Dementia Clinical Trial
Official title:
Influence of the Pre-existing Cognitive Status on the Outcome in Patients Treated by Thrombolytic Therapy for Acute Cerebral Ischaemia
At the acute stage of cerebral ischaemia, the only effective drug that increases the
proportion of patients who survive without dependency is thrombolytic therapy by intravenous
(i.v.) tissue-plasminogen activator (t-PA). This treatment is entered into routine practice
with similar results than in trials, in various places of the world including Europe and
Japan.
Stroke and dementia are closely related. About one patient in ten has dementia before a
first-ever stroke, and more than one in three has dementia after a recurrent stroke.
Pre-existing dementia is associated with a worse outcome of stroke, and pre-existing
cognitive impairment without dementia is associated with a higher rate of
institutionalisation within 3 years. In many patients cognitive impairment is due to the
summation of the effects of vascular and Alzheimer lesions of the brain.
More and more patients nowadays who are eligible for rt-PA are already known as demented at
admission. A retrospective study conducted in a cohort of patients with dementia who had an
ischaemic stroke and were treated by rtPA suggested that there is no increased risk of
cerebral bleeding and death as compared with non demented patients. However, pre-existing
cognitive impairment is possibly associated with (i) an increased risk of bleeding in
patients with cognitive impairment, and (ii) a higher sensitivity to the neurotoxic effect
of rt-PA on the brain tissue.
Japanese patients differ from European patients by a higher risk of spontaneous intracranial
haemorrhage, and a higher proportion of patients with small-vessel diseases.
The primary objective of the OPHELIE-COG study is to determine whether ischaemic stroke
patients who are treated with i.v. rt-PA are more likely to have a poor outcome (defined as
a modified Rankin scale 2 to 6 at month 3) in the presence of pre-existing cognitive
impairment or dementia. The secondary objectives are to determine whether (i) they have an
increased risk of symptomatic intracerebral haemorrhages, (ii) the proportion of patients
who have a poor outcome is lower than expected from the placebo group of randomised trials
for patients with a similar range of baseline severity, and (iii) the influence of the
cognitive state on outcome differs between Japanese and European patients.
The French part of OPHELIE-COG is run as an ancillary study of OPHELIE, a multicenter French
study conducted in the clinical centres of the Strokavenir research network (co-PI Didier
Leys, Lille and Denis Vivien, Caen). OPHELIE has been approved by the ethical committee and
is an investigator-driven study supported by the INSERM, the University Lille Nord de France
and the Lille University hospital. OPHELIE includes prospectively all patients who are
treated by i.v. rt-PA for an acute cerebral ischaemia in the participating centres and tests
the hypothesis that the single/two chain-tPA ratio in the infusion influences the 3-month
outcome, evaluated by a score 0 or 1 at the modified Rankin scale(mRS). OPHELIE-COG is
conducted in the same cohort of patients as an ancillary analysis of OPHELIE.
The Japanese part of OPHELIE-COG will be conducted In patients who receive i.v. rt-PA for
acute cerebral ischaemia in participating Japanese centres. Japanese centres will not be
part of the OPHELIE study.
No specific investigation is necessary for the purpose of the study. There is no variable
recorded that is not part of the usual management of stroke patients treated by i.v. rt-PA.
Following-up patients at 3 months and having mRS is recommended to monitor the results of
thrombolysis in all centres able to deliver the treatment. The informant Questionnaire on
Cognitive Decline in the Elderly (IQCODE)is not part of the care in all centres but is
however highly recommended because of the influence of the pre-existing cognitive state on
stroke outcome in general.
The systematic assessment of pre-existing dementia is conducted within 48 hours of stroke
onset by French or Japanese translations of the short version of the IQCODE. Patients who
are already followed-up by a neurologist and diagnosed as demented before stroke are
classified as previously demented irrespective of the IQCODE score. Patients who cannot have
an IQCODE but have a MMSE score of 30 before discharge are classified as cognitively normal.
Patients who cannot have an IQCODE and have a MMSE score of 29 or less are not eligible.
The sample size calculation for the French patients has been performed for the primary
objective of OPHELIE assuming an expected difference of 5% for the primary end-point with
alpha and beta risks of 5% and 20% respectively and a expected proportion of patients with a
mRS score 0-1 of 40% at month-3, according to trials, observational registries and data
published in the Lille centre for a baseline NIH score of 11: 900 patients will be
necessary. To detect an absolute difference of 10 % for the primary end-point with an alpha
risk of 5% and a power of 80%, a sample size of 1040 eligible patients is necessary,
assuming that 12 to 16% of patients will have criteria for pre-existing dementia. This 10%
absolute difference in the proportion of patients with mRS 0-1 at month 3 between those with
and without pre-existing dementia corresponds to the difference below which the beneficial
effect of rt-PA may be lost, taking into account that approximately 30% of patients under
placebo, and 40% under rt-PA have a mRS 0-1 at month 3 for a median baseline NIH score of
11. Assuming that 20% of patients included in OPHELIE will not be eligible for OPHELIE-COG
according to the proportion of exclusions found in previous studies with the IQCODE, we can
expect a recruitment of 720 patients in the French arm of the study. The 320 other patients
will be recruited in Japan, meaning that 400 patients have to be recruited to compensate the
usual 20% rate of patients who cannot have an IQCODE in due time.
An intermediate analysis will be performed after inclusion of 500 patients arrived at 3
months of follow-up to re-evaluate the sample size.
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