| Title |
CerebroVascular Disease - Cognition (CVD-Cog)
|
| Acronym |
CVD-Cog
|
| Chief investigator |
Professor Philip M Bath
|
| Objectives |
To assess:
a) Feasibility: Recruitment of 400 patients from 25 UK sites at average
recruitment rate of 0.9/site/month.
b) Retention: >90% participants at end-of-trial/6-months.
c) Adherence: >75% of participants are taking >50% trial dose at
end-of-trial.1-3
d) Completeness of primary clinical outcome: >85% of participants have
a DSM-5-7L ordinal cognition scale at end-of-trial.
|
| Trial configuration |
Parallel group randomised controlled superiority.
|
| Setting |
Secondary/tertiary care.
|
| Sample size estimate |
As a feasibility trial, there is no formal sample size calculation.
However, recruitment of 400 participants will be sufficient to assess the
feasibility, retention, adherence, safety and proof of concept aims.
|
| Number of participants |
400 participants
|
| Eligibility criteria |
Inclusions
-
Aged 50 years old and above
-
Clinical syndrome of cortical or large subcortical stroke or
TIA (TACS, PACS or cerebellar POCS)
-
At least 7 days after the index event
-
Stable medically according to the PI
- Has completed any phase of dual anti-platelet therapy
(so avoiding increased risk of bleeding with triple APT 9)
-
Independent functionally or requires only limited help (mRS 0-3)
-
Able to swallow or has established enteral feeding route
-
Brain imaging (CT or MRI scan) at the time of the index stroke/TIA
shows moderate-severe white matter hyperintensities, Fazekas Score
periventricular and deep 2 or greater (Appendix *).30
-
The relevant radiology report will be uploaded as part of
eligibility and assessed for these criteria
-
Consent:
-
Patient has capacity to give consent in the opinion of the PI or
any delegated member of the research team, OR
-
Patient lacks capacity and a legal representative is available
to give consent on their behalf
-
Likely to be available for follow-up at 6 months.
-
Women of childbearing potential and men who have a partner of
childbearing potential must be willing to use
contraception – see later section which details this.
Acceptable contraceptive methods include established use of
oral, injected or implanted hormonal methods; placement of an
intrauterine device (IUD) or intrauterine system (IUS); condom or
occlusive cap (diaphragm or cervical/vault caps) with spermicide;
true abstinence (when this is in line with the preferred and usual
lifestyle of the participant); or vasectomised partner.
Exclusions
-
Lacunar stroke (LACS; so is eligible for LACI-3 trial)
-
Brain stem-only posterior circulation stroke syndrome (POCS).
Note: cerebellar POCS are eligible
-
Known monogenic cerebral small vessel disease
-
Index event was an intracranial haemorrhage.
Note: a past history of ICH before the index event is eligible
for randomisation to ISMN vs no ISMN but not to cilostazol vs
no cilostazol
-
Other active brain disease (e.g. brain tumour, multiple sclerosis,
Parkinson’s disease, recurrent seizures, neurodevelopmental
disorder).
Note: well-controlled epilepsy present prior to the
stroke, a single seizure at onset of the stroke, or provoked seizure,
is not an exclusion
-
Clinical diagnosis dementia (e.g. letter from a memory clinic
and/or taking acetylcholinesterase inhibitor or memantine)
-
Contraindication to both trial drugs (as per SmPC).
Note: Patients on one antiplatelet agent with a contraindication to
cilostazolone trial drug may still be randomised to isosorbide
mononitratethe other trial drug.
Note: Patients taking an OAC
who cannot take ISMN will not be able to enter the trial
-
Indication for both trial drugs (as per SmPC);
Note: A patient
already prescribed one trial drug may still be randomised to the
other trial drug
-
Planned surgery during the trial period including carotid
endarterectomy;
Note: Patient becomes eligible after planned
surgery. Prior and apparently successful carotid endarterectomy
(or other surgery) is not an exclusion criterion and patients who
would otherwise be eligible but require endarterectomy first may be
randomised after recovery from successful endarterectomy
-
Diagnosis of hypotension, defined as sitting systolic blood pressure
less than 100mmHg
-
History of drug overdose or attempted suicide
-
Person is a visitor to the hospital’s region so cannot be
followed (e.g. on holiday/from overseas)
-
Unlikely to comply with study procedures and follow-up procedures for
whatever reason (e.g. history of poor medication compliance) in the
opinion of the randomising physician
-
Pregnancy, breast-feeding, or of child-bearing potential (a negative
pregnancy test is needed prior to enrolment) and not using highly
effective contraception. (Women of childbearing potential and men
with partners of child-bearing potential must be willing to use
contraception)
-
Known renal impairment (most recent creatinine clearance under
25 ml/min)
-
Known hepatic impairment (most recent transaminase greater than 3
times upper limit normal)
-
Previously enrolled in CVD-Cog
-
Enrolled in a study that does not have an agreement with CVD-Cog
allowing co-enrolment (see up to date list of trials allowing
co-enrolment on CVD-Cog website)
|
| Description of interventions |
|
| Duration of study |
The trial's funding is for last 3 years.
Participants will be treated and followed for 6 months in total
|
| Randomisation and blinding |
Computerised randomisation to reduce bias with:
Stratification:
No oral anticoagulation - ISMN: cilostazol: both: neither 1:1:1:1),
versus
On oral anticoagulation - ISMN: no ISMN 1:1.
Minimisation:
Scoring 2 points - age, premorbid mRS, stroke impairment (NIHSS), age of
leaving education;
Scoring 1 point - sex, onset from stroke to randomisation, systolic BP,
smoking.
Treatment is given open label (PROBE design).
|
| Outcome measures |
Feasibility: Recruitment of 400 patients from 25 UK sites.
Retention: >90% participants at end of trial/6-months.
Adherence: >75% of participants are taking >50% trial
dose.
Completeness of primary clinical outcome: >85% of participants
have a DSM-5-7L ordinal cognition scale at end-of-trial.
Safety: All cause death; serious adverse events targeted
drug-related adverse events (headache, loose stools, palpitations,
nausea, dizziness, falls).
Proof-of-concept: Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5) 7-level ordinal cognition scale at
end-of-trial.
Health economics: Not to be assessed.
Process evaluation: Not to be assessed.
|
| Statistical methods |
Tabulations of feasibility, retention, adherence, completeness of
follow-up, safety and proof-of-concept. Data will be shown as number (%),
median [interquartile range] or mean (standard deviation). Safety,
symptoms and proof of concept will involve statistical comparisons
between ISMN vs no ISMN, cilostazol vs no cilostazol and dual therapy vs
no therapy. Comparisons will use binary logistic regression, Cox
proportional hazards regression, ordinal logistic regression or multiple
linear regression. Primary analyses will use modified intention-to-treat
(no imputation). There will be no adjustment for multiplicity.
|
