Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02122718 |
| Other study ID # |
GN12MT494 |
| Secondary ID |
TSA BHF 2013/01 |
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
May 2014 |
| Est. completion date |
February 2021 |
Study information
| Verified date |
November 2021 |
| Source |
NHS Greater Glasgow and Clyde |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Recurrent stroke and cognitive decline are common after ischaemic stroke. Allopurinol, a drug
usually used to treat gout, has been shown to reduce heart ischaemia, heart size, and
arterial stiffness and to relax brain blood vessels and may reduce the blood pressure. All of
these properties may be associated with a lower risk of second stroke and cognitive decline.
We now aim to explore whether allopurinol will reduce further damage to the brain (called
white matter hyper-intensities) after stroke and also whether it reduces heart size and blood
pressure after stroke.
We will conduct a multi-centre randomised, double-blind placebo controlled study to
investigate whether two years allopurinol 300 mg twice per day (BD) improves these 3
outcomes, which are inextricably linked to risk of recurrence and cognitive decline after
ischaemic stroke.
Description:
New strategies are needed to improve long-term outcomes after ischaemic stroke or transient
ischaemic attack (TIA). Approximately 13% of participants suffered recurrent stroke in recent
secondary preventative trials , 40% of patients with TIA experience recurrent cardiovascular
(CV) events during long-term follow up and there is an additional substantial burden from
incident post-stroke dementia (~ 10% after first stroke and higher still after recurrent
events) , cognitive decline (over 30%) and decline in physical function. Improving these
outcomes is a recognised priority area for stroke research (as identified by stroke survivors
through the recent James Lind Alliance priority setting workshops ).
Such adverse outcomes are particularly common in those with brain white matter
hyper-intensities (WMH) on brain magnetic resonance imaging (MRI) . WMH are seen in as many
as 90% of patients with ischaemic stroke , , are at least moderately severe in 50%6 and such
'severe' WMH are associated with substantially higher stroke recurrence rates (43% in one
study)6, death and increased cognitive and physical decline. The burden of WMH increases
during longitudinal follow up and this is associated with increased incident stroke, dementia
and cognitive decline5. In the longitudinal population based Rotterdam scan study, 39% of
elderly participants had WMH progression (over a mean period of 3.4 years) , as did 50% in
the recent PROFeSS MRI sub-study (over 2 years)7 and 74% (over 3 years) in the Leukoariosis
and Disability study (LADIS) .Similarly, silent brain infarction (SBI) is also associated
with recurrent stroke and 14% developed incident infarcts on brain MRI in the Rotterdam scan
study9. Thus, treatments that reduce WMH progression and incident silent brain infarction
could have potentially profound effects on a variety of outcomes after stroke including
cognition, functional outcome and recurrent stroke.
The pathological basis for WMH development and progression is poorly understood. Post mortem
studies show presence of varied pathologies including demyelination, infarction,
arteriosclerosis and breakdown of the blood-brain barrier. Key risk factors for development
and progression of WMH are age, arterial hypertension and previous stroke9 and associations
with other cardiovascular risk factors and left ventricular hypertrophy (LVH) have been
demonstrated . Blood pressure (BP) lowering reduces WMH progression, as demonstrated by the
PROGRESS MRI sub-study . In the PROFeSS MRI sub-study WMH progression was unaffected by the
angiotensin receptor blocker telmisartan7 but unlike PROGRESS, there was no significant
difference in BP between groups. In addition, WMH are less clearly related to hypertension in
older patients with established cardiovascular disease meaning that novel strategies which
reduce WMH progression and SBI would be particularly promising in this group.
The association between WMH and LVH is of particular interest; it appears independent of
arterial BP , and may be mediated by aortic stiffness . There are additional potential
mechanisms for this association (e.g., LVH is the strongest predictor of left atrial
appendage thrombi, stronger than any left atrial parameter) . Regression of LVH is associated
with reduced risk of stroke. In a recent meta-analysis of 14 studies in 12,809 patients, LVH
regression was independently associated with a 25% reduction in future strokes, whereas the
composite endpoint of CV events/mortality was only 15% lower . Similar findings were seen in
the LIFE echo sub-study which utilised measures of left ventricular mass (LVM) . LVH
regression is thus a promising therapeutic target in devising new ways to prevent strokes,
especially if the same treatment were found to reduce WMH.
