with septic shock treated with hydrocortisone,

1. The addition of fludrocortisone to hydrocortisone results in improved vascular responsiveness to vasopressors as compared to hydrocortisone alone
2. The improvement of vascular responsiveness with fludrocortisone is in a dose dependent manner
3. Enterally administered fludrocortisone results in adequate plasma level
4. Patients who have early reversal of shock have higher concentrations of, angiotensin II and angiotensin II-receptor expression and reduced angiotensin converting enzyme 2 (ACE 2) concentrations at baseline and throughout the course of their illness
5. Patients who have early reversal of shock have higher concentrations of plasma free cortisol, aldosterone and glucocorticoid and mineralocorticoid receptor expression at baseline and throughout the course of their illness.
6. Patients who demonstrate evidence of both greater angiotensin II and glucocorticoid receptor expression will have earlier shock reversal than those who have an increase in expression of either of these receptors.

7. There is a different temporal change in the plasma concentrations and receptor expression profiles in early shock reversal patients vs. delayed shock reversal patients.

   300 patients will be recruited and randomised to enteral doses of 50mcg fludrocortisone Q24H, Q12H, Q6H or to the control arm of the study. The study will enrol patients admitted to a participating intensive care unit and who meet all the inclusion criteria and no exclusion criteria. Patients in a fludrocortisone arm will receive enteral fludrocortisone for a maximum of 7 days or until sustained shock reversal or until discharge from ICU whichever is earlier.

   Blood samples acquired will be analysed for:

   • Endocrine - Cortisol, free cortisol, aldosterone and metabolites
   • Inflammatory - Cytokine profiles, markers of vasoplegia
   • Gene Expression - Whole genome RNA sequencing and single cell sequencing
   • To assess the plasma levels following enteral administration of fludrocortisone in all patients enrolled to undertake detailed analysis of fludrocortisone kinetics in a subgroup of 30 patients enrolled (10 patients in each dosing group).

   For all patients, data will be collected at baseline and daily whilst in the ICU for up to 8 days. Patients will be followed up to time of discharge from hospital or day 28 if they are still in hospital, whichever occurs first

• Study Type: Interventional
• Enrollment (Actual): 155
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia
      • Blacktown Hospital
    • Sydney, New South Wales, Australia
      • Royal North Shore Hospital
  • Queensland
    • Brisbane, Queensland, Australia
      • Royal Brisbane Women's Hospital
    • Brisbane, Queensland, Australia
      • Wesley Hospital
    • Gold Coast, Queensland, Australia
      • Gold Coast University Hospital
    • Raymond Terrace, Queensland, Australia, 4101
      • Mater Misericordiae
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospiital
  • South Australia
    • Adelaide, South Australia, Australia
      • Queen Elizabeth II Hospital
  • Victoria
    • Melbourne, Victoria, Australia
      • Austin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 18 years or older

2. Documented site, or strong suspicion of infection with 2 of the 4 clinical signs of inflammation:

   1. Core temperature > 38oC or < 35oC
   2. Heart rate > 90bpm
   3. Respiratory rate > 20bpm, or PaCO2 < 32mmHg, or mechanical ventilation
   4. White cell count > 12 x 109/L or < 4 x 109/L or > 10% immature neutrophils\
3. Being treated with Hydrocortisone at a daily dose of 200mg / day as adjunctive treatment for sepsis
4. Being treated with mechanical ventilation at the time of randomisation (includes mask BiPAP/CPAP)
5. Being treated with continuous vasopressors or inotropes to maintain a systolic blood pressure > 90mmHg, or mean arterial pressure > 60mmHg or a MAP target set by the treating clinician for maintaining perfusion
6. Administration of vasopressors or inotropes for > 4 hours and present at time of randomisation

Exclusion Criteria:

1. Met all inclusion criteria more than 24 hours ago
2. Patients taking long term corticosteroids or fludrocortisone
3. Patients with systemic fungal infection
4. Death is deemed inevitable or imminent during this admission and either the attending physician, patient or surrogate legal decision maker is not committed to active treatment
5. Patient unable to receive enteral medication
6. Death from underlying disease likely within 90 days
7. Patient has been previously enrolled 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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fludrocortisone dosing regime: 24hrs; Receive 50mcg doses of fludrocortisone every 24hrs	Drug: Fludrocortisone Acetate; 50mcg; Drug: Fludrocortisone Acetate; 100mcg; Drug: Fludrocortisone Acetate; 200mcg
Active Comparator: Fludrocortisone dosing regime: 12hrs; Receive 50mcg doses of fludrocortisone every 12hrs	Drug: Fludrocortisone Acetate; 50mcg; Drug: Fludrocortisone Acetate; 100mcg; Drug: Fludrocortisone Acetate; 200mcg
Active Comparator: Fludrocortisone dosing regime: 6hrs; Receive 50mcg doses of fludrocortisone every 6hrs	Drug: Fludrocortisone Acetate; 50mcg; Drug: Fludrocortisone Acetate; 100mcg; Drug: Fludrocortisone Acetate; 200mcg
Placebo Comparator: Control Arm; Receives standard treatment without fludrocortisone dosing regime	Other: Standard Therapy; NO Fludrocortisone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to resolution of shock by Intervention group allocation	To the assess the time it takes for shock to resolve in each intervention arm	7 DAYS
Time to resolution of shock and Fludrocortisone Levels	Assess the levels of fludrocortisone in the interventional groups at time of resolution of shock	7 days
Vasopressor Responsiveness by Intervention group allocation	Area under the curve of vasopressor dose in each intervention arm	7 days
Vasopressor Responsiveness and Fludrocortisone Levels	Area under the curve of vasopressor dose associated with fludrocortisone levels	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence of shock	Time between a new episode of shock after reversal of the initial episode	censored at day 28
Ventilation free days	Number of Days that are without ventilation during admission	censored at day 28
ICU and hospital length of Stay	Total number of days in ICU and in hospital for the index admission	censored at day 28
ICU and hospital mortality	The number of deaths that are recorded in participants and the location of the deaths when in hospital - ICU or ward. This will include cause of death	censored at day 28
Delta SOFA Score	Baseline SOFA score to SOFAmax - numerical calculation based on scoring system of each participant during their admission	censored at day 28
Maximal SOFA score	Maximum SOFA score for each participant during their admission	censored at day 28
Superinfection	This is the number of new infections that occur >48hrs after commencing study drug	censored at day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Outcome To assess the plasma levels of enterally administered fludrocortisone in all patients enrolled	Time to peak concentration of Fludrocortisone	7 days
Pharmacokinetic Outcomes - To undertake detailed analysis of fludrocortisone kinetics in a subgroup of 30 patients enrolled (10 patients in each dosing group)	Time to absorption, clearance and metabolism of fludrocortisone in participants in each intervention arm except for the control arm	7 days
Vascular Responsiveness Analysis	Acquisition of blood samples at 4 timepoints over the first 7 days or until discharge from ICU for exploratory analysis to assess a range of biomarkers and their interactions with the primary outcomes	7 days

Collaborators and Investigators

• Sponsor: The George Institute
• Investigators: Principal Investigator: James Walsham, MB ChB, MRCP, FCICM., Princess Alexandra Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2021
• Primary Completion (Actual): April 30, 2023
• Study Completion (Actual): June 30, 2023

Study Registration Dates

• First Submitted: July 19, 2020
• First Submitted That Met QC Criteria: July 28, 2020
• First Posted (Actual): July 31, 2020

Study Record Updates

• Last Update Posted (Actual): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Sepsis; Shock, Septic; Shock; Critical Illness; Anti-Inflammatory Agents; Fludrocortisone
• Other Study ID Numbers: GI-CC35837377

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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