Clinical Trials Register

Summary
EudraCT Number:	2008-004012-13
Sponsor's Protocol Code Number:	WN22018
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:	2009-04-14
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

2008-004012-13

A.3

Full title of the trial

A dose ranging, randomized, double blind, parallel-group placebo-controlled multi-center study of RO5313534 used as add-on to donepezil treatment in patients with mild to moderate symptoms of Alzheimer s Disease.

Studio multicentrico, a dosaggio differenziato, randomizzato, in doppio cieco, a gruppi paralleli, controllato verso placebo di RO5313534 quale aggiunta al trattamento con donepezil in pazienti affetti da malattia di Alzheimer con sintomatologia da lieve a moderata.

A.4.1

Sponsor's protocol code number

WN22018

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	F.Hoffmann-La Roche Ltd - Pharmaceutical Division, PDR
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
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	NA
D.3.2	Product code	RO5313534/F02 (MEM3454)
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	OTHER NERVOUS SYSTEM DRUGS
D.3.9.1	CAS number	667305-02-1
D.3.9.2	Current sponsor code	RO5313534
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	1
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	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	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	NA
D.3.2	Product code	RO5313534/F03 (MEM3454)
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	OTHER NERVOUS SYSTEM DRUGS
D.3.9.1	CAS number	667305-02-1
D.3.9.2	Current sponsor code	RO5313534
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	5
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	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	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
D.8 Placebo: 2
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

Mild to moderate Alzheimer s Disease

Malattia di Alzheimer da lieve a moderata

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	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

The primary objective is to evaluate efficacy of 24 weeks treatment of 3 fixed doses of RO5313534 (1, 5 and 15 mg/day) added to donepezil (5 or 10 mg/day) on a cognitive endpoint (measured with the ADAS-Cog) as compared to placebo added to donepezil.

L obiettivo primario e` valutare l efficacia di 24 settimane di trattamento con 3 dosi fisse di RO5313534 (1, 5 e 15 mg/die) aggiunto a donepezil (5 o 10 mg/die) su un endpoint cognitivo (misurato mediante ADAS-Cog) rispetto a placebo aggiunto a donepezil.

E.2.2

Secondary objectives of the trial

1. To evaluate the tolerability and safety of 24 weeks treatment of the 3 fixed doses of RO5313534 (1, 5 and 15 mg/day) as adjunctive therapy of donepezil (5 or 10 mg/day). 2. To evaluate efficacy on behavioral, global and functional endpoints 3. To evaluate on cognitive endpoints measured with the cognitive battery CANTAB (The Cambridge Neuropsychological Test Automated Battery) 4. To evaluate maintenance of efficacy (primary and secondary variables) 4 weeks after discontinuation of treatment 5. To investigate by a population PK analysis approach the pharmacokinetics of RO5313534 in the target population, including the influence of covariates such as age, gender, body-weight and renal function. 6. To explore the relationship between PK exposure and response using population PK-PD methods. Et al.

1.Valutare la tollerabilita` e la sicurezza di 24 settimane di trattamento con 3 dosi fisse di RO5313534 (1,5 e 15 mg/die) come terapia aggiuntiva a donepezil (5 o 10 mg/die).2.Valutare l efficacia su endpoint comportamentali,globali e funzionali rispetto a placebo aggiunto a donepezil (misurata mediante Behave-AD-FW,ADCS-ADL,CGIC,ZARIT).3.Valutare endpoint cognitivi misurati mediante la batteria di test cognitivi CANTAB (Cambridge Neuropsychological Test Automated Battery) e MMSE rispetto a placebo aggiunto a donepezil.4.Valutare il mantenimento dell efficacia (variabili primarie e secondarie) 4 settimane dopo la fine del trattamento.5.Investigare tramite un approccio di analisi della PK di popolazione la farmacocinetica di RO5313534 nella popolazione target,includendo l influenza di covariate come eta`,sesso,peso corporeo e funzionalita` renale.6.Esplorare la relazione tra l esposizione PK e la risposta.Et al.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Probable AD, based on the NINCDS/ADRDA and DSM-IV criteria. 2. Males, females of non-childbearing potential: i.e. more than two years after the cessation of menses or surgically sterile by means of hysterectomy, bilateral oopherectomy or tubal ligation). Additional blood tests will be done if required by the local regulations/guidelines/EC/IRB for further confirmation of non-childbearing potential. 3. Age range: a minimum of 50 years of age at the time of screening visit. 4. Non smokers and not using nicotine-containing products for at least 3 months prior to baseline. 5. Have a MMSE score at screening between 13 and 22 inclusive. 6. Have a Modified Hachinski Ischemia Scale score of `‰¤ 4 (see Appendix 5) 7. Are under stable donepezil treatment given at a fixed dose either 5 or 10 mg daily for at least 4 months prior to baseline. 8. Adequate vision & hearing (physical ability to perform all the study assessments). 9. Not requiring nursing home care. 10. Have a caregiver or some other identified responsible person (e.g., family member, social worker, caseworker or nurse) who is considered reliable by the Investigator in providing support to the patient to ensure compliance with study treatment, accompany patient to study visits and help with protocol procedures, and who is also able and willing to provide input for completing the caregiver scales and sign the caregiver consent form. 11. Are cooperative, willing and able to complete all aspects of the study, and capable of doing so either alone or with the help of a responsible caregiver. Patients who make an effortful attempt to perform CANTAB at screening but are unable to complete all aspects may be considered eligible if other eligibility criteria are met. 12. Signed a written consent for participation in the study (cosigned by the patient s next of kin or caregiver, if required by the local regulations/guidelines/EC/IRB).

1. Probabile AD, in base ai criteri NINCDS/ADRDA e DSM-IV. 2. Maschi o femmine non in eta` fertile, cioe` piu` di 2 anni dopo la cessazione del ciclo mestruale o sterili in seguito a procedura chirurgica di isterectomia, ooferectomia bilaterale o legamento delle tube. Ulteriori analisi del sangue saranno eseguite se richiesto da normative locali/linee guida/Comitati etici per ulteriore conferma che le pazienti non siano fertili). 3. Eta`: minimo 50 anni al momento della visita di screening. 4. Non fumatori ne` utilizzatori di prodotti che contengono nicotina da almeno 3 mesi prima del basale. 5. Punteggio MMSE allo screening tra 13 e 22 incluso. 6. Punteggio `‰¤ 4 nella scala ischemica di Hachinski modificata (vedi Appendice 5). 7. Trattamento stabile con donepezil somministrato a una dose fissa giornaliera di 5 o10 mg da almeno 4 mesi prima del basale. 8. Vista e udito adeguati (capacita` fisica di effettuare tutti gli accertamenti di studio). 9. Assenza di dipendenza da cure infermieristiche domiciliari. 10. Presenza di un caregiver o di un altra persona responsabile identificata (es. familiare, assistente sociale, operatore socio-sanitario o infermiere) che sia considerata affidabile dallo sperimentatore nel fornire supporto al paziente per assicurare la compliance al trattamento di studio, accompagnare il paziente alle visite e aiutarlo con le procedure del protocollo, e che sia in grado e intenzionato a fornire indicazioni per compilare le scale di valutazione sottoposte al caregiver e firmare il consenso informato del caregiver. 11. Cooperativo, disposto a partecipare e in grado di completare tutti gli aspetti dello studio, e in grado di farlo sia da solo sia con l aiuto del caregiver responsabile. I pazienti che si impegnano nell eseguire i test con il CANTAB durante la visita di screening possono essere considerati arruolabili anche se incapaci di completare tutti i test purche` siano rispettati tutti gli altri criteri di inclusione. 12. Consenso informato firmato per la partecipazione allo studio (co-firmato dal familiare piu` stretto o caregiver del paziente, se richiesto da normative locali/linee guida/Comitato etico).

E.4

Principal exclusion criteria

CNS 1. Dementia due to condition other than AD; 2. Other significant neurological disorder, including current diagnosis of epilepsy, stroke (patients found with clinically silent lacunar stroke at MRI or CT may be allowed if the lesion is unique, less than or equal to 1 cm in maximal diameter and not located in any of the following regions:hippocampus of either hemisphere, head of the left caudate, dorsomedial region of the left thalamus), history of brain injury, Parkinson's disease; 3. Background of mental retardation; 4. Untreated/non stabilized Major Depressive Disorder (DSMIV); 5. Bipolar disorder, schizophrenia or any serious psychiatric condition (Axis I Disorder, DSM-IV-TR); 6. At risk of suicide in the opinion of the investigator; 7. Uncontrolled behavioral symptoms incompatible with compliance or evaluability: e.g. severe agitation, lack of impulse control, violence, severe dysphoria;8. Alcohol and/or substance abuse or dependence (DSM 'IV) in the past 2 years. Et al..

SNC 1.Demenza dovuta a condizioni differenti dall'AD; 2.Altri disordini neurologici significativi, inclusa la diagnosi di epilessia, colpo apoplettico (i pazienti con ictus lacunare silente confermato da RM o TAC possono essere ammessi se la lesione e` unica, con diametro massimo inferiore o uguale a 1 cm e non localizzata in nessuna delle seguenti regioni: ippocampo di entrambi gli emisferi, testa del nucleo caudato sinistro, regione dorso mediale del talamo sinistro), storia di lesioni cerebrali, morbo di Parkinson; 3.Background di ritardo mentale. 4.Disturbo depressivo maggiore non trattato/non stabilizzato (DSM-IV); 5.Disturbo bipolare, schizofrenia o qualsiasi condizione psichiatrica seria (disturbo d'Asse I, DSM-IV-TR); 6.A rischio di suicidio nell'opinione dello sperimentatore; 7.Sintomi comportamentali incontrollati incompatibili con la compliance o la valutabilita`: p. es. grave agitazione, perdita del controllo degli impulsi, violenza, disforia grave; 8.Abuso o dipendenza da alcol e/o sostanze (DSM 'IV) negli ultimi due anni. Et al..

E.5 End points

E.5.1

Primary end point(s)

ADAS-Cog score change from baseline at week 24

Variazione del punteggio ADAS-Cog dal basale alla settimana 24

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

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

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

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

La sperimentazione verra' considerata conclusa alla data dell'ultima visita - incluso il follow up - dell'ultimo paziente in studio

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

Number of subjects for this age range:

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.1.3

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Pazienti che necessitano del supporto del caregiver o altra persona responsabile per firmare l'ICF

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

180

F.4.2.2

In the whole clinical trial

360

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

2009-04-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-04-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2010-11-19

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