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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2014-000217-30
    Trial protocol
    		 DE   CZ   FI   PL   BG   RO   HR  
    Global end of trial date
    09 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Oct 2018
    First version publication date
    18 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3098012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02471196
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Orion Pharma
    Sponsor organisation address
    Orionintie 1, Espoo, Finland, 02200
    Public contact
    clinicaltrials@orionpharma.com, Orion Corporation, Orion Pharma, +358 104261,
    Scientific contact
    clinicaltrials@orionpharma.com, Orion Corporation, Orion Pharma , +358 104261,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main 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.
    Protection of trial subjects
    The study data was monitored regularly by the Sponsor, and an independent data and safety monitoring board (DSMB) was established to protect the ethical and safety interest of the study subjects and all others who could possibly be exposed to the study treatments. In addition, at the time of the scheduled interim analysis the DSMB evaluated the analyses for the efficacy. Safety measurements including blood pressure, heart rate, 12-lead ECG and safety laboratory tests were performed before the study treatment, during each study visit and at the end of the study. Adverse events were collected throughout the study. Lorazepam (or oxazepam/alprazolam) were used as rescue therapy, if needed. Patients were free to leave the study at any time but were also withdrawn in the event of a safety finding of clinical concern.
    Background therapy
    		 Existing Alzheimer's disease therapy was allowed (cholinesterase inhibitors and memantine).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Romania: 12
    Country: Number of subjects enrolled
    Slovakia: 39
    Country: Number of subjects enrolled
    Croatia: 48
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Serbia: 21
    Country: Number of subjects enrolled
    Russian Federation: 57
    Country: Number of subjects enrolled
    Ukraine: 86
    Worldwide total number of subjects
    308
    EEA total number of subjects
    144
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    62
    From 65 to 84 years
    231
    85 years and over
    15

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with mild to moderate Alzheimer's disease were recruited.

    Pre-assignment
    Screening details
    		 Male or female subjects with a diagnosis of probable AD, written informed consent (IC) obtained from the subject and his/her caregiver. The subject had to have a history of progressive cognitive deterioration, brain imaging consistent with a diagnosis of AD, and a mini-mental state examination (MMSE) score between 10-24 (inclusive), at screening.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The study was double-blind. Blinding was done with double-dummy technique. None of the persons directly involved in the conduct of the study had access to the treatment code. The DSMB had access to the treatment code. In addition, the bioanalytical laboratories and specified personnel responsible for the interim analysis had access to the treatment code.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ORM-12741 60 mg IR
    Arm description
    		 ORM-12741 IR 60 mg twice a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    ORM-12741 IR 60 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One ORM-12741 60 mg immediate-release capsule was given twice a day at about 12 h intervals for 12 weeks.

    Arm title
    		 ORM-12741 120 mg MR
    Arm description
    		 ORM-12741 MR 120 mg twice a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    ORM-12741 MR 120 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One ORM-12741 120 mg modified-release capsule was given twice a day at about 12 h intervals for 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo ORM-1271 capsules twice a day
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo ORM-12741 capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 Placebo ORM-12741 capsules were given twice a day at about 12 h intervals for 12 weeks.

    Number of subjects in period 1
    		ORM-12741 60 mg IR ORM-12741 120 mg MR Placebo
    Started
    102
    103
    103
    Completed
    85
    91
    84
    Not completed
    17
    12
    19
         Adverse event, serious fatal
    1
    2
    1
         Sponsor's decision
    -
    -
    1
         Adverse event, non-fatal
    8
    4
    3
         Other, caregiver's illness
    1
    -
    -
         Personal reason
    6
    5
    12
         Non-compliance
    1
    -
    -
         Lost to follow-up
    -
    1
    1
         Ache medic. stopped right before random.
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 308 308
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 62 62
        From 65-84 years
    		 231 231
        85 years and over
    		 15 15
    Gender categorical
    Units: Subjects
        Female
    		 191 191
        Male
    		 117 117

    End points

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    End points reporting groups
    Reporting group title
    ORM-12741 60 mg IR
    Reporting group description
    		 ORM-12741 IR 60 mg twice a day

    Reporting group title
    ORM-12741 120 mg MR
    Reporting group description
    		 ORM-12741 MR 120 mg twice a day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo ORM-1271 capsules twice a day

    Primary: NPI-C agitation and aggression score (A+A)

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    End point title
    		 NPI-C agitation and aggression score (A+A)
    End point description
    Results of modifed ITT-population.
    End point type
    Primary
    End point timeframe
    Difference from baseline after 12 weeks of treatment.
    End point values
    		 ORM-12741 60 mg IR ORM-12741 120 mg MR Placebo
    Number of subjects analysed
    84 [1]
    94 [2]
    82 [3]
    Units: Difference from baseline
        arithmetic mean (standard deviation)
    -11.43 ± 10.21
    -13.72 ± 11.43
    -12.41 ± 9.89
    Notes
    [1] - Modified ITT-population, table 14.1.2.3
    [2] - Modified ITT-population, table 14.1.2.3
    [3] - Modified ITT-population, table 14.1.2.3
    Statistical analysis title
    		 Change from baseline, A+A scores
    Statistical analysis description
    Treatment effect between placebo and ORM-12741 treatments, Repeated measurements ANCOVA
    Comparison groups
    ORM-12741 60 mg IR v Placebo
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 3.5
    Variability estimate
    Standard error of the mean
    Notes
    [4] - For multiple repeated continuous variables (normal distributed scores and sub-scores) comparisons between the treatment groups were performed using a repeated measurements of analysis of covariance (RM-ANCOVA) model with 95% confidence intervals (CIs).
    Statistical analysis title
    		 Change from baseline, A+A scores
    Statistical analysis description
    Treatment effect between placebo and ORM-12741 treatments, repeated measurements ANCOVA
    Comparison groups
    ORM-12741 120 mg MR v Placebo
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.82
         upper limit
    		 1.94
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of the study treatment until the end-of study visit.
    Adverse event reporting additional description
    In this study normal fluctuation in agitation symptoms was not to be reported as an AE.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    ORM-12741 60 mg IR
    Reporting group description
    		 ORM-12741 IR 60 mg twice a day, table 14.5.1.1

    Reporting group title
    ORM-12741 120 mg MR
    Reporting group description
    		 ORM-12741 MR 120 mg twice a day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo ORM-1271 capsules twice a day

    Serious adverse events
    		 ORM-12741 60 mg IR ORM-12741 120 mg MR Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 102 (3.92%)
    5 / 103 (4.85%)
    1 / 103 (0.97%)
         number of deaths (all causes)
    1
    1
    1
         number of deaths resulting from adverse events
    1
    1
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolytic uremic syndrome
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Psychotic behaviour
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 103 (0.97%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 ORM-12741 60 mg IR ORM-12741 120 mg MR Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 102 (22.55%)
    30 / 103 (29.13%)
    28 / 103 (27.18%)
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 103 (0.00%)
    3 / 103 (2.91%)
         occurrences all number
    2
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 103 (2.91%)
    0 / 103 (0.00%)
         occurrences all number
    1
    3
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 102 (0.98%)
    2 / 103 (1.94%)
    1 / 103 (0.97%)
         occurrences all number
    1
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 102 (2.94%)
    5 / 103 (4.85%)
    1 / 103 (0.97%)
         occurrences all number
    5
    5
    2
    Dizziness
         subjects affected / exposed
    0 / 102 (0.00%)
    6 / 103 (5.83%)
    2 / 103 (1.94%)
         occurrences all number
    0
    8
    3
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    4 / 102 (3.92%)
    1 / 103 (0.97%)
    3 / 103 (2.91%)
         occurrences all number
    4
    1
    3
    Sleep disorder
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    3 / 103 (2.91%)
         occurrences all number
    1
    0
    3
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 103 (0.97%)
    2 / 103 (1.94%)
         occurrences all number
    1
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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