Effect of Standard vs Intensive Blood Pressure Control on Cerebral Blood Flow in Small Vessel Disease

Key Points Question Does intensive blood pressure lowering cause hypoperfusion in severe cerebral small vessel disease? Findings This randomized clinical trial used arterial spin labeling to examine the effect of standard (n = 33) vs intensive (n = 29) blood pressure treatment regimens on cerebral blood flow in patients with severe small vessel disease over 3 months. Change in whole-brain cerebral blood flow did not significantly differ between standard vs intensive groups. Meaning Intensive blood pressure lowering did not cause hypoperfusion in severe cerebral small vessel disease.

To determine whether a strategy of intensive, versus standard, treatment of BP in hypertensive individuals with cerebral small vessel disease (SVD) and leukoaraiosis is associated with reduced cognitive decline.

Secondary
Objective: 1. In a subgroup of the overall RCT to determine whether a strategy of intensive, versus standard, treatment of BP in hypertensive individuals with SVD and leukoaraiosis is associated with brain changes detectable on serial MRI imaging: namely a reduced rate of white matter damage assessed by Diffusion Tensor Imaging, a reduced rate of brain atrophy and an increase in cerebral blood flow (CBF) 2. To compare the sensitivity of diffusion tensor MRI and brain atrophy as surrogate markers of white matter damage for therapeutic trials and their relationship to cognitive decline, compared with the conventional MRI marker of T2 white matter lesion volume

Study population:
Patients with clinical and radiological features of cerebral small vessel disease

Methodology:
Randomised trial of two treatment regimens with primary outcome of change in cognition and secondary outcome of change in MRI parameters

Study drugs, Dose and Mode of Administration: Not applicable
Duration of Treatment: 2 years 4 Introduction

Background
Cerebral small vessel disease (SVD) accounts for about 20% of all stroke (lacunar stroke) and is now recognised to be the major cause of vascular cognitive impairment and dementia (1).
Therefore, it presents a major public health problem. It arises from disease in the small perforating arteries supplying the white matter and deep gray matter structures. Radiologically one sees a combination of small discrete lacunar infarcts with or without more diffuse ischaemic changes, best seen on T2-weighted Magnetic Resonance Imaging (MRI) as high signal and referred to as leukoaraiosis (or white matter hyperintensities).
In patients with cognitive impairment due to SVD a characteristic picture of "subcortical" cognitive impairment is seen with impairment of executive function and information processing speed being prominent while episodic memory is preserved.(2,3) Commonly used screening tools for cognitive impairment, such as the Mini Mental State Examination score (MMSE), were designed for the pattern of impairment seen in cortical dementias such as Alzheimer's disease and are insensitive to the deficits seen in SVD. However, using a cognitive battery tailored to the deficit seen in SVD we have shown (previously and more recently in a Stroke Association project grant) that as many as 50% of patients with lacunar stroke have cognitive deficits. (4,5) Cognitive deficits are much more common in SVD patients with accompanying leukoaraiosis.
Leukoaraiosis in this patient group is related to progressive cognitive impairment and a high risk of developing dementia and disability. (6,7) The recent prospective LADIS study in 639 subjects showed leukoaraiosis specifically contributed to the deterioration in psychomotor speed and executive function which occurred during follow-up. (7) Despite this association between leukoaraiosis and cognition, the correlation between cognition and MRI T2-lesion volume (leukoaraiosis volume) in patients presenting with clinical SVD is weak. (8,9) This may be because T2-high signal does not differentiate between areas of increased water content and structural damage.(10) Using Diffusion Tensor Imaging (DTI) it is possible to better image white matter tract structure, and we have shown that DTI parameters correlate highly significantly with cognitive impairment in this group, and to a greater extent than T2-lesion volume. (8,9,11) This supports a role for white matter tract damage and subsequent cortical-subcortical disconnection in causing cognitive impairment in these patients. Hypertension is the major risk factor for SVD, being present in up to 80-90% of patients with lacunar stroke and leukoaraiosis. (12) In asymptomatic individuals there is a strong relationship between blood pressure(BP) and leukoaraiosis volume, and treatment of BP reduces leukoaraiosis progression. (13,14) However, the situation is more complex in patients with symptomatic SVD, particularly in those with accompanying leukoaraiosis. In stroke patients as a whole there is strong evidence that treating BP, even in individuals with BP in the "normal" range, reduces recurrent stroke as well as heart and renal disease. (15) However, it has also been suggested that over-zealous treatment of BP in this group with extensive leukoaraiosis could have deleterious consequences. (16) An important mechanism underlying leukoaraiosis is believed to be hypoperfusion in the internal watershed areas at the distal supply of the perforating arteries. We, and others, have confirmed reduced white matter cerebral blood flow (CBF) in SVD, (17,18) and impaired cerebral autoregulation has also been reported. ( The relationship between hypertensive therapy and cognition is also complex. Prospective out of those with cognitive decline, and particularly the use of cognitive tests such as the MMSE which are insensitive to the cognitive profile of SVD as outlined above. For example a substudy of the SCOPE trial (29), which overall showed no difference in MMSE between groups (28), found a possible reduction in cognition in the candesartan treated group when more appropriate cognitive tests were used. The above studies have been in unselected individuals with hypertension: the situation is even less clear in patients with SVD and leukoaraiosis. In this group a reduction in BP could be protective due to increasing CBF and/or delaying progression of leukoaraiosis. (16) Conversely it has been proposed that reduced BP could cause a reduction in CBF in individuals with already established SVD and irreversible vessel damage which results in impaired autoregulation, and this could worsen cognition. (16) Uncertainty about the risk and benefits of BP lowering in this patient group with SVD and leukoaraiosis means that some clinicians treat BP aggressively in this group while others are cautious particularly in older patients. (16) Individual case reports and small series have suggested excessive BP lowering can be hazardous and the optimal target BP remains unclear.
There are no randomised controlled trials which have adequately addressed the issue of benefits and risks from different target BP.
We have reviewed the available data (16,30) and identified a number of issues making CBF in older patients with hypertension without SVD (see above). We will apply this technique to SVD with leukoaraiosis to determine the relationship between BP lowering and CBF.
To investigate these questions we will perform this current clinical trial with nested sub-studies.
Specifically this will include: 1. A randomised controlled trial (RCT) of intensive versus usual blood pressure lowering treatment with cognition as a primary end point.
2. Nested within the RCT in a subgroup of the overall trial population, a sub-study with progression of white matter damage, assessed using DTI, as the primary endpoint.
3. Nested with the RCT a pathophysiological sub-study determining the effect of intensive blood pressure lowering on cerebral perfusion.
This series of clinical studies will allow us to answer all our research objectives listed above in the most efficient manner.

Study objectives Primary objective
To determine whether a strategy of intensive, versus standard, treatment of BP in hypertensive individuals with SVD and leukoaraiosis is associated with reduced cognitive decline.

Secondary objectives
A. In a subgroup of the overall RCT to determine whether a strategy of intensive, versus standard, treatment of BP in hypertensive individuals with SVD and leukoaraiosis is associated with brain changes detectable on serial MRI imaging: A reduced rate of white matter damage assessed by Diffusion Tensor Imaging A reduced rate of brain atrophy (global, or grey or white matter) To compare the sensitivity of diffusion tensor MRI and brain atrophy as surrogate markers of white matter damage for therapeutic trials and their relationship to cognitive decline, compared with the conventional MRI marker of T2 white matter lesion volume.
6 Trial design

Overall design
This is a randomised trial of two treatment strategies (intensive versus standard) for lowering blood pressure in patients with SVD and radiological leukoaraiosis.
Within this overall study there will be two nested sub-studies which some, but not all, patients will also enter:

Vascular Cognitive Impairment
To be entered into the study with vascular cognitive impairment, the patient must meet each of the following criteria: 1. Cognitive concern reflecting a change in cognition reported by patient or informant or clinician (i.e., historical or observed evidence of decline over time 3. Sponsor has conducted the trial initiation procedure.
All sites participating in the trial will also be asked to provide a copy of the following: All patients will give informed consent. Informed consent must be obtained before any trialrelated procedures are undertaken.
Informed consent will be taken by medical staff at SpR level or above or Senior Research nursing staff (Band 6 and above).
Patient will be given up to 7 days to decide whether they wish to take part.

Participant Loss of Capacity
Because cognitive dementia is common among patients with cerebral small vessel disease, it is possible that individual participants may lose capacity to consent over the course of the study. At the point of recruitment, it is specified in the inclusion criteria that all participants must be able to provide consent to join the study. If, during the course of the study, there are any concerns about a participant's capacity to consent (using the Mental Capacity Act (2005) as a guide), a consultee will be approached to provide advice on the participant's continued participation. We will ask the participant to identify a consultee, usually a partner or family member or carer, at the baseline visit

Randomisation procedure
Patients will be randomised to Usual or Intensive blood pressure lowering. Randomisation will be in the ratio 1:1 and performed via an online randomisation system, available 24 hours, based at the Mental Health & Neuroscience Clinical Trials Unit (MH&N CTU) at the Institute of Psychiatry.
Randomisation will be stratified by centre.

Treatment strategies
Patients will be randomised between two treatment strategies: Both groups will be given home blood pressure monitors and asked to perform daily blood pressure readings for at least three days prior to each pre-arranged telephone follow-up. On each occasion they will take a reading in the seated position always from the same arm (left unless specified).

1.
The intensive BP lowering group will have BP lowering treatment increased at baseline assessment and be reviewed by telephone at two weekly intervals. If average BP at any followup is >125 mmHg treatment will be increased until target systolic BP of <125 mm Hg is achieved (average of 2nd and 3rd of three seated BP readings), or symptoms of hypotension prevent treatment being intensified. If dose of an existing drug is instituted this can be done over the telephone but if a new agent is required the patient will attend for the prescription.

2.
The usual BP lowering group will have treatment unchanged at study entry. They will be contacted for two weekly intervals for the first month and then seen for regular follow-up as outlined blow. At follow-up if average systolic BP is above 140 mmHg treatment will be increased until target systolic BP of <140mmHg or symptoms of hypotension prevent treatment being intensified.
Note: Patients taking part in the perfusion MRI study will not have their treatment altered until they have had their baseline MRI scan.
The NICE/British Hypertension Society guideline based algorithm will act as a guide to treatment but all treatment decisions will be made by the local principal investigator. In both treatment groups treatment will be changed if the patient experiences adverse effects considered by the local PI to be related to the BP lowering treatment.

Screening assessments
At a screening assessment potential study participants will be reviewed with the following to ensure they meet the inclusion criteria and do not have exclusion criteria and the researcher will fill in a screening checklist. Assessments will include:

Assessment of cognition
The primary outcome will be changes in a composite cognitive score with cognition assessed by a battery of tests known to be sensitive to impairments in attention, information processing and executive function due to subcortical white matter disease (1). This will yield a composite score comprising data from the following tests. Times each test takes are shown in brackets. In addition premorbid intellectual functioning at baseline will be assessed using the National Adult Reading Test -Restandardised (NART-R) (39) (5 minutes). At baseline the contact details of a partner/relative or other close informant will also be taken to allow information to be collected if the participant loses capacity during the study.

Subsequent assessments
All subjects will be seen at 1, 3, 6, 12, 18 and 24 months (measured from the baseline visit) for a clinical assessment and monitoring of BP. Cognitive assessments will be performed at 1 year and 2 years except for the MOCA which will also be performed at 3 months. When a cognitive assessment is required at the same time, both will be carried out on the same visit.

Summary flow table of study assessments
See Appendix 1 and 2

Laboratory procedures
Blood will be taken at baseline for both DNA extraction and storage of serum. Genotyping of polymorphisms discovered as part of ongoing genome wide association studies will be performed.
Blood will be taken by venupuncture into tubes for serum and into EDTA tubes for DNA. Serum samples will be centrifuged and serum separated and pipetted into a storage tube and both extracted serum and EDTA will be stored in a freezer at ≤ -70 o C in the local centre until transferred to CUH. Extracted DNA samples may be sent for additional genotyping to other centres in the UK or Europe for specific analyses as part of future collaborative projects.

Radiology or any other procedure(s)
Only patients who have undergone an MRI brain scan prior to screening can be assessed for suitability for the study. It is anticipated that patients will have already had an MRI scan performed for clinical management purposes. Patients who have a MRI scan planned can be screened for eligibility prior to this being performed. All MRI used at screening to confirm eligibility must have been performed within 2 years of randomisation and the patient must have suffered no new stroke with residual disability since the scan was performed.
Only patients within the MRI substudies will have MRI scans as part of the study. All patients recruited to the MRI substudies will be part of the larger RCT. Subjects can be in either or both of the MRI substudies. All of these additional MRI scans will be performed using clinical MRI scanners at field strengths of 1.5 or 3T and do not involve exposure to radiation. MRI does not involve radiation and there will be no contrast administration.

DTI-MRI sub-study
A standardised MRI protocol will be performed at baseline and after 2 years.
This will include: high resolution 3D T1-weighted images (for brain volume) ~4.5 minutes T2-weighted gradient echo (GE) images (for identification of microbleeds) ~7 minutes FLAIR (for computation of lesion volume) ~4.5 minutes DTI (for white matter structural analysis). DTI provides quantitative measures (fractional anisotropy and diffusivity (including axial, radial and mean diffusivity) which can be compared both longitudinally and across sites. High angular resolution diffusion-weighted images will be acquired using a pulsed gradient spin echo planar imaging (EPI) sequence in approximately 11 minutes.

Perfusion sub-study
Subjects in this substudy will have the standard MRI protocol above and in addition will have cerebral blood flow (CBF) / perfusion studies CBF MRI will be performed at baseline, 3 months, and at 2 years.
The CBF MRI will take place in two sites (

Definition of the End of Trial
This is the Last Patient Last Visit (LPLV) (i.e. telephone call, home visit, hospital visit).

Drop outs
If subjects discontinue for any reason, if possible an assessment including cognitive assessment will be performed just prior to study exit

Recording Adverse Events (AEs)
A record of adverse events will be recorded and the relationship to treatment assessed and forwarded to the study co-ordinating centre A record of adverse events will be collected at each follow-up visit.
Specifically we will ask at each visit about Falls Dizzyness/postural instability 13 Data management and quality assurance

Confidentiality
All data will be handled in accordance with the Data Protection Act 1998.
The Case Report Forms (CRFs) will not bear the subject's name or other personal identifiable data. The subject's initials, Date of Birth (DOB) and trial Identification Number (ID), will be used for identification.

Data collection tool
All on case report forms, data will be entered legibly in black ink with a ball-point pen. If the Investigator makes an error, it will be crossed through with a single line in such a way to ensure that the original entry can still be read. The correct entry will then be clearly inserted. The amendment will be initialled and dated by the person making the correction immediately.
Overwriting or use of correction fluid will not be permitted. It is the Investigator's responsibility to ensure the accuracy of all data entered and recorded in the CRFs. The Delegation of Responsibilities Log will identify all trial personnel responsible for data collection, entry, handling and managing the database.

Data handling and analysis
Data will be entered onto the online InferMed MACRO data entry system, hosted at the Mental Health and Neurosciences Clinical Trials Unit. The system is compliant with GCP, with a full audit trail and formal database lock functionality.
Data will also be stored on a two level password protected database in the Stroke and In time, study management will transfer to CUH completely. The Study Manager will, in either case, be supervised by and report to the trial steering committee. They will also work closely with the MHClinical Trials Unit, which will assist in study monitoring. An independent Data Monitoring Committee will monitor trial progress.
Data entry quality will be checked by a random check on CRFs and their corresponding database entry 14 Archiving arrangements

Site Archiving
The trial documents (including the site File (SF), Informed Consent Forms along with the CRFs will be kept at sites for a minimum of five years, in line with local hospital protocol.

Trial Management Archiving
The Trial Master File will be stored in locked offices within the CUH site. The Chief Investigator is responsible for the secure archiving of trial documents which will be archived at CUH. The trial database will also be kept electronically on the UC computer network, for a minimum of five years.

DTI-MRI substudy
We will include 180 subjects (90 in each arm) in this substudy; sample sizes are based on FA values from our DTI longitudinal study. With p<0.05, and power of 0.9, and with SD in control group of 6.0 x 10-3 and difference between 2 interventions of 3.1x10-3 we require 80 in each group ie 160 total, which we have increased by 12.5 % ( a figure based on our SCANS prospective MRI study) to 180 to account for attrition.

Perfusion substudy
Global CBF, and white and grey matter CBF will be determined. We will determine whether there are significant differences in change in CBF between the two groups.

Primary endpoint analysis
To avoid bias due to multiple testing of the large number of neuropsychological tests a composite executive function score will be calculated by averaging z scores (calculated using the DKEFS normative data) for the Trail Making, Digit Symbol Coding and Verbal Fluency tests. For Trail Making adjusted outcome scores will be the difference between the TMT-B and TMT-A times and the difference between the TMT-B and motor speed. Data will be analysed on an intention to treat basis.
The primary analysis will be change between baseline and year 2.
The primary analysis will be intention to treat after patients excluded after review of the screening scan for not having small vessel disease/lacunar infarction have been excluded A per protocol analysis will also be performed.

Secondary endpoint analysis
The secondary endpoint analysis will be intention to treat after patients excluded after review of the screening scan for not having small vessel disease/lacunar infarction have been excluded A per protocol analysis will also be performed.

Randomisation
There may be differences between sites in MRI system characteristics and for this reason randomisation to the MRI substudy is stratified by site.

Committees in involved in the trial
1. Trial Management Group (TMG) -This will be responsible for day-to-day management of the trial and will comprise the CI, the trial manager, and study clinical research fellows and neuropsychologist. They will co-ordinate regular teleconferences (eg monthly) with co-ordinating staff from St. George's University of London, University of Cambridge, Oxford University and Newcastle University. The role of the group is to monitor all aspects of the conduct and progress of the trial, ensure that the protocol is adhered to and take appropriate action to safeguard participants and the quality of the trial itself.

Trial Steering Committee (TSC)
-This will provides overall supervision of the trial and ensures that it is being conducted in accordance with the principles of GCP and the relevant regulations.

Independent Data Monitoring Committee (IDMC)
-This will regularly monitor trial progress assess whether there are any safety issues that should be brought to participants' attention or any reasons for the trial not to continue.

Direct access to source data
The Investigator(s)/institution(s) will permit trial-related monitoring, audits, REC review, and regulatory inspection(s), providing direct access to source data/documents. Trial participants are informed of this during the informed consent discussion. Participants will consent to provide access to their medical notes.

Ethics and regulatory requirements
The Sponsor will ensure that the trial protocol, Patient Information Sheet (PIS), Informed Consent Within 90 days after the end of the trial, the CI and Sponsor will ensure that the main REC are notified that the trial has finished. If the trial is terminated prematurely, those reports will be made within 15 days after the end of the trial.
The CI will supply a summary report of the clinical trial to the main REC within one year after the end of the trial.

Monitoring plan for the trial
The trial will be monitored according to the monitoring plan agreed and written by the Sponsor, based on the internal risk assessment procedure.

Finance and funding
The study is funded by a Stroke Association/British Heart Foundation Programme Grant.

Publication policy
Results will be published in peer reviewed journals and presented at conferences. Publications policy will be decided by the steering committee.

Statement of compliance
The trial will be conducted in compliance with the protocol, Sponsor's Standard Operating Procedures (SOPs), GCP and the applicable regulatory requirement(s). This study will be conducted in compliance with the protocol approved by the REC and according to GCP standards. No deviation from the protocol will be implemented without the prior review and approval of the Sponsor and REC except where it may be necessary to eliminate an immediate hazard to a research subject. In such case, the deviation will be reported to the Sponsor and REC as soon as possible. The Analyses 31 General statistical bookkeeping 32  Check distribution of all variables in main treatment and subgroups. 33  Homogeneity of variance tests between variables after being split into groupings 34 based on treatment / bp. 35  Examinations to make sure the different experimental groups (both treatment arm 36 and achieved bp groupings) are similar, i.e. groupwise testing to examine for any 37 baseline differences in:  Independent t-tests to statistically examine bp change between treatment groups. 56 Testing our main objectives 57  Primary outcome of change in CBF between treatment groups will be tested using an 58 ANOVA which also controls for site.

59
 Secondary outcomes of the different tissue ROI's will also be tested between 60 treatment groups in an ANOVA, controlling for site.

61
 These tests will be repeated using the different groupings based on patients who 62 "achieved" their bp (intensive= <125, standard= >130).

63
 Where appropriate after an ANOVA, post-hoc tests looking at exact means / hazard 64 ratios etc. will be conducted. Levines Test of equal variances will also be used to see 65 that ANOVA assumptions have been met. Analysis will be repeated using non-66 parametric testing when necessary.
67  A regression model will use change in CBF as the DV and baseline / 3 month change 68 in bp as a predictor variable to examine this relationship (while controlling for site).
 The distribution of residuals will be inspected for normality following regressions to 70 ensure that regression assumptions have been met. 71  The number of Adverse Events/SAE's (deemed to have been "possible" or greater in 72 their chance of being related to the study drug) will be compared between groups by 73 independent t-tests / Mann Whittney U as appropriate.