Clinical Trials Register

Summary
EudraCT Number:	2007-005995-14
Sponsor's Protocol Code Number:	3133K1-3001-WWB2521002
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2008-05-07
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

Austria - BASG

A.2

EudraCT number

2007-005995-14

A.3

Full title of the trial

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Trial of Bapineuzumab (AAB-001, ELN115727) in Subjects With Mild to Moderate Alzheimer Disease Who Are Apolipoprotein E ε4 Carriers

A.3.1

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

Study Evaluating the Efficacy and Safety of Bapineuzumab in Alzheimer Disease Patients Who Are Apolipoprotein E ε4 Carriers

A.4.1

Sponsor's protocol code number

3133K1-3001-WWB2521002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00676143

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	Wyeth Pharmaceuticals Inc, a wholly owned subsidiary of Pfizer Inc, 500 Arcola road, Collegeville, PA 19426 USA
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Wyeth, a Pfizer company
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	Pfizer Inc
B.5.2	Functional name of contact point	Clinical Trials.gov Call Centre
B.5.3	Address:
B.5.3.1	Street Address	235 E 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+18007181021
B.5.5	Fax number	+13037391119
B.5.6	E-mail	ClinicalTrials.govCallCentre@pfizer.com

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	No
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	AAB-001
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Bapineuzumab
D.3.9.1	CAS number	n/a
D.3.9.2	Current sponsor code	AAB-001, WAY 203740
D.3.9.3	Other descriptive name	anti-Abeta
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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)	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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	Humanized anti-Abeta peptide IgG1 monoclonal antibody

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	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Alzheimer Disease

E.1.1.1

Medical condition in easily understood language

Alzheimer Disease

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	14.1
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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the safety and efficacy of multiple doses of intravenously (IV) administered bapineuzumab at 0.5 mg/kg compared with placebo in subjects with mild to moderate AD as measured by:
Primary: Change in total scores from baseline to week 78 in the Alzheimer’s Disease Assessment Scale– Cognitive Subscale 11-item score (ADAS-Cog/11) and the Disability Assessment for Dementia (DAD) (coprimary measures).

E.2.2

Secondary objectives of the trial

These Include:
Biomarker Objective
Divergence of effect Objective
Clinical and Health Outcomes Objective
Other

Please refer to section 10.3 of Protocol

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

Substudies are incorporated into the main protocol, and so do not have a separate title/date/version. Three substudies are included: a volumetric MRI substudy, a cerebrospinal fluid (CSF) substudy, and a PIB [Pittsburgh Compound] PET substudy.

Objectives:
To evaluate the effect of multiple doses of IV administered bapineuzumab compared with placebo on biomarkers that may be indicative of disease modification in subsets of subjects with mild to moderate AD.
• The change from baseline total tau or phospho-tau levels in the CSF to week 71 in a subset of subjects.
• The change from baseline brain boundary shift integral (BBSI) assessed by MRI to week 71 in a subset of subjects.
the change from screening WBV, VV and VBSI to week 71 as assessed by MRI
• The change from baseline brain amyloid burden to week 71 assessed by PIB PET imaging in a subset of subjects.

E.3

Principal inclusion criteria

1. Signed and dated written informed consent obtained from the subject or the subject’s legally acceptable representative (if applicable) in accordance with the local regulations.
The subject’s caregiver must also consent to participate in the study.
2. Man or surgically sterile or postmenopausal woman, aged ≥50 to <89 years.
3. Diagnosis of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria (Attachment 1).
4. MMSE score of 16 to 26, inclusive.
5. Rosen Modified Hachinski Ischemic Score ≤4.
6. Lives at home with appropriate caregiver capable of accompanying the subject on all clinic visits, or community dwelling with caregiver capable of accompanying the subject on all clinic visits and visiting with the subject approximately 5 times per week for the duration of the study.
7. Screening visit brain MRI scan consistent with the diagnosis of AD.
8. Fluency in local language and evidence of adequate premorbid intellectual functioning.
9. NOTE: With sponsor approval, subjects fluent in their native language may be included if appropriate staff at the intended site are also fluent in that language and if required study documents (e.g. rating assessments and informed consent form) are available in the native language of the subject.
10. Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.
11. Receiving stable doses of medication(s) for the treatment of nonexcluded medical condition(s) for at least 30 days prior to screening, and, if treated with cholinesterase inhibitors and/or memantine, all of the following conditions are also met:
a. The subject is maintained on a stable dose regimen for at least 120 days prior to screening.
b. The subject is free of any clinically important side effects attributable to the drug.
c. The subject and caregiver agree that, barring unforeseen circumstances, they will continue the same regimen for the duration of the trial.
12. The subject and caregiver are likely to be able to participate in all scheduled evaluations and complete all required tests.
13. Willing to undergo apolipoprotein E (ApoE) genotype testing.
14. Carrier of ApoE4 according to genotyping at screening (ie, has 1 or 2 copies of ApoE4).
15. In the opinion of the investigator, the subject and caregiver will be compliant and have a high probability of completing the study.

E.4

Principal exclusion criteria

1) Significant neurologic disease, other than AD, that may affect cognition.
2) History of or screening visit brain MRI scan indicative of any other significant abnormality, including but not limited to multiple microhemorrhages (two or more), evidence of a single prior hemorrhage >1 cm3, multiple lacunar infarcts or evidence of a single prior infarct >1 cm3, evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or space-occupying lesions (eg, arachnoid cysts or brain tumors, such as meningioma).
NOTE : the screening MRI scan shall be interpreted by the local and central radiologists prior to enrolling the subject. Both local and central interpretations shall be reviewed by the investigator for determination of subject eligibility relative to inclusion criteria # 7 and exclusion criteria # 2.
3) Current presence of a clinically important major psychiatric disorder (eg, major depressive disorder) according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) or symptom (eg, hallucinations, suicidal ideation/behaviour) that could affect the subject’s ability to complete the study or is a safety concern.
4) Current clinically important systemic illness that is likely to result in deterioration of the subject’s condition or affect the subject’s safety during the study.
5) History of clinically evident stroke or history of clinically important carotid or vertebrobasilar stenosis or plaque.
6) History of seizures, excluding febrile seizures in childhood.
7) Weight greater than 120 kg (264 lb).
8) History or evidence of any clinically important autoimmune disease or disorder of the immune system (eg, Crohn disease, rheumatoid arthritis).
9) Clinically important infection within the last 30 days (eg, chronic persistent or acute infection, such as bronchitis or urinary tract infection [UTI]).
10) Treatment with immunosuppressive medications (eg, systemic corticosteroids) within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last 3 years.
11) Myocardial infarction within the last 2 years.
12) History of cancer within the last 5 years, with the exception of nonmetastatic basal cell carcinoma, and squamous cell carcinoma of the skin.
13) Uncontrolled hypertension within 6 months prior to screening.
14) Other clinically important abnormality on vital signs, physical examination, neurologic examination, laboratory results, or electrocardiogram (ECG) examination (eg, atrial fibrillation) that could compromise the study or be detrimental to the subject.
15) Hemoglobin level less than 11 g/dL.

E.5 End points

E.5.1

Primary end point(s)

ADAS-Cog/11 total score and DAD.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline and weeks 13, 26, 39, 52, 65, 78

E.5.2

Secondary end point(s)

The change from baseline to week 71 in brain amyloid burden (average standard uptake value ratio [SUVr] in prespecified regions of interest [ROIs]) assessed by PIB PET imaging in a subset of subjects;
• The change from baseline to week 71 in phospho-tau levels in the CSF in a subset of subjects;
• The change from baseline to week 71 in brain volume, assessed by MRI BBSI in a subset of subjects.
• Divergence of effect on the ADAS-Cog/11 total scores from week 39 to week 78 between bapineuzumab and placebo;
• Divergence of effect on the DAD total scores from week 39 to week 78 between bapineuzumab and placebo.
• Time to median placebo deterioration on ADAS-Cog/11 total score
• Time to median placebo deterioration on DAD
• Change from baseline to Week 78 in the total Dependence Scale scores
• Please refer to Section 10.3.2 of the Protocol for Other Secondary Objectives

E.5.2.1

Timepoint(s) of evaluation of this end point

•PIB PET: Baseline, Weeks 45 and 71
• CSF: Baseline and week 71
• Volumetric MRI: Baseline, Weeks 6, 19, 32, 45, 58, and 71
• ADAS-Cog and DAD (for secondary endpoint): Weeks 39, 52, 65 and 78
• Time to median placebo deterioration on ADAS-Cog and DAD: Baseline and week 78
• Dependence scale: Baseline, Weeks 26, 52 and 78

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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

Yes

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

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

140

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Austria

Belgium

Chile

Croatia

Finland

France

Germany

Italy

Japan

Mexico

Netherlands

New Zealand

Poland

Portugal

Serbia

Slovakia

South Africa

Spain

Sweden

Switzerland

United Kingdom

United States

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

As per protocol

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