Clinical Trials Register

Summary
EudraCT Number:	2016-002598-36
Sponsor's Protocol Code Number:	16IC3372
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2016-07-13
Trial 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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2016-002598-36

A.3

Full title of the trial

Randomised Clinical Trial of Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer's
Disease

A.3.1

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

A Trial of Long-Acting Guanfacine in addition to Standard Therapy in Mild to Moderate Alzheimer's Disease

A.3.2

Name or abbreviated title of the trial where available

NorAD

A.4.1

Sponsor's protocol code number

16IC3372

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03116126

A.5.4

Other Identifiers

Name:

NIHR Reference

Number:

PB-PG-0214-33098

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	Imperial College London
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	National Institute of Health Research
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Shire Pharmaceuticals
B.4.2	Country	Jersey
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Imperial College London
B.5.2	Functional name of contact point	Paresh Malhotra
B.5.3	Address:
B.5.3.1	Street Address	Room 10L20A, Charing Cross Campus, St Dunstan's Road
B.5.3.2	Town/ city	London
B.5.3.3	Post code	W6 8RP
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	00442033117286
B.5.6	E-mail	p.malhotra@imperial.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	Intuniv
D.2.1.1.2	Name of the Marketing Authorisation holder	Shire Pharmaceuticals Ireland 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	Intuniv
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.3.11 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
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Alzheimer's Disease

E.1.1.1

Medical condition in easily understood language

Dementia

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	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10001897
E.1.2	Term	Alzheimer's disease (incl subtypes)
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10012271
E.1.2	Term	Dementia Alzheimer's type
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10001896
E.1.2	Term	Alzheimer's disease
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

To find out whether the addition of extended release guanfacine (GXR) to standard therapy in Alzheimer's disease is
beneficial (improves thinking) in comparison to standard therapy on its own.

E.2.2

Secondary objectives of the trial

To find out whether combined treatment (GXR + standard therapy) is more effective in patients with mild or moderate
Alzheimer's 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

We have Ethical approval for a sub-study (PCNorAD) to investigate the effects of combined
treatment (guanfacine plus standard treatments) on biomarkers (functional magnetic resonance imaging,
electroencephalography, pupillometry) that have been shown to be an index of attention. This would only take place in
a subset of patients who participate in the current study. If we receive this funding, then we will submit a second
ethics application for this add-on study.

E.3

Principal inclusion criteria

NINCDS/ADRDA criteria for probable AD
MMSE at assessment = 10-30.
Identified informant to accompany patient at all visits
Patient must have been on stable dose of donepezil, galantamine or rivastigmine for preceding 12 weeks

E.4

Principal exclusion criteria

Labile blood pressure or new antihypertensive medication started within 3 weeks;
Severe coronary insufficiency or myocardial infarction in previous 6 months;
History of unexplained syncope within the preceding 12 months; Cardiac Conduction Block
Severe Hepatic Impairment (ALT > 120 (Upper Limit of Normal (ULN) is 40) OR Alkaline Phosphatase > 390 (ULN is
130)) OR Both ALT and total bilirubin > ULN OR Total bilirubin > 60 (ULN is 30) ; Severe Renal Impairment (eGFR<40)
(Lower Limit of Normal is 59)
Treatment with other medications known to potentiate guanfacine’s hypotensive effects or cause arrhythmia
(specifically antipsychotics (including sultopride,
chlorpromazine, thioridazine, amisulpiride, sulpiride, haloperidol), and moxifloxacin, baclofen, verapamil, quinidine,
hydroquinidine, dispyramide, amiodarone, dofetilide, ibutilide, sotalol, pimazide, bepridil, cisapride, diphemanil,
erythromycin, halofantrine, pentamidine, sparfloxacin, vincamine, alfuzosin, prazosin, terazosin, tamsulosin,
amifostine;
weight less than 45kg (In order to ensure that an excessive dose per body weight is not used in the study).
Pregnancy (Pre-menopausal women will only be entered into the study of they are surgically sterile or using effective
birth control methods: These are abstinence for the period of the study, intrauterine contraception/device, male sexual
partners with vasectomy)

E.5 End points

E.5.1

Primary end point(s)

The primary outcome measure for the study is cognition as measured by the ADAS-Cog (Alzheimer’s Disease
Assessment Scale- Cognition). This is the standard measure of cognition for trials of therapeutic agents in
Alzheimer's Disease.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks (and 4 weeks)

E.5.2

Secondary end point(s)

Secondary outcome measures are specific tests of attention and performance of activities of daily living:
Tests of Attention
Trails A and B
The trail-making test is one of the most widely used in neuropsychology. Both parts consist of 25 circles distributed
over a sheet of paper. In Part A, the circles are numbered 1 – 25, and the patient should draw lines to connect the
numbers in ascending order. In Part B, the circles include both numbers (1 – 13) and letters (A – L); as in Part A, the
patient draws lines to connect the circles in an ascending pattern, but with the added task of alternating between the
numbers and letters (i.e., 1-A-2-B-3-C, etc.). Results for both TMT A and B are reported as the number of seconds
required to complete the task; therefore, higher scores reveal greater impairment.
Digit-Symbol Substitution
The test requires the subject to transcribe a unique geometric symbol with its corresponding Arabic number. The
examinee is initially shown a key containing the numbers from 1 to 9. Under each number there is a corresponding
geometric symbol. It is scored by totaling the number of successful transcriptions during 60s, and is a measure of
processing speed.
Test of Everyday Attention-Map Search and Elevator Counting
In the map search subtest, which is a test of selective attention, participants search for symbols on a coloured map.
The score is the number out of 80 found in 2 minutes. This subtest is age-sensitive and usable with almost all braindamaged
patients, including those with Alzheimer’s disease. It measures selective attention.
In the ‘Elevator Counting with Distraction’ subtest, subjects have to count the low tones in a pretend elevator while
ignoring the high tones. This is a test of auditory selective attention.
CANTAB-RVP
THE RVP (Rapid Visual Information Processing) component of the CANTAB computerised test battery is a test of
sustained attention that lasts 10 minutes. A white box appears in the centre of the computer screen, inside which
digits, from 2 to 9, appear in a pseudo-random order, at the rate of 100 digits per minute. Participants are requested to
detect target sequences of digits (for example, 2-4-6, 3-5-7, 4-6-8) and to register responses using a press pad.
Carer Input and Activities of Daily Living
Neuropsychiatric Inventory
The Neuropsychiatric Inventory is a validated instrumented that was designed to detect the presence of
neuropsychiatric symptoms in individuals with dementia. It is based on responses from an informed caregiver,
preferably one living with the patient. It is the most widely used behaviour instrument in clinical trials of treatments for
dementia.
Zarit Burden Interview
This interview was specifically designed to assess the effects of dementia on caregivers. Each item on the interview is
a statement that the caregiver is asked to endorse using a 5-point scale. Response options range from 0 (Never) to 4
(Nearly Always). We will employ the 22-point version of this interview.
ADCS-ADL
The ADCS-ADL is a measure of activities of daily living based on caregiver answers
are measures of carer input and activities of daily living. We will employ the 23-item version (ADCS-ADL23), which
includes more complex ADL for the assessment of mild to moderate AD, such as reading books or magazines,
pastime activities, or household chores. Ratings take about 20 minutes and are based on information obtained from
the patient and caregiver. The scores range from 0 to 78, higher scores indicating less functional impairment.
Safety Measures
Epworth Sleepiness Scale
The Epworth sleepiness scale was designed to address daytime sleepiness. We will use a modified version of the
scale to include responses from caregivers.
Side Effect Questionnaire
We will ask patients and caregivers about a number of side effects that have been associated with GXR treatment.
These include dry mouth, headache and increased sleepiness.

E.5.2.1

Timepoint(s) of evaluation of this end point

4 weeks and 12 weeks
(Safety measures will be tested at these points and also at 1 week and 8 weeks)

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

Yes

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

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

LVLS

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

140

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Some patients who participate may not have capacity to give consent. We have aimed to tailor the information sheets and consent forms as much as possible for our patient
population, patients with mild to moderate Alzheimer's Disease.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

160

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

If the trial is successful, it is likely that that a license will be applied for, such that the drug will be available for the
treatment of mild-moderate Alzheimer's Disease within the next 5 years.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-03-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-12

P. End of Trial
P.	End of Trial Status	Temporarily Halted

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials