Clinical Trials Register

Summary
EudraCT Number:	2009-012394-35
Sponsor's Protocol Code Number:	CAD106A2203
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-02-17
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2009-012394-35

A.3

Full title of the trial

A 90-week, multi-center, randomized, double-blind, placebo-controlled study in patients with mild Alzheimer s Disease (AD) to investigate the safety, tolerability and Abeta-specific antibody response following repeated i.m. injections of adjuvanted CAD106

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

CAD106A2203

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	NOVARTIS FARMA
B.1.3.4	Country	Italy
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Not available yet
D.3.2	Product code	CAD106A
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	CAD106A
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	450
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Mild Alzheimer s Disease (AD)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	12.1
E.1.2	Level	LLT
E.1.2	Classification code	10001896
E.1.2	Term	Alzheimer's disease

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 assess the safety and tolerability of up to 7 repeated injections of CAD106 with Alum or MF59 in patients with mild Alzheimer s Disease (AD) over 90 weeks. To compare the immunogenicity of CAD106 with Alum vs MF59 after up to 7 injections in patients with mild Alzheimer s Disease (AD) as measured by the titers of Aβ-specific IgG in serum across regimens and in reference to non-adjuvanted CAD106.

E.2.2

Secondary objectives of the trial

To characterize the Aβ- and Qβ-specific antibody response to CAD106 (with Alum or MF59) in serum and CSF, e.g. by measuring Aβ-specific IgMs and Qβ-specific IgGs in serum, and markers of the quality of the immune response. To characterize Aβ-specific and Qβ-specific T-cell response to CAD106 (with Alum or MF59) using PBMCs. To evaluate changes over time of the concentrations of disease related markers (Aβ1-40 and Aβ1-42 in plasma; Aβ1-40, Aβ1-42, total-tau, phospho-tau in CSF, or other markers) in patients with mild AD receiving CAD106 (with Alum or MF59) compared to placebo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients have to meet all of the following criteria at Screening to enter into the study: 1. Written informed consent obtained before any assessment is performed according to local requirements for obtaining consent in mild AD patients (see Section 10.2). 2. Male and female patients below the age of 85 years. 3. Female patients must be without childbearing potential (post-menopausal or surgically sterilized). If sterilized, female patients must have been surgically sterilized at least 6 months prior to screening. Surgical sterilization procedures must be supported with clinical documentation made available to the Novartis Monitor and noted in the Relevant Medical History / Current Medical Conditions section of the eCRF. OR: Postmenopausal women must have no regular menstrual bleeding for at least 1 year prior to inclusion as documented in the patient s records. 4. Diagnosis of dementia of the Alzheimer s type according to the DSM-IV criteria (Diagnostic and Statistical Manual of Mental Disorders, 4th edition). 5. Patients who satisfy the criteria for a clinical diagnosis of probable AD established by a Work Group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer s Disease and Related Disorders Association (NINCDSADRDA). 6. Mild AD as confirmed by a MMSE score of 20 to 26 (both inclusive) at screening, and either untreated or on stable dose of cholinesterase inhibitor and/or other AD treatment over the last 4 weeks prior to the clinical assessments. 7. Sufficient education to have been able to read, write, and communicate effectively during the pre-morbid state (e.g. completion of at least 6 years of regular schooling or sustained employment). 8. Cooperative, willing to complete all aspects and attend all visits of the study including lumbar puncture/CSF samplings (primarily for safety reasons), and capable of doing so, either alone or with the aid of a responsible caregiver. 9. Residing with someone in the community throughout the study or, if living alone, who have daily contact with a primary caregiver. 10. Primary caregiver is present and willing to assent in writing to taking the responsibility for assessing the condition of the patient throughout the study, and for providing input to safety and tolerability assessments in accordance with all protocol requirements.

E.4

Principal exclusion criteria

Patients meeting any of the following criteria during Screening or Baseline evaluations (i.e. prior to the time of randomization) will be excluded from randomization into the study: NB. In case of assessments repeated during the Screening period the latest measurements will qualify for the criteria below. Exclusion criteria related to CNS 1. Any medical or neurological condition, other than AD, that contributes significantly to the patient s dementia (e.g., abnormal thyroid function tests, Vitamin B12 or folate deficiency, post-traumatic conditions, Huntington s disease, Parkinson s disease, Lyme s disease, syphilis, HIV dementia), including any CSF and/or brain MRI findings at screening. 2. History in the past two years or current diagnosis of CNS inflammation as indicated by: either MRI findings indicative of meningoencephalitis or another concurrent disease (according to central reader evaluation at screening and clinical judgment); or signs of inflammation in CSF as defined by clinical judgment. In most cases, in a CSF sample not contaminated by blood, this will be shown by >5 leukocytes/μl. 3. Evidence of vascular dementia or other cerebrovascular disease, assessed by investigator and/or MRI central reader, defined as any of the following: one or more large infarct (> 2 cm) or two or more lacunar infarcts (< 2 cm); or confluent white matter lesions, considered likely to contribute to patients dementia; or intracranial aneurysms or hemorrhages, except for up to two cerebral microhemorrhages, defined as a focal T2* hypointensity < 1 cm; or NB. If a MR machine with field strength > 1.5 T is used, higher number of microhemorrhages will be acceptable as defined by the MRI central reader. Hachinski score of > 4 at screening, or any transitory ischemic attack or unexplained loss of consciousness in the past year. 4. Current DSM-IV diagnosis of major depression and/or any other DSM-IV Axis 1 diagnosis that may interfere with the evaluation of the patient s response to study medication, including other primary neurodegenerative dementia, schizophrenia, or bipolar disorder. 5. History or current diagnosis of seizure disorder. Exclusion criteria related to other medical conditions 6. Any advanced, severe, progressive, or unstable disease that may interfere with the safety, tolerability and pharmacodynamic assessments and/or with the antibody titer response in the study or put the patient at special risk (e.g. indication for anticoagulant therapies, Hepatitis B or C, HIV). 7. History or current diagnosis of an active autoimmune disease (e.g. psoriasis, rheumatoid arthritis, Crohn s disease, systemic lupus erythematosus, Type I diabetes mellitus, Hashimoto tyroiditis). 8. Evidence of systemic inflammation as shown by e.g. an elevated CRP above normal range at Screening or fever (i.e. axillary body temperature ≥ 38C (100.4 F)) before dosing on the day of 1st injection, as measured at the site). (NB. In case of positive findings at Screening which are considered to be due to a known transient condition (e.g. common cold, urinary tract infection), the randomization can be postponed until findings have normalized.) 9. Coronary heart disease as shown by: history of myocardial infarction or coronary stent placement within the last year, or current diagnosis of unstable angina pectoris or atherosclerotic coronary artery disease of clinical significance. 10. Symptomatic heart failure fulfilling the criteria of New York Heart Association (NYHA) Category > II or known left ventricular dysfunction with left ventricular ejection fraction <45%, or any other severe or unstable cardiovascular disease. 11. Vital signs outside of the following ranges at screening and baseline evaluations (as measured after at least 3 minutes resting in the supine position): PLS SEE PROTOCOL

E.5 End points

E.5.1

Primary end point(s)

The first primary objective of the study is the assessment of safety and tolerability of CAD106 with Alum or MF59.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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)

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

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

Yes

E.8.2.3.1

Comparator description

- same IMP used at different dosage

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	No
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	No
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	25
F.4.2	For a multinational trial
F.4.2.1	In the EEA	90
F.4.2.2	In the whole clinical trial	120

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

2010-02-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-01-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-12-18

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