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    Summary
    EudraCT Number:2014-000217-30
    Sponsor's Protocol Code Number:3098012
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-07-08
    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.1Member State ConcernedBulgarian Drug Agency
    A.2EudraCT number2014-000217-30
    A.3Full title of the trial
    EFFICACY OF ORM-12741 ON AGITATION/AGGRESSION SYMPTOMS IN PATIENTS
    WITH ALZHEIMER’S DISEASE: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED,
    PARALLEL GROUP, MULTICENTRE STUDY OF 12 WEEKS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 12 week, multicentre, study investigating the efficacy of ORM-12741 on agitation/aggression symptoms in patients with Alzheimer's Disease.
    A.3.2Name or abbreviated title of the trial where available
    NEBULA
    A.4.1Sponsor's protocol code number3098012
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOrion Corporation
    B.1.3.4CountryFinland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOrion Corporation
    B.4.2CountryFinland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationWorldwide Clinical Trials
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street Address2nd Floor, 172 Tottenham Court Road
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW1T 7NS
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+440207121 61 61
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameORM-12741
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNORM-12741
    D.3.9.3Other descriptive nameORM-12741 (Immediate Release)
    D.3.9.4EV Substance CodeSUB166637
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameORM-12741
    D.3.4Pharmaceutical form Modified-release capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNORM-12741
    D.3.9.3Other descriptive nameORM-12741 (Modified Release A)
    D.3.9.4EV Substance CodeSUB166637
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameORM-12741
    D.3.4Pharmaceutical form Modified-release capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNORM-12741
    D.3.9.3Other descriptive nameORM-12741 (Modified Release B)
    D.3.9.4EV Substance CodeSUB166637
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The agitation/aggression symptoms in patients with Alzheimer’s disease
    E.1.1.1Medical condition in easily understood language
    The agitation/aggression symptoms in patients with Alzheimer’s disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate efficacy of ORM-12741 on agitation/aggression symptoms in patients with mild to moderate Alzheimer’s disease. The efficacy of ORM-12741 administered both as immediate release (IR) and modified release (MR) formulations will be evaluated and compared to placebo.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to evaluate the efficacy of ORM-12741 on cognition and psychotic and depressive symptoms, as well as to evaluate the safety of ORM-12741.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    All subjects participating in this study will provide a blood sample for extraction of DNA to determine the carrier status for the following genes (markers): apolipoprotein E and alpha-2C AR. These markers have been associated with cognitive or neuropsychiatric symptoms in AD, or affect the target receptor, and may predict the subject’s response to the study treatment. In addition, other markers relevant to the absorption, distribution, metabolism, excretion, efficacy, and safety of ORM-12741 or its metabolites, may be studied.

    This sub-study is in accordance with Protocol V1.0 dated 19Dec2014
    E.3Principal inclusion criteria
    1. Written informed consent (IC) for participation in the study (co-signed by the subject’s next of kin or caregiver, or other legally acceptable representative, if required by the local regulations/guidelines/ethics committee [EC]) obtained from the subject.

    2. Written IC obtained from a consistently available caregiver informant who is knowledgeable of the subject’s condition and its progression and is willing to accompany the subject to all visits and supervise the administration of the study medication. The caregiver should be in contact with the subject on most days, as the contact is necessary to ensure accurate reporting of the subject’s behaviour on rating scales.

    3. Age of 55-90 years (inclusive). Inclusion of subjects above the age of 80 years will need the medical monitor’s approval before enrolment.

    4. Male or female subjects with diagnosis of probable AD according to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease

    5. History of progressive cognitive deterioration prior to baseline (via caregiver or medical record review).

    6. Brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) consistent with a diagnosis of AD (within 18 months or at screening). In case the medical history suggests a neurological event between the previous scan and the screening, the scan should be repeated.

    7. Mini-mental state examination (MMSE) score between 10-24 (inclusive) at screening visit.

    8. Clinically significant agitation meeting the IPA Provisional Criteria for Agitation in Cognitive Impairment (Appendix 3), both at screening and baseline visits. The agitation symptoms need to have been present for at least 4 weeks before the screening visit and also have to be sustained up to the baseline visit.

    9. NPI agitation/aggression item score ≥ 4 at screening visit (on original NPI scale, as derived from the NPI-C).
    E.4Principal exclusion criteria
    1. Any other type of dementia than AD.

    2. Modified Hachinski Ischemia Score (MHIS) > 4.

    3. Changes in AChE inhibitor (donepezil, rivastigmine or galantamine) dosing within 2 months prior to screening.

    4. Changes in memantine dosing within 2 months prior to the screening.

    5. Changes in antidepressant dosing or addition of another antidepressant medication within 2 months prior to the screening.

    6. Use of antipsychotics at any dose within 1 month prior to screening (even for sleep). In the event of previous use of long-acting injectable antipsychotics the duration of required wash-out (at least 5 times the elimination half-life) needs to be agreed with the medical monitor before enrollment.

    7. Use of benzodiazepines, other than short-acting sleep medications, for night at a maximum of 3 nights/week, within 2 months prior to screening.

    8. Use of any anticholinergic medication within 2 months prior to screening (including those used to treat overactive bladder and tricyclic antidepressants).

    9. Current use (within the 30 days prior to screening) of medications with known relevant alpha-2C AR affinity (e.g. mirtazapine, mianserine, clonidine, guanfacine or tizanidine) or with high noradrenaline transporter affinity (reboxetine, venlafaxine or duloxetine).

    10. Current use of other psychotropic agents, unless the dosing has been stable during the last 2 months prior to the screening and is expected to remain stable during the study, and permission has been obtained from the medical monitor before enrolment.

    11. Myocardial infarction or other clinically significant ischemic cardiac disease, heart failure, or arrhythmia tendency within the past 2 years.

    12. Poorly controlled diabetes mellitus

    13. Current or history of malignancy within 5 years before screening (some exceptions)

    14. Suicidal ideation in the 6 months before screening or current suicide risk.

    15. Known or suspected history of alcoholism or drug abuse.

    16. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological (e.g. epilepsy) or psychiatric disorder (e.g. lifetime schizophrenia, or bipolar disorder within last 5 years) or any other major concurrent illness that in the opinion of the investigator may interfere with the interpretation of the study results or constitute a health risk for the subject

    17. Specific findings in MRI or CT that could in the opinion of the investigator affect cognitive function

    18. Supine HR < 48 bpm or > 100 bpm after a 5-minute rest at screening visit.

    19. Systolic blood pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) > 100 mmHg after a 5-minute rest at screening visit.

    20. Symptomatic orthostatic hypotension at screening visit.

    21. QTc-Fridericia (QTcF) repeatedly > 450 ms in males or > 470 ms in females at screening visit.

    22. Clinically significantly abnormal thyroid-stimulating hormone (TSH), vitamin B12 or folate serum levels at screening.

    23. 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

    24. Female patients of childbearing potential

    25. Pre-planned elective surgery for the study period

    26. Known hypersensitivity to the active substance.

    27. Blood donation or loss of significant amount of blood within 60 days prior to the screening.

    28. Participation in a drug study within 60 days prior to the screening or previous participation in clinical study with ORM-12741.

    29. Inability to complete the CDR System test battery despite having undergone 2 training sessions.

    30. Resides in a skilled nursing facility.

    31. Any other condition that in the opinion of the investigator may interfere with the interpretation of the study results or constitute a health risk for the subject if he/she takes part in the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy evaluation will be done for the sum of the NPI-C agitation and
    aggression domains (NPI-C-A+A).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Will be assessed at screening, baseline (day 1 predose) and at the week 4, 8 and 12 visits by a trained clinician rater
    E.5.2Secondary end point(s)
    The key secondary evaluation will be done for the CDR System Quality of Memory. In addition, special priority will be put to preplanned analyses of CGIC-A/A (agitation), CGIC-O (overall clinical condition), CMAI-C total score, NPI-C-D+H and NPI-C dysphoria/depression domains.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The CDR System computerised cognitive test battery will be assessed at screening and baseline (day 1 predose). At week 4, week 8 and week 12 visits.

    The CDR Assessment System cognitive test battery will be assessed 1 hour after study treatment administration and at week 8 visit additionally 4h after study treatment.

    CMAI-C will be assessed based on the caregiver interview at baseline (day 1) and at the week 4, 8 and 12 visits after NPI-C

    mADCS-CGIC - will be assessed at week 4, 8 and 12 visits by mADCS-CGIC scale based on both caregiver and subject interviews.

    The following variables will be derived from the NPI/NPI-C rating:
    - Sum of the NPI-C delusion and hallucination domain scores
    - Individual NPI-C domain scores
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Bulgaria
    Croatia
    Czech Republic
    Finland
    Germany
    Macedonia, the former Yugoslav Republic of
    Poland
    Romania
    Russian Federation
    Serbia
    Slovakia
    Ukraine
    E.8.7Trial 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.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 250
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects diagnosed with probable Alzheimer's Disease who may or may not be able to consent personally. Full, written consent will be obtained from each subject or his/her legal representative/caregiver where applicable, prior to recruitment.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 256
    F.4.2.2In the whole clinical trial 300
    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)
    Subsequent treatments of the study subject will be at the discretion of the investigator.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-07-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-09
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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