Prevention of Hypertensive Injury to the Brain by Intensive Treatment of Blood Pressure After Intracerebral Haemorrhage
Phase: NA
Conditions: Intracerebral Hemorrhage
Sponsor: University College, London

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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Clinical Investigational Plan (CIP) for Medical Device Studies 
 
 
Full title of Investigation: 
 
PRevention Of Hypertensive Injury to the Brain 
by Intensive Treatment after IntraCerebral 
Haemorrhage: a pilot randomised trial of home 
telemetry-guided treatment 
Short title: 
 
PROHIBIT-ICH 
Version and date of Clinical 
Investigation Plan (CIP): 
Version 5.0, 13th June 2018 
Sponsor: 
 
University College London 
Sponsor CIP number: 
PROHIBIT-ICH01 
Funder (s): 
Stroke Association Priority Programme Grant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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Revision History: 
 
Version 
numbers 
Date 
Summary of revisions in the 
case of amendments 
 
Protocol Updated by [insert 
name & Signature] 
1.0 
12/12/2017 Template 
and 
list 
of 
amendments 
requested 
by 
Sponsor 
Professor David Werring 
Professor Peter Rothwell 
Shahena Butt 
Ian McGurgan 
Louise Silver 
 
2.0 
21/02/2018 
Section: a.7.4 who will hand the 
information sheets out, who will 
go through this with the patients. 
when does the research team 
get involved, do they do the 
second approach 
 
Section: A8 when will consent 
be taken, how long between 
receiving the PIS will the 
patients be expected to consent 
 
Shahena Butt 
3.0 
15/03/2018 
this needs to state how capacity 
will be assessed by who and 
how  
 
Shahena Butt 
4.0 
18/04/2018 
Section 13.5 of the protocol 
states that only initials and 
unique trial number will be 
stored on the CRF. Please 
consider updating this section 
so it is consistent with the 
information in section A11 of the 
Protocol  
 
Shahena Butt 
 
 
 
 
 
 
 
 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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Signatures 
 
The Chief Investigator (CI) and the JRO have discussed this Clinical Investigation Plan (CIP). The 
investigator agrees to perform the investigations and to abide by this CIP.  
 
The investigator agrees to conduct the Investigation in compliance with the approved CIP, EU Good 
Clinical Practice (GCP) and UK Regulations for Devices (SI 2002/618; as amended) for regulated 
studies, the UK Data Protection Act (1998), the Trust Information Governance Policy (or other local 
equivalent), the Research Governance Framework (2005 2nd Edition; as amended), the Sponsor’s 
SOPs, and other regulatory requirements as amended. 
 
Chief investigator 
Professor David Werring 
 
 
 
Signature 
Date 
Co-Chief investigator 
Professor Peter Rothwell 
 
 
University of Oxford 
Signature 
Date 
Sponsor Representative 
Tabitha Kavoi 
 
 
UCL 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13/06/2018 
13/06/2018 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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Contents 
 
Clinical Investigational Plan (CIP) for Medical Device Studies ................................................................ 0 
Signatures ............................................................................................................................................ 2 
Sponsor ................................................................................................................................................ 7 
Principal Investigator, Coordinating Investigator and Investigation site(s) .................................... 7 
A.1 Overall Synopsis of Clinical Investigation ................................................................................... 9 
A.2 Background and Rationale ......................................................................................................... 13 
A.3 Identification and description of the Investigational Device .................................................... 13 
A.4 Justification for the design of the clinical investigation ........................................................... 15 
A.5 Risks and benefits of the Investigational device and clinical Investigation ............................ 18 
A.6 Objectives and hypotheses of the clinical investigation .......................................................... 19 
A.7 Design of the clinical investigation ............................................................................................ 21 
A.7.1 General .............................................................................................................................. 21 
A.7.2 Investigational device and comparators ............................................................................. 21 
A.7.3 Subjects ............................................................................................................................. 23 
Inclusion criteria ................................................................................................................................... 23 
Exclusion criteria .................................................................................................................................. 23 
Subject Eligibility .................................................................................................................................. 24 
Subject Identfication. ............................................................................................................................ 24 
A.7.4 Recruitment ....................................................................................................................... 25 
A.7.5 Randomisation Procedures ................................................................................................ 25 
A.7.6 Procedures ........................................................................................................................ 25 
A.8 Informed Consent Process ......................................................................................................... 25 
A.9 Schedule of assessments and interventions by visit ............................................................... 27 
A.9.1 Laboratory Assessments and Procedures ................................................................................... 27 
A.10 Device accountability ................................................................................................................ 28 
A.11 Monitoring Plan ......................................................................................................................... 28 
Confidentiality ...................................................................................................................................... 29 
Record keeping and archiving .............................................................................................................. 29 
A.12 Statistical Considerations ......................................................................................................... 29 
A.13 Data Management ...................................................................................................................... 34 
         A.13.1 Procedures for data review, database cleaning, and issuing and resolving data queries. . 34 
         A.13.2 Procedures for verification, validation and securing of electronic clinical data systems .... 35 
         A.13.3 Data retention. ................................................................................................................. 35 
         A.13.4 Clinical quality assurance ................................................................................................. 35 
         A.13.5 Completion of Case Report Forms ................................................................................... 35 
         A.13.6 Retention of Documentation ............................................................................................. 36 
A.13.7 Training ........................................................................................................................... 36 
A.14 Amendments to the CIP ............................................................................................................ 37 
A.15 Deviations from clinical investigation plan ............................................................................. 37 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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         A.15.1 Procedures for recording, reporting and analysing CIP deviations. .................................. 37 
         A.15.2 Procedure for reporting any protocol deviations ............................................................... 38 
A.16 Insurance ................................................................................................................................... 38 
A.17 Adverse events, adverse device effects and device deficiencies .......................................... 39 
a-c) Definitions ..................................................................................................................................... 39 
Seriousness ......................................................................................................................................... 42 
Causality .............................................................................................................................................. 42 
Expectedness ...................................................................................................................................... 42 
f) Procedures for recording and reporting Adverse Events and Device Deficiencies ................... 43 
Investigator responsibilities: ................................................................................................................. 43 
Reporting of all Adverse Events and Device Deficiencies: Investigator and Sponsor 
responsibilities ............................................................................................................................ 43 
Progress reports .................................................................................................................................. 44 
A.18 Oversight Committees .............................................................................................................. 44 
A.19 Vulnerable population ............................................................................................................... 44 
A.20 Suspension or premature termination of the clinical investigation ....................................... 44 
A.21 Definition of End of Trial ........................................................................................................... 45 
A.22 Publication policy ...................................................................................................................... 45 
A.23 Bibliography .............................................................................................................................. 45 
Appendix 1: Schedule of Assessments ............................................................................................ 49 
Appendix 2: Cognitive functional change (modified mentreal cognitive assessment) ................. 50 
Appendix 3: EQ-5D Questionnaire .................................................................................................... 52 
Appendix 4: Home BP participant acceptability questionnaire ...................................................... 54 
 
 
 
 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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LIST OF ABBREVIATIONS  
 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ABPM 
Ambulatory Blood Pressure Monitoring 
BP 
Blood Pressure 
CMB 
Cerebral microbleed 
CA 
Competent Authority 
CI 
Chief Investigator 
CIA 
Clinical Investigation Agreement 
CIP 
Clinical Investigation Plan 
eCRF 
electronic Case Report Form 
CRO 
Contract Research Organisation 
DCF 
Data Clarification Form 
DD 
Device Deficiency 
EC 
European Commission 
EU 
European Union 
EUDAMED 
European Medical Devices Regulatory Database 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
HRA 
Health Research Authority 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IMD 
Investigational Medical Device 
ISF 
Investigator Site File 
JRO 
Joint Research Office 
MA 
Marketing Authorisation 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NCA 
National Competent Authority 
NHS 
National Health Service 
NHS R&D 
National Health Service Research & Development   
NICE 
National Institute of Clinical Excellence 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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NIST 
National Institute of Standards and Technology 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure  
SVD 
Small Vessel Disease 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UADE 
Unanticipated Adverse Device Effect 
UK 
United Kingdom 
USADE 
Unanticipated Serious Adverse Device Effect 
WMH 
White Matter Hyperintensities 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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Sponsor 
Sponsor’s representative 
Tabitha Kavoi 
Joint Research Office, UCL, 1st Floor Maple House, 
149 Tottenham Court Road, 
London W1T 7NF 
Postal address: 
Joint Research Office, UCL 
Gower Street,  
London WC1E 6BT  
Principal Investigator, Coordinating Investigator and Investigation site(s) 
 
Chief Investigator (CI) 
[CI of Imaging study] 
Professor David Werring 
Professor of Clinical Neurology 
Stroke Research Centre 
UCL institute of Neurology 
Russell Square House 
10-12 Russell Square  
London WC1B 5EH 
d.werring@ucl.ac.uk 
+44 (0)20 3108 7493 
Co-Chief Investigator 
[CI of BP study] 
Professor Peter Rothwell 
Action Research Professor of Neurology and Director of the 
stroke prevention research unit 
Centre for Prevention of Stroke and Dementia 
University of Oxford 
Level 6, West Wing 
John Radcliffe Hospital 
Headley Way 
Oxford OX3 9DU 
peter.rothwell@ndcn.ox.ac.uk 
Tel: 01865 231603 
Trial Coordinator 
Shahena Butt 
Stroke Research Centre 
UCL Institute of Neurology 
Russell Square House 
10-12 Russell Square, First Floor 
London WC1B 5EH 
shahena.butt@ucl.ac.uk 
Tel: 0203 108 6181 
Imaging study co-lead (UCL) 
Professor Rolf Jager 
Neuroimaging Centre 
UCL Institute of Neurology 
Queen Square 
London WC1N 3BG 
r.jager@ucl.ac.uk 
Tel: 020 34484726 
Imaging study co-lead (UCL) 
Professor Frederik Barkhof 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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Chair of Neuroradiology 
Brain Repair and Rehabilitation 
UCL Institute of Neurology 
Faculty of Brain Sciences 
f.barkhof@ucl.ac.uk    
MR Physicist (UCL) 
Dr David Thomas 
Neuroimaging Analysis Centre 
Department of Brain Repair and Rehabilitation,  
UCL Institute of Neurology 
d.thomas@ucl.ac.uk 
Tel: 020 3448 3115  
BP Clinical Research Fellow: 
(BP Monitoring Centre) 
Iain McGurgan 
Centre for Prevention of Stroke and Dementia 
University of Oxford 
Level 6, West Wing 
John Radcliffe Hospital 
Headley Way 
Oxford OX3 9DU 
ian.mcgurgan@ndcn.ox.ac.uk 
Tel: 01865 231601 
BP Research Coordinator:  
(BP Monitoring Centre) 
Louise Silver 
Centre for Prevention of Stroke and Dementia 
University of Oxford 
Level 6, West Wing 
John Radcliffe Hospital 
Headley Way 
Oxford OX3 9DU 
louise.silver@ndcn.ox.ac.uk 
Tel: 01865 234622 
BP Clinical Research Therapist: 
(BP Monitoring Centre) 
Michelle Wilson 
Centre for Prevention of Stroke and Dementia 
University of Oxford 
Level 6, West Wing 
John Radcliffe Hospital 
Headley Way 
Oxford OX3 9DU 
michelle.wilson@ndcn.ox.ac.uk 
Tel: 01865 231601 
Statistician 
Ziyah Mehta 
Centre for Prevention of Stroke and Dementia 
University of Oxford 
Level 6, West Wing 
John Radcliffe Hospital 
Headley Way 
Oxford OX3 9DU 
Tel: 01865 234622 
ziyah.mehta@ndcn.ox.ac.uk 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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A.1 Overall Synopsis of Clinical Investigation 
 
Title: 
PRevention Of Hypertensive Injury to the Brain by 
Intensive Treatment after IntraCerebral Haemorrhage: a 
pilot 
randomised 
trial 
of 
home 
telemetry-guided 
treatment 
 
Short title: 
 
PROHIBIT-ICH 
 
Device: 
A&D BP Digital Blood Pressure Monitor (UA-767PBT-Ci) 
CE Declaration UA-767PBT-Ci 
 
Objectives: 
The trial will investigate whether intensive lowering of blood 
pressure (BP) using telemetric home monitoring in survivors 
of intracerebral haemorrhage (ICH) is feasible, safe and 
effective in reducing brain injury. If successful this study will 
be a precursor for a larger definitive trial. Our intervention 
should allow survivors of ICH to know, understand, and 
manage their own BP to prevent strokes and cognitive 
impairment, and improve outcomes. 
 
Our primary objectives are: 
(i) BP study. Does the use of centralised telemetric home 
BP monitoring in patients with spontaneous (non-traumatic) 
ICH achieve a reduction in 3-month BP compared with 
standard care? 
(ii) Imaging study. Does intensive BP treatment using 
centralised telemetric home monitoring result in a reduction 
in progression of small vessel disease (SVD)-related brain 
injury assessed on MRI (including, but not limited to, white 
matter hyperintensities (WMH), white matter structural 
integrity, incident cerebral microbleeds (CMBs), and brain 
atrophy) compared with standard care? 
 
Our secondary objectives are: 
(i) BP study 
1. Is it feasible in a multi-site setting to intensively lower BP 
using centralised telemetric home BP monitoring for an 
extended period of time following spontaneous ICH? 
2. Is it safe to intensively lower BP for an extended period of 
time following spontaneous ICH, or are there adverse 
responses (including increased progression of cognitive 
decline)? 
3. Is the intervention acceptable to participants, including 
measures of quality of life? 
(ii) Imaging study 
1. Does any reduction in recurrent vascular events 
(including ICH) or progression of cognitive decline on 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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intensive BP treatment correlate with baseline measures of 
changes in quantitative and structural brain scan markers of 
small blood vessel health? 
2. Are there any adverse effects on neuroimaging measures 
(e.g. increased white matter ischaemic injury) associated 
with intensive BP treatment? 
 
Type of Investigation: 
A pilot multi-site randomised controlled trial in approximately 
112 adult survivors of spontaneous (SVD-related) ICH. 
 
 
Investigation design 
and methods: 
PROHIBIT-ICH will randomise participants to compare a 
strategy of intensive BP treatment (target <120/80 mm Hg) 
guided by telemetric home monitoring, versus standard 
primary care (current RCP guideline is 130/80 mm Hg), in 
112 adult survivors of hypertension-related ICH. We will 
establish the feasibility and safety of the intervention, the 
efficacy of BP reduction, and explore whether it reduces the 
progression of SVD-related injury on brain MRI.  
 
Investigation duration 
per participant: 
12 Months 
 
Estimated total 
Investigation duration:  
 
 
36 Months 
Planned Investigation 
sites: 
 
Multi-Site 
 
Total number of 
participants planned: 
 
112 
Main 
inclusion/exclusion 
criteria: 
Inclusion criteria: 
  
1. Adults (≥40 years) with spontaneous primary ICH (i.e. 
without known underlying structural, macrovascular or other 
cause (e.g. arteriovenous malformation, tumour) after 
adequate investigation at the discretion of the local 
investigator). This will include participants presumed to have 
cerebral SVD (both hypertensive arteriopathy and cerebral 
amyloid angiopathy)  
2. Clinical team opinion that BP control since the ICH is not 
adequate AND the measured SBP prior to randomisation is 
≥130 mm Hg 
3. Recruitment soon after ICH, ideally at hospital discharge 
or within weeks, is encouraged; recruitment at a later stage 
after ICH is also exceptionally allowed if there is evidence of 
inadequate BP control AND SBP at randomisation is ≥130 
mm Hg  
4. For patients recruited in hospital there should be a plan 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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for home discharge (not to a nursing or care home) after 
their inpatient stay, or living at home at the time of 
recruitment 
5. Willingness and demonstration of ability to undertake 
home BP measurements, either unassisted or with the help 
of a relative, friend or carer  
6. Ability and willingness to complete an MRI scan  
7. Ability and willingness to attend and complete the study 
assessments including cognitive screen  
8. Ability and willingness to provide informed consent, or 
with a suitable consultee available and able to participate in 
the intervention (e.g. with a motivated carer) 
 
Exclusion criteria:  
1. Inability to provide informed consent or lack of suitable 
consultee (if unable to provide personal consent, lack of 
suitable consultee) 
2. Evidence of a macrovascular or structural cause for ICH 
(e.g. AVM or tumour) 
3. Diagnosis of dementia (DSM IV criteria, or self-reported 
or documented in medical records) 
4. Low Functional status (MRS ≥4) before or after ICH or 
frailty likely to make participation in 1-year follow-up difficult 
for the participant  
5. Life expectancy <2 years 
6. Taking more than 2 BP-lowering medications (i.e. 3 or 
more) at the time of consent 
7. Consistently good BP control (below 130/80 mm Hg on 
measures taken as part of routine clinical care) prior to 
planned recruitment, judged not to require more intensive 
treatment 
8. Known flow-restricting intracranial/extracranial large 
arterial stenosis 
9. Known contraindication to MRI 
10. Known absence of mobile phone coverage from all 
network operators and home internet at the participant’s 
home 
11. Known sensitivity or contra-indication to BP treatments 
(e.g. symptomatic postural hypotension) is not an absolute 
exclusion criterion, but more information must be provided 
12. Note that participation in other CTIMP or device trial is 
NOT an automatic exclusion criterion 
 
Statistical 
methodology and 
analysis: 
Primary outcomes:  
(a) BP study  
(i) 
Efficacy: the magnitude of difference in BP at 3 months 
in the intervention arm versus control arm compared 
with baseline measures 
(ii) Feasibility: consent rate; dropout rate from the 

Short Title: PROHIBIT-ICH   Sponsor code:  PROHIBIT-ICH01 
 
 
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intervention prior to 1 month; patient approval of the 
monitoring process   
(iii) Safety: serious adverse event related to reducing BP in 
intervention arm 
(b) Imaging study 
(i) Efficacy: 
the 
progression 
in 
MRI 
white 
matter 
hyperintensity (WMH) volume over 1 year 
 
Secondary outcomes: 
(a) BP study: clinical outcomes including recurrent vascular 
events and cognition; number of BP lowering drugs at 3 
months and at 1 year follow-up visits; mean daytime BP at 1 
year on 24-hour ABPM 
(b) Imaging study: neuroimaging outcomes including (but 
not limited to) the proportion of patients who develop new 
cerebral microbleeds (CMBs) over 1 year; number of new 
CMBs at 1 year; new infarcts or intracerebral haemorrhages 
at 1 year; change in mean diffusivity (MD), fractional 
anisotropy (FA) and other 3T DTI metrics; change in 
cerebral blood flow (CBF) on 3T PCASL; change in total 
brain volume, white matter volume and grey matter volume 
on 3T T1 volumetric images; composite neuroimaging 
measures (e.g summary SVD scores) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A.2 Background and Rationale 
 
Intracerebral haemorrhage (ICH)  
Spontaneous intracerebral haemorrhage (ICH) is a type of stroke due to bleeding within the brain 
parenchyma (which may also extend to ventricular and subarachnoid space) that is not caused by 
trauma.(1) ICH accounts for 10-15% of all strokes in Western populations, while in Asia it accounts for 
15-30%.(1, 2) In the UK, out of the total 150,000 strokes per year, about 15,000 to 23,000 are due to 
ICH. The 30-day case-fatality for ICH is about 40%(2) (higher than the other stroke types, ischaemic 
stroke (IS) or subarachnoid haemorrhage (SAH)). Less than a half of patients with ICH survive 1 year 
and less than a third survive 5 years, while survivors have substantial cognitive and physical 
impairments.(3) ICH additionally places a substantial economic burden on society, a challenge which 
will increase with our ageing population;(4) a meta-analysis demonstrated that ICH incidence remained 
constant between 1980 and 2008,(2) making ICH a persistent challenge for stroke research.  
 
The challenge of secondary prevention after ICH 
 
About 40% of ICH strokes are recurrent, resulting in higher mortality and disability than the first 
occurrence.(5) A recent systematic review of mainly hospital-based ICH cohorts found that the rate of 
recurrent ICH is between about 1.4% and 7.4% per year.(3) There is also a high risk of dementia after 
ICH (incidence 14.1% at one year in a recent prospective observational cohort study),(6) making 
reduction of cognitive and physical disability a key research challenge. Recurrent ICH risk seems to 
reduce over time: one study found that in the first year, the rate of recurrence was 2.1 out of 100 
patients per year, which decreased to 1.2 out of 100 patients per year, but remained comparable with 
ischaemic stroke recurrence rates (1.3 out of 100 patients per year)).(7)  ‘Lobar-lobar’(8) is reported to 
be the most common pattern of ICH recurrence, likely due to cerebral amyloid angiopathy (CAA); 
moreover, CAA-related ICH has been reported to have a much higher recurrence risk than other 
types.(9) With the high incidence, prevalence, mortality, disability, socioeconomic impact and 
recurrence rates of ICH, the benefits of high-quality research to improve outcome are likely to be 
significant. However, there remains a lack of randomised controlled trials of interventions in ICH 
survivors to reduce recurrence, brain injury, and cognitive impairment. Well-established risk factors for 
ICH recurrence include increasing age,(10) hypertension,(11) smoking,(12) excessive alcohol use,(13) 
and the presence of cerebral microbleeds on magnetic resonance imaging (MRI).(8) The most 
important and prevalent risk factor for recurrent stroke, including ICH, is hypertension, making this an 
obvious therapeutic target. Recent observational research suggests that improving long-term lowering 
of BP after stroke due to ICH might reduce recurrence.(11)  
 
Hypertension and ICH 
Long-term hypertension is the most significant risk factor for stroke in general, but particularly for ICH. 
People with hypertension have five times the risk of ICH compared to those without.(14) This 
association might be explained by the effect of poorly controlled hypertension on small blood vessel 
walls, leading to hypertensive arteriopathy, a form of cerebral small vessel disease (SVD) which causes 

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them to weaken and rupture. Small vessel disease (including hypertensive arteriopathy and CAA) is the 
major cause of spontaneous (non-traumatic) ICH.  
 
Research on lowering blood pressure after ICH 
Following ICH, patients often have early hematoma expansion, a marker of poor prognosis.(15) 
Admission systolic BP (SBP) of ≥200 mm Hg is associated with haematoma expansion and higher 
mortality.(16) A recent trial showed that acute lowering of BP (within the first 6 hours) improves 
outcomes after ICH (INTERACT-2).(17) Recent observational data suggests that even short-term 
increases in BP might trigger ICH(18) and emphasises the important role of BP management as means 
of secondary prevention for ICH. BP variability (e.g. day-to-day or between hospital visits) has also 
recently been shown to be an independent risk factor for stroke, and to influence outcome after 
ICH.(19) 
 
Less research has focused on sustained post-acute BP management, which holds the most potential to 
improve long-term prognosis and recurrence following an ICH. There have been no dedicated trials 
targeting long term BP reduction after ICH. The main prospective randomised data on the effects of 
long term BP lowering after ICH come from the PROGRESS trial, in which treatment of patients with 
ICH with the BP lowering agents perindopril (an angiotensin-converting enzyme inhibitor) and 
indapamide (a thiazide-like diuretic) led to a mean difference of 11 mm Hg systolic and 4 mm Hg 
diastolic BP between treated and placebo arm participants, with a reduction in the absolute rate of ICH 
from 2% to 1% over 3.9 years of follow-up. This 50% relative risk reduction for ICH was higher than the 
24% reduction in ischaemic stroke.(20, 21) Consistent with this substantial risk reduction in ICH, a 
recent trial in 3020 patients with recent subcortical infarction (presumed due to SVD, the main cause of 
ICH) showed that the risk of future ICH was significantly reduced (by 60%) by intensive BP lowering 
(target systolic BP <130 mm Hg compared with 130-139 mm Hg).(22)  There are, nevertheless, also 
concerns that intensive BP lowering may have an adverse impact in older populations by reducing 
cerebral perfusion, causing cerebral ischaemia, progression of cognitive impairment and falls.(23) 
Thus, although intensive BP lowering is a very promising secondary prevention intervention in ICH, the 
optimum long term target BP remains uncertain. 
 
The challenge of long-term sustained blood pressure control after stroke  
 
Current UK guidelines suggest a systolic BP target after stroke of 130 mm Hg (Royal College of 
Physicians National Guideline for Stroke, 2016). Nevertheless, in practice control of BP remains poor. 
In the UK, only 35% of stroke patients achieved the guideline standard,(24) while 41% of stroke 
patients in the PROFESS study had systolic BP >140 mm Hg at follow-up, with an increased risk of 
recurrent stroke.(25) The proportion of stroke patients taking antihypertensive drugs declines rapidly 
(by about 25%) in the first 2 years after stroke,(26) suggesting that patient adherence is an important 
barrier to effective BP treatment. Poor adherence to BP medications is also clearly associated with an 
increased risk of stroke.(27) Adherence for secondary prevention after stroke is challenging because: 
(1) many new medications (e.g. antithrombotic drugs, statins, antihypertensives) are all started at once; 
(2) there are often physical or cognitive impairments; (3) there is no immediate relief of symptoms; and 

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(4) reductions in future vascular events may take months or years to accrue. A systematic review of 
interventions to improve adherence found few high-quality studies, with a need to improve objective 
monitoring of adherence and BP.(28) A recent comprehensive review of research gaps in BP treatment 
after stroke concluded that clinical trials evaluating implementation of evidence-based strategies for BP 
control to prevent recurrent stroke are needed.(29) 
A.3 Identification and description of the investigational device 
 
Home telemetric home monitoring device for PROHIBIT-ICH 
 
Telemetric home monitoring is a promising strategy to facilitate home BP monitoring after stroke, which 
should improve adherence and optimize medication to better control BP. Telemetry allows patients with 
hypertension to monitor their own BP and automatically send the information to a secure website, 
available to their clinicians to monitor and adjust their treatment. Home telemetric Bluetooth BP 
monitoring has been evaluated in patients with TIA and predominantly non-disabling stroke in the 
setting of the Oxford Vascular (OXVASC) Study by the Centrally Observed home telemetric Monitoring 
of BP to Manage Intensive Treatment (COMMIT) Study. In this population, the intervention was safe 
and effective, with few adverse events and high patient satisfaction. However, more research is 
required on the feasibility of use of this strategy in more disabling stroke and in patients with ICH, as 
well as on transferability to multiple centres beyond the previous research setting in Oxfordshire. A key 
aim of the present application is to obtain essential feasibility data in a pilot randomised controlled trial 
in a cohort of ICH survivors (in whom the expected benefit of the intervention is the largest of all stroke 
types) in a multi-site setting. In the COMMIT Study, we studied consecutive eligible consenting patients 
in the Oxford Vascular Study. After prescription of initial BP-lowering therapy, if required, patients 
measured their BP 3 times over 10 minutes on 3 occasions per day at home with a Bluetooth-equipped 
monitor for 1-3 months, depending on control. Measurements transmitted automatically in real time 
were checked daily on a secure web page. If BP was consistently above 130/80 mm Hg or below 
100/60 mm Hg antihypertensive therapy was adjusted. The results outlined below are from the first 
1000 recruits (mean/SD age=69/13; range=21-98yr; 23% ≥ 80 years): (1) Rates and risk factors for 
masked hypertension.  The prevalence of hypertension after TIA and stroke is often underestimated, 
with rates of “masked” hypertension (normal clinic BP but elevated home readings) ranging from 10-
30%. In COMMIT, masked hypertension (BP ≤ 140/90 mm Hg at initial assessment and mean BP > 
135/85 mm Hg across the first 3 days of monitoring; AHA definition) was found in 344 (34.4%). The 
much more detailed record of BP obtained on home telemetric BP-monitoring thus provided clinically 
important data that were not available from occasional clinic measurements. Masked hypertension has 
not been investigated in ICH; (2) Feasibility, medication changes and control of BP.  BP-lowering 
medication was initiated or increased at the pre-monitoring baseline visit in 555 (55.5%) patients. 
Medication was further initiated or adjusted at least once within the first month of home-monitoring in 
558 (55.8%) patients and from 1-3 months in 393 (39%) patients. Mean BP measured on clinic follow-
up fell from 141/83 mm Hg at entry to 130/74 mm Hg at 1-month (p<0.001) and to 127/72 mm Hg at 3-
months (p<0.001) (see Figure 1 for an example BP trace). Telemetric home BP monitoring was feasible 
irrespective of age, and informed titration of medication in the majority of patients and was associated 

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with good BP control; (3) Acceptability of telemetric home-monitoring to patients.  Of 1000 patients 
recruited, 576 (57.6%) returned an anonymised questionnaire after 1 month of monitoring. 533 (90.8%) 
approved of the intensive monitoring, 522 (89%) felt reassured by the central surveillance and 500 
(85.2%) thought it helpful to be able to discuss their BP readings over the phone. However, 72 (12.3%) 
patients reported that monitoring their BP made them anxious and 83 (14.1%) felt it was time 
consuming. Mean (SD) overall satisfaction (0%-extremely dissatisfied to 100%–extremely satisfied) 
was 89 (14) %; (4) Comparison with 24-hour ambulatory monitoring (ABPM).  We validated telemetric 
HBPM and ABPM by association with hypertensive arteriopathy and risk of recurrent vascular events. 
Mean SBP at 1-month on nocturnal ABPM, awake ABPM and HBPM (3 measurements, 3 times daily 
for 7 days) was related to five markers of hypertensive arteriopathy (creatinine > 120 mmol/L; aortic 
pulse wave velocity > 12m/s; advanced leukoaraiosis on brain imaging; Montreal Cognitive Assessment 
< 25; stroke vs. TIA) and to risk of recurrent stroke, coronary events and death. Among 1000 patients, 
hypertensive arteriopathy was more strongly associated (p-diff=0.007) with HBPM-SBP (odds ratio per 
10 mm Hg: 1.42, 1.28-1.56, p<0.0001) than with awake or nocturnal ABPM (awake 1.11, 1.00-1.24; 
nocturnal 1.28, 1.17-1.40). During 2775 patient-years of follow-up, residual hypertension at 1-month on 
HBPM (n=218/23%) predicted the risk of recurrent events (HR=2.00, 1.28-3.12, p=0.002) better than on 
awake ABPM (n=207/20%, HR=1.24, 0.78-1.98, p=0.37) or nocturnal ABPM (n=307/39%, HR=1.47, 
0.95-2.26, p=0.08). In models combining all 3 measures, only HBPM independently predicted recurrent 
events (HR=1.34, 1.11–1.63, p=0.003). Thus, residual hypertension is more strongly associated with 
hypertensive arteriopathy and risk of recurrent vascular events on HBPM than on ABPM. HBPM is 
therefore likely to be the better measure of BP-control after TIA/stroke, but has not yet been tested in 
major stroke or ICH. 
 
Figure 1: Home monitoring BP  
cuff and monitor (left), and a BP 
trace from the COMMIT study 
showing improved BP control 
over time (right) 
 
 
 
 
 
 
 
Potential role of MRI in understanding the effects of BP treatment after ICH 
 
MRI has rapidly improved our ability to see SVD disease processes related to ICH in vivo. Markers of 
small vessel disease on standard MRI include white matter hyperintensities (WMH), dilated 
perivascular spaces, lacunes and cerebral microbleeds (CMBs) whereas quantitative measures (e.g. 
diffusion tensor imaging (DTI)) provides information on microscopic tissue changes. White matter 
hyperintensities are the commonest marker of SVD, and can assessed semi-quantitatively using rating 
scales or quantitatively. The inter-rater and intra-rater reliability for both qualitative and quantitative 

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analysis of white matter hyperintensity is high if done by trained raters, with intraclass correlation 
coefficients generally above 0.90.(30) CMBs are small areas of bleeding detected on blood-sensitive 
MRI sequences (including T2*-weighted gradient-echo and susceptibility–weighted imaging), found in 
about 50-80% of patients with ICH, with value in diagnosing the type of SVD.(31) CMBs are also 
related to the risk of future ICH.(8) We showed that in patients with ischaemic stroke and TIA that the 
development of new CMBs was strongly related to baseline BP (Figure 2).(32) CMB accumulation 
might thus be plausibly reduced by intensive BP lowering 
 
 
 
In spontaneous ICH there is also a high prevalence of clinically "silent" acute ischaemic lesions (about 
20% of patients),(33, 34) which has been associated with rapid acute BP lowering.(35) Longer term BP 
lowering in SVD has been hypothesised to cause white matter ischaemia or infarction, potentially 
worsening cognitive outcomes.(23) Thus, any treatment aiming to reduce recurrent ICH must also 
consider the risk of ischaemic brain injury. The key MRI manifestations of SVD have recently been 
reviewed (including WMH, lacunes, and CMBs).(30) These abnormalities evolve over time, and reflect 
brain injury relevant to the adverse consequences of SVD, including cognitive impairment. Measuring 
these as a surrogate outcome marker is attractive for a clinical trial, because it may be possible to 
assess beneficial or hazardous effects of an intervention in a much small number of participants in 
comparison to clinical event outcomes (e.g. recurrent stroke). Observational longitudinal studies in SVD 
indicate that WMH volume and diffusion tensor imaging (DTI) parameters are most sensitive to change 
and therefore have the smallest sample size estimates for trials of interventions, and progress over 
shorter time periods than cognition.(36) A recent review of imaging outcome markers for clinical trials in 
CAA suggested that CMBs and WMH were promising surrogate measures of SVD-injury, but further 
prospective data are needed to validate them.(37) In the PROHIBIT-ICH trial, we will test the 
hypothesis that intensive and sustained long-term BP control after ICH might reduce the progression of 
MRI markers of SVD, the underlying process that is likely to cause the long term adverse outcomes 
following ICH.  
 
 
 
 
 
 
 
 
Figure 2. Axial GRE T2* MRI scans at baseline and 
follow-up (after 5 years) showing the development 
of new CMBs (small black dots; white arrows).  The 
development of new CMBs was strongly related to 
baseline systolic BP (OR 1.28 per unit increase, 
95%CI 1.23-1.33, p<0.001). (from ref 32)  

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A.4 Justification for the design of the clinical investigation 
 
Summary of rationale for the trial 
 
ICH remains a devastating disease for which prevention of recurrent stroke is a research priority. BP 
lowering is the most promising preventive strategy, but adherence and BP control in clinical practice 
remain poor. There is thus an urgent need to improve ICH secondary prevention through improved long 
term BP control, including outcomes related to cognition and progression of the underlying SVD 
process. The concerns and views of stroke survivors, the recent development of home telemetric 
monitoring technology and improved understanding of MRI markers of SVD make this a unique and 
timely opportunity to commence a pilot a trial addressing these important research questions.  
A.5 Risks and benefits of the investigational device and clinical investigation 
 
 
The table below summaries the risks and mitigations of the investigational procedures that are being 
performed: 
 
Table 1  
 
Name of IMD  
Potential 
risk 
Risk 
Frequency 
 
Risk Management 
To be invited in the study by giving 
them an invitation letter and patient 
information sheet (PIS) 
No potential 
Risk 
0 
Research practitioner or 
member of research/ clinical 
teams, in hospital ward or clinic. 
Baseline consent 
No potential 
Risk 
0 
Research practitioner or 
member of research/ clinical 
teams, in hospital ward or clinic. 
Completion of eCRFs (baseline (visit 
one), 3 month follow up (visit two) and 
12 month follow up (last visit)). 
No potential 
Risk 
0 
Research practitioner or 
member of research/ clinical 
teams, in hospital ward or clinic. 
Cognitive functional assessment 
(Montreal Cognitive Assessment) 
No potential 
Risk 
0 
Research practitioner or 
member of research/ clinical 
teams, in hospital ward or clinic. 
EQ-5D questionnaire 
No potential 
Risk 
0 
Research practitioner or 
member of research/ clinical 
teams, in hospital ward or clinic. 
 
 
 
The table below summaries the risks and mitigations of all tests above standard care that are being 
performed: 
 
 
 

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Table 2  
 
Intervention  
Potential risk 
Risk Management 
Blood Test 
May cause discomfort or result in 
brusing 
Performed by trained 
phlebotomist. Follow trust 
standard operational 
procedures. 
MRI Scan 
Patients may experience 
claustrophobia  
Performed by a competent 
professional. Follow trust 
standard operational 
procedures. 
Blood Pressure 
The squeezing sensation may be 
uncomfortable but only lasts a 
few seconds. 
Performed by the informed 
participant (if at home) and a 
competent professional. 
 
The classification of medical devices in the European Union is outlined in Annex IX of the Council 
Directive 93/42/EEC (as amended). There are four classes, ranging from low risk to high risk. 
 
    Class I  
    Class IIa 
    Class IIb 
    Class III 
 
The Medical Device used in this investigation is classified as Class I 
 
 
A.6 Objectives and hypotheses of the clinical investigation 
 
A.6.1 Hypotheses  
 
Primary and secondary, to be accepted or rejected by statistical data from the clinical investigation. 
A.6.2 Primary Objective 
 
(i) BP study 
 
Does the use of centralised telemetric home BP monitoring to guide intensive BP treatment in patients 
with spontaneous (non-traumatic) ICH achieve a reduction in 3-month BP compared with standard 
primary care? 
 
(ii) Imaging study  
 
Does intensive BP treatment using centralised telemetric home monitoring result in a reduction in 
progression of small vessel disease (SVD)-related brain injury assessed on MRI (including, but not 
limited to, white matter hyperintensities (WMH), white matter structural integrity, incident cerebral 
microbleeds (CMBs), and brain atrophy) compared with standard care? 
 

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A.6.3 Secondary Objective(s) 
 
(i) BP study 
1. Is it feasible in a multi-site setting to intensively lower BP using telemetric home BP 
monitoring for an extended period of time following spontaneous ICH? 
2. Is it safe to intensively lower BP for an extended period of time following a spontaneous 
ICH, or are there adverse responses (including increased progression of cognitive decline)? 
3. Is the intervention acceptable to participants, including measures of quality of life? 
 
 
(ii) Imaging study 
 
1. Does any reduction in recurrent vascular events (including ICH) or progression of cognitive 
decline on intensive BP treatment correlate with baseline measures of changes in 
quantitative and structural brain scan markers of small blood vessel health? 
2. Are there any adverse effects on neuroimaging measures (e.g. increased white matter 
ischaemic injury) associated with intensive BP treatment? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A.7 Design of the clinical investigation  
A.7.1 General 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligible patients will be identified by the research practitioner or member of 
research/ clinical teams, from acute stroke units or high dependency units at 
participating hospitals, outpatient clinics (stroke, neurology, geriatric, neurosurgical) 
and from primary care centres 
Enrolment of eligible participants (invitation, information and informed consent) 
Patient details recorded (including information on medical history, prior BP 
medications, inpatient BP records), BP measured, 24 hour-ABPM, blood sample 
taken and stored, modified MOCA, EQ-5D questionnaire.  
MRI scan performed before randomisation. 
Baseline data collection
Intervention 
Comparator 
Standard clinical care including usual 
BP treatment, without home 
monitoring, undertaken in the clinical 
care setting 
Telemetric Bluetooth home BP 
monitors  will be provided to 
participants during their inpatient stay 
or clinic visit, and will commence 3-
times-daily readings immediately. The 
BP monitoring team will assess BP 
readings daily and advise medication 
adjustments to achieve a target BP of 
<120/80 mm Hg 
0 Months
3 month follow-up (24-hour ABPM, modified MOCA, EQ-5D,  
BP questionnaire) 
12 month follow-up (MRI scan, 24-hour ABPM, modified MOCA, EQ-5D) 
Follow-up 
Analysis 
Randomisation 
12 months 
Recruitment 
12 months 
Follow-up 

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A.7.2 Investigational device and comparators 
 
Patients will be assessed for their eligibility during hospital inpatient stays, in outpatient clinics or 
primary care centres. At the time of hospital discharge or at a dedicated clinic session with a research 
practitioner, eligible patients will be randomised in a 1:1 group assignment ratio to either telemetric 
home BP monitor-guided intensive BP lowering (intervention group) or standard care (control group) 
constituting usual primary-care led BP treatment, without home telemetric monitoring. For inpatients, 
the randomisation process will be undertaken as close as possible to discharge. All participants will be 
fitted with a 24-hour ABPM on the day of discharge (or in a dedicated clinic session for outpatients) by 
the research practitioner. The intervention group will also receive a telemetric Bluetooth home BP-
monitoring device in addition to the ABPM and will be trained how to set this up in their home and use 
it.  For the control group, the results of the baseline 24-hour ABPM (as for subsequent follow-up 24-
hour ABPM) will not be communicated to the patient or GP unless mean daytime BP is sufficiently 
different to the patient’s known recent daytime BP (based on recorded inpatient and baseline BP 
measurements) to justify informing on the basis of clinical need. 
 
Intervention: 
 
Participants randomised to the intervention group will receive a telemetric Bluetooth home BP-
monitoring device. It will facilitate the Oxford BP-monitoring team to closely monitor the participant’s BP 
to keep to the target of <120/80 mm Hg. If this is not achieved then BP medication will be adjusted 
accordingly in order to achieve the target by the 3 month follow-up visit. BP readings (3 readings over 
10-minutes in the seated position in the non-dominant arm, unless there is severe hemiparesis) will be 
taken 3 times daily (early morning, early afternoon and evening). All BP data will be automatically 
transmitted centrally in real time to the device coordination site in Oxford. A dedicated BP-monitoring 
research team will be responsible for checking all BP data daily, and will directly advise patients by 
telephone on starting or adjusting BP medication according to a standard protocol based on the latest 
British Hypertension Society guideline, to ensure that BP is lowered to the intervention arm target. For 
the treatment-naïve participant, first line treatment (in the absence of contraindications) will usually be 
either combination therapy with perindopril arginine 5mg and indapamide MR 1.5mg per day, or 
amlodipine 5mg, increased to 10mg if needed. Subsequent treatment will be decided on a patient-
specific basis, taking into account previous treatment trials and treatment responses, but will be likely to 
include the addition of spironolactone 25mg per day, doxasozin 4mg per day and nebivolol 2.5-5mg per 
day, alone or in combination. All such medication changes will be notified to the local research team 
and GP, with the GP providing prescriptions to participants based on correspondence from the central 
BP-monitoring team. If the target BP is consistently achieved after a minimum of one month of 
monitoring, Bluetooth monitors will be collected and conventional monitors issued to the intervention 
group only. At the 3 month follow-up visit, it is expected that the majority of patients will be able to 
replace their Bluetooth monitor for a conventional monitor, unless extenuating circumstances result in a 
need for prolonged monitoring and further treatment to achieve the BP target. The conventional 
monitors will be used at the patient’s discretion to allow them to assess their own BP and contact their 
GP with any concerns about high/low readings. The responsibility for BP treatment will return to the GP 

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after 3 months of follow-up. Participants will also be asked to record a weekly BP reading on a sheet 
which will be returned with the monitor at the end of the 12 month follow-up period. 
 
 
A.7.3 Subjects 
 
Inclusion criteria 
 
1. Adults (≥40 years) with spontaneous primary ICH (i.e. without known underlying structural, 
macrovascular or other cause (e.g. arteriovenous malformation, tumour) after adequate 
investigation at the discretion of the local investigator). This will include participants presumed to 
have cerebral SVD (both hypertensive arteriopathy and cerebral amyloid angiopathy)  
2. Clinical team opinion that BP control since the ICH is not adequate AND the measured SBP 
prior to randomisation is ≥130 mm Hg 
3. Recruitment soon after ICH, ideally at hospital discharge or within weeks, is encouraged; 
recruitment at a later stage after ICH is also exceptionally allowed if there is evidence of 
inadequate BP control AND SBP at randomisation is ≥130 mm Hg  
4. For patients recruited in hospital there should be a plan for home discharge (not to a nursing or 
care home) after their inpatient stay, or living at home at the time of recruitment 
5. Willingness and demonstration of ability to undertake home BP measurements, either 
unassisted or with the help of a relative, friend or carer  
6. Ability and willingness to complete an MRI scan  
7. Ability and willingness to attend and complete the study assessments including cognitive screen  
8. Ability and willingness to provide informed consent, or with a suitable consultee available and 
able to participate in the intervention (e.g. with a motivated carer) 
 
Exclusion criteria:  
 
1. Inability to provide informed consent or lack of suitable consultee (if unable to provide personal 
consent, lack of suitable consultee) 
2. Evidence of a macrovascular or structural cause for ICH (e.g. AVM or tumour) 
3. Diagnosis of dementia (DSM IV criteria, or self-reported or documented in medical records) 
4. Low Functional status (MRS ≥4) before or after ICH or frailty likely to make participation in 1-
year follow-up difficult for the participant  
5. Life expectancy <2 years 
6. Taking more than 2 BP-lowering medications (i.e. 3 or more) at the time of consent 
7. Consistently good BP control (below 130/80 mm Hg on measures taken as part of routine 
clinical care) prior to planned recruitment, judged not to require more intensive treatment 
8. Known flow-restricting intracranial/extracranial large arterial stenosis 
9. Known contraindication to MRI 
10. Known absence of mobile phone coverage from all network operators and home internet at the 
participant’s home 
11. Known sensitivity or contra-indication to BP treatments (e.g. symptomatic postural hypotension) 
is not an absolute exclusion criterion, but more information must be provided 
12. Note that participation in other CTIMP or device trial is NOT an automatic exclusion criterion 

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Subject Eligibility  
 
Once written informed consent has been obtained, the electronic case report form (eCRF) will be 
completed to document adherence to the inclusion and exclusion criteria.  
 
Where a subject fails to fulfil any element of the inclusion and exclusion criteria, this will be documented 
and the signed consent form and completed inclusion/exclusion criteria retained by the principal 
investigator. The subject will not be advanced any further into this clinical investigation. 
  
Subject Identification 
 
Patients will be identified by members of the care team from the expected NHS hospital sites (acute 
stroke units or high dependency units), from outpatient clinics (stroke clinics, neurology clinics, geriatric 
clinics, neurosurgical clinics) and at primary care sites.  
 
When a subject is identified and considered eligible for entry into this clinical investigation, the subject 
will be allocated the next available investigation number (subject ID number). 
 
For subjects enrolled, this number will consist of 01 for the first subject, 02 for the second subject and 
so on.  This number will be the unique identifier of the subject and noted on the electronic CRF and all 
other documentation relating to that subject. 
 
Each subject that is enrolled into the study will have their study participation recorded and details of the 
device recorded in their hospital notes, a copy of their signed consent form and  patient information 
sheet should also be placed on his/her hospitals notes to identify the subject as participating in a 
clinical investigation.  
 
A.7.4 Recruitment  
 
Participant recruitment at a site will only commence when the trial has been initiated by the Sponsor (or 
it’s delegated representative), and issued with the ‘open to recruitment’ letter. 
 
Potentially eligible participants will be identified in person by the clinical staff at site during their 
inpatient stay or when they attend a clinic or primary care appointment. The participants will be handed 
an information leaflet and a letter of invitation by the clinical staff at the site. Patients will have at least 
24 hours to consider the information before being telephoned or approached by a member of the 
research practitioner or member of research/clinical teams at the NHS site to see if they are interested 
in taking part in the trial. If they are, a convenient time will be arranged for them to meet a research staff 
member delegated by the CI to discuss the study, go through the information sheet, assess eligibility 
and answer any questions they may have.  Patients who are eligible and give consent will be enrolled 
and randomised to an intervention group or control group. 
Patients will be provided with a participant information leaflet. An opportunity to meet a member of the 
research team will be arranged in person by a member of the clinical care team or subsequently by 
phone by a member of the research team. All interested participants will have an opportunity to ask 

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questions about the study and these will be answered by a member of the research team prior to 
enrolment. 
 
A.7.5 Randomisation Procedures 
 
Following participant consent and confirmation of eligibility, the registration/randomisation procedure 
described below will be carried out.  
Participants will be considered to be enrolled into the trial following: consent, pre-treatment 
assessments (see section A.7.6), confirmation of eligibility, completion of the registration/randomisation 
process, allocation of the participant trial number and treatment by the central coordinating team. 
When a person agrees to participate, demographic, contact and medical history information necessary 
to conduct the study, including a record/chart of their inpatient BP measurements, will be recorded. 
Each participant will be allocated a unique trial number. Relevant sections of medical notes and data 
collected during the study may be looked at by the researchers from regulatory authorities or from the 
NHS Trust, where it is relevant to the subject’s participation in the trial. 
Patients will be randomised in a 1:1 group assignment ratio to intensive BP lowering (intervention 
group) or standard care (control group) using an online randomisation service (Sealed Envelope), 
available 24 hours a day. 
Clinical data will be collected by an established electronic randomisation and eCRF system with a 
database managed from UCL by the study coordinator. 
 
A.7.6 Procedures 
 
The following examinations and investigations (if not already performed as part of routine standard of 
care) shall be performed for determining eligibility for enrolment into this investigation:  
 
Pre-intervention assessments  
 
Baseline 
   
We will request that recruiting sites collect data on the number of patients who are potentially eligible 
for the study. At baseline, the following trial-specific procedures will be carried out after consent as a 
requirement for the study to commence: 
 
Medical history recorded, including details of the ICH, previous medical history, and inpatient BP 
records for every participant. The most recent three consecutive inpatient/outpatient BP 
readings, not including any taken specifically to assess for entry eligibility, will be used to assess 
for the BP inclusion and exclusion criteria 
 
Blood pressure medication and dose recorded, including reactions to prior poorly-tolerated BP 
medications, if applicable 
 
3 BP measurements (2 seated and one standing after a minimum of 3 minutes). The initial 
measurement should be taken in both arms; if there is a significant difference (>20 mm Hg 
systolic) between them then the arm with the higher value should be used for subsequent 
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 
Baseline 24-hour ABPM will be fitted and recorded in all participants 
 
Blood test (venepuncture) 
 
MRI brain scan (performed prior to randomisation).  
 
Cognitive functional assessment (modified Montreal Cognitive Assessment; see appendix 2) 
 
Completion of the EQ-5D questionnaire (appendix 3) 
 
All pre-treatment procedures will be carried out as specified in the schedule of assessments (appendix 
1). 
 
The MRI protocol will be harmonised at all study sites based on EPAD (European Prevention of 
Alzheimer’s Dementia) protocols for each major MRI scanner manufacturer (Siemens, GE, Philips), and 
will include the following sequences (with approximate timings): 
1. 3D T1                         
(5min) 
2. 3D FLAIR                          (5min) 
3. DTI (simplified) 
    
(5min) 
4. 3D SWI                               (5min) 
5. Axial T2                             (2min) 
Other advanced MRI sequences (including, but not limited to, Arterial Spin Labelling (PCASL)) will be 
acquired as optional extra sequences at sites with capacity to undertake them. We aim to keep the total 
MRI scan time below 1 hour.  
A.8 Informed Consent Process 
 
It is the responsibility of the investigator, or a person delegated by the investigator to obtain written 
informed consent from each subject prior to participation in the Investigation, following adequate 
explanation of the aims, methods, anticipated benefits and potential hazards of the study.  
The capacity of the patient will be assessed by a trained clinician on site that will be managing their 
clinical care. 
 
The person taking consent must be GCP trained, suitably qualified and experienced, and have been 
delegated this duty by the CI/PI on the delegation log.  
 
“Adequate time” will be given given for consideration by the patient before taking part. The PI must 
record when the patient information leaflet has been given to the patient. It must be recorded in the 
medical notes when the participant information leaflet has been given to the participant. Patients will 
have at least 24 hours to consider the information before being telephoned or approached by a member 
of the research practitioner or member of research/clinical teams at the NHS site to see if they are 
interested in taking part in the trial. If they are, a convenient time will be arranged for them to meet a 
research staff member delegated by the CI to discuss the study, go through the information sheet, 
assess eligibility and answer any questions they may have and Informed consent will be obtained. 
 
The investigator or designee will explain the patients are under no obligation to enter the investigation 
and that they can withdraw at any time during the Investigation, without having to give a reason. 

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No clinical investigation procedures will be conducted prior to taking consent from the participant. 
Consent will not denote enrolment into investigation. A copy of the signed informed consent document 
will be given to the participant.  The original signed form will be retained at the study site and a copy 
placed in the medical notes. 
 
If new safety information results in significant changes in the risk/benefit assessment, the consent form 
will be reviewed and updated if necessary and subjects will be re-consented as appropriate. 
 
A.9 Schedule of assessments and interventions by visit  
         (see also Appendix 1) 
 
Baseline (visit one): See section 7.6 for details of the procedure 
Patients in the intervention group will be in telephone or email contact with the BP-monitoring team in 
Oxford throughout the trial. Completion of baseline eCRF and all enrolled participants will attend their 
local hospital clinic for one in person follow-up visit at 3 months and a final follow-up visit and an MRI 
scan at an average time of 1 year.   
 
3 month follow-up (visit two): Completion of 3 month eCRF, BP recorded and completion of modified 
Montreal Cognitive assessment (appendix 2), EQ-5D questionnaire (appendix 3) and home blood 
pressure acceptability questionnaire (appendix 4). 24-hour ABPM to be performed at the time of the 3 
month follow-up visit.  
 
12 month follow-up (final visit): Completion of 12 month eCRF, BP recorded, and completion of 
modified Montreal Cognitive assessment (appendix 2) and EQ-5D questionnaire (appendix 3). 24-hour 
ABPM to be performed at the time of the 12 month follow-up visit. 
 
An MRI scan will be performed at baseline and the 12 month follow-up visit on all participants to identify 
markers of cerebral small vessel disease including (but not limited to): 
- 
change in white matter hyperintensity volume 
- 
change in white matter microstructure (DTI) 
- 
change in the number of CMBs 
- 
change in cerebral atrophy 
 
A schedule of all trial assessments and procedures is set-out in Appendix 1. Where an in-person visit is 
not possible, every effort will be made to assess the participant by other means, including telephone, 
postal, email, or home visit contact.  
 
A.9.1 Laboratory Assessments and Procedures 
 
Translational research samples  
Blood will be collected at baseline by a trained member of staff at the site. As soon as blood is 
collected, the member of the research team at the site will be responsible for sending the sample in a 
Safebox to the coordinating office, UCL.  Blood samples will be stored for future research. An 
appropriate SOP will be in place for each site.  

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Sample storage and transfer 
About 5-10mls of blood in EDTA plasma sampling tube will be collected from patients in accordance 
with the patient consent form and patient information sheet. The EDTA blood samples will be 
appropriately sent in a Safebox from the sites to Shahena Butt, the research coordinator; Stroke 
Research Centre, UCL Institute of Neurology, Russell Square House, 10-12 Russell Square, First 
Floor, London, WC1B 5EH for DNA extraction and storage. 
 
The neurogenetics lab, UCL will process, store and dispose of EDTA blood samples in accordance with 
all applicable legal and regulatory requirements, including the Human Tissue Act 2004 and any 
amendments thereto. 
The EDTA blood samples will not be transferred to any party not identified in this protocol and are not 
to be processed and/or transferred other than in accordance with the patients’ consent.  At the co-
ordinating centre, DNA will be extracted and stored at -70 degrees C in the UCL Institute of Neurology.  
A.10 Device accountability 
 
The BP equipment will be purchased by the monitoring team in Oxford. The telemetric BP readings will 
be checked every working day by this team. In the absence of any readings, the monitoring team will 
troubleshoot the most common equipment problems over the telephone where possible, or arrange a 
replacement where necessary. There will be a service contract in place to replace or mend any 
monitors that are not working.  
A.11 Monitoring Plan  
 
The sponsor will determine the appropriate level and nature of monitoring required for the trial.  Risk will 
be assessed on an ongoing basis and adjustments made accordingly. 
The degree of monitoring will be proportionate to the risks associated with the trial. 
A trial specific oversight and monitoring plan will be established for studies. The trial will be monitored 
in accordance with the agreed plan.  
 
Low risk: central monitoring  
Each site to email to the sponsor annually: delegation log, adverse event log, deviation log, minutes of 
Trial Steering Committee (or equivalent), annual progress report (lead site only) when sent to Ethics 
Committee. 
a) 
Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 1998. 
The  electronic CRFs (eCRF) will not bear the participant’s name or other personal identifiable data.  
The participant’s year of birth and trial identification number, will be used for identification and this will 

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be clearly explained to the patient in the Patient information sheet.  Patient consent for this will be 
sought. 
The team will ensure that their identities are protected from any unauthorised parties. Information with 
regards to study patients will be kept confidential and managed in accordance with the Data Protection 
Act, and Research Ethics Committee Approval. All participant identifiable information will be 
anonymised with regard to any report. The same standard will be followed if any patient information 
needs to be sent to a third party.  
b) 
Record keeping and archiving 
At the end of the trial, all essential documentation will be archived securely by the CI for a minimum of 
20 years from the declaration of end of trial.  
Essential documents are those which enable both the conduct of the trial and the quality of the data 
produced to be evaluated and show whether the site complied with all applicable regulatory 
requirements. The sponsor will notify sites when trial documentation can be archived. All archived 
documents must continue to be available for inspection by appropriate authorities upon request.  
 
 
A.12 Statistical Considerations 
 
A.12.1 Primary Outcomes 
 
(i) BP study: 
 
1. The efficacy of telemetric BP monitoring to guide intensive BP treatment in ICH survivors; detection 
of a statistically significant reduction in BP in the intervention compared to the control arm at 3 months. 
We expect a 10 mm Hg difference in systolic BP between the intervention and control arms at 3 months 
(based on assessment of mean daytime BP on 24-hour ABPM at 3 months), and will be able to 
estimate this difference to within +/- 8 mm Hg with 112 patients if the standard deviation of systolic BP 
does not exceed 20 mm Hg (in either arm). 
 
2. The feasibility and safety of telemetric BP lowering in ICH survivors 
Feasibility criteria are:  
(a) ≥50% of eligible participants agree to participate;  
(b) <30% dropout from the intervention arm (discontinuation of home BP monitoring against the advice 
of the BP monitoring centre) prior to 1 month;  
(c) Patient approval of the monitoring process in ≥70% of those randomised to the intervention arm. 
 
Safety is measured by serious adverse events related to reducing BP in the intervention arm, cognitive 
function change over 1 year (modified Montreal Cognitive Assessment) and a composite of all recurrent 
major cerebrovascular and cardiovascular events. 
 
(ii) Imaging study: 

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Previous studies have shown that WMH volume increases over time in both older community and 
hospital stroke populations.(38-42) Data of WMH progression in ICH are limited but one small study 
showed a progressive increase in white matter lesions in subjects with cererbral amyloid angiopathy 
over a year.(43) Because of the strong relationship between BP and WMH severity and 
progression;(36, 44) we hypothesise that lowering BP might reduce the increase in volume of WMH 
over 1 year. However, a key concern regarding intensive BP lowering is that this might reduce white 
matter perfusion and cause an increase in ischaemic injury to the brain. The primary imaging outcome 
is therefore the change in WMH volume (measured on 3T FLAIR images) at 1 year. We will develop 
and use an in-house automated volumetric lesion detection method,(45) but will also use validated 
progression scales including the Rotterdam and Schmidt progression scores; progression over 2 years 
has previously been demonstrated in only 20 scan pairs of patients with cerebral small vessel 
disease.(46) We will exclude WMH directly related to the index symptomatic ICH (i.e. close to the ICH 
in the ipsilateral hemisphere). We will investigate WMH progression in subgroups of ICH including lobar 
and deep categories, and probable or possible cerebral amyloid angiopathy.(47) WMH progression 
analyses will adjust for important predictors including baseline WMH and age.  
 
A.12.2 Secondary outcomes 
 
(i) BP study 
 
1. Clinical outcomes including recurrent vascular events and cognition. 
2. Number of BP-lowering drugs at 3 month and at 1 year follow-up visits. 
3. Mean daytime BP at 1 year on 24-hour ABPM. 
 
(ii) Imaging study 
 
1. We will quantify white matter structure integrity using 1 year change in mean diffusivity (MD), 
fractional anisotropy (FA) and other 3T DTI metrics including tract-based spatial statistics.(48) 
2. We hypothesise that intensive BP lowering will reduce the development of new haemorrhagic 
SVD-related brain injury. We will measure the proportion of patients developing new CMBs at 1 
year (measured using a validated visual rating scale)(49) and the number of new CMBs in each 
participant. We will exclude CMBs adjacent to the index symptomatic ICH. A previous study 
showed that 48% (95% CI, 40–55) of 168 patients with ICH developed incident CMBs over a 
3.4-year period. 
3. Any new infarcts or intracerebral haemorrhage 
4. 1 year change in cerebral blood flow (CBF) on 3T PCASL 
5. 1 year change in total brain volume, white matter volume and grey matter volume on 3T T1 
volumetric images 
6. Composite neuroimaging measures (e.g summary SVD scores)(50) 
7. We will investigate progression of neuroimaging markers in subgroups of ICH including lobar 
and deep ICH,(51) and probable or possible cerebral amyloid angiopathy.(47, 52)  
 

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A.12.3 Sample size calculation 
 
(i) BP study 
 
Our data will allow accurate sample size calculation for an adequately powered efficacy trial and the 
ability to estimate a difference in systolic BP between arms.  We will assess 3-month BP based on both 
clinic measurements and separately on 3-month ABPM.  Power will be least for the comparison of clinic 
BP measurements. If we expect an effect in one direction (i.e. BP lowering in the intervention group), 
sample size calculations based on a mean group difference in SBP of 10 mm Hg between the 
intervention and control arms (and standard deviations of 10 mm Hg and 15 mm Hg respectively) at 3 
month gives: 
One-tailed significance level = 0.05, power = 0.9, n in each group = 56. We will be able to estimate this 
difference to within +/- 8 mm Hg with 112 patients if the standard deviation of systolic BP does not 
exceed 20 mm Hg.  
 
(ii) Imaging study 
 
There are insufficient data on WMH progression in patients with ICH on which to base accurate power 
calculations, making formal sample size estimation challenging. One study in 26 patients (mean age 
69.1) with probable or possible CAA scanned over about a year found a rapid median WMH growth of 
0.5 mL per year (interquartile range 0.1-2.8 mL per year).(43) In a substudy of 192 participants in the 
PROGRESS (Perindopril Protection Against Recurrent Stroke Study) trial the mean total volume of new 
WMHs was significantly reduced in the active treatment group (0.4 mm3 [SE=0.8]) compared with the 
placebo group (2.0 mm3 [SE=0.7]; P=0.012).(53) This difference in WMH progression was greatest for 
patients with severe WMH at entry, 0.0 mm3 (SE=0) in the active treatment group versus 7.6 mm3 
(SE=1.0) in the placebo group (P<0.0001). The BP reduction in the active arm compared with the 
placebo arm was 11.2 mm Hg for systolic BP and 4.3 mm Hg for diastolic BP. With 56 patients in each 
arm we would be able to estimate a similar difference in new WMH lesion volume (2.0mm3 vs 0.4mm3) 
(if the SD does not exceed 2.0 mm3) to that shown overall in PROGRESS, with power 80% at an alpha 
significance level of P=0.05.  
 
A.12.4 Planned recruitment rate 
 
We plan a screening, randomisation and recruitment period of 12 months from beginning to last patient 
randomised. We will approach about 145 patients, given an expected consent rate for randomisation of 
60%,hence achieving the goal of 112 patients),allowing the consent rate to be estimated to within +/-
7%. 
Regarding dropouts from the intervention arm prior to 1 month, we expect less than 20% of individuals 
to drop out. With an intervention arm sample size of 56 the dropout rate can be estimated to within +/- 
11%. 
 
Regarding patient approval of intervention, we expect that 90% of individuals in the intervention arm will 
approve the monitoring process (based on a semi-structured questionnaire). With an intervention arm 
sample size of 56, this approval rate can be estimated to within +/- 8%. 

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Recruiting sites will be selected on their suitability to conduct the study and perform the necessary MR 
imaging, and site initiation visits will be completed by teleconference and online training tools with 
follow up by the study coordinators. 
 
 
A.12.5 Randomisation methods 
 
Patients will be randomised in a 1:1 group assignment ratio to intensive BP lowering or standard care 
using an online randomisation service (Sealed Envelope), available 24 hours a day. There will be equal 
allocation between treatment arms; a sample size of 112 will consist of patients randomised equally to 
the intervention and control groups (56 each).  
 
We will use a web-based randomisation service with the following pre-specified features: 
 
- 
Web-based randomisation is by random permuted blocks to active or control treatment in a 1:1 
ratio 
- 
The system is accessed via a secure internet connection (SSL). This connection encrypts data 
between the user’s internet browser and the server 
- 
Online randomisation is achieved by the user entering a patient identifier (text field - must be 
unique) and stratification information, confirming eligibility 
- 
The patient is randomised to the next treatment or code and the chosen treatment group or 
code shown or texted to the user 
- 
An email notification is generated displaying the chosen treatment group or code and sent to the 
email address given by the user randomising and the administrator email address. The 
administrator email address is the one provided when the system is set up (usually a trial 
coordinator or central trial email address) 
- 
A list of all randomisations performed to date may be sent to the administrator email address by 
entering the password 
- 
The randomisation list cannot be viewed through the system 
- 
There is only one password and anyone with knowledge of the password can perform a 
randomisation  
- 
Sealed Envelope will not edit or delete any data held by the system 
    
 
A.12.6 Statistical analysis 
 
In general, the most suitable statistical analysis consistent with the form of data will be used and the 
underlying assumptions of the statistical method will be verified. Baseline BP, modified MoCA and 
EQ5D will also be compared between randomised groups. Descriptive statistics, as appropriate (e.g. 
means and standard deviations for continuous variables; proportions for categorical variables), will be 
reported for variables measured at baseline. A consort flow diagram will be included. 
 

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A.12.6.1  
Summary of baseline data and flow of participants 
Age (SD), sex, vascular risk factors and other medical history, and 24-hour ABPM will be used for 
baseline comparability of the randomised groups. 
 
 
A.12.6.2 
Primary outcome analysis 
Analysis will be performed according to the intention to treat and the per protocol principles.  
Efficacy: The difference in BP (and the difference in change from baseline BP) between randomised 
groups at 3 months will be compared using t-tests. The change in white matter hyperintensity volume in 
the intervention and control groups will be compared using appropriate tests (e.g. t-tests or 
nonparametric tests) depending on whether the values are normally distributed. Automated analysis 
pipelines for WMH segmentation and quantification will be used to measure change.(45)  
Feasibility: Proportions for the consent rate, drop-out rate and patient approval at 3 months will be 
calculated to determine if the required feasibility criteria were met. 
 
Safety: Proportions of adverse events and recurrent events between randomised groups will be 
compared using Fisher’s exact test. Randomised groups will be compared for cognitive impairment 
based on (1) the modified MoCA score as a continuous variable using the Mann-Whitney U-test and (2) 
numbers below cut-off thresholds of the modified MoCA score using Fisher’s exact test. The change in 
modified MoCA score from baseline will also be compared between randomised groups similarly. 
 
 
A.12.6.3  
Secondary outcome analysis 
Randomised groups will be compared for recurrent vascular events using Fisher’s exact test and for the 
number of BP-lowering drugs at 3 month and at 1 year follow-up visits using the Chi-squared test. The 
mean daytime BP at 1 year on 24-hour ABPM will be analysed using a t-test to compare the 
intervention and control groups.  
 
Changes in all neuroimaging measures (CMBs,(49) DTI measures,(48) atrophy, etc., measured using 
validated methods) will be compared between the intervention and control arms using appropriate 
statistical tests. Specific automated analysis pipelines will be developed for each measure.  
The study sample size has been based on the primary efficacy outcome of a reduction in BP and may 
lack power for the secondary outcomes; therefore results will be interpreted in the light of these 
limitations. 
 
 
 
 
A12.6.4  
Sensitivity and other planned analyses 
It may be necessary to address potential imbalances between randomised groups for influencing risk 
factors. 
 
 

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A.13 Data Management 
 
When a person agrees to participate, demographic, contact and medical history information necessary 
to conduct the study will be recorded in accordance with the patient consent form, patient information 
sheet and section 7 of this protocol. Each participant will be allocated a unique trial number. This data 
will be collected on an eCRF, on a secure server; sealed envelope. Access to this data, will be granted 
to authorized research staff and representatives from the sponsor, host institution and regulatory 
authorities, by arrangement with the CI, to permit trial-related activities, monitoring and audit. All 
records will be kept securely and confidentially and the data will be pseudo-anonymised for analysis.  
All records are the responsibility of the investigators and will be kept in secure conditions. They will 
ensure that patients’ identities are protected from any unauthorised parties. Participants’ information will 
be kept confidential and managed in accordance with the Data Protection Act and Research Ethics 
Committee Approval. 
 
For BP data acquired via the Bluetooth-enabled telemetric BP monitors (A&D UA-767 BT), anonymised 
measures are transmitted securely to a server hosting a password-protected website for daily review 
(t+ Medical, Abingdon, UK). BP data are acquired from the secure server and are exported in .mat 
(Matlab) format before being stored for offline analysis within the Centre for Prevention of Stroke and 
Dementia (CPSD) along with the data securely downloaded from all 24-hour ABPM. All BP data will be 
stored only at the University of Oxford site in accordance to the data governance policy of the 
University of Oxford, and will be the responsibility of Professor Rothwell.   
 
Neuroimaging data will be transferred from participating sites in an anonymised form, and then stored 
on secure servers within UCL accessible to the Stroke Research Centre. Any patient related 
documents will not be transferred to any unauthorised party and are will not be processed and/or 
transferred other than in accordance with the patients’ consent.  
All baseline, follow up data will be entered on an electronic CRF. The CI will manage and maintain the 
study database throughout the investigation. Information on the eCRF will, where relevant, be accepted 
as source data and transferred, in part, and as appropriate, to a sealed envelope database, password 
protected to defined users and with an audit trial managed from the study coordinating site at UCL. 
Direct access to data, source data and documents will be granted to authorized representatives, host 
institution and regulatory authorities, by arrangement with the CI, to permit trial-related monitoring and 
audit. 
 
A.13.1 Procedures for data review, database cleaning, and issuing and resolving data queries.  
 
Data entered on the eCRFs will be 100 % source verified by a sponsor representative trained on the 
CIP and who has current GCP training. Data Clarification Forms (DCF) will be issued to the investigator 
should a discrepancy be found between the source and eCRF. The investigator will be required to 
verify and correct all errors or provide an explanation for the discrepant data. Sponsor representatives 
will re-verify the corrected data and mark the clarification as resolved at the next monitoring visit.  

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A.13.2 Procedures for verification, validation and securing of electronic clinical data systems  
 
 
All data from the examinations and investigations listed in Appendix 1 will be transferred to media 
provided by the sponsor and collected at the time of eCRF collection.  
 
The CI will manage and maintain the study database throughout the investigation. At the conclusion of 
the investigation, the database will then be locked and data transferred for analysis. A final copy of the 
database will be provided to the study site. Where data is transferred electronically, this will be in 
accordance with the UK Data Protection Act 1998 as well as Trust Information Governance Policy. 
There will be a documented record of data transfer and measures in place for the recovery of original 
information after transfer. 
 
The database maintained by the CI, shall be validated and secured according to the sponsor standard 
operating procedures. Access to the data shall be limited to sponsor representatives directly involved in 
the collection, analysis, maintenance or safety monitoring of the data. Any study data released shall be 
done according to the publication policy and in accordance with the UK Data Protection Act 1998.  
 
A.13.3 Data retention 
 
At the end of the trial, all essential documentation will be archived securely by the CI for a minimum of 
20 years from the declaration of end of trial.  
Essential documents are those which enable both the conduct of the trial and the quality of the data 
produced to be evaluated and show whether the site complied with all applicable regulatory 
requirements. The sponsor will notify sites when trial documentation can be archived. All archived 
documents must continue to be available for inspection by appropriate authorities upon request.  
 
A.13.4 Clinical quality assurance 
 
The clinical investigators will meet every fortnight to discuss any issues with data quality and any 
concerns will be discussed with the sponsor.  
 
A.13.5 Completion of electronic Case Report Forms 
 
The local research team will be responsible for completion of an eCRF for each participant. This will be 
maintained by the local PI or delegated research staff. The eCRF will include participant’s year of birth 
and unique trial number), medical history, visit details and dates, questionnaires and any related AEs 
and details of withdrawal from the study if appropriate.   
 
The principal investigator will be responsible for the timing, accuracy and completeness of eCRF for 
each individual subject.  All the data should be entered into sealed envelope, on the eCRF; access to 

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this secure serve will be granted only to secure personnel. The personal data recorded on all 
documents will be regarded as confidential.   
 
The principal investigator must record the subject’s participation in this clinical investigation in the 
subject’s hospital notes.  In addition, the principal investigator must keep a separate list of all subjects 
entered into the clinical investigation showing each subject’s name, date of birth and assigned subject 
number (for identification purposes). A subject identification log will also be provided in the investigation 
site file to record the subject’s initials and assigned subject number. 
All data will be handled in accordance with the UK Data Protection Act 1998. 
 
A.13.6 Retention of Documentation 
 
The principal investigator will retain all copies of the records for a period of 20 years from the 
discontinuation of the clinical investigation.  In all cases, the principal investigator must contact the 
sponsor prior to disposing of any records related to the clinical investigation.  Included in records to be 
maintained are the signed clinical investigation plan, , signed consent forms, ethics committee approval 
letters, product accountability records, correspondence concerning the clinical and any other 
documents to identify the subjects.  
 
In addition, if the principal investigator moves/retires, etc., he should provide University College London 
with the name and address of the person who will look after and be responsible for the clinical 
investigation related records. 
 
A.13.7  Training 
During the initiation of the investigation site, the sponsor will ensure the investigators and the site study 
staff are trained on the device. The investigator is then responsible for ensuring that the investigation 
staff uses the device in the same way. All training will be documented in a Site Training Log.  
The monitor will also ensure that the investigator and investigation site team have received and 
understood the requirements and content of:  
* CIP (Clinical Investigation Plan)  
* IB (Investigators Brochure)  
* The informed consent forms  
* eCRFs (electronic Case Report Forms)  
* IFUs (Instructions For Use)  
* All written clinical investigation agreements as appropriate  

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A.14 Amendments to the CIP 
 
Amendments to this CIP may be necessary to protect the safety of the patients and integrity of the data. 
In collaboration with the Investigator(s), the CIP amendments will be documented and submitted for 
ethical and regulatory approval (as required) prior to implementation. All changes will be evaluated for 
impact per sponsor SOPs. Amendments will be considered implemented after all ethical and regulatory 
approvals (as required) are received and all key sponsor and site staff has been trained. This process 
does not affect the individual clinician’s responsibility to take immediate action if thought necessary to 
protect the health and interest of individual patients. 
A.15 Deviations from clinical investigation plan 
 
A deviation is considered a departure from the conditions and principles of GCP in connection with that 
investigation; or the CIP relating to that Investigation, as amended from time to time.  
 
The investigator shall not deviate from this CIP except in situations that affect the subject’s rights, 
safety and well-being, or the scientific integrity of the clinical investigation.  
 
A.15.1 Procedures for recording, reporting and analysing CIP deviations 
 
If possible, prior approval from the sponsor and REC, if appropriate, shall be obtained by the 
investigator. All spontaneous CIP deviations shall be recorded and reported to the sponsor as agreed. 
A deviation log shall be maintained by the study site. Deviations shall be reported to the REC and the 
regulatory authorities if required by national regulations. All deviations will be included, as required in 
the final study report.  
 
Notification requirements and time frames.  
 
Requests for deviations by the investigator will be responded to within 48 hours of receipt.  
 
Corrective and preventive actions and principal investigator disqualification criteria. 
 
Refer to the Monitoring Plan (as applicable) for corrective and preventative actions and principal 
investigator disqualification criteria.  
 
A.15.2 Procedure for reporting any protocol deviations 
 
Any deviation from the protocol that has not been previously approved by the sponsor (JRO at 
University College London), must be reported to the sponsor within 2 working days of the deviation 
occurrence.  Any deviations from the clinical investigation plan that are identified during routine 

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monitoring visits will be reported to the sponsor (JRO, University College London) within 24 hours of 
being identified.A.16 Statements of compliance 
 
The clinical investigation shall be conducted in accordance with the ethical principles of the Declaration 
of Helsinki, ISO standard 14155 and all other applicable device and UK regulations.  
The clinical investigation shall not commence recruitment until all REC, regulatory (if applicable) and 
local (NHS permission) is received. All additional requirements imposed by the REC or regulatory 
authority will be followed.  
 
A.16 Insurance  
University College London holds insurance against claims from participants for injury caused by their 
participation in the clinical trial. Participants may be able to claim compensation if they can prove that 
UCL has been negligent. However, as this clinical trial is being carried out in a hospital, the hospital 
continues to have a duty of care to the participant of the clinical trial.  University College London does 
not accept liability for any breach in the hospital’s duty of care, or any negligence on the part of hospital 
employees. This applies whether the hospital is an NHS Trust or otherwise.   
Participants may also be able to claim compensation for injury caused by participation in this clinical 
trial without the need to prove negligence on the part of University College London or another party.  
Participants who sustain injury and wish to make a claim for compensation should do so in writing in the 
first instance to the Chief Investigator, who will pass the claim to the Sponsor’s Insurers, via the 
Sponsor’s office. 
Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance cover for 
harm caused by their employees and a copy of the relevant insurance policy or summary shall be 
provided to University College London, upon request. 
 
A.17 Adverse events, adverse device effects and device deficiencies 
a-c) Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or 
other persons, whether or not related to the investigational medical device. 
Note 1: This definition includes events related to the investigational medical 
device or the comparator 
Note 2: This definition includes events related to the procedures involved 
Note 3: For users or other persons, this definition is restricted to events 
related to investigational medical devices 

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Adverse Device Effect 
(ADE) 
Adverse Event related to the use of an investigational device.  
Note 1: This definition includes AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or 
any malfunction of the investigational device 
Note 2: This definition includes any event resulting from use error or from 
intentional misuse of the investigational medical device 
Serious Adverse Event 
(SAE) 
Any adverse event that: 
• 
Led to death, 
• 
Led to serious deterioration in the health of the subject, that either 
resulted in  
• a life-threatening illness or injury, or 
• a permanent impairment of a body structure or a body function, or 
• in-patient or prolonged hospitialisation, or 
• medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body 
function, 
• 
Led to foetal distress, foetal death or a congenital anomaly or birth defect 
 
 
Serious Adverse Device 
Effect (SADE) 
An ADE that has resulted in any of the consequences characteristic of 
an SAE 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
An SADE, which by its nature, incidence, severity or outcome, has not 
been identified in the current version of the risk analysis report.  
Device Deficiency (DD) 
Inadequately of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. 
Note 1: this includes malfunctions, use errors, and inadequate labeling 
 
An adverse event does not include: 
 
Medical or surgical procedures; the condition that leads to the procedure is an adverse event. 
 
Pre-existing disease, conditions, or laboratory abnormalities present at the start of the study that 
do not worsen in frequency or intensity. 
 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalizations for 
cosmetic or elective surgery or social/convenience admissions); 
 
The disease being studied or signs/symptoms associated with the disease unless more severe 
than expected for the subject’s condition. 
 
Expected post-operative course (see section x) 
d) Reporting requirements and timelines 
 
AEs and ADEs are not considered reportable.  
 
Term 
Reporter 
Reported to 
Reporting 
Timeline 
from 
awareness of the event 
Adverse Event (AE) 
Investigator 
Sponsor 
As agreed with sponsor. CI to 
record fully all AEs. 

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Adverse Device 
Effect (ADE) 
Investigator 
Sponsor/Manufacturer 
As agreed with sponsor. CI to 
record fully all ADEs. 
 
 
The following events are considered reportable events in accordance with Annex 7, section 2.3.5 and 
Annex X, section 2.3.5 of DIRECTIVES 90/385/EEC AND 93/42/EEC respectively. 
 
Term 
Reporter 
Reported to 
Reporting 
Timeline 
from 
awareness of the event 
Serious Adverse 
Event (SAE)**/ 
Serious Adverse 
Device Effect 
(SADE) 
Investigator 
Sponsor 
Immediately, but no more than 3 
calendar days after becoming 
aware of the event  
CI 
MHRA 
aic@mhra.gsi.gov.uk 
 
Immediately, but not later than 2* 
calendar days after awareness  
*For SAEs which indicate an 
imminent risk of death, serious 
injury, or serious illness and 
that require prompt remedial 
action for other patients/subjects, 
users or other persons 
 
All other events immediately but 
not later than 7 calendar days 
following date of awareness.   
CI 
REC 
N/A 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
Investigator 
 
Sponsor 
 
Immediately, but no more than 3 
calendar days after becoming 
aware of the event 
CI 
MHRA 
 
Immediately, but not later than 2* 
calendar days after awareness  
*For SAEs which indicate an 
imminent risk of death, serious 
injury, or serious illness and 
that require prompt remedial 
action for other patients/subjects, 
users or other persons. 
All other events immediately but 
not later than 7 calendar days 
following date of awareness.   
CI 
REC 
Within 15 days of the chief 
investigator becoming aware of 
the event.  
Only reports of related and 
unexpected 
Serious 
Adverse 

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Events 
(SAEs) 
should 
be 
submitted to the REC.  
 
 
Term 
Reporter 
Reported to 
Reporting 
Timeline 
from 
awareness of the event 
Device Deficiency 
(DD) 
Investigator 
Sponsor 
 
Immediately, no more than 24 
hours of becoming aware of the 
event 
CI 
 
MHRA 
7 calendar days 
 
Only reportable if the event may 
have led to an SAE if; 
 
suitable action had not 
taken 
 
intervention had not been 
made 
 
if 
circumstances 
had 
been less fortunate  
Urgent Safety 
Measures 
CI 
REC 
(i) 
Immediately-By 
telephone 
(ii) 
Within 3 days-Notice in 
writing 
setting 
out 
reasons for the USM and 
plan for further action 
 
** Note Planned hospitalisation for a pre-existing condition, or a procedure required by the CIP, without 
serious deterioration in health, is not considered a serious adverse event. 
e) Assessments of adverse events 
 

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Each adverse event will be assessed for the following criteria: 
 
Severity  
 
Category 
Definition 
Mild 
The adverse event does not interfere with the subjects daily routine, and 
does not require intervention; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the subjects routine, 
or requires intervention, but is not damaging to health; it causes 
moderate discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is 
clearly damaging to health 
Note: A severity rating of severe does not necessarily categorise the 
event as an SAE. 
Seriousness 
Seriousness as defined for an SAE in section a) above. Causality 
The assessment of relationship of adverse events to the study procedure and the investigational device 
will be a clinical decision based on all available information at the time of the completion of the eCRF. 
The following categories will be used to define the causality of the adverse event: 
 
Category 
Definition 
Yes 
There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. 
the event occurred within a reasonable time after procedure). 
However, the influence of other factors may have contributed 
to the event (e.g. the patient’s clinical condition, other 
concomitant events). 
No 
There is no evidence of any causal relationship. 
 
 
 
 
 
Expectedness 
Category 
Definition 
Expected 
An adverse event that is consistent with the information about 

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the device listed in the Investigator Brochure or clearly defined 
in this CIP. 
Unexpected 
An adverse event that is not consistent with the information 
about the device listed in the Investigator Brochure  
 
The reference document to be used to assess expectedness against the intervention is the IB. The CIP 
will be used as the reference document to assess disease related and/or procedural expected events.  
f) Procedures for recording and reporting Adverse Events and Device Deficiencies 
Investigator responsibilities:  
All adverse events and SAEs will be recorded in the medical records and eCRF following consent. 
 
All serious adverse events will need to be reported to the sponsor on a SAE form (using MEDDEV form 
2.7/3) unless stated in the CIP that some expected SAEs will not be reported to the sponsor, with a 
justification as to why they will not be reported.   
 
For patients on the control arm of an Investigation, SAEs may not have to be reported to the sponsor 
but will be recorded in the eCRF and medical records. 
 
The Chief or Principal Investigator will complete the serious adverse event form and the form will be 
emailed to the sponsor to add, within 3 working day of his/her becoming aware of the event. The Chief 
or Principal Investigator will respond to any SAE queries raised by the sponsor as soon as possible. 
 
The Investigator will report to the MHRA and REC (as applicable) all reportable events within the 
specified timeframes as per section d above.  
 
“All deaths will be reported to the sponsor irrespective of whether the death is related to disease 
progression, the device, or an unrelated event”.  
 
“Only deaths that are assessed to be caused by the device will be reported to the sponsor.  This report 
will be immediate”. 
 
“All deaths, including deaths deemed unrelated to the device, if they occur earlier than expected will be 
reported to the sponsor”. 
 
 
All SAEs and UADEs should be reported to the following; 
e-mail: randd@uclh.nhs.uk  
Reporting of all Adverse Events and Device Deficiencies: Investigator and Sponsor 
responsibilities 
 
Any adverse incident involving a medical device should be reported to the manufacturer of the device.  

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This is especially important where the incident has led to or, was it to occur again could lead to an 
event classified as serious. Other minor safety or quality problems should be reported along with 
incidents that appear to be caused by human error.  
All adverse incidents involving the telemetric medical device must be reported to the device co-
ordination site in Oxford, John Radcliffe Hospital, Centre for Prevention of Stroke and Dementia. 
Incidents will be reported as soon as possible (usually within 24 hours).  
Local trust reporting procedures may also need to be followed. It is the responsibility of the PI and trial 
site team to ensure they are aware of any specific local requirements for reporting device incidents.  
Progress reports 
Progress reports will be submitted to the REC as per the REC requirements. The chief investigator will 
prepare the annual progress reports. 
A.18 Oversight Committees  
 
Trial Management Group (TMG) 
The TMG will include the Co-Chief Investigators and co-ordinating site trial staff.  The TMG will be 
responsible for overseeing the trial.  The group will meet regularly [approximately every month] in 
person, or by teleconference, and will send updates to local PIs and their teams. The TMG will review 
recruitment figures, SAEs and substantial amendments to the protocol prior to submission to the REC.  
All PIs will be kept informed of substantial amendments through their nominated responsible 
individuals. A Data Monitoring Committee (DMC) will regularly monitor outcome events including 
adverse events and will report to the TMG.  
 
Trial Steering Committee (TSC ) 
The role of the TSC will provide overall supervision of the trial.  The TSC will review the on-going of the 
trial and recommend any appropriate amendments/actions for the trial as necessary.  The TSC will be 
determined by the TMG team, and will include members of the original grant application and other 
invitees with expertise relevant to the trial. The TSC is expected to meet either in person or by 
teleconference 1-2 times per year. 
 
Independent Data Monitoring Committee (IDMC) 
N/A 
 
A.19 Vulnerable population 
N/A 
A.20 Suspension or premature termination of the clinical investigation 
 

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Both the Sponsor and the Principal investigator reserve the right to terminate the clinical investigation at 
any time. Should this be necessary, the procedures will be arranged on an individual basis after review 
and consultation by both parties. In terminating the clinical investigation, the JRO at University College 
London and the Principal investigator will assure that adequate consideration is given to the protection 
of the subject’s interests. 
 
A.20.1 Subject Withdrawals and Discontinuation 
 
Participants who have consented to intervention, assessments, follow-up and data collection, their 
participation 
is 
voluntary 
and 
they 
are 
free 
to 
withdraw 
at 
any 
time 
and without their medical care or legal rights being affected. A participant may be withdrawn from trial 
whenever continued participation is no longer in the participant’s best interests, and the reason for 
withdrawal will be recorded.  Reasons for discontinuing the trial may include: 
- 
intercurrent illness  
- 
patients withdrawing consent  
- 
persistent non-compliance to protocol requirements 
The decision to withdraw a participant from treatment will be recorded in the eCRF and medical notes. 
If a participant explicitly states they do not wish to contribute further data to the trial their decision must 
be respected and recorded in the eCRF and medical notes. 
A.21 Definition of End of Trial 
 
The expected duration of the trial is 36 months from recruitment of the first participant. 
The end of trial is the date of the last follow up of the last participant. 
A.22 Publication policy 
 
We plan to present the results of the study at scientific meetings and publish the results in scientific 
journals. All participant data will be anonymised for this purpose. Authorship of publications will be 
determined by the ICMJE criteria.  
 
 
 
 

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A.23 Bibliography 
 
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Wilson D, Adams ME, Robertson F, Murphy M, Werring DJ. Investigating intracerebral 
haemorrhage. BMJ. 2015;350:h2484. 
2. 
van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, 
and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic 
origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9(2):167-76. 
3. 
Poon MT, Fonville AF, Al-Shahi Salman R. Long-term prognosis after intracerebral 
haemorrhage: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2014;85(6):660-7. 
4. 
Cox AM, McKevitt C, Rudd AG, Wolfe CD. Socioeconomic status and stroke. Lancet Neurol. 
2006;5(2):181-8. 
5. 
Jorgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Stroke recurrence: predictors, 
severity, and prognosis. The Copenhagen Stroke Study. Neurology. 1997;48(4):891-5. 
6. 
Moulin S, Labreuche J, Bombois S, Rossi C, Boulouis G, Henon H, et al. Dementia risk after 
spontaneous intracerebral haemorrhage: a prospective cohort study. Lancet Neurol. 2016;15(8):820-9. 
7. 
Hanger HC, Wilkinson TJ, Fayez-Iskander N, Sainsbury R. The risk of recurrent stroke after 
intracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 2007;78(8):836-40. 
8. 
Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J. Hemorrhage burden predicts recurrent 
intracerebral hemorrhage after lobar hemorrhage. Stroke. 2004;35(6):1415-20. 
9. 
O'Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, et al. Apolipoprotein E 
genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000;342(4):240-5. 
10. 
Fang MC, Chang Y, Hylek EM, Rosand J, Greenberg SM, Go AS, et al. Advanced age, 
anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial 
fibrillation. Ann Intern Med. 2004;141(10):745-52. 
11. 
Biffi A, Anderson CD, Battey TW, Ayres AM, Greenberg SM, Viswanathan A, et al. Association 
Between Blood Pressure Control and Risk of Recurrent Intracerebral Hemorrhage. JAMA. 
2015;314(9):904-12. 
12. 
Inagawa T. Recurrent primary intracerebral hemorrhage in Izumo City, Japan. Surg Neurol. 
2005;64(1):28-35; discussion -6. 
13. 
Casolla B, Dequatre-Ponchelle N, Rossi C, Henon H, Leys D, Cordonnier C. Heavy alcohol 
intake and intracerebral hemorrhage: characteristics and effect on outcome. Neurology. 
2012;79(11):1109-15. 
14. 
Feldmann E, Broderick JP, Kernan WN, Viscoli CM, Brass LM, Brott T, et al. Major risk factors 
for intracerebral hemorrhage in the young are modifiable. Stroke. 2005;36(9):1881-5. 
15. 
Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, et al. Hematoma growth 
is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 
2006;66(8):1175-81. 
16. 
Dandapani BK, Suzuki S, Kelley RE, Reyes-Iglesias Y, Duncan RC. Relation between blood 
pressure and outcome in intracerebral hemorrhage. Stroke. 1995;26(1):21-4. 
17. 
Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, et al. Rapid blood-pressure 
lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368(25):2355-65. 
18. 
Fischer U, Cooney MT, Bull LM, Silver LE, Chalmers J, Anderson CS, et al. Acute post-stroke 
blood pressure relative to premorbid levels in intracerebral haemorrhage versus major ischaemic 
stroke: a population-based study. Lancet Neurol. 2014;13(4):374-84. 
19. 
Manning L, Hirakawa Y, Arima H, Wang X, Chalmers J, Wang J, et al. Blood pressure variability 
and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised 
controlled trial. Lancet Neurol. 2014;13(4):364-73. 
20. 
Group PC. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 
6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287):1033-41. 

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21. 
Chapman N, Huxley R, Anderson C, Bousser MG, Chalmers J, Colman S, et al. Effects of a 
perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke 
subtype and medical history: the PROGRESS Trial. Stroke. 2004;35(1):116-21. 
22. 
Group SPSS, Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, et al. Blood-pressure 
targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382(9891):507-
15. 
23. 
Birns J, Markus H, Kalra L. Blood pressure reduction for vascular risk: is there a price to be 
paid? Stroke. 2005;36(6):1308-13. 
24. 
Lager KE, Wilson A, Khunti K, Mistri AK. Quality of secondary prevention measures in TIA 
patients: a retrospective cohort study. Postgrad Med J. 2012;88(1040):305-11. 
25. 
Ovbiagele B, Diener HC, Yusuf S, Martin RH, Cotton D, Vinisko R, et al. Level of systolic blood 
pressure within the normal range and risk of recurrent stroke. JAMA. 2011;306(19):2137-44. 
26. 
Glader EL, Sjolander M, Eriksson M, Lundberg M. Persistent use of secondary preventive drugs 
declines rapidly during the first 2 years after stroke. Stroke. 2010;41(2):397-401. 
27. 
Herttua K, Tabak AG, Martikainen P, Vahtera J, Kivimaki M. Adherence to antihypertensive 
therapy prior to the first presentation of stroke in hypertensive adults: population-based study. Eur 
Heart J. 2013;34(38):2933-9. 
28. 
De Simoni A, Hardeman W, Mant J, Farmer AJ, Kinmonth AL. Trials to improve blood pressure 
through adherence to antihypertensives in stroke/TIA: systematic review and meta-analysis. J Am 
Heart Assoc. 2013;2(4):e000251. 
29. 
Boan AD, Lackland DT, Ovbiagele B. Lowering of blood pressure for recurrent stroke 
prevention. Stroke. 2014;45(8):2506-13. 
30. 
Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging 
standards for research into small vessel disease and its contribution to ageing and neurodegeneration. 
Lancet Neurol. 2013;12(8):822-38. 
31. 
Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et 
al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009;8(2):165-74. 
32. 
Gregoire SM, Brown MM, Kallis C, Jager HR, Yousry TA, Werring DJ. MRI detection of new 
microbleeds in patients with ischemic stroke: five-year cohort follow-up study. Stroke. 2010;41(1):184-6. 
33. 
Kimberly WT, Gilson A, Rost NS, Rosand J, Viswanathan A, Smith EE, et al. Silent ischemic 
infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy. Neurology. 
2009;72(14):1230-5. 
34. 
Gregoire SM, Charidimou A, Gadapa N, Dolan E, Antoun N, Peeters A, et al. Acute ischaemic 
brain lesions in intracerebral haemorrhage: multicentre cross-sectional magnetic resonance imaging 
study. Brain. 2011;134(Pt 8):2376-86. 
35. 
Menon RS, Burgess RE, Wing JJ, Gibbons MC, Shara NM, Fernandez S, et al. Predictors of 
highly prevalent brain ischemia in intracerebral hemorrhage. Ann Neurol. 2012;71(2):199-205. 
36. 
Benjamin P, Zeestraten E, Lambert C, Ster IC, Williams OA, Lawrence AJ, et al. Progression of 
MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials. J Cereb 
Blood Flow Metab. 2016;36(1):228-40. 
37. 
Greenberg SM, Al-Shahi Salman R, Biessels GJ, van Buchem M, Cordonnier C, Lee JM, et al. 
Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol. 2014;13(4):419-28. 
38. 
Gouw AA, van der Flier WM, Fazekas F, van Straaten EC, Pantoni L, Poggesi A, et al. 
Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the 
Leukoaraiosis and Disability study. Stroke. 2008;39(5):1414-20. 
39. 
van Dijk EJ, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM. Progression of 
cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan 
study. Stroke. 2008;39(10):2712-9. 

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40. 
Schmidt R, Enzinger C, Ropele S, Schmidt H, Fazekas F, Austrian Stroke Prevention S. 
Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. 
Lancet. 2003;361(9374):2046-8. 
41. 
Schmidt R, Fazekas F, Kapeller P, Schmidt H, Hartung HP. MRI white matter hyperintensities: 
three-year follow-up of the Austrian Stroke Prevention Study. Neurology. 1999;53(1):132-9. 
42. 
Chappell FM, Del Carmen Valdes Hernandez M, Makin SD, Shuler K, Sakka E, Dennis MS, et 
al. Sample size considerations for trials using cerebral white matter hyperintensity progression as an 
intermediate outcome at 1 year after mild stroke: results of a prospective cohort study. Trials. 
2017;18(1):78. 
43. 
Chen YW, Gurol ME, Rosand J, Viswanathan A, Rakich SM, Groover TR, et al. Progression of 
white matter lesions and hemorrhages in cerebral amyloid angiopathy. Neurology. 2006;67(1):83-7. 
44. 
Mok V, Kim JS. Prevention and Management of Cerebral Small Vessel Disease. J Stroke. 
2015;17(2):111-22. 
45. 
Sudre CH, Cardoso MJ, Ourselin S, Alzheimer's Disease Neuroimaging I. Longitudinal 
segmentation of age-related white matter hyperintensities. Med Image Anal. 2017;38:50-64. 
46. 
Gouw AA, van der Flier WM, van Straaten EC, Pantoni L, Bastos-Leite AJ, Inzitari D, et al. 
Reliability and sensitivity of visual scales versus volumetry for evaluating white matter hyperintensity 
progression. Cerebrovasc Dis. 2008;25(3):247-53. 
47. 
Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid 
angiopathy: validation of the Boston criteria. Neurology. 2001;56(4):537-9. 
48. 
Baykara E, Gesierich B, Adam R, Tuladhar AM, Biesbroek JM, Koek HL, et al. A Novel Imaging 
Marker for Small Vessel Disease Based on Skeletonization of White Matter Tracts and Diffusion 
Histograms. Ann Neurol. 2016;80(4):581-92. 
49. 
Gregoire SM, Chaudhary UJ, Brown MM, Yousry TA, Kallis C, Jager HR, et al. The Microbleed 
Anatomical Rating Scale (MARS): reliability of a tool to map brain microbleeds. Neurology. 
2009;73(21):1759-66. 
50. 
Staals J, Makin SD, Doubal FN, Dennis MS, Wardlaw JM. Stroke subtype, vascular risk factors, 
and total MRI brain small-vessel disease burden. Neurology. 2014;83(14):1228-34. 
51. 
Charidimou A, Schmitt A, Wilson D, Yakushiji Y, Gregoire SM, Fox Z, et al. The Cerebral 
Haemorrhage Anatomical RaTing inStrument (CHARTS): Development and assessment of reliability. J 
Neurol Sci. 2017;372:178-83. 
52. 
Linn J, Halpin A, Demaerel P, Ruhland J, Giese AD, Dichgans M, et al. Prevalence of superficial 
siderosis in patients with cerebral amyloid angiopathy. Neurology. 2010;74(17):1346-50. 
53. 
Dufouil C, Chalmers J, Coskun O, Besancon V, Bousser MG, Guillon P, et al. Effects of blood 
pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS 
(Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. 
Circulation. 2005;112(11):1644-50. 

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Appendix 1 - Schedule of assessments    
 
 
 
Screening  
(Pre-treatment assessment) 
Intervention phase and Follow-ups  
 
Baseline 
3 Month follow-up 
12 Month follow-up 
Visit No: 
1 
2 
Final Visit 
Window of flexibility for timing of visits: 
 
e.g.  +/- 2 days 
e.g.  +/- 2 days 
Informed Consent 
X 
 
 
Medical History 
X 
 
 
Eligibility confirmation 
X 
 
 
Blood test 
X 
 
 
MRI Scan (before randomisation) 
X 
 
X 
Blood Pressure 
X 
X 
X 
24-hour ABPM 
X 
X 
X 
Cognitive assessment  
X 
X 
X 
Quality of life assessment (EQ-5D) 
X 
X 
X 
BP acceptability questionnaire  
 
X 
 
Randomisation  
X 
 
 
Adverse Events review 
X 
X 
X 

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Appendix 2 - Cognitive functional change Assessment (modified Montreal 
Cognitive Assessment)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3 – EQ-5D Questionnaire Under each heading, please tick the ONE box 
that best describes your health TODAY 
MOBILITY 
I have no problems in walking about  
 
 
 
 
 
 
I have slight problems in walking about    
 
 
 
 
 
I have moderate problems in walking about  
 
 
 
 
 
I have severe problems in walking about   
 
 
 
 
 
I am unable to walk about   
 
 
 
 
 
 
 
SELF-CARE  
I have no problems washing or dressing myself  
 
 
 
 
I have slight problems washing or dressing myself   
 
 
 
 
I have moderate problems washing or dressing myself  
 
 
 
I have severe problems washing or dressing myself   
 
 
 
I am unable to wash or dress myself 
 
 
 
 
 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities  
 
 
 
 
 
I have slight problems doing my usual activities  
 
 
 
 
I have moderate problems doing my usual activities    
 
 
 
I have severe problems doing my usual activities  
 
 
 
 
I am unable to do my usual activities   
 
 
 
 
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort  
 
 
 
 
 
 
 
I have slight pain or discomfort    
 
 
 
 
 
 
I have moderate pain or discomfort  
 
 
 
 
 
 
I have severe pain or discomfort   
 
 
 
 
 
 
I have extreme pain or discomfort   
 
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
 
 
 
I am slightly anxious or depressed   
 
 
 
 
 
 
I am moderately anxious or depressed   
 
 
 
 
 
I am severely anxious or depressed  
 
 
 
 
 
 
I am extremely anxious or depressed  
 
 
 
 
 
We would like to know how good or bad your health is TODAY 

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This scale is numbered from 0 to 100 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
Mark an X on the scale to indicate how your health is TODAY 
 
Now, please write the number you marked on the scale in the box below.  
 
 
 
 
YOUR HEALTH TODAY = 
 

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Appendix 4 – Home BP monitoring participant acceptability questionnaire 
HOME BLOOD PRESSURE MONITORING QUESTIONNAIRE  
We would be very grateful if you could help us by answering some short questions about your experience using the home blood pressure monitor as part of the PROHIBIT-ICH 
study.  Please tick the box that most closely matches your level of agreement with each of the following statements.  Please give only one answer per line. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Definitely 
Moderately 
Neither agree 
         Moderately Definitely 
 
 
 
 
 
 
 
 
  agree  
  agree  
nor disagree 
           disagree  disagree 
 
1 
I liked the fact that the regular readings would 
provide better information about my blood pressure 
    
 
2 
It reassured me to know that the equipment would 
 
transmit my readings directly to the hospital  
 
 
3 
It was helpful to have a telephone number 
 
that I could call to discuss my blood pressure  
 
readings and treatment 
 
Measuring my blood pressure at home: 
 
 
 
4 
was not uncomfortable 
 
5 
was not too time consuming  
 
 
6 
caused me no anxiety 
 
 
 
 
 
 
7 
I found it very easy to remember to 
 
do it regularly 
 
 
 
 
   
 
Please rate your overall satisfaction with monitoring  
your blood pressure at home by marking a cross on  
 
            0                        25                           50 
                75 
                   100 
the following line      
 
 
 
 
 
             ------------------------------------------------------------------------------------------------------ 
 
 
 
 
 
 
 
     Extremely satisfied        
 
 
 
 
 
Extremely dissatisfied 
 
 
 
 
 
 
 
                         
Has anyone helped you to fill in the questionnaire?  (Please circle)                 YES    or      NO 
 
 
 
 
 
 
Thank you very much for taking the time to complete this questionnaire.   
Please return it to us in the attached prepaid envelope.  
If you would like to make any additional comments please use the space provided below: