FLudrocortisone Administration in Aneurysmal Subarachnoid Haemorrhage (FLASH)

December 8, 2025 updated by: The George Institute

A Prospective, Blinded, Randomised Clinical Trial of Fludrocortisone Compared With Placebo in Critically Ill Patients Presenting With Aneurysmal Subarachnoid Haemorrhage

A multi-centre, prospective, blinded, randomised clinical trial of fludrocortisone compared with placebo in patients presenting with aneurysmal subarachnoid haemorrhage.

The study aim is to determine if early administration of enteral fludrocortisone in aneurysmal subarachnoid haemorrhage reduce death and dependency at six months.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Aneurysmal subarachnoid haemorrhage (aSAH)is a devastating form of stroke, that predominately affects a younger age group. There are approximately 2000 cases per year in Australia, with the majority occurring in patients between 45 and 64 years of age and with a significant female preponderance. The burden of mortality of this condition is high; a review of 11,327 cases from 2000 to 2015 by our group revealed a mortality rate of 29% in patients who survived to hospital admission, with no annual improvement in that rate from 2003 onwards. Moreover, a substantial proportion of survivors from aSAH are left with residual neurological deficits. Persistent neurocognitive changes including deficits in memory, executive functioning and language, fatigue, depression and post-traumatic stress have been reported in survivors, resulting in lower than normal health related quality of life (HRQoL).

Cognitive impairment persists even in patients with supposedly good neurological recovery, with up to 40% of patients unable to return to their previous occupation. Data from our group support these findings, suggesting that approximately 50% of patients report at least a moderate disability six months after hospital discharge.

The healthcare costs associated with aSAH are substantial. In Australia and New Zealand, most patients with aSAH are admitted to an Intensive Care Unit (ICU), and have a median length of stay of 9 and 20 days in ICU and hospital, respectively. The median hospital cost for managing a patient with high grade aSAH is A$41,824 (interquartile range A$9,933-A$97,332); without considering the need for rehabilitation, ongoing care, and loss of earnings. Data from a single centre estimated total hospital costs over a ten year period for this cohort at $8.3 million; only 52 patients out of 139 survived hospitalisation. In contrast, a 14 day course of fludrocortisone costs just over A$12 compared with A$4800 for an occupied ICU bed day. A low cost intervention which reduced ICU stay and improved outcomes would therefore be anticipated to have a substantial economic benefit.

There are a number of complications associated with aSAH, of which hyponatraemia (defined as a serum sodium concentration <135mmol/L) is one of the most common with a reported prevalence of between 35% to 77%.7,8 The primary cause appears to be a salt wasting syndrome caused by secretion of natriuretic peptides and associated with large urine outputs and hypovolaemia. Hyponatraemia in the setting of aSAH is of particular concern, as it may exacerbate cerebral oedema and is also associated with an increased risk of cerebrovascular vasospasm and cerebral infarction, as well as a longer duration of ICU admission. Our group has recently completed a prospective analysis of 356 patients with aSAH from Australia and New Zealand and demonstrated that patients in whom the sodium concentration decreases over the ICU stay have a higher likelihood of a worse neurological outcome at 6-months compared to those patients in whom the sodium concentration remains steady.

Management of hyponatraemia in aSAH is complicated by the need to maintain a neutral fluid balance, as a reduced circulating blood volume is associated with an increased risk of cerebral vasospasm and delayed neurological deficit. Standard treatment comprises IV volume resuscitation and use of hypertonic saline solutions. These interventions require frequent blood tests, strict attention to fluid balance and central venous access, which can only be provided in ICU or high dependency units.

Fludrocortisone is a synthetic adrenocortical steroid possessing potent mineralocorticoid activity. In standard doses it produces significant sodium and fluid retention and increases urinary potassium excretion. It is currently only approved by the Therapeutic Goods Association for treatment of Addison's disease and salt losing adrenogenital syndrome and is priced at 20c per dose (100µg tablet).

There are two previous randomised trials which have examined the effect of fludrocortisone treatment on hyponatraemia and sodium balance in aSAH. Mori et al randomised 30 patients with aSAH and demonstrated that fludrocortisone significantly reduced urinary sodium excretion and reduced the incidence of hyponatraemia compared to standard management. Similar findings were noted in a study of 91 aSAH patients by Hasan et al, who also reported a lower incidence of cerebral ischaemia in the group that received fludrocortisone compared to standard treatment (22% vs 31% respectively, p=0.3). The trials were not blinded, and hyponatraemia was not an inclusion criterion. A more recent trial in the treatment of cerebral salt wasting secondary to tuberculous meningitis demonstrated that patients receiving fludrocortisone corrected their serum sodium concentration significantly faster than those who received placebo (4 days vs 15 days; p=0.004), and had a significantly lower incidence of deep border zone cerebral infarction (6% vs 33%, p=0.04).

Two systematic reviews have examined the role of fludrocortisone in preventing hyponatraemia and improving outcomes in aSAH. A Cochrane review published in 2005 identified the two previous trials of fludrocortisone in aSAH described above, both of which were performed over twenty years ago. A study using hydrocortisone (which also has mineralocorticoid action) was also included in the analysis. Mineralocorticoid treatment with fludrocortisone was reported to reduce the relative risk of delayed cerebral ischaemia (DCI); (RR 0.65; 95% CI 0.33-1.27) and of poor outcome; (RR 0.33;95% CI 0.03-3.20). A pooled estimate demonstrated that these treatments were associated with an increased rate of adverse effects; (RR 1.75;95% CI 1.03-2.95). However, this finding appeared to be generated mainly by the increased rate of hyperglycaemia in the hydrocortisone trial, whereas the two trials of fludrocortisone reported no increase in adverse effects. The authors concluded that participant numbers were too small to draw definitive conclusions on the efficacy of fludrocortisone and that further randomised controlled trials were required.

The second systematic review published in 2017 identified only one additional study of fludrocortisone to those in the 2005 analysis; this was however a before and after observational study, not a clinical trial. The authors identified that fludrocortisone treatment led to a reduction in hyponatremia, natriuresis and circulating volume contraction. There was no statistically significant effect of mineralocorticoid treatment on symptomatic vasospasm or DCI (RR 0.6; 95% CI 0.35-1.03), although the 95% CI were in favour of clinical benefit (Figure 2). The authors concluded the current evidence was not sufficient to determine the effect of fludrocortisone treatment because the included studies were underpowered, and that larger randomised trials were warranted.

The Neurocritical Care Society treatment guidelines for aSAH comment that fludrocortisone may be used for treatment of hyponatremia and/or hypovolaemia, but make no recommendation for its use in prevention. It appears to be safe and well tolerated - anticipated adverse effects include hypokalaemia, hypertension and pulmonary oedema, but these appear to be rare. Mori et al reported an increased incidence of transient hypokalaemia. Hasan et al noted 4 episodes of pulmonary oedema - 2 each in the fludrocortisone and control groups.

Although some clinical guidelines have suggested fludrocortisone as a potential treatment for hyponatremia in aSAH, it is not widely used; our observational data from Australasian ICUs has shown that less than 10% of the patient cohort were prescribed fludrocortisone. Of note, these patients had better functional outcomes at six months. The likely reason for the lack of widespread adoption into clinical practice is that the trials by Mori and Hasan discussed above were small, unblinded, and published over twenty years ago. Not only has management of aSAH substantially changed in that time period, but neither trial was sufficiently powered to detect improvements in patient centred outcomes. The authors of the most recent meta-analysis concluded that the existing data did not reflect current practice, the trials were small, and so large prospective RCTs were required to confirm these findings.

Recent reviews have highlighted that fludrocortisone may be a useful adjunct in the treatment and prevention of hyponatremia in aSAH, but that the current evidence is insufficient to make treatment recommendations. Fludrocortisone therefore has the potential to prevent the onset of hyponatraemia in aSAH and lead to improved outcomes; this will be the first adequately designed trial to test this hypothesis.

Study Type

Interventional

Enrollment (Estimated)

524

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age 18 years or older
  2. Diagnosed with subarachnoid haemorrhage from an aneurysm confirmed on computed tomography angiography (CTA) or digital subtraction angiography (DSA) of the intra-cranial arteries
  3. Aneurysm has been secured
  4. Hospital admission for aSAH within 96 hours
  5. Currently being treated in a critical care environment

Exclusion Criteria:

  1. Unable to receive enteral medications
  2. Pre-existing glucocorticoid or mineralocorticoid treatment
  3. Previous allergic reaction to fludrocortisone
  4. History of cardiac, hepatic, or renal failure
  5. Hypernatremia or hyponatremia (Na>145mmol/L or Na<125mmol/L) on the most recent blood sample at the time of screening.
  6. Death deemed imminent or inevitable
  7. Pregnancy (confirmed or suspected)
  8. Previous inclusion in the FLASH trial

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Study drug
Fludrocortisone Acetate 100ug Q6 hourly, given enterally for 14 days
Drug: Fludrocortisone
small white tablet containing 100mcg of fludrocortsone
Other Names:
  • Flurinef
Placebo Comparator: Placebo
Matched placebo tablet Q6 hourly, given enterally for 14 days
Drug: Placebo
Matched placebo tablet,

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Modified Rankin Scale
Time Frame: Six months after randomisation
The primary outcome measure will be the modified Rankin Scale (mRS) score. Scores range from 0-5 with 0 is no disability and 5 is severe.
Six months after randomisation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Subarachnoid Haemorrhage Outcome Tool (SAHOT)
Time Frame: Six months after randomisation
The secondary outcome measure will be the Subarachnoid Haemorrhage Outcome Tool (SAHOT) score. Fifty-six questions, possible score 0-2, maximum total score = 112.
Six months after randomisation

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
mortality
Time Frame: 90 days
90-day mortality
90 days
Days alive and free of ICU
Time Frame: 90 days

Days alive and free of ICU

Days alive and free of ICU from randomisation to 90 days
90 days
Days alive and at home
Time Frame: 90 days
Number of days alive and free of ICU
90 days
Incidence of readmission to ICU
Time Frame: 90 days
Incidence of readmission to ICU
90 days
Incidence of radiologically confirmed cerebral infarction
Time Frame: 90 days
Incidence of radiologically confirmed cerebral infarction
90 days
Incidence of aneurysm rebleeding
Time Frame: 90 days
Incidence of aneurysm rebleeding
90 days
Incidence of hydrocephalus
Time Frame: 90 days
Incidence of hydrocephalus
90 days
Incidence of hypokalaemia
Time Frame: 90 days
number of hypokalaemia episodes
90 days
Incidence of hypernatraemia
Time Frame: 90 days
number of incidences of hypernatraemia
90 days
Incidence of fluid overload
Time Frame: 90 days
number of incidences of fluid overload
90 days
Major disability or death (Modified Rankin Score (mRS) or >=3)
Time Frame: 90 days
Major disability or death at day 90 (mRS>=3). Scores range from 0-5 with 0 is no disability and 5 is severe. to meet this outcome the mRS >=3.
90 days
World Health Organisation Disability Assessment Schedule (WHODAS) at 90 days post randomisation
Time Frame: 90 days
WHO Disability Assessment Schedule (WHODAS) at 90 days post randomisation. The scoring has three steps: Step 1 - Summing of recoded item scores within each domain. Step 2 - Summing of all six domain scores. Step 3 - Converting the summary score into a metric ranging from 0 to 100 (where 0 = no disability; 100 = full disability).
90 days
Quality of life survey at 90 days post randomisation
Time Frame: 90 days
EQ-5D-5L at 90 days post randomisation. descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems.
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The George Institute

Investigators

  • Principal Investigator: Jeremy Cohen, MBBS, Royal Brisbane Hospital, Brisbane, Australia
  • Principal Investigator: Anthony Delaney, MBBS, Royal North Shore Hospital, Sydney, Australia
  • Principal Investigator: Torg Westerlund, MBBS, John Hunter Hospital, Newcastle, Australia
  • Principal Investigator: Andrew Udy, BHB MB ChB, The Alfred Hospital, Melbourne, Australia
  • Principal Investigator: Ian Sepppelt, MBBS, Nepean Blue Mountains Local Health District
  • Principal Investigator: Mak Wei-Yun, MBBS, Monash Medical Centre
  • Principal Investigator: David Bowen, MBBS, Westmead Hospital
  • Principal Investigator: James McCulloch, MBChB, Gold Coast University Hospital
  • Principal Investigator: Humphrey Walker, MBBS, St Vincent's Hospital Melbourne
  • Principal Investigator: Sananta Dash, MBBS, Townsville University Hospital
  • Principal Investigator: Matthew MacPartlin, MBBS, Wollongong Hospital
  • Principal Investigator: Andrew Turner, MBBS, Royal Hobart Hospital
  • Principal Investigator: Gavin Salt, MBBS, Prince of Wales Hospital
  • Principal Investigator: Laura Tincknell, MBBS, Auckland City Hospital
  • Principal Investigator: Jason Wright, MBBS, Wellington City Hospital
  • Principal Investigator: Alex Nesbitt, MBBS, Princess Alexandra Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 13, 2025

Primary Completion (Estimated)

July 31, 2029

Study Completion (Estimated)

July 31, 2030

Study Registration Dates

First Submitted

May 7, 2024

First Submitted That Met QC Criteria

May 7, 2024

First Posted (Actual)

May 10, 2024

Study Record Updates

Last Update Posted (Actual)

December 16, 2025

Last Update Submitted That Met QC Criteria

December 8, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TGI-CCP-35274
  • 2030936 (Other Grant/Funding Number: Australian government, Medical Research Future Fund (MRFF) 2023)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Proposed RNA analysis sub-study

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Aneurysmal Subarachnoid Hemorrhage

Clinical Trials on Fludrocortisone

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Ethiopia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe