Clinical Trials Register

Summary
EudraCT Number:	2016-002976-28
Sponsor's Protocol Code Number:	CCNP520A2202J
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-05-25
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

2016-002976-28

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of CNP520 in participants at risk for the onset of clinical symptoms of Alzheimer's Disease (AD)

Studio randomizzato, in doppio-cieco, controllato con placebo, a gruppi paralleli, per valutare l’efficacia e la sicurezza di CNP520 in soggetti a rischio di insorgenza dei sintomi clinici della malattia di Alzheimer

A.3.1

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

To evaluate the efficacy and safety of CNP520 in participants at risk for the onset of clinical symptoms of Alzheimer's Disease (AD)

Studio di efficacia e sicurezza di CNP520 in confronto a placebo in soggetti a rischio di insorgenza dei sintomi clinici della malattia di Alzheimer.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

CCNP520A2202J

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 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 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 Farma S.P.A.
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1 -
B.5.3.2	Town/ city	Origgio (VA) -
B.5.3.3	Post code	21040
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390296541
B.5.5	Fax number	0039029659066
B.5.6	E-mail	info.studiclinici@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.3.1	Product name	CNP520 50 mg
D.3.2	Product code	[CNP520]
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CNP520
D.3.9.2	Current sponsor code	CNP520
D.3.9.4	EV Substance Code	SUB166276
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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.IMP: 2
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	CNP520 15 mg
D.3.2	Product code	[CNP520]
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CNP520
D.3.9.2	Current sponsor code	CNP520
D.3.9.4	EV Substance Code	SUB166276
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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	Capsule, hard
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	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 demonstrate the effect of CNP520 vs placebo on time to diagnosis of MCI due to AD or dementia due to AD, whichever occurs first during the course of the study.
- To demonstrate the effect of CNP520 vs placebo on cognition using APCC.

E.2.2

Secondary objectives of the trial

Key secondary objective:
- To demonstrate the effects of CNP520 vs placebo on global clinical status.
Secondary objectives:
- To demonstrate the safety and tolerability of CNP520 vs placebo.
- To demonstrate the effects of CNP520 vs placebo on cognition using Repeatable Battery for the Assessment of Neuropsychological Status
(RBANS).
- To demonstrate the effects of CNP520 vs placebo on function.
- To demonstrate the effects of CNP520 vs placebo on Magnetic Resonance Imaging (MRI) measures suggestive of cerebral amyloid angiopathy (CAA).
- To demonstrate the effects of CNP520 vs placebo on brain atrophy.
- To demonstrate the effects of CNP520 vs placebo on AD-related biomarkers.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Screening part I: Participants eligible for inclusion must fulfill all of the following criteria prior to scheduling the genetic disclosure.
1. Written informed consent must be obtained before any assessment is performed as part of the study, including consent to receive disclosure of their risk estimates to develop clinical symptoms of AD based on their APOE genotype and, if HTs, with evidence of elevated brain amyloid.
2. Male or female, age 60-75 years inclusive, at the time of signing the informed consent. To ensure that no more than 20% of participants in the age group 60-64 years are randomized across the whole recruitment period, a site level process will be implemented.
3. 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. history of vasomotor symptoms), or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation.
4. Intellectually, visually and auditorily capable, fluent in, and able to read, the language in which study assessments are administered (e.g. completion of at least 6 years of regular schooling or sustained employment or equivalent local level of knowledge).
5. Mini-Mental State Examination total score =24.
6. Willing to have a study partner throughout the study. Screening part II: Participants eligible for inclusion must fulfill all of the following criteria prior to randomization based on the results from the screening test procedures.
7. Carrier of at least one e4 allele of the APOE gene: HMs with elevated or not elevated brain amyloid OR HTs with elevated brain amyloid (as measured in CSF collected via lumbar puncture or by amyloid PET imaging).
Note: In cases where both lumbar puncture (CSF) amyloid and amyloid PET imaging tests are performed, at least one should be indicative of elevated brain amyloid.
8. Cognitively unimpaired at screening visit as defined by: Score of 85 or greater on the RBANS delayed memory index score AND CDR global score of 0 with two special exceptions: a) 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; b) 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.
9. Having a study partner who agrees to participate in the study and who is intellectually, visually, and auditorily capable, and fluent in, and able to read, the language in which study assessments are administered. Additionally, the study partner must be capable of and willing to: a) Accompany the participant to visits that requires the input of the study partner; b) Meet the definition of a "study partner".
Other protocol defined inclusion criteria may apply.

E.4

Principal exclusion criteria

Screening part I: Participants will be excluded if they fulfill any of the following criteria prior to scheduling the genetic disclosure.
1. Current medical or neurological condition that might impact cognition or performance on cognitive assessments e.g. MCI, dementia, Huntington's or Parkinson's disease etc.
2. 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 etc.
3. 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, in-situ cervical cancer are
permitted. 4. Current treatment with Cholinesterase Inhibitors and/or another AD treatment.
5. Clinically relevant depigmenting or hypopigmenting conditions or active/history of chronic urticaria in the past year.
6. Score "yes" on item 4 or 5 of the Suicidal Ideation section of the eCSSRS patient-reported outcome, if this ideation occurred in the past 6 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 2 years prior to screening.
7. Lacking psychological readiness to receive APOE genotype/amyloid status results, as assessed based on investigator's judgement supported by the pre-disclosure rating scales: Geriatric Depression Scale total score >6; Six Item Subset Inventory of the modified State Trait Anxiety Inventory total score >17.
8. Use of other investigational drugs prior to screening until: Small molecules: after 5 half-lives, or within 30 days until the expected pharmacodynamic effect has returned to baseline, whichever is longer; Biologicals: blood concentration has returned to baseline (or below serological responder threshold) for antibodies induced by active immunotherapy; or 5 half-lives for monoclonal antibodies or other biologicals.
9. Treatment a) in the 4 weeks prior to randomization with any drug or treatment known for the potential to cause major organ system toxicity i.e. drugs that may require periodic safety monitoring of a specific organ or body fluid.
b) in the 4 weeks prior to randomization and/or current treatment with any CNS active drugs with the exceptions.
10. Current chronic treatment (>3 months) with: Strong CYP3A4 inducers or inhibitors; Drugs with a narrow therapeutic index known to be primarily metabolized by CYP2C or CYP3A isoenzymes and sensitive P-gp substrates.
11. Violations of concomitant medication restrictions.
12. Donation or loss of 400 mL or more of blood within 8 weeks prior to screening blood sampling and/or lumbar puncture if applicable.
13. Contraindication or intolerance to MRI investigations. Screening part II: Participants fulfilling any of the following criteria based on results from the screening test procedures will be excluded.
14. A positive drug screen, 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.
15. Previous participation in a CNP520 study with >3-month exposure to active treatment.
16. 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.
17. Current significant ECG findings from central reader that are assessed as clinically significant by the investigator. QTc interval >500 ms is exclusionary.
Other protocol defined exclusion criteria may apply.

E.5 End points

E.5.1

Primary end point(s)

- Time to the first event with event defined as the first confirmed diagnosis of MCI due to AD or dementia due to AD.
- Change from baseline to month 60 in APCC score.

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)

- Change from baseline to month 60 in Clinical Dementia Rating Scale - Sum of Boxes (CDRSOB) score.
- Frequencies, changes from baseline, Kaplan-Meyer estimates when applicable of: Adverse events; Skin events based on a centralized dermatological monitoring; Safety findings from brain structural MRI central reader; Laboratory tests; Vital signs; ECG findings; Prospective suicidality assessment (ideation and behavior) from eC-SSRS.
- Change from baseline to month 60 in total RBANS score and individual neurocognitive domain index scores.
- Change from baseline to month 60 in total score of the Everyday Cognitive (ECog) scale: ECogsubject and ECog- informant.

E.5.2.1

Timepoint(s) of evaluation of this end point

- Baseline to month 60.
- Baseline to month 60.
- Baseline to month 60.
- 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

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

Yes

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

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

Australia

Canada

Chile

China

Israel

Japan

Korea, Democratic People's Republic of

Mexico

Singapore

South Africa

Taiwan

United States

Belgium

Finland

France

Germany

Italy

Netherlands

Portugal

Spain

Sweden

United Kingdom

Argentina

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

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.1.1.1

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:

400

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1600

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

Yes

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

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

708

F.4.2.2

In the whole clinical trial

2000

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)

Upon study completion (assuming futility was not met), participants may have the opportunity to enter an extension under a separate study, if eligible.

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

2017-11-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-04

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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