Clinical Trials Register

Summary
EudraCT Number:	2015-001953-33
Sponsor's Protocol Code Number:	PrevSVD-2015
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-08-27
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2015-001953-33

A.3

Full title of the trial

Preventing cognitive decline and dementia from cerebral
small vessel disease

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Preventing Cognitive Decline and Dementia from Cerebral Small Vessel Disease

A.3.2

Name or abbreviated title of the trial where available

Prevent-SVD

A.4.1

Sponsor's protocol code number

PrevSVD-2015

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN12580546

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02481323

A.5.4

Other Identifiers

Name:

Alzheimer's Society

Number:

252 (AS-PG-14-033)

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University of Edinburgh
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Alzheimer's Society
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Edinburgh
B.5.2	Functional name of contact point	Trial Manager (Kirsten Shuler)
B.5.3	Address:
B.5.3.1	Street Address	CCBS, Chancellor's Building, 49 Little France Crescent
B.5.3.2	Town/ city	Edinburgh
B.5.3.3	Post code	EH16 4SB
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 (0)131 465 9599
B.5.6	E-mail	k.shuler@ed.ac.uk
B.Sponsor: 2
B.1.1	Name of Sponsor	NHS Lothian
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Alzheimer's Society
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Edinburgh
B.5.2	Functional name of contact point	Trial Manager (Kirsten Shuler)
B.5.3	Address:
B.5.3.1	Street Address	CCBS, Chancellor's Building, 49 Little France Crescent
B.5.3.2	Town/ city	Edinburgh
B.5.3.3	Post code	EH16 4SB
B.5.4	Telephone number	+44 (0)131 465 9599
B.5.5	Fax number	01313325150
B.5.6	E-mail	k.shuler@ed.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Isotard 25 mg XL
D.2.1.1.2	Name of the Marketing Authorisation holder	ProStraken Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Isotard 25 mg XL (isosorbide mononitrate 25mg extended release)
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Isosorbide mononitrate
D.3.9.1	CAS number	16051-77-7
D.3.9.3	Other descriptive name	Isotard
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Cilostazol 50 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Generics [UK] Ltd t/a Mylan
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cilostazol 50 mg tablets
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cilostazol
D.3.9.1	CAS number	73963-72-1
D.3.9.3	Other descriptive name	Cilostazol 50 mg tablets
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Pletal 50 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Otsuka Pharmaceutical Europe Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Pletal 50 mg tablets
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cilostazol
D.3.9.1	CAS number	73963-72-1
D.3.9.3	Other descriptive name	Pletal 50 mg tablets
D.3.9.4	EV Substance Code	AS3
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Lacunar (small vessel) ischaemic stroke

E.1.1.1

Medical condition in easily understood language

A type of stroke caused by damage to the small blood vessels in the brain

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10023987
E.1.2	Term	Late effects of cerebrovascular disease
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10042244
E.1.2	Term	Stroke
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10061256
E.1.2	Term	Ischaemic stroke
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10068644
E.1.2	Term	Brain stem stroke
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10071043
E.1.2	Term	Basal ganglia stroke
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

We propose to do a small clinical trial to test how well Cilostazol and ISMN are tolerated by lacunar stroke patients when given individually or in combination, at increasing doses. We will monitor symptoms like headache, heart thumping, dizziness, bruising, other brain and leg symptoms, to see how patients find taking the drugs.

E.2.2

Secondary objectives of the trial

Do these drugs improve the function of the small vessels in the brain?
To what extent do these drugs "thin" the patients' blood?
What effects do these drugs have on blood pressure in this group of patients?

This knowledge will help us to set up a larger trial to test the overall effects of Cilostazol and ISMN on preventing brain damage from small vessel disease.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Patients recruited in Edinburgh will be invited to undergo a brain scan to assess the reactivity of the small blood vessels inside the brain (cerebrovascular reactivity, or CVR). Details of the procedure are described in A6-2 and A13. The patient lies in the magnetic resonance scanner and breathes alternately air and air enriched with 6% carbon dioxide for periods of three minutes while being scanned. The scan detects the ability of the blood vessels to expand to deliver more blood to the brain. We will see if the trial drugs alter the ability of the blood vessels to expand as one of the intermediary outcome measures. The scan method is already set up and about 40 patients have been examined with this method as part of an observational study. In the trial, the scan will be done before starting the drugs and at the end of the treatment period when on target dose. It will only be done in Edinburgh because the method is established in Edinburgh including the extra equipment required. There will be no other difference in trial assessments and procedures.

E.3

Principal inclusion criteria

• Mild symptomatic ischaemic stroke in the past four years compatible with a 1. Clinical lacunar stroke syndrome, with brain MRI or CT scanning that is compatible with a symptomatic small subcortical (lacunar) infarct, or if no recent relevant infarct is visible, that excluded other cause for symptoms
2. Age > 35 years
3. Independent in activities of daily living (modified Rankin ≤2)
4. Able to give consent themselves

E.4

Principal exclusion criteria

• Other significant active neurological illness present since suffering stroke
(e.g. seizures, multiple sclerosis, brain tumour)
• Age < 35
• Montreal Cognitive Assessment score <20
• Requiring assistance with activities of daily living (Modified Rankin ≥3)
• Active cardiac disease (atrial fibrillation, myocardial infarction in past 6
months, active angina, symptomatic cardiac failure)
• Carotid stenosis > 50% NASCET in the symptomatic artery territory requiring
carotid endarterectomy (prior and apparently successful carotid
endarterectomy is not an exclusion criterion)
• Definite indication for (i.e. already prescribed either trial medication),
or definite contraindication to either trial drug as per SmPCs.
• Unable to swallow
• Bleeding tendency (platelets<100, active peptic ulcer, taking anticoagulant
medication)
• Unlikely to comply with trial medication based on knowledge of past history,
lifestyle (cognitive impairment is an exclusion)
• Planned surgery during the trial period
• History of intracranial haemorrhage (subdural haematoma, subarachnoid
haemorrhage, intracerebral haemorrhage, but not asymptomatic haemorrhagic
transformation of infarction)
• Other life threatening illness
• History of drug overdose or attempted suicide or significant active mental
illness
• Pregnant or breastfeeding women, women of childbearing age not taking
contraception. Minimum contraception is an oral contraceptive.
• Prohibited medications (see sections 4.5 of the SmPCs and protocol section
6.6.3, plus no anticoagulant drugs)
• Renal impairment (creatinine clearance <25 ml/min)
• Hepatic impairment
• Current enrolment in another Clinical Trial of Investigational Medicinal
Product (CTIMP)

EXCLUSION CRITERIA FOR MRI CVR SUB-STUDY PARTICIPANTS (EDINBURGH ONLY)
• Active respiratory illness (such as moderate to severe asthma or COPD),
unable to tolerate MRI or unable to lie flat
• Claustrophobia
• Pacemaker

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients able to reach target dose of the allocated individual or combination of drugs as per trial groups 1-4.

E.5.1.1

Timepoint(s) of evaluation of this end point

Eight weeks

E.5.2

Secondary end point(s)

1. Symptoms, as recorded on structured questionnaire, reported whilst taking each drug alone, during dose escalation, at target dose and with both drugs combined.
2. Safety (symptoms of systemic or intracranial bleeding, recurrent vascular events, death) during the trial.
3. Effects on blood pressure of taking each drug alone, and combined versus none.
4. Effects on platelet function of taking each drug alone, and combined, versus none.
5. Effect on cerebrovascular reactivity of taking each drug alone and combined versus none.
6. Effect on arterial stiffness measured by pulse wave velocity and pulse wave analysis and cerebrospinal fluid pulsatility of taking each drug alone and combined versus none.

E.5.2.1

Timepoint(s) of evaluation of this end point

All to be assessed after three and eight weeks of trial medication.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

No active drug

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of the study is defined as the completion of analysis of the study data

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1