Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE July 19, 2020
First Posted Date  ICMJE July 31, 2020
Last Update Posted Date April 1, 2021
Actual Study Start Date  ICMJE February 11, 2021
Estimated Primary Completion Date December 12, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 28, 2020)
  • 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
  • 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
  • Vasopressor Responsiveness by Intervention group allocation [ Time Frame: 7 days ]
    Area under the curve of vasopressor dose in each intervention arm
  • Vasopressor Responsiveness and Fludrocortisone Levels [ Time Frame: 7 days ]
    Area under the curve of vasopressor dose associated with fludrocortisone levels
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 28, 2020)
  • Recurrence of shock [ Time Frame: censored at day 28 ]
    Time between a new episode of shock after reversal of the initial episode
  • Ventilation free days [ Time Frame: censored at day 28 ]
    Number of Days that are without ventilation during admission
  • 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
  • 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
  • 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
  • Maximal SOFA score [ Time Frame: censored at day 28 ]
    Maximum SOFA score for each participant during their admission
  • Superinfection [ Time Frame: censored at day 28 ]
    This is the number of new infections that occur >48hrs after commencing study drug
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 28, 2020)
  • 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
  • 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
  • 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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Fludrocortisone Dose Response Relationship in Septic Shock - FluDReSS
Official Title  ICMJE 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
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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Critically Ill
  • Septic Shock
Intervention  ICMJE
  • Drug: Fludrocortisone Acetate
    50mcg
  • Drug: Fludrocortisone Acetate
    100mcg
  • Drug: Fludrocortisone Acetate
    200mcg
  • Other: Standard Therapy
    NO Fludrocortisone
Study Arms  ICMJE
  • Active Comparator: Fludrocortisone dosing regime: 24hrs
    Receive 50mcg doses of fludrocortisone every 24hrs
    Intervention: Drug: Fludrocortisone Acetate
  • Active Comparator: Fludrocortisone dosing regime: 12hrs
    Receive 50mcg doses of fludrocortisone every 12hrs
    Intervention: Drug: Fludrocortisone Acetate
  • Active Comparator: Fludrocortisone dosing regime: 6hrs
    Receive 50mcg doses of fludrocortisone every 6hrs
    Intervention: Drug: Fludrocortisone Acetate
  • Placebo Comparator: Control Arm
    Receives standard treatment without fludrocortisone dosing regime
    Intervention: Other: Standard Therapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 28, 2020)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 12, 2022
Estimated Primary Completion Date December 12, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Dorrilyn Rajbhandari 0410530548 drajbhandari@georegeinstitute.org.au
Contact: Naomi Hammond, PhD RN BN MN (Crit. Care) MPH nhammond@georgeinstitiute.org.au
Listed Location Countries  ICMJE Australia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04494789
Other Study ID Numbers  ICMJE GI-CC35837377
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party The George Institute
Study Sponsor  ICMJE The George Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: James Walsham, MB ChB, MRCP, FCICM. Princess Alexandra Hospital
PRS Account The George Institute
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP