Ignite Creation Date:
2024-05-11 @ 8:30 AM
Last Modification Date:
2024-10-26 @ 3:29 PM
Study NCT ID:
NCT06409364
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-24
First Post:
2024-05-07
Brief Title:
FLudrocortisone Administration in Aneurysmal Subarachnoid Haemorrhage
Sponsor:
The George Institute
Organization:
The George Institute
Study Overview
Official Title:
A Prospective Blinded Randomised Clinical Trial of Fludrocortisone Compared With Placebo in Critically Ill Patients Presenting With Aneurysmal Subarachnoid Haemorrhage
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
FLASH
Brief Summary:
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
The study aim is to determine if early administration of enteral fludrocortisone in aneurysmal subarachnoid haemorrhage reduce death and dependency at six months
Detailed Description:
Aneurysmal subarachnoid haemorrhage aSAHis 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 11327 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 A41824 interquartile range A9933-A97332 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 83 million only 52 patients out of 139 survived hospitalisation In contrast a 14 day course of fludrocortisone costs just over A12 compared with A4800 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 135mmolL is one of the most common with a reported prevalence of between 35 to 7778 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 Addisons 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 p03 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 p0004 and had a significantly lower incidence of deep border zone cerebral infarction 6 vs 33 p004
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 065 95 CI 033-127 and of poor outcome RR 03395 CI 003-320 A pooled estimate demonstrated that these treatments were associated with an increased rate of adverse effects RR 17595 CI 103-295 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 06 95 CI 035-103 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 andor 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
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 A41824 interquartile range A9933-A97332 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 83 million only 52 patients out of 139 survived hospitalisation In contrast a 14 day course of fludrocortisone costs just over A12 compared with A4800 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 135mmolL is one of the most common with a reported prevalence of between 35 to 7778 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 Addisons 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 p03 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 p0004 and had a significantly lower incidence of deep border zone cerebral infarction 6 vs 33 p004
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 065 95 CI 033-127 and of poor outcome RR 03395 CI 003-320 A pooled estimate demonstrated that these treatments were associated with an increased rate of adverse effects RR 17595 CI 103-295 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 06 95 CI 035-103 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 andor 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2030936 | OTHER_GRANT | Australian government Medical Research Future Fund MRFF 2023 | None |