Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06409364 |
| Other study ID # |
TGI-CCP-35274 |
| Secondary ID |
2030936 |
| Status |
Not yet recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2024 |
| Est. completion date |
July 31, 2030 |
Study information
| Verified date |
April 2024 |
| Source |
The George Institute |
| Contact |
Jeremy Cohen, MBBS |
| Phone |
+610732327000 |
| Email |
cohenjeremy[@]me.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
