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Pre-stroke Cognitive Status and Thrombolytic Therapy (OPHELIE-COG)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01713491
Recruitment Status : Completed
First Posted : October 24, 2012
Last Update Posted : October 27, 2016
Information provided by (Responsible Party):
University Hospital, Lille

Brief Summary:

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.

Condition or disease
Brain Ischemia Adverse Effect of Thrombolytic Drugs Impaired Cognition Dementia

Detailed Description:

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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Study Type : Observational
Actual Enrollment : 205 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Influence of the Pre-existing Cognitive Status on the Outcome in Patients Treated by Thrombolytic Therapy for Acute Cerebral Ischaemia
Study Start Date : November 2011
Actual Primary Completion Date : December 2014
Actual Study Completion Date : March 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dementia

Cognitively normal
Patients with IQCODE score of 52 or less
Cognitively impaired - no dementia
IQCODE score 53 - 63
IQCODE score 64 or more

Primary Outcome Measures :
  1. Modified Rankin Scale score 0 or 1 [ Time Frame: Month-3 ]

Secondary Outcome Measures :
  1. Symptomatic intracerebral haemorrhage defined according to the ECASS2 definition [ Time Frame: 7 days ]
  2. Death [ Time Frame: Day 7 ]
  3. Modified Rankin Scale 0-2 [ Time Frame: Month-3 ]
  4. Death [ Time Frame: Month-3 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients treated by iv tPA for acute cerebral ischaemia in routine practice

Inclusion Criteria:

  • All patients treated by iv tPA for cerebral ischaemia in routine practice in participating centres

Exclusion Criteria:

  • index ischaemic stroke sparing MCA territory;
  • thrombolytic therapy administered intra-arterially or combined with thrombectomy
  • pre-stroke mRS of 2 or more
  • impossibility to perform an IQCODE for any reason (no reliable informant available within 48 hours, not fluent in French or in Japanese or in a language spoken by the investigator), except when the patient had been diagnosed as demented by a specialist used to diagnose dementia (e.g. neurologist, psychiatrist, geriatrician) before stroke, or has a MMSE score of 30 at discharge.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01713491

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Lille University Hospital
Lille, France, 59000
Fukuoka Redcross Hospital
Fukuoka, Japan
Fukuoka-Higashi Medical center
Fukuoka, Japan
Kyushu Medical Center
Fukuoka, Japan
Kyushu University
Fukuoka, Japan
Kyushu Rosai Hospital
Kitakyushu, Japan
Steel Memorial Yawata Hospital
Kitakyushu, Japan
Kawasaki Medical University
Kurashiki, Japan
St. Mary's Hospital
Kurume, Japan
Sponsors and Collaborators
University Hospital, Lille
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Study Director: Kei Murao, MD Lille University Hospital

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Responsible Party: University Hospital, Lille Identifier: NCT01713491     History of Changes
Other Study ID Numbers: 2010_04
912079 ( Other Identifier: CNIL number )
First Posted: October 24, 2012    Key Record Dates
Last Update Posted: October 27, 2016
Last Verified: October 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by University Hospital, Lille:
brain ischemia
thrombolytic therapy
Impaired cognition
Additional relevant MeSH terms:
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Brain Ischemia
Cognitive Dysfunction
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Pathologic Processes
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Cognition Disorders
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action