Clinical trial NCT04494789: Fludrocortisone Dose Response Relationship in Septic Shock - FluDReSS
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Critically Ill
Septic Shock
Lead sponsor: The George Institute
Sponsor class: OTHER
First posted: 2020-07-31
Enrollment: 155
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility 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

Primary outcomes:
measure: Time to resolution of shock by Intervention group allocation
timeFrame: 7 DAYS
measure: Time to resolution of shock and Fludrocortisone Levels
timeFrame: 7 days
measure: Vasopressor Responsiveness by Intervention group allocation
timeFrame: 7 days
measure: Vasopressor Responsiveness and Fludrocortisone Levels
timeFrame: 7 days
Secondary outcomes:
measure: Recurrence of shock
timeFrame: censored at day 28
measure: Ventilation free days
timeFrame: censored at day 28
measure: ICU and hospital length of Stay
timeFrame: censored at day 28
measure: ICU and hospital mortality
timeFrame: censored at day 28
measure: Delta SOFA Score
timeFrame: censored at day 28
measure: Maximal SOFA score
timeFrame: censored at day 28
measure: Superinfection
timeFrame: censored at day 28
Other outcomes:
measure: Pharmacokinetic Outcome To assess the plasma levels of enterally administered fludrocortisone in all patients enrolled
timeFrame: 7 days
measure: Pharmacokinetic Outcomes - To undertake detailed analysis of fludrocortisone kinetics in a subgroup of 30 patients enrolled (10 patients in each dosing group)
timeFrame: 7 days
measure: Vascular Responsiveness Analysis
timeFrame: 7 days
Locations:
city: Sydney
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane Women's Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Wesley Hospital
state: Queensland
city: Gold Coast
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Raymond Terrace
country: Australia
facility: Mater Misericordiae
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospiital
state: Queensland
city: Adelaide
country: Australia
facility: Queen Elizabeth II Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Austin Hospital
state: Victoria
Study officials:
affiliation: Princess Alexandra Hospital
name: James Walsham, MB ChB, MRCP, FCICM.
role: PRINCIPAL_INVESTIGATOR
References: