Clinical Trials Register

Summary
EudraCT Number:	2015-002145-63
Sponsor's Protocol Code Number:	INMiND-02
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-03-21
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

2015-002145-63

A.3

Full title of the trial

A double-blind, placebo-controlled study of the effect of a TNF alpha inhibitor, etanercept (Enbrel), on microglial activation in amyloid PET positive patients with Mild Cognitive Impairment due to AD-Intermediate likelihood

A.3.1

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

A study examining the effect of etanercept (Enbrel)on inflammation in the brain.

A.3.2

Name or abbreviated title of the trial where available

Study examining the effect of Etanercept on inflammation in the brain

A.4.1

Sponsor's protocol code number

INMiND-02

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN12472821

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 Southampton
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	European Union FP7 grant
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Alzheimer's Society UK and Alzheimer Drug Discovery Foundation
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Southampton
B.5.2	Functional name of contact point	Prof Holmes
B.5.3	Address:
B.5.3.1	Street Address	Memory Assessment and Research Centre, Tom Rudd Unit, Moorgreen Hospital
B.5.3.2	Town/ city	Botley Road, West End
B.5.3.3	Post code	SO30 3JB
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02380475206
B.5.5	Fax number	02380463022
B.5.6	E-mail	ch4@soton.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	Enbrel
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
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	Enbrel
D.3.2	Product code	Not applicable
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Etanercept
D.3.9.1	CAS number	185243690
D.3.9.2	Current sponsor code	None
D.3.9.3	Other descriptive name	None
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	U/g unit(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.7 x 10^9
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
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	Powder and solvent for solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Mild Cognitive impairment- due to Alzheimer's disease- intermediate likelihood

E.1.1.1

Medical condition in easily understood language

Early memory problems

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10001896
E.1.2	Term	Alzheimer's disease
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

STUDY HYPOTHESIS:

In Mild Cognitive Impairment (MCI)-due to Alzheimer's Disease (AD), systemic inflammation and elevated systemic levels of TNFα cause partially activated, or primed, microglial cells, to become fully activated, which can be modulated by the administration of a peripheral TNFα inhibitor, etanercept (Enbrel).

STUDY QUESTION:

Will the administration of a peripheral TNFα inhibitor, etanercept (Enbrel),
over a 12 month treatment period, reduce microglial activation in patients with Mild
Cognitive Impairment due to AD- Intermediate likelihood,compared to placebo?

The level of microglial activation will be directly measured with a specialist brain scan, which is called a [11C] (R)-PK-111-95 PET scan, at base-line and at the end of the 12 month treatment period.

E.2.2

Secondary objectives of the trial

Secondary Objectives

1. To ascertain the change in the primary cognitive outcome measure, the Montreal Cognitive Assessment, (MOCA), from baseline to final treatment visit in the treatment group compared to the placebo group. (The MOCA is a well validated and widely used assessment tool which measures 8 cognitive domains within a series of 13 tests: visuospatial/executive function, memory, language, abstraction, delayed recall and orientation. The highest possible score is 30. A score above 26 represents normal cognitive function.)

2. To ascertain the change in cortical amyloid load on Amyvid PET scans from base-line to the final imaging visit in the treatment group compared to the placebo group.(Amyloid is a sticky protein which builds up in plaques around the brain cells of patients with AD,and it causes damage to the brain cells. It is present in the brain up to 15 years before the onset of symptoms of AD. It is not known if inflammation causes amyloid to build up in the

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria:

Subjects will have to meet all of the following criteria at screening to enter the study:

1. All subjects must have the capacity to make an informed decision as to whether they would like to take part in this specific clinical research trial.
2. A subject can be male or female and they must be between 50 to 90 years old, inclusive.
3. A subject must have received a minimum of 7 years of formal education.
4. A subject must be able to hear, read, write and perform study neuro-psychological tests in English.
5. A subject must have adequate visual and auditory acuity to allow neuro-psychological testing, based on the research clinician’s judgement.
6. A subject must fulfil the NIA-AA criteria for the diagnosis of Mild Cognitive Impairment due to AD at the screening visit (Albert et al, 2011.) A subject must have a MOCA score of 19 to 25 inclusive at screening, at the discretion of the Principal Investigator.
7. A subject must have a study partner who spends at least eight hours a month with the subject. The study partner may be a close friend or a neighbour and not necessarily a close relative, spouse, son or daughter, and should be present at all visits. Every effort should be made to ensure that the study partner will be the same throughout the study. If it becomes necessary for the study partner to change, the new study partner must satisfy the requirements of this criterion and the change of study partner must be clearly documented.
8. A subject must have been on a stable medication regime for more than 3 months prior to screening.
9. Women of child bearing potential must use adequate contraception to prevent pregnancy during the study and must continue to us contraception for at least four weeks after the last study dose.

E.4

Principal exclusion criteria

Exclusion criteria:

Subjects meeting any of the following criteria during screening or baseline will be excluded from the study:

General criteria
1. Inability or refusal to provide informed consent from subject or study partner.
2. Absence of study partner.
3. Unlikely to cooperate in the study, not able to attend scheduled examinations and visits, or not able to follow study instructions, left to the research clinician’s judgement.
4. Participation in another study with administration of any investigational drug in the previous 3 months or already enrolled in another study.
Medical and therapeutic criteria
5. Parkinson’s disease, Dementia with Lewy Bodies or clinically significant Parkinsonian symptoms.
6. Vascular disorder (Modified Hachinski Ischaemic Scale score > 4).
7. Recent Transient Ischaemic Attack (TIA) – within the last 3 months.
8. Signs of major cerebrovascular disease on MRI or CT scan prior to entry into study, (i.e. evidence of an established cortical or basal ganglia infarct).
9. Signs of major cerebrovascular disease on the MRI performed at the screening imaging visit prior to the amyloid and microglial PET scans.
10. Any other previous or ongoing chronic or recurrent disease of the central nervous system, including demyelinating disease or psychiatric diseases, that may have an impact on cognitive performance, left to the research clinician’s judgement.
11. Any of the following laboratory abnormalities at the screening visit:
i) Clinically significant Vitamin B12 levels less than the lower limit of normal.
ii) Clinically significant folate levels less than the lower limit of normal.
iii) Clinically significant thyroid-stimulating hormone (TSH) levels greater than the upper limit of normal and a clinically significant free thyroxine (FT4) level lower than the lower limit of normal.
(Subjects who are successfully treated for folate and vitamin B12 deficiencies or hypothyroidism may be re-screened after 3 months.)
12. Subjects with a previous or present history of severe medical conditions, or medical conditions which are poorly controlled, such as hypertension or diabetes, left to the research clinician’s judgement.
13. History of alcohol or drug dependence or abuse within the last 2 years. Current alcohol >35 units per week for men, or >28 units per week for women, or drug abuse, at the discretion of the research clinician.
14. Surgical intervention planned during the study period.
15. Treatment with immunosuppressive drugs including any systemic corticosteroid drugs. (Topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted.)
16. Treatment with benzodiazepines within a period of three days prior to [11C] (R)-PK-111-95 PET scans imaging.
17. Vaccination or immunization with any live vaccine (e.g.: polio, rubella, yellow fever) within the past 30 days.
18. Pregnancy or breast feeding.
19. Severe hepatic, renal or cardiac disease.
20. Previous use of a TNFα agent.
21. Known skin photosensitivity.
22. Infection in past 4 weeks or active infection.
23. Heart failure: New York Heart Association (NYHA) Grade 3-4.
24. History of blood disorders or current WCC ≤ 3.5 x 109/l; platelet count ≤ 100x109/l; Hb ≤ 10g/dl.
25. Active or latent tuberculosis.
26. Rheumatoid arthritis; psoriasis; psoriatic arthritis or ankylosing spondylitis.
27. Septic arthritis in past 12 months.
28. Sepsis of prosthesis in past 12 months.
29. Chronic leg ulcers.
30. Indwelling urinary catheter.
31. Pulmonary fibrosis.
32. History of neoplasms / malignancies in past 5 years.
33. Pre-malignant conditions including Barrett’s oesophagus; cervical dysplasia; large bowel polyps.
34. Other clinically significant abnormality on physical, neurological, ECG or laboratory examination that could compromise the study evaluations or be detrimental to the patient during the course of the study.
35. Use of experimental medications for AD, or any other investigational medication or device, within 60 days. Patients who have been involved in a monoclonal antibody study are excluded unless it is known that they were receiving placebo in that trial.

Imaging exclusion criteria

36. Subjects with significant cortical or basal ganglia infarct or other significant pathology found on MRI brain scan.
37. Subject with a negative Amyloid PET scan. NB: Subjects with a positive Amyloid PET scan or a border-line positive PET scan will be included in the study. The final decision on whether the Amyloid PET scan is negative, border-line positive, or positive, will rest with the Principle Investigators at the Wolfson Molecular Imaging Centre.

E.5 End points

E.5.1

Primary end point(s)

The primary objective is to ascertain the change in microglial activation on PK 111 95 PET scans from base-line to the final imaging visit in the treatment group compared to the placebo group. The study is powered on the basis that a positive result would be a 50% reduction in microglial activation in subjects receiving the IP, versus the reduction in microglial activation in the placebo group.

E.5.1.1

Timepoint(s) of evaluation of this end point

The first PK 111 95 PET scan to evaluate microglial activation in a subject will be done during the screening period of the study. The comparator scan will be done at a final imaging visit wihich will take place at week 51 of the 52 week treatment period.

E.5.2

Secondary end point(s)

Secondary Objectives

1. To ascertain the change in the primary cognitive outcome measure, the Montreal Cognitive Assessment, (MOCA), from baseline to final treatment visit in the treatment group compared to the placebo group.

2. To ascertain the change in cortical amyloid load on AMYVID PET scans from baseline to the final imaging visit in the treatment group compared to the placebo group.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. MOCA: evaluated at baseline (week 0), weeks 13, 26, 39 and at the end of treatment period, week 52.

2. AMYVID PET scan: The baseline scan will be done duing the screening period (8
to 0 weeks), and one week before the end of the 52 week treatment period.

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

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)

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

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.8.3

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

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

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

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