Fludrocortisone Dose Response Relationship in Septic Shock - FluDReSS

NCT ID: NCT04494789

Last Updated: 2024-01-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 155 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-11
• Study Completion Date: 2023-06-30

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

Conditions

Critically Ill; Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Fludrocortisone dosing regime: 24hrs

Receive 50mcg doses of fludrocortisone every 24hrs

Group Type: ACTIVE_COMPARATOR

Fludrocortisone Acetate

Intervention Type: DRUG

50mcg

Fludrocortisone dosing regime: 12hrs

Receive 50mcg doses of fludrocortisone every 12hrs

Group Type: ACTIVE_COMPARATOR

Fludrocortisone Acetate

Intervention Type: DRUG

100mcg

Fludrocortisone dosing regime: 6hrs

Receive 50mcg doses of fludrocortisone every 6hrs

Group Type: ACTIVE_COMPARATOR

Fludrocortisone Acetate

Intervention Type: DRUG

200mcg

Control Arm

Receives standard treatment without fludrocortisone dosing regime

Group Type: PLACEBO_COMPARATOR

Standard Therapy

Intervention Type: OTHER

NO Fludrocortisone

Interventions

Fludrocortisone Acetate

50mcg

Intervention Type: DRUG

Fludrocortisone Acetate

100mcg

Intervention Type: DRUG

Fludrocortisone Acetate

200mcg

Intervention Type: DRUG

Standard Therapy

NO Fludrocortisone

Intervention Type: OTHER

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The George Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

James Walsham, MB ChB, MRCP, FCICM.

Role: PRINCIPAL_INVESTIGATOR

Princess Alexandra Hospital

Locations

Blacktown Hospital

Sydney, New South Wales, Australia

Royal North Shore Hospital

Sydney, New South Wales, Australia

Royal Brisbane Women's Hospital

Brisbane, Queensland, Australia

Wesley Hospital

Brisbane, Queensland, Australia

Gold Coast University Hospital

Gold Coast, Queensland, Australia

Mater Misericordiae

Raymond Terrace, Queensland, Australia

Princess Alexandra Hospiital

Woolloongabba, Queensland, Australia

Queen Elizabeth II Hospital

Adelaide, South Australia, Australia

Austin Hospital

Melbourne, Victoria, Australia

Countries

Australia

Other Identifiers

GI-CC35837377

Identifier Type: -

Identifier Source: org_study_id