Clinical Trials Register

Summary
EudraCT Number:	2015-002715-15
Sponsor's Protocol Code Number:	CAPI015A2201J
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-04-11
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

Netherlands - Competent Authority

A.2

EudraCT number

2015-002715-15

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, two-cohort parallel group study to evaluate the efficacy of CAD106 and CNP520 in participants at risk for the onset of clinical symptoms of Alzheimer’s disease

A.3.1

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

To evaluate the efficacy of CAD106 and CNP520 in participants at risk for the onset of Alzheimer’s disease

A.4.1

Sponsor's protocol code number

CAPI015A2201J

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma Services AG
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Lichtstrasse 35
B.5.3.2	Town/ city	Bazel
B.5.3.3	Post code	4056
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4461324 1111
B.5.5	Fax number	+4461324 8001
B.5.6	E-mail	clinicaltrial.enquiries@novartis.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.3.2	Product code	CAD106
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	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not established
D.3.9.2	Current sponsor code	CAD106
D.3.9.3	Other descriptive name	QΒ VLP COUPLED VIA A CHEMICAL LINKER (SMPH) TO AΒ1-6 PEPTIDE
D.3.9.4	EV Substance Code	SUB180233
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)	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	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	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 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

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	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

- To assess the effects of CAD106 and CNP520, respectively, vs. placebo on Time-to-event, with event defined as a diagnosis of MCI due to AD or dementia due to AD, whichever occurs first during the course of the study.
- To assess the effects of CAD106 and CNP520, respectively, vs. placebo on cognition as measured by the change from Baseline to Month 60 in the APCC test score.

E.2.2

Secondary objectives of the trial

- To assess the effects of CAD106 / CNP520, respectively vs. placebo on global clinical status as measured by the change from Baseline to Month 60 in Clinical Dementia Rating Scale Sum of Boxes score.
- To assess the safety and tolerability of CAD106 / CNP520, respectively vs. placebo by measured AEs, changes in MRI, lab tests, vital signs, ECG, C-SSRS and injection-related reactions from Cohort I.
- To assess the effects of CAD106 / CNP520, respectively vs. placebo on cognition as measured by changes from Baseline to Month 60 on the Total Scale score and individual neurocognitive domain index scores of the RBANS.
- To assess the effects of CAD106 / CNP520, respectively vs. placebo on function as measured by the change from Baseline to Month 60 in the ECog total scores reported by the participant and study partner, respectively.
- To assess the effects of CAD106 / CNP520, respectively vs. placebo on AD-related biomarkers as measured by change from Baseline to Months 24 and 60.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Pre-screening Epoch and Genetic Disclosure Follow-up inclusion criteria:
1. Written informed consent (Informed consent #1) obtained before any assessment is performed, including consent to receive disclosure of their APOE genotype.
2. Male or female, age 60 to 75 years inclusive, before signing the prescreening informed consent.
a. When approximately 20% of the participants expected to be randomized are 60-64 years old, a restriction to this age group will apply.
3. Females must be considered post-menopausal and not of child bearing potential. Confirmation will be obtained for those who continue on to the Screening Epoch.
4. Fluency in, and ability to read, the language in which study assessments are administered.
5. Mini-Mental State Examination (MMSE) total score ≥24.
6. For those without prior genotype information, deemed capable of receiving their genotype information based on pre-disclosure rating scales, specifically:
a. Geriatric Depression Scale (GDS short form) total score <6.
If the score is between 6 and 10 (inclusive), the participant can only be included based on investigator’s judgment assessing in particular the scores of the questions:
i. Item 3: “Do you feel your life is empty?”
ii. Item 6: “Are you afraid that something bad is going to happen to you?”
iii. Item 12: “Do you feel pretty worthless the way you are now?”
iv. Item 14: “Do you feel your situation is hopeless?”
b. Six Item Subset Inventory of the STAI-AD total score <17.
If the score is between 17 and 19 (inclusive), the participant can only be included based on the investigator’s judgment.
7. Participant has evidence of adequate functioning (e.g. intellectual, visual and auditory) (e.g. completion of at least 6 years of regular schooling or sustained employment).
8. Participant’s willingness to have a study partner for the Screening and Treatment Epoch.
Screening and Treatment Epoch inclusion criteria:
Participants eligible for inclusion must fulfill all of the following criteria prior to randomization:
1. Written informed consent (Informed consent #2) for participation to the Screening and Treatment Epochs.
2. Continue to meet all eligibility criteria from Pre-screening Epoch and Genetic Disclosure Follow-up, as confirmed by the review of the medical records by the Investigator.
3. Homozygous APOE4 genotype.
4. Cognitively unimpaired as defined by:
- Score of 85 or greater on the RBANS delayed memory index score AND CDR global score of 0.
With two exceptions:
- If the RBANS delayed memory index score is between 70 and 84 (inclusive) AND the global CDR = 0, the participant may be allowed to continue ONLY if the Investigator judges that cognition is unimpaired following review of the MCI/dementia criteria.
- If the global CDR score = 0.5 AND the RBANS delayed memory index score is 85 or greater, the participant may be allowed to continue ONLY if the Investigator judges that cognition is unimpaired following review of the MCI/dementia criteria.
5. Females must be considered post-menopausal and not of child bearing potential, i.e. they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before the amyloid test.
- In the case of bilateral oophorectomy alone (without hysterectomy or tubal ligation), the reproductive status of the woman has to be confirmed by follow-up Follicle Stimulating Hormone level of >40 mIU/mL.

E.4

Principal exclusion criteria

Pre-screening Epoch and Genetic Disclosure Follow-up exclusion criteria:
1. Any disability that may prevent the participants from completing all study requirements.
2. Current medical or neurological condition that might impact cognition or performance on cognitive assessments e.g., MCI, dementia, Huntington’s disease, Parkinson’s disease, Lyme disease, schizophrenia, bipolar disorder, major depression, active seizure disorder, history of multiple traumatic brain injuries, alcohol/drug abuse or dependence currently, or dependence within the last two years.
3. Advanced, severe progressive or unstable disease that may interfere with the safety, tolerability and study assessments, or put the participant at special risk, e.g. active hepatitis, HIV infection, severe renal impairment, severe hepatic impairment, uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure.
4. History of malignancy of any organ system, treated or untreated, within the past 60 months, regardless of whether there is evidence of local recurrence or metastases. However, localized nonmalignant tumors not requiring systemic chemo- or radio-therapy, localized basal or squamous cell carcinoma of the skin, or in-situ cervical cancer are permitted.
5. History of hypersensitivity to any of the investigational drugs or their excipients/adjuvant, or to drugs of similar chemical classes.
6. Indication for or current treatment with ChEIs and/or another AD treatment.
7. Contraindication or intolerance to MRI or PET investigations.
Screening and Treatment Epoch exclusion criteria:
Participants fulfilling any of the following criteria prior to randomization will be excluded.
Participants, who fulfill one or more exclusion criteria due to a temporary condition, or the use of treatment requiring a specific time window prior to randomization, can be re-screened at a later stage:
1. Brain MRI results showing findings unrelated to AD that, in the opinion of the Investigator might be a leading cause of cognitive decline, might pose a risk to the participant, or might prevent a satisfactory MRI assessment for safety monitoring.
For Cohort I (CAD 106) only, in addition, evidence of ARIAH as demonstrated by:
- More than four cerebral microhemorrhages regardless of their anatomical location;
- Single area of superficial siderosis of the CNS or evidence of a prior cerebral macrohemorrhage.
2. Score “yes” on item four or item five of the Suicidal Ideation Section of the C-SSRS if this ideation occurred in the past six months, or “yes” on any item of the Suicidal Behavior Section, except for the “Non-Suicidal Self-Injurious Behavior” if this behavior occurred in the past two years prior to screening.
3. A positive drug screen at Screening, if, in the Investigator’s opinion, this is due to drug abuse. Participants with a positive drug screen not believed to be related to drug abuse, can be re-screened once.
4. Significantly abnormal laboratory results at Screening, meeting the exclusionary alert values specified in the Laboratory Manual. If, in the opinion of the Investigator, an abnormal finding is the result of a temporary condition, the laboratory test can be repeated once.
5. Current clinically significant ECG findings.
6. Use of other investigational drugs until:
- Blood concentration has returned to Baseline for biologics, e.g. monoclonal antibodies or antibodies induced by active immunotherapy; or
- Within 30 days or 5 half-lives, whichever is the longest for small molecules e.g. BACE-1 inhibitors.
7. Treatment with warfarin or other coumarin derivatives, or with a combination of acetylsalicylic acid and an anti-platelet agent within seven days prior to randomization.
8. Treatment in the four weeks prior to randomization with any drug or treatment known for their potential to cause major organ system toxicity, i.e. drugs that may require monitoring of a specific organ.
9. Violations of concomitant medication restrictions as described in Table 5-3.
10. Donation or loss of 400 mL or more of blood within 8 weeks prior to randomization.
11. Previous or planned Nuclear Medicine Radiology exposure that will exceed the dosimetry acceptable exposure in the country, when adding the scheduled study PET scans.
Exclusion criteria for participation in the biomarker CSF sampling:
12. Contraindication to lumbar puncture, e.g. low platelet count, abnormal prothrombin time international normalized ratio, history of back surgery, signs or symptoms of intracranial pressure, spinal deformities or other spinal conditions that in the judgment of the Investigator would preclude a lumbar puncture.
No additional exclusions may be applied by the Investigator in order to ensure that the study population will be representative of all eligible participants.

E.5 End points

E.5.1

Primary end point(s)

- Time-to-event (MCI or dementia due to AD) measured by the MCI/dementia criteria check list that includes measurements of cognitive function (RBANS, MMSE), function/cognition (CDR-SOB), daily function and subjective/observer memory concerns (ECog), plus Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale, and safety MRI.
- API Preclinical Composite Cognitive Battery (APCC) derived from tests performed as part of the cognitive scales (MMSE, RBANS, and a subset of Raven’s Progressive Matrices) administered during the study.

E.5.1.1

Timepoint(s) of evaluation of this end point

- Baseline to Month 60.
- Baseline to Month 60.

E.5.2

Secondary end point(s)

- Global clinical status as measured by the change in Clinical Dementia Rating Scale Sum of Boxes score.

E.5.2.1

Timepoint(s) of evaluation of this end point

- Baseline to Month 60.

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

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

Australia

Belgium

Canada

Finland

France

Germany

Italy

Netherlands

Spain

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

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:

268

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1072

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

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Participants at risk for the onset of clinical symptoms of AD based on their APOE4 HM genotype

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

835

F.4.2.2

In the whole clinical trial

1340

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)

None

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

2016-04-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-04-30

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