Fludrocortisone Dose Response Relationship in Septic Shock - FluDReSS (FluDReSS)
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|ClinicalTrials.gov Identifier: NCT04494789|
Recruitment Status : Not yet recruiting
First Posted : July 31, 2020
Last Update Posted : November 3, 2020
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|
- 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.
- To assess the temporal changes in endocrine inflammatory and gene expression markers in septic shock patients.
In patients with septic shock treated with hydrocortisone,
- The addition of fludrocortisone to hydrocortisone results in improved vascular responsiveness to vasopressors as compared to hydrocortisone alone
- The improvement of vascular responsiveness with fludrocortisone is in a dose dependent manner
- Enterally administered fludrocortisone results in adequate plasma level
- 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
- 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.
- 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.
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 (Clinical Trial)|
|Estimated Enrollment :||300 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|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|
|Estimated Study Start Date :||November 10, 2020|
|Estimated Primary Completion Date :||December 12, 2022|
|Estimated Study Completion Date :||December 12, 2022|
Active Comparator: Fludrocortisone dosing regime: 24hrs
Receive 50mcg doses of fludrocortisone every 24hrs
Drug: Fludrocortisone Acetate
Active Comparator: Fludrocortisone dosing regime: 12hrs
Receive 50mcg doses of fludrocortisone every 12hrs
Drug: Fludrocortisone Acetate
Active Comparator: Fludrocortisone dosing regime: 6hrs
Receive 50mcg doses of fludrocortisone every 6hrs
Drug: Fludrocortisone Acetate
Placebo Comparator: Control Arm
Receives standard treatment without fludrocortisone dosing regime
Other: Standard Therapy
- 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
- 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
- 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
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
|Contact: Dorrilyn Rajbhandarifirstname.lastname@example.org|
|Contact: Naomi Hammond, PhD RN BN MN (Crit. Care) MPHemail@example.com|
|Princess Alexandra Hospiital|
|Woolloongabba, Queensland, Australia, 4102|
|Contact: James Walsham, FRANZCA|
|Principal Investigator: James Walsham, FRANZCA|
|Principal Investigator:||James Walsham, MB ChB, MRCP, FCICM.||Princess Alexandra Hospital|