Clinical Trials Register

Summary
EudraCT Number:	2017-000569-61
Sponsor's Protocol Code Number:	CHUBX2016/27
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-10-30
Trial 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

France - ANSM

A.2

EudraCT number

2017-000569-61

A.3

Full title of the trial

Comparison of therapeutic strategies with Cholinesterase Inhibitors: stop or still (SOS) trial

A.3.1

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

Comparison of therapeutic strategies with Cholinesterase Inhibitors: stop or still (SOS) trial

A.3.2

Name or abbreviated title of the trial where available

SOSTrial

A.4.1

Sponsor's protocol code number

CHUBX2016/27

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	CHU de Bordeaux
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DGOS PHRC N 2016
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHU de Bordeaux
B.5.2	Functional name of contact point	Clinical Trials Manager
B.5.3	Address:
B.5.3.1	Street Address	12 rue Dubernat
B.5.3.2	Town/ city	Talence
B.5.3.3	Post code	33404
B.5.3.4	Country	France
B.5.4	Telephone number	33557821065
B.5.5	Fax number	33556794926
B.5.6	E-mail	christelle.turuban@chu-bordeaux.fr

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	Yes
D.2.1.1.1	Trade name	ARICEPT
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare France SAS
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Donepezil
D.3.2	Product code	Donepezil
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Buccal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DONEPEZIL
D.3.9.1	CAS number	340092662627
D.3.9.2	Current sponsor code	DONEPEZIL
D.3.9.4	EV Substance Code	SUB06362MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 10
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	Yes
D.2.1.1.1	Trade name	REMINYL
D.2.1.1.2	Name of the Marketing Authorisation holder	Arrow Génériques
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Galantamine
D.3.2	Product code	N06DA04
D.3.4	Pharmaceutical form	Prolonged-release capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Buccal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GALANTAMINE
D.3.9.1	CAS number	340092201180
D.3.9.2	Current sponsor code	GALANTAMINE
D.3.9.4	EV Substance Code	SUB06362MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	8 to 24
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: 3
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	Yes
D.2.1.1.1	Trade name	RIVASTIGMINE
D.2.1.1.2	Name of the Marketing Authorisation holder	Arrow Génériques
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Rivastigmine
D.3.2	Product code	N06DA03
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Buccal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RIVASTIGMINE
D.3.9.1	CAS number	340092685120
D.3.9.2	Current sponsor code	RIVASTIGMINE
D.3.9.4	EV Substance Code	SUB06362MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1,5 to 6
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Alzheimer disease

Maladie d'Alzheimer

E.1.1.1

Medical condition in easily understood language

Diagnosis of probable or possible AD, defined according to the NINCDS-ARDRA criteria
cMild to moderate stage, defined by a MMSE score above 15 at the time of pré-inclusion

Nouveau cas de Maladie d'Alzheimer
Diagnostic de MA probable ou possible définie selon les critères NINCDS-ARDRA

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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 compare two therapeutic strategies for the long-term risk (at 2 years) of dependency, institutionalization and death in mild to moderate AD patients who respond or do not respond to treatment after an initial 6-month period of CI treatment: continuation (still) or cessation (stop) of CI. This comparison will be performed separately for patients who respond to treatment and for those who do not respond to treatment at 6 months.

E.2.2

Secondary objectives of the trial

Secondary objectives:
1) To compare the same two therapeutic strategies on other outcomes: hospitalization rate, psychotropic drug consumption, MMSE score evolution, dependency to 5 basic activities of daily living (BADL), AGGIR scale, and separately on each criteria of the combined outcome (dependency, institutionalization and death).
2) To compare severe and cardiac adverse events between treatment arms.
3) To analyse the factors associated with initial response to CI at 6 months and with the long-term response at two years.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

ELIGIBILITY CRITERIA FOR THE OBSERVATIONAL PHASE: EVALUATED AT THE BEGINNING OF THE STUDY:
a) New case of AD referring to a CMRR or memory clinics.
b) Diagnosis of probable or possible AD, defined according to the NINCDS-ARDRA criteria
c) Mild to moderate stage, defined by a MMSE score equal or above 15 at the time of pre-inclusion
d) Patients with indication to CI treatment according to the 2011 HAS recommendations
e) Patients naïve to CI treatment
f) Patients aged 50 years or more
g) Menopause or effective contraception (for women)
h) Affiliated persons or beneficiary of a social security scheme
i) Patients agree to participate, with free, informed and written consent signed by the patient and his caregiver
ELIGIBILITY CRITERIA FOR THE RCT PHASE: EVALUATED AT 6 MONTHS:
Inclusion criteria for the RCT phase
a) Patients included in the observational phase of the SOS protocol
b) With an assessable 6-month response
c) Still under CI treatment at the time of randomization

E.4

Principal exclusion criteria

ELIGIBILITY CRITERIA FOR THE OBSERVATIONAL PHASE: EVALUATED AT THE BEGINNING OF THE STUDY
Non-inclusion criteria
a) Patients diagnosed with Lewy bodies disease, fronto-temporal dementia, or dementia from a cause other than Alzheimer Disease
b) More severe stage of the disease, defined by a MMSE below 15 at the time of pre-inclusion
c) Patients with contraindication to CI treatment
d) Patients residing in an institution at the time of pre-inclusion
e) Patients with a complete dependency for bathing and dressing at the time of pre-inclusion
f) Patients under tutorship or curatorship, patients unable to express consent
g) Patients with unstable severe general disease compromising the follow-up
h) Patients without caregiver
i) Patients included in another pharmacological trial
j) Pregnant or breastfeeding women
ELIGIBILITY CRITERIA FOR THE RCT PHASE: EVALUATED AT 6 MONTHS:
Non-inclusion criteria for the RCT phase
a) Patients with complete dependency for bathing and dressing at the time of randomization
b) Patients residing in an institution at the time of randomization

E.5 End points

E.5.1

Primary end point(s)

The primary outcome is a combination of complete BADL dependency in bathing and dressing and/or institutionalization or death at 2 years after randomization.

E.5.1.1

Timepoint(s) of evaluation of this end point

At 30 months ± 1 month after the inclusion visit ;

E.5.2

Secondary end point(s)

The secondary end points are :
- each of the components of the combined primary outcome analyzed separately,
- global BADL dependency on 5 items,
- AGGIR scale GIR 3,
- MMSE score evolution,
- number of hospitalizations,
- psychotropic drug consumption,
- severe and cardiac adverse events,
- response to CI after 6 months of treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

At 30 months ± 1 month after the inclusion visit ; At 3, 6, 12, 18, 24 months following the inclusion visit ;

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

nothing

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

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

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 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:

205

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1000

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

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.3.3.6.1

Details of subjects incapable of giving consent

women of child-bearing potential using effective contraception

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

1205

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)

The principal analysis will be performed according to the intent to treat principle. The binary primary outcome will be compared between randomization groups using a Chi² test or a Fisher's exact test, according to the size of the expected values under the hypothesis of independence. A logistic regression model will be used to adjust on stratification factors of the randomization and other major baseline factors. Assumption of the models will be systematically checked.

L’analyse principale sera faîte en intention de traiter. Le critère de jugement principal sera comparé entre les deux groupes de randomisation avec un test du Chi² ou un test exact de Fisher, selon la taille des valeurs théoriques sous l’hypothèse d’indépendance. Une régression logistique sera effectuée pour ajuster sur les facteurs de confusion. Les hypothèses d’application des modèles statistiques seront systématiquement vérifiées (log-linéarité des associations).

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

2021-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-01

P. End of Trial
P.	End of Trial Status	Ongoing

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