Clinical Trials Register

Summary
EudraCT Number:	2010-022922-34
Sponsor's Protocol Code Number:	3098006
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-12-23
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Finland - Fimea

A.2

EudraCT number

2010-022922-34

A.3

Full title of the trial

Safety and efficacy of ORM-12741 on cognitive and behavioural symptoms in patients with Alzheimer’s disease: A randomised, double-blind, placebo-controlled, parallel group, multicentre study of 12 weeks

A.3.1

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

A study of ORM-12741 on cognitive and behavioural symptoms such e.g. memory, orientation, learning in patients with Alzheimer’s disease (form of dementia)

A.3.2

Name or abbreviated title of the trial where available

ALPO

A.4.1

Sponsor's protocol code number

3098006

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	Orion Corporation Orion Pharma
B.1.3.4	Country	Finland
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	Orion Corporation Orion Pharma
B.4.2	Country	Finland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Orion Corporation Orion Pharma
B.5.2	Functional name of contact point	Jutta Hänninen
B.5.3	Address:
B.5.3.1	Street Address	Tengströminkatu 8
B.5.3.2	Town/ city	Turku
B.5.3.3	Post code	FI-20360
B.5.3.4	Country	Finland
B.5.4	Telephone number	+358 50 966 7792
B.5.5	Fax number	+358 10 426 7487
B.5.6	E-mail	clinicaltrials@orionpharma.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	ORM-12741
D.3.2	Product code	ORM-12741
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.3.9.2	Current sponsor code	ORM-12741
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	30
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	ORM-12741
D.3.2	Product code	ORM-12741
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.3.9.2	Current sponsor code	ORM-12741
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	100
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

Alzheimer’s disease (AD)

E.1.1.1

Medical condition in easily understood language

Form of dementia

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10001896
E.1.2	Term	Alzheimer's disease
E.1.2	System Organ Class	10029205 - Nervous system disorders

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 objectives of the study are to evaluate the safety and tolerability of ORM-12741, and the efficacy of ORM-12741 on cognitive symptoms in patients with Alzheimer’s disease (AD) receiving acetylcholinesterase (AChE) inhibitor therapy.

E.2.2

Secondary objectives of the trial

The secondary objectives are to evaluate the efficacy of ORM-12741 on behavioural symptoms, and plasma trough concentrations of ORM-12741 in patients with AD receiving AChE inhibitor therapy, and to evaluate the effects of ORM-12741 on plasma trough concentrations of the AChE inhibitors.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

An optional, exploratory pharmacogenetic sub-study is part of the main protocol. In the context of the study, the objective is to assess possible genetic factors that influence the absorption, distribution, metabolism, excretion, efficacy, and safety of ORM-12741 or its metabolites or AChE inhibitor treatments.

E.3

Principal inclusion criteria

Male or female patients with diagnosis of probable AD, written informed consent (IC) obtained from the subject and/or his/her caregiver. The subject must have a history of progressive cognitive deterioration, brain imaging consistent with AD, at least a mild level of behavioural symptoms present with a neuropsychiatric inventory (NPI) score > 15, mini-mental state examination (MMSE) score 12-21 at screening visit and be treated with donepezil, rivastigmine or galantamine for at least 3 months. The subject must be 55-90 years of age and fulfil all of the inclusion criteria and none of the exclusion criteria.

E.4

Principal exclusion criteria

1. Any other type of dementia than AD.
2. Modified Hachinski Ischemia Score > 4.
4. Use of antipsychotics within 2 months prior to screening (even for sleep).
5. Use of benzodiazepines, other than short acting sleep medication, for night at a maximum of 3 nights/week, within 2 months prior to screening.
6. Use of any anticholinergic medication within 2 months prior to screening (including those used to treat overactive bladder and tricyclic antidepressants).
7. Changes in antidepressant dosing during the last 2 months prior to the screening.
8. Current use of other psychotropic agents, like antiepileptics or opioid analgesics
9. Myocardial infarction within the past 2 years.
10. Current or history of malignancy within the past 5 year.
11. Suicidal ideation in the 6 months before screening or current suicide risk based on the Columbia-Suicide Severity Rating Scale (C-SSRS) (items 4 and 5 exclusionary) or current risk of suicide based on the investigator’s judgement.
12. Subjects with known or suspected history of alcoholism or drug abuse (within the past 5 years).
13. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological or psychiatric disorder or any other major concurrent illness that in the opinion of the investigator would interfere with the interpretation of the study results or constitute a health risk for the patient if he/she takes part in the study.
14. Specific findings in MRI that might in the opinion of the investigator affect cognitive function such as cortical infarct, micro-haemorrhage, or silent lacuna (≤ 1 cm) in a region known to affect cognition such as the hippocampus of either hemisphere, the head of the left caudate, or the dorsomedial region of the left thalamus. With the exception of neuroanatomical areas defined, a maximum of one “clinically silent” lacunar infarct is permitted provided the maximal diameter in any dimension is ≤ 1 cm detected on both T1 and T2 weighted MRI images or observed on CT scan images. Multiple white matter lesions consistent with leukoaraiosis are not exclusionary in an otherwise eligible subject.
15. Supine HR > 100 bpm after a 5-minute rest at screening visit.
16. Supine systolic BP (SPB) > 160 or diastolic BP (DPB) > 100 mmHg after a 5-minute rest at screening visit.
17. Symptomatic orthostatic hypotension at screening visit.
18. QTc-Fridericia (QTcF) repeatedly > 450 ms in males or > 470 ms in females at screening visit.
19. Abnormal thyroid-stimulating hormone (TSH), vitamin B12 or folate serum levels at screening (which can not be corrected with substitute therapy).
20. Any other abnormal value in laboratory tests, vital signs or ECG which may in the opinion of the investigator interfere with the interpretation of the study results (e.g. affect cognition) or cause a health risk for the patient if he/she takes part in the study.
21. Female patients of childbearing potential (i.e. menstruating or less than 2 years postmenopausal).
22. Patients with pre-planned elective surgery.
23. Known hypersensitivity to the active substance or to any of the excipients of the study drugs.
24. Blood donation or loss of significant amount of blood within 60 days prior to the screening.
25. Participation in a drug study within 60 days prior to the screening.
26. Previous AD immunotherapy treatment.
27. Patient cannot complete the Cognitive Drug Research Ltd. (CDR) cognitive test battery despite having undergone 2 training sessions.
28. Subjects who reside in a skilled nursing facility.
29. The subject is not able to swallow test capsule at screening.
30. Any other condition that in the opinion of the investigator would interfere with the interpretation of the study results or constitute a health risk for the patient if he/she takes part in the study.

E.5 End points

E.5.1

Primary end point(s)

Efficacy variables:
The following cognitive tests will be assessed: the Cognitive Drug Research Ltd. (CDR) cognitive test battery, the Controlled Oral Word Association Test (COWAT) and the Category Fluency Test (CFT).
Safety variables:
Safety will be assessed by adverse events (AEs), vital signs, 12-lead electrocardiogram (ECG), physical examination and laboratory safety assessments. Suicidality will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS).

E.5.1.1

Timepoint(s) of evaluation of this end point

The CDR cognitive test will be assessed at screening and baseline. At week 1, 2, 4, 8 and 12 - 1 hour after investigational medicinal product (IMP) administration.
COWAT and CFT will be assessed at baseline and at week 1, 2, 4, 8 and 12 visits.

E.5.2

Secondary end point(s)

Efficacy:
The following behavioural and psychological symptom tests will be assessed: the NPI and the Cornell Scale for Depression in Dementia (CSDD). In addition, the Cognitive Failures Questionnaire (CFQ) and the overall change in subject’s clinical condition by Clinical Global Impression of Change (CGI-C) will be assessed.
Pharmacokinetic (PK) variables:
Plasma concentrations of ORM-12741, ORM-13720, ORM-13859, ORM-13861, donepezile, galantamine and rivastigmine will be tabulated.
Pharmacogenetic (PG) variables:
All subjects participating in this study will provide a blood sample for extraction of DNA to determine the carrier status for the genes (markers) that have been associated with behavioural and psychological symptoms in AD, or affect the target receptor, and may predict the subject’s response to the study treatment. An additional blood sample for DNA extraction will be taken from those subjects who agree to take part in the optional study-related exploratory PG study.
Sample collection for exploratory studies:
Blood samples will be collected for metabolomics studies to allow possible exploratory studies related to the pharmacokinetics, pharmacodynamics, or safety of ORM-12741, its metabolites or AChE inhibitor treatments.

E.5.2.1

Timepoint(s) of evaluation of this end point

NPI behavioural test will be performed at screening, baseline and at week 4 and 12 visits.
CSDD and CGI-C test will be performed at baseline and at week 4 and 12 visits.
CFQ assessed at baseline and week 12 visit.
PK sampling for determination of ORM-12741, ORM-13720, ORM-13859 and ORM-13861 and AChEI is taken before the morning dose of the IMP on day 1 and at week 1, 2, 4, 8 and 12 visits

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

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

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

Last subject's last visit. A decision to continue the study beyond the time covered by the study protocol must be based on a mutual agreement between the investigator and Orion Pharma

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