Clinical Trials Register

Summary
EudraCT Number:	2008-002226-11
Sponsor's Protocol Code Number:	SIMaMCI
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-09-03
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

Germany - BfArM

A.2

EudraCT number

2008-002226-11

A.3

Full title of the trial

Randomized Controlled Trial of Simvastatin in Amnestic MCI Patients

A.3.1

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

SIMaMCI: Prevention of Alzheimer´s dementia by administration of simvastatin

A.4.1

Sponsor's protocol code number

SIMaMCI

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	Charité - Unversitätsmedizin Berlin
B.1.3.4	Country	Germany
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	Bundesministerium für Bildung und Forschung
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Charité - Unversitätsmedizin Berlin
B.5.2	Functional name of contact point	Klinik für Psychiatrie
B.5.3	Address:
B.5.3.1	Street Address	Hindenburgdamm 30
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	12203
B.5.3.4	Country	Germany
B.5.5	Fax number	0049030450517942

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	SimvaHexal
D.2.1.1.2	Name of the Marketing Authorisation holder	Hexal AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Simvastatin
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	Simvastatin
D.3.9.1	CAS number	79902-63-9
D.3.9.2	Current sponsor code	Simvastatin
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	60
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	Comparator
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	Simvahexal
D.2.1.1.2	Name of the Marketing Authorisation holder	Hexal AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Simvastatin
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.3.11 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Amnestic mild cognitive impairment (MCI) denotes clinical conditions in the border zone between normal cognitive functioning and dementia. The definition of amnestic MCI by Petersen and his co-workers is an attempt to focus on those MCI patients who are at greatest risk to develop Alzheimer´s disease. There has to be subjective and objective memory impairment, but general cognitive function and activities of daily living must be essentially intact.

E.1.1.1

Medical condition in easily understood language

Mild impairment of Memory-functioning, without significant impact on functioning in the activities of daily living.

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

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

Simvastatin significantly reduces the conversion rate to Alzheimer’s dementia in probands with MCI as compared to MCI receiving placebo

E.2.2

Secondary objectives of the trial

1) The benefit from simvastatin treatment is larger in probands with a low level of β-amyloid (Aβ42 530ng/l; Aβ40 5612 ng/l) / increased level of Tau (t-Tau 350 ng/l; p-Tau 60 ng/l) in CSF as compared to patients above/below the respective cut-off values.
(2)The benefit from simvastatin treatment is larger in APO-E4 allele carriers than in other APO-E allele individuals

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

(1) Self and informant report of gradually increasing memory impairment for at least six months.
(2) Objective memory impairment
(3) Intact basic activities of daily living
(4) Preserved general cognitive function, not demented
(5) Absence of a detectable cause of memory disorder
(6) Age 55 to 85.
(7) Females without childbearing potential
(8) A total cholesterol ≥90 mg/dl
(9) LDL-cholesterol < 130 mg/dl. LDL-cholesterol 130-160 mg/dl ≤ 3 risk factors including age or 160-190 mg/dl and ≤2 risk factors (only controlled hypertension and age);
(10) Informed consent (according AMG §40 (1) 3b)
(11) No participation in other clinical trials 2 months before and after participation in this study

E.4

Principal exclusion criteria

(1) Hypersensitivity against Simvastatin, active liver disease or lasting increase of serum transaminases for unclear reason
(2) Unstable medical, neurological or psychiatric disease
(3) Lack of a spouse or a close relative
(4) Use of a registered anti-dementia drug or a nootropic
(5) Chronic use of anti-inflammatory drugs
(6) History of stroke or myocardial infarction
(7) LDL-cholesterol 130-160 mg/dl and > 3 risk factors or 160-190 mg/dl and > 2 risk factors including age. LDL-cholesterol >190 mg/dl
(8) Comedication with Diltiazem, Verapamil, Amiodaron, Itraconazol, Ketokonazol, Erythromycin, Clarithromycin, Telithromycin, Ciclosporin, Gemfibrozil, Nefazodon, HIV-protease inhibitors, benzodiazepines, tricyclic antipsychotics or other anticholinergic drugs; co-medication of statins in high doses; low doses equivalent to 20 mg Simvastatin are allowed if taken for max. 2 years before randomization
(9) Persons who are detained officially or legally to an official institute

E.5 End points

E.5.1

Primary end point(s)

Prevention of conversion to Alzheimer’s dementia in probands with amnestic MCI by administration of simvastatin. Primary efficacy endpoint: Change in CDR-SOB at 24 months of Treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months

E.5.2

Secondary end point(s)

1) Change in ADAS-Cog and FCSRT score
2) Length of conversion-free Intervall, starting at the time of randomization, with conversion being defined as an increase of the CDR-Score beyond 0.5
3) Change in ADCS-ADL score
4) Change in volumetric brain measures (structural MRI)
5) Change in CSF and blood measures of beta-amyloid peptides, total and phosphorylized TAU Proteins and measures of cerebral cholesterol metabolites
6) Impact on cost efficacy Ratio (ICER)
7) Pharmacogenetic prediction parameters

E.5.2.1

Timepoint(s) of evaluation of this end point

Time to AD conversion will be tested by means of a log-rank test for differences between two survival functions.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

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

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)

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

Yes

E.8.2.3.1

Comparator description

20 mg Simvastatin

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

The individual trial duration depends on the cognitive status of the proband, and in particular on the time until conversion to AD. The Maximum follow-up time for non-converting probands will be four years. The participation is no longer possible when dementia (CDR = 1) is diagnosed.

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

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:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

370

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

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

520

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)

Subjects will be followed up by the memory clinics in which they have been recruited for the study. There are no fixed plans for treatment of subjects still fulfilling the criteria of MCI at the end of the trial. Subjetcs fulfilling the criteria for dementia will receive standard treatment from the time of conversion onwards.

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

2008-10-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-10-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-10-23

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