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

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ClinicalTrials.gov Identifier: NCT04494789
Recruitment Status : Recruiting
First Posted : July 31, 2020
Last Update Posted : April 1, 2021
Sponsor:
Information provided by (Responsible Party):
The George Institute

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Critically Ill Septic Shock Drug: Fludrocortisone Acetate Other: Standard Therapy Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 11, 2021
Estimated Primary Completion Date : December 12, 2022
Estimated Study Completion Date : December 12, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Shock

Arm Intervention/treatment
Active Comparator: Fludrocortisone dosing regime: 24hrs
Receive 50mcg doses of fludrocortisone every 24hrs
Drug: Fludrocortisone Acetate
50mcg

Active Comparator: Fludrocortisone dosing regime: 12hrs
Receive 50mcg doses of fludrocortisone every 12hrs
Drug: Fludrocortisone Acetate
100mcg

Active Comparator: Fludrocortisone dosing regime: 6hrs
Receive 50mcg doses of fludrocortisone every 6hrs
Drug: Fludrocortisone Acetate
200mcg

Placebo Comparator: Control Arm
Receives standard treatment without fludrocortisone dosing regime
Other: Standard Therapy
NO Fludrocortisone




Primary Outcome Measures :
  1. Time to resolution of shock by Intervention group allocation [ Time Frame: 7 DAYS ]
    To the assess the time it takes for shock to resolve in each intervention arm

  2. Time to resolution of shock and Fludrocortisone Levels [ Time Frame: 7 days ]
    Assess the levels of fludrocortisone in the interventional groups at time of resolution of shock

  3. Vasopressor Responsiveness by Intervention group allocation [ Time Frame: 7 days ]
    Area under the curve of vasopressor dose in each intervention arm

  4. Vasopressor Responsiveness and Fludrocortisone Levels [ Time Frame: 7 days ]
    Area under the curve of vasopressor dose associated with fludrocortisone levels


Secondary Outcome Measures :
  1. Recurrence of shock [ Time Frame: censored at day 28 ]
    Time between a new episode of shock after reversal of the initial episode

  2. Ventilation free days [ Time Frame: censored at day 28 ]
    Number of Days that are without ventilation during admission

  3. ICU and hospital length of Stay [ Time Frame: censored at day 28 ]
    Total number of days in ICU and in hospital for the index admission

  4. ICU and hospital mortality [ Time Frame: censored at day 28 ]
    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

  5. Delta SOFA Score [ Time Frame: censored at day 28 ]
    Baseline SOFA score to SOFAmax - numerical calculation based on scoring system of each participant during their admission

  6. Maximal SOFA score [ Time Frame: censored at day 28 ]
    Maximum SOFA score for each participant during their admission

  7. Superinfection [ Time Frame: censored at day 28 ]
    This is the number of new infections that occur >48hrs after commencing study drug


Other Outcome Measures:
  1. Pharmacokinetic Outcome To assess the plasma levels of enterally administered fludrocortisone in all patients enrolled [ Time Frame: 7 days ]
    Time to peak concentration of Fludrocortisone

  2. Pharmacokinetic Outcomes - To undertake detailed analysis of fludrocortisone kinetics in a subgroup of 30 patients enrolled (10 patients in each dosing group) [ Time Frame: 7 days ]
    Time to absorption, clearance and metabolism of fludrocortisone in participants in each intervention arm except for the control arm

  3. Vascular Responsiveness Analysis [ Time Frame: 7 days ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04494789


Contacts
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Contact: Dorrilyn Rajbhandari 0410530548 drajbhandari@georegeinstitute.org.au
Contact: Naomi Hammond, PhD RN BN MN (Crit. Care) MPH nhammond@georgeinstitiute.org.au

Locations
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Australia, New South Wales
Bankstown Hospital Not yet recruiting
Sydney, New South Wales, Australia
Contact: Manoj Saxena       Manoj.Saxena@health.nsw.gov.au   
Blacktown Hospital Not yet recruiting
Sydney, New South Wales, Australia
Contact: Dhaval Ghelani       Dhaval.Ghelani@health.nsw.gov.au   
Royal North Shore Hospital Not yet recruiting
Sydney, New South Wales, Australia
Contact: Lachlan Donaldson       ldonaldson@georgeinstitute.org.au   
Australia, Queensland
Royal Brisbane Women's Hospital Not yet recruiting
Brisbane, Queensland, Australia
Contact: Jeremy Cohan       cohenjeremy@me.com   
Wesley Hospital Recruiting
Brisbane, Queensland, Australia
Contact: Bala Venkatesh       bmvenkat@bigpond.net.au   
Contact: Jeremy Cohan       cohenjeremy@me.com   
Gold Coast University Hospital Not yet recruiting
Gold Coast, Queensland, Australia
Contact: James McCullough         
Princess Alexandra Hospiital Recruiting
Woolloongabba, Queensland, Australia, 4102
Contact: James Walsham, FRANZCA       James.Walsham@health.qld.gov.au   
Principal Investigator: James Walsham, FRANZCA         
Australia, South Australia
Queen Elizabeth II Hospital Not yet recruiting
Adelaide, South Australia, Australia
Contact: Sandra Peake       sandra.peake@sa.gov.au   
Australia, Victoria
Austin Hospital Not yet recruiting
Melbourne, Victoria, Australia
Contact: Rinaldo Bellomo       Rinaldo.BELLOMO@austin.org.au   
Sponsors and Collaborators
The George Institute
Investigators
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Principal Investigator: James Walsham, MB ChB, MRCP, FCICM. Princess Alexandra Hospital
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Responsible Party: The George Institute
ClinicalTrials.gov Identifier: NCT04494789    
Other Study ID Numbers: GI-CC35837377
First Posted: July 31, 2020    Key Record Dates
Last Update Posted: April 1, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Shock, Septic
Shock
Critical Illness
Pathologic Processes
Disease Attributes
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Fludrocortisone
Anti-Inflammatory Agents