Clinical Trials Register

Summary
EudraCT Number:	2010-019858-41
Sponsor's Protocol Code Number:	CR100101/CO15570
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2010-09-30
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

Germany - BfArM

A.2

EudraCT number

2010-019858-41

A.3

Full title of the trial

A 6-month prospective, multi-center, double-blind, placebo-controlled, randomized, adaptive-trial-design study to evaluate the safety and efficacy of 80mg b.i.d. ladostigil in patients with mild to moderate probable Alzheimer’s Disease with a 6-month open label follow-up period

A.3.1

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

Efficacy of Ladostigil to treat Patients with Mild to Moderate Alzheimer's Disease

A.3.2

Name or abbreviated title of the trial where available

CR100101/CO15570

A.4.1

Sponsor's protocol code number

CR100101/CO15570

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	Avraham Pharmaceuticals Ltd.
B.1.3.4	Country	Israel
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	Avraham Pharmaceuticals Ltd.
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Avraham Pharmaceuticals Ltd.
B.5.2	Functional name of contact point	Vice President of Clin Development
B.5.3	Address:
B.5.3.1	Street Address	42 Hayarkon Street
B.5.3.2	Town/ city	Yavneh
B.5.3.3	Post code	81227
B.5.3.4	Country	Israel
B.5.4	Telephone number	0097289324000
B.5.5	Fax number	0097289324001
B.5.6	E-mail	yg@avphar.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	Ladostigil hemitartrate
D.3.2	Product code	Ladostigil hemitartrate
D.3.4	Pharmaceutical form	Capsule
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	Ladostigil
D.3.9.1	CAS number	209394-46-7
D.3.9.2	Current sponsor code	Ladostigil hemitartrate
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	40
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	Ladostigil hemitartrate
D.3.2	Product code	Ladostigil hemitartrate
D.3.4	Pharmaceutical form	Capsule
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	Ladostigil
D.3.9.1	CAS number	209394-46-7
D.3.9.2	Current sponsor code	Ladostigil hemitartrate
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: 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	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	Ladostigil hemitartrate
D.3.2	Product code	Ladostigil hemitartrate
D.3.4	Pharmaceutical form	Capsule
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	Ladostigil
D.3.9.1	CAS number	209394-46-7
D.3.9.2	Current sponsor code	Ladostigil hemitartrate
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	80
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
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

Patient with mild to moderate Alzheimer's Disease

E.1.1.1

Medical condition in easily understood language

Patient with mild to moderate Alzheimer's Disease

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

To evaluate the efficacy of ladostigil (80mg b.i.d) administered for 26 weeks versus matched placebo and the safety of ladostigil (80mg b.i.d) following administration for up to 52 weeks
- Alzheimer’s Disease Assessment Scale-Cognitive Subscale (Unmodified, 11 Item, total score = 70): (ADAS-Cog)
- Safety evaluation: 26-week and 52-week assessment of safety and tolerability of ladostigil dosing.

E.2.2

Secondary objectives of the trial

Secondary objective:
To evaluate additional efficacy metrics of ladostigil (80mg b.i.d) administered for 26 weeks versus matched placebo
- Neuropsychiatric Inventory (NPI)
- Cornell Scale for Depression in Dementia (CSDD)
- AD Cooperative Study - Activities of Daily Living (ADCS-ADL)
- Mini-Mental State Evaluation (MMSE)

Exploratory objective:
To evaluate the efficacy of ladostigil (80mg b.i.d) following 26 versus 52 weeks administration according to following metrics:

- Alzheimer’s Disease Assessment Scale-Cognitive Subscale (Unmodified, 11 Item, total score = 70): (ADAS-Cog)
- Neuropsychiatric Inventory (NPI)
- Cornell Scale for Depression in Dementia (CSDD)
- AD Cooperative Study - Activities of Daily Living (ADCS-ADL)
- Mini-Mental State Evaluation (MMSE)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Men and women (non-childbearing potential) with a diagnosis of Alzheimer’s disease according to the NINCDS-ADRDA clinical criteria.
2.Age 60 - 85 years.
3.MRI or CT assessment within six months before baseline, corroborating the clinical diagnosis and excluding other potential causes of dementia, especially cerebrovascular lesions (see exclusion criteria, number 3).
4.Mild to moderate stage of Alzheimer’s disease according to MMSE 14 - 24 inclusive.
5.Absence of major depressive disease according to CSDD of ≤18.
6.Modified Hachinski Ischemic Scale equal to or below 4.
7.Education for eight or more years.
8.Previous decline in cognition for more than six months as documented in patient medical records.
9.A caregiver available and living in the same household or interacting with the patient at least four times each week and available if necessary to assure administration of drug.
10.Patients living at home or nursing home setting without continuous nursing care.
11.General health status acceptable for a participation in a 12-month clinical trial.
12.Ability to swallow capsules.
13.No history of treatment with rivastigmine (Exelon®).
14.For patients with either donepezil (Aricept®) or galantamine (Razadyne®) anti-cholinesterase inhibitor treatment prescribed, stopped treatment four weeks prior to screening (Visit 1).
15.For patients with memantine (Namenda®) treatment prescribed, stopped treatment four weeks prior to screening (Visit 1).
16.Stable pharmacological treatment of any other chronic condition for at least one month prior to screening.
17.No regular intake of medications acting on central nervous system except as noted in Section 9.1.20
18.Signed informed consent by caregiver and patient prior to the initiation of any study specific procedure.

E.4

Principal exclusion criteria

1.Failure to perform screening or baseline examinations.
2.Hospitalization or change of chronic concomitant medication one month prior to screening or during screening period.
3.Clinical, laboratory or neuro-imaging findings consistent with:
•Other primary degenerative dementia, (dementia with Lewy bodies, fronto-temporal dementia, Huntington’s disease, Jacob-Creutzfeld Disease, Down’s syndrome, etc.)
•Other neurodegenerative condition (Parkinson’s disease, amyotrophic lateral sclerosis, etc.)
•Cerebrovascular disease (major infarct, one strategic or multiple lacunar infarcts, extensive white matter lesions > one quarter of the total white matter)
•Other central nervous system diseases (severe head trauma, tumours, subdural haematoma or other space occupying processes, etc.)
•Seizure disorder
•Other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc.)
4.A current DSM-IV diagnosis of active major depression, schizophrenia or bipolar disorder.
5.Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations, and which may bias the assessment of the clinical or mental status of the patient or put the patient at special risk, such as:
•chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency (ALT, AST, Gamma GT, alkaline phosphatase > 2.5 ULN)
•Respiratory insufficiency, moderate/severe chronic obstructive lung diseases (moderate/severe COPD)
•Renal insufficiency (serum creatinine >2mg/dl) or creatinine clearance ≤ 45 mL/min according to Cockgroft-Gault formula). In case of creatinine clearance ≤45mL/min, an alternative verification of the renal function must be completed using Cystatin C analysis. In case of normal level of Cystatin C the patient can be included.
•Heart disease (myocardial infarction, unstable angina, heart failure, Cardiomyopathy within six months before screening)
•Bradycardia (heart beat <50/min.) or tachycardia (heart beat >95/min.)
•Hypertension or hypotension requiring treatment with more than three drugs
•AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males >450 and females >470msec)
•Uncontrolled diabetes defined by HbA1c >8.5
•Malignant tumours within the last five years except skin malignancies (other than melanoma) or indolent prostate cancer
•Metastases
6.Disability that may prevent the subject from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc.)
7.Women who are fertile and of child bearing potential.
8.Chronic daily drug intake of ≥ 14 days or expected for ≥ 14 days:
•benzodiazepines, neuroleptics or major sedatives
•Antiepileptics
•Nootropics (including Ginkgo)
•Centrally active anti-hypertensive drugs (clonidine, l-methyl dopa, guanidine, guanfacine, etc.)
•Opioid containing analgesics
•Non-steroidal anti-inflammatory agents, cortico-steroids or immunosuppressants
9.Suspected or known drug or alcohol abuse, i.e. more than approximately 60 g alcohol (approximately 1 liter of beer or 0.5 liter of wine) per day indicated by elevated MCV significantly above normal value at screening.
10.Suspected or known allergy to any components of the study treatments.
11.Enrollment in another investigational study or intake of investigational drug within the previous three months.
12.Any condition which in the opinion of the investigator makes the patient unsuitable for inclusion, e.g. currently stable treatment of AD.

E.5 End points

E.5.1

Primary end point(s)

Alzheimer’s Disease Assessment Scale-Cognitive Subscale (Unmodified, 11 Item, total score = 70): (ADAS-Cog)
Primary hypothesis: a 3.5 point average improvement in ADAS-Cog (the Effect Size) for the treated group compared with the control group

E.5.1.1

Timepoint(s) of evaluation of this end point

26 weeks, 52 weeks

E.5.2

Secondary end point(s)

- Neuropsychiatric Inventory (NPI)
- Cornell Scale for Depression in Dementia (CSDD)
- AD Cooperative Study - Activities of Daily Living (ADCS-ADL)
- Mini Mental State Examination (MMSE)

E.5.2.1

Timepoint(s) of evaluation of this end point

26 weeks, 52 weeks

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

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

Yes

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

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

Croatia

Serbia

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

A total of 188 patients will be recruited at 18 study sites in a treatment ratio of 1:1. The study will be finished when the last patient attends at the last visit.
188 reflects the minimum number of patients required and also allows a drop-out rate of 20%. Additional subjects may be recruited based on interim analysis.

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.1.3

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

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

188

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)

standard medical treatment for Alzheimer's disease

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

2011-02-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-12-01

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2012-12-20

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