Critically IllPhase 2FluDReSSNCT04494789
Fludrocortisone Dose Response Relationship in Septic Shock - FluDReSS
A Phase 2 study testing Fludrocortisone Acetate and Standard Therapy in people with Critically Ill and Septic Shock, run by The George Institute at 9 sites in Australia.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Critically Ill, Septic Shock
- What is being tested?
- Fludrocortisone Acetate and Standard Therapy
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 155 participants
- Where
- 9 sitesAustralia
- Study dates
- 11 Feb 2021to 30 Jun 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Aged 18 years or older
- Documented site, or strong suspicion of infection with 2 of the 4 clinical signs of inflammation:
- Core temperature > 38oC or < 35oC
- Heart rate > 90bpm
- Respiratory rate > 20bpm, or PaCO2 < 32mmHg, or mechanical ventilation
- White cell count > 12 x 109/L or < 4 x 109/L or > 10% immature neutrophils\
Show all 10Show fewer
- Being treated with Hydrocortisone at a daily dose of 200mg / day as adjunctive treatment for sepsis
- Being treated with mechanical ventilation at the time of randomisation (includes mask BiPAP/CPAP)
- 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
- Administration of vasopressors or inotropes for > 4 hours and present at time of randomisation
Who cannot join
- Met all inclusion criteria more than 24 hours ago
- Patients taking long term corticosteroids or fludrocortisone
- Patients with systemic fungal infection
- 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
- Patient unable to receive enteral medication
- Death from underlying disease likely within 90 days
- Patient has been previously enrolled in the study
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
Australia9 sites
Queen Elizabeth II Hospital
Adelaide, South Australia
Royal Brisbane Women's Hospital
Brisbane, Queensland
Wesley Hospital
Brisbane, Queensland
Gold Coast University Hospital
Gold Coast, Queensland
Austin Hospital
Melbourne, Victoria
Mater Misericordiae
Raymond Terrace, Queensland, 4101
Blacktown Hospital
Sydney, New South Wales
Royal North Shore Hospital
Sydney, New South Wales
Princess Alexandra Hospiital
Woolloongabba, Queensland, 4102
About this study
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
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.
Read more
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.
Read the detailed description
Aim:
- 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.
Hypotheses:
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
- Conditions
- Critically Ill, Septic Shock
- Being tested
- Fludrocortisone Acetate, Standard Therapy
- Medical subject headings
- Critical Illness, Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Fludrocortisone AcetateDrug
50mcg
Fludrocortisone AcetateDrug
100mcg
Fludrocortisone AcetateDrug
200mcg
Standard TherapyOther
NO Fludrocortisone
| Study group | Role | What they receive |
|---|---|---|
| Fludrocortisone dosing regime: 24hrs | Active comparator | Receive 50mcg doses of fludrocortisone every 24hrs Receives: Drug: Fludrocortisone Acetate |
| Fludrocortisone dosing regime: 12hrs | Active comparator | Receive 50mcg doses of fludrocortisone every 12hrs Receives: Drug: Fludrocortisone Acetate |
| Fludrocortisone dosing regime: 6hrs | Active comparator | Receive 50mcg doses of fludrocortisone every 6hrs Receives: Drug: Fludrocortisone Acetate |
| Control Arm | Placebo comparator | Receives standard treatment without fludrocortisone dosing regime Receives: Other: Standard Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to resolution of shock by Intervention group allocation
To the assess the time it takes for shock to resolve in each intervention arm
Measured: 7 DAYS
Time to resolution of shock and Fludrocortisone Levels
Assess the levels of fludrocortisone in the interventional groups at time of resolution of shock
Measured: 7 days
Vasopressor Responsiveness by Intervention group allocation
Area under the curve of vasopressor dose in each intervention arm
Measured: 7 days
Vasopressor Responsiveness and Fludrocortisone Levels
Area under the curve of vasopressor dose associated with fludrocortisone levels
Measured: 7 days
Secondary outcomes (7)
Recurrence of shock
Time between a new episode of shock after reversal of the initial episode
Measured: censored at day 28
Ventilation free days
Number of Days that are without ventilation during admission
Measured: censored at day 28
ICU and hospital length of Stay
Total number of days in ICU and in hospital for the index admission
Measured: censored at day 28
ICU and hospital mortality
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
Measured: censored at day 28
Delta SOFA Score
Baseline SOFA score to SOFAmax - numerical calculation based on scoring system of each participant during their admission
Measured: censored at day 28
Maximal SOFA score
Maximum SOFA score for each participant during their admission
Measured: censored at day 28
Superinfection
This is the number of new infections that occur >48hrs after commencing study drug
Measured: censored at day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jul 2020
- Study start11 Feb 2021
- Primary completion30 Apr 2023
- Study completion30 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Critically IllStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 155 participants (actual)
Sponsor and investigators
- Lead sponsor
- The George Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- James Walsham, MB ChB, MRCP, FCICM., Principal investigator, Princess Alexandra Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04494789
- Sponsor's protocol ID
- GI-CC35837377
- Acronym
- FluDReSS
- Status last verified
- Jan 2024
- First submitted
- 19 Jul 2020
- Last updated
- 18 Jan 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Walsham J, Hammond N, Blumenthal A, Cohen J, Myburgh J, Finfer S, Evans D, Peake S, Kruger P, McCullough J, Johnk L, Ghelani D, Billot L, Shan S, Meyer J, Rajbhandari D, Koch C, Bellomo R, Burrell LM, Young M, Roberts M, Mackenzie L, Medley G, Dalton J, Venkatesh B. Fludrocortisone dose-response relationship in septic shock: a randomised phase II trial. Intensive Care Med. 2024 Dec;50(12):2050-2060. doi: 10.1007/s00134-024-07616-z. Epub 2024 Sep 5.
PubMed 39235623
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04494789
- Acronym / sponsor ID
- FluDReSS / GI-CC35837377
- Conditions
- Critically Ill, Septic Shock
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 155 participants (actual)
- Lead sponsor
- The George InstituteUniversity, hospital or other
- Study start
- 11 Feb 2021 (actual)
- Primary completion
- 30 Apr 2023 (actual)
- Study completion
- 30 Jun 2023 (actual)
- First posted
- 31 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
Hypotheses:
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Fludrocortisone dosing regime: 24hrs | Active comparator | Drug: Fludrocortisone AcetateReceive 50mcg doses of fludrocortisone every 24hrs |
| Fludrocortisone dosing regime: 12hrs | Active comparator | Drug: Fludrocortisone AcetateReceive 50mcg doses of fludrocortisone every 12hrs |
| Fludrocortisone dosing regime: 6hrs | Active comparator | Drug: Fludrocortisone AcetateReceive 50mcg doses of fludrocortisone every 6hrs |
| Control Arm | Placebo comparator | Other: Standard TherapyReceives standard treatment without fludrocortisone dosing regime |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Aged 18 years or older
- Documented site, or strong suspicion of infection with 2 of the 4 clinical signs of inflammation:
- Being treated with Hydrocortisone at a daily dose of 200mg / day as adjunctive treatment for sepsis
- Being treated with mechanical ventilation at the time of randomisation (includes mask BiPAP/CPAP)
- 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
Key exclusion criteria (7 listed)
- Met all inclusion criteria more than 24 hours ago
- Patients taking long term corticosteroids or fludrocortisone
- Patients with systemic fungal infection
- 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
- Patient unable to receive enteral medication
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Fludrocortisone Acetate50mcg | Drug | Fludrocortisone dosing regime: 24hrs |
| Fludrocortisone Acetate100mcg | Drug | Fludrocortisone dosing regime: 12hrs |
| Fludrocortisone Acetate200mcg | Drug | Fludrocortisone dosing regime: 6hrs |
| Standard TherapyNO Fludrocortisone | Other | Control Arm |
Primary outcome
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
7 secondary outcomes
Recurrence of shock
Time frame: censored at day 28
Ventilation free days
Time frame: censored at day 28
ICU and hospital length of Stay
Time frame: censored at day 28
ICU and hospital mortality
Time frame: censored at day 28
Delta SOFA Score
Time frame: censored at day 28
Maximal SOFA score
Time frame: censored at day 28
Superinfection
Time frame: censored at day 28
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2024.
- Derived from this study: PubMed 39235623Walsham J, Hammond N, Blumenthal A, Cohen J, Myburgh J, Finfer S, Evans D, Peake S, Kruger P, McCullough J, Johnk L, Ghelani D, Billot L, Shan S, Meyer J, Rajbhandari D, Koch C, Bellomo R, Burrell LM, Young M, Roberts M, Mackenzie L, Medley G, Dalton J, Venkatesh B. Fludrocortisone dose-response relationship in septic shock: a randomised phase II trial. Intensive Care Med. 2024 Dec;50(12):2050-2060. doi: 10.1007/s00134-024-07616-z. Epub 2024 Sep 5.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James Walsham, MB ChB, MRCP, FCICM. principal investigator
Princess Alexandra Hospital
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Fludrocortisone Acetate and Standard Therapy in people with Critically Ill and Septic Shock, run by The George Institute at 9 sites in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to resolution of shock by Intervention group allocation (time frame: 7 DAYS). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04494789, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jan 2024.