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    Clinical Trial Results:
    Nabilone for non-motor symptoms in Parkinson’s disease: An open-label study to evaluate long-term safety and efficacy

    Summary
    EudraCT number
    2017-004253-16
    Trial protocol
    AT  
    Global end of trial date
    31 Jan 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Feb 2021
    First version publication date
    10 Feb 2021
    Other versions
    Summary report(s)
    Adverse event Log
    IMPD Nabilone
    Data Safety Board Meeting
    Demographics of Individual Patients
    SAE Form_002
    SAE Form_003
    SAE Form_004
    SAE Form_006
    Clinical study protocol V1.3
    Final report

    Trial information

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    Trial identification
    Sponsor protocol code
    NMSNab2study
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03773796
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Medical University of Innsbruck, Department of Neurology
    Sponsor organisation address
    Anichstraße 35, Innsbruck, Austria, 6020
    Public contact
    Clinical Trial Center Neurology, Medical University of Innsbruck, Department of Neurology, 6801449268 51250425810, klaus.seppi@tirol-kliniken.at
    Scientific contact
    Clinical Trial Center Neurology, Medical University of Innsbruck, Department of Neurology, 6801449268 51250425810, klaus.seppi@tirol-kliniken.at
    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
    23 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate long-term safety and tolerability of nabilone in PD patients.
    Protection of trial subjects
    For all work involving data collection or management of subjects, the study centre adhered to the law as laid down in the European Regulation (EU) 2016/679 as well as to the national data protection law. Permission for the conduct of the trial was received from the ethics committee (IEC) of the Medical University of Innsbruck (MUI) on February 07th, 2018 (reference number: 1214/2017) and the Austrian regulatory authorities approved the study on the 13th of April 2018. One substantial amendment with changes in prohibited concomitant medication, study team members, and to conform to the EU Data Protection Law 2018 have been approved by the EC of the MUI and non-prohibited by the regulatory authorities. Two amendments for changes in study team members were approved by the EC of the MUI. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (IEC MUI, reference number 1214/2017 and the national regulatory authorities) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. As the trials primary endpoint was safety, (serious) adverse events, reasons for discontinuation of the study, clinical examination, vital signs, compliance, and suicidality were documented and/or closely monitored.
    Background therapy
    All Anti-PD Medications were allowed in this study. The addition of any new anti-PD medication or other prescribed / non-prescribed drugs were allowed during the study as well as changes to frequency or intervals between doses. All non-pharmacological therapies (e.g., physical therapy, exercise, yoga) the patient wanted to perform to improve his/her Parkinson symptoms were allowed to be continued during participation in the study. During the trial, such non-pharmacological therapies were allowed to be started as well. The concomitant non-pharmacological therapies should have been kept on the same level during the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    8
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Twenty-two patients participated in the NMS-Nab2 study between August 10, 2018, and January 31, 2020 (last patient last visit). There was no screening failure. Up-titration was started in all patients. One patient was a non-responder and therefore discontinued before V 1. Two patients were drop-outs (reasons: AE, own will).

    Pre-assignment
    Screening details
    All 38 patients that finished the double-blind phase of the preceding NMS-Nab study were assessed for eligibility. Reasons for declined partic. in NMS-Nab2: satisfaction with symptomatic control (4), planned surgery (2), wish for modification of PD treatment regime (4), cannabinoid treatment outside of study (2), scheduling difficulties (3), other

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    no blinding, open-label study

    Arms
    Arm title
    Nabilone
    Arm description
    Nabilone, manufactured by AOP Orphan Pharmaceuticals AG (Vienna, Austria), was given orally daily starting with a dose of 0.25 milligrams (mg, one capsule) in the evening after the screening visit. It was titrated in 0.25 mg-increments every one to four days after consultation with the study team during regular telephone calls. Dose adjustments were performed until patients met the responder criterion defined as a patient-based rating of their NMS as “much improved” (CGI-I Rating Scale: 2) or “very much improved” (CGI-I Rating Scale: 1) on the 7-point CGI-I Scale. Patients failing to meet this response criterion at the maximum daily dose of 2 mg or patients with intolerable side effects believed to be related to the study drug were discontinued.
    Arm type
    Experimental

    Investigational medicinal product name
    Nabilone
    Investigational medicinal product code
    verum
    Other name
    Canemes
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    nabilone, manufactured by AOP Orphan Pharmaceuticals AG (Vienna, Austria), was given orally daily. Dose specified during titration phase of the trial

    Number of subjects in period 1
    Nabilone
    Started
    22
    Completed
    19
    Not completed
    3
         Lack of efficacy
    1
         Adverse event, non-fatal
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    -

    Reporting group values
    overall trial Total
    Number of subjects
    22 22
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    8 8
        From 65-84 years
    14 14
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.50 ± 6.75 -
    Gender categorical
    Units: Subjects
        Female
    12 12
        Male
    10 10
    Disease duration
    Units: years
        arithmetic mean (standard deviation)
    9.02 ± 5.91 -
    Subject analysis sets

    Subject analysis set title
    Full data set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Safety and tolerability summaries were based on a safety set which included all patients receiving at least one dose of study medication and completing at least V 1. Additionally, summaries of baseline and demographic data were produced out of the safety set. The efficacy analyses for the secondary endpoints included all screened subjects with at least one Visit after screening.

    Subject analysis sets values
    Full data set
    Number of subjects
    21
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    7
        From 65-84 years
    14
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    67.23 ± 6.15
    Gender categorical
    Units: Subjects
        Female
    11
        Male
    10
    Disease duration
    Units: years
        arithmetic mean (standard deviation)
    9.30 ± 6.04

    End points

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    End points reporting groups
    Reporting group title
    Nabilone
    Reporting group description
    Nabilone, manufactured by AOP Orphan Pharmaceuticals AG (Vienna, Austria), was given orally daily starting with a dose of 0.25 milligrams (mg, one capsule) in the evening after the screening visit. It was titrated in 0.25 mg-increments every one to four days after consultation with the study team during regular telephone calls. Dose adjustments were performed until patients met the responder criterion defined as a patient-based rating of their NMS as “much improved” (CGI-I Rating Scale: 2) or “very much improved” (CGI-I Rating Scale: 1) on the 7-point CGI-I Scale. Patients failing to meet this response criterion at the maximum daily dose of 2 mg or patients with intolerable side effects believed to be related to the study drug were discontinued.

    Subject analysis set title
    Full data set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Safety and tolerability summaries were based on a safety set which included all patients receiving at least one dose of study medication and completing at least V 1. Additionally, summaries of baseline and demographic data were produced out of the safety set. The efficacy analyses for the secondary endpoints included all screened subjects with at least one Visit after screening.

    Primary: primary endpoint

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    End point title
    primary endpoint [1]
    End point description
    The primary endpoint of the study was safety (see AE page). On parameter assessed in this category was the C-SSRS describing suicidality. No patient experienced suicidality, therefore the count is 0.
    End point type
    Primary
    End point timeframe
    V 1 to V 3, 6 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary endpoint was safety. Please refer to the Adverse event - section.
    End point values
    Full data set
    Number of subjects analysed
    19
    Units: yes or no
    0
    No statistical analyses for this end point

    Secondary: change of the different MDS-UPDRDS Parts

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    End point title
    change of the different MDS-UPDRDS Parts
    End point description
    The secondary efficacy criteria were measured as the change in the different clinical scales and questionnaires regarding motor symptoms and different domains of non-motor symptoms in Parkinson´s Disease between V 1 and V 3.
    End point type
    Secondary
    End point timeframe
    V 1 to V 3, 6 months
    End point values
    Nabilone
    Number of subjects analysed
    19
    Units: points
    arithmetic mean (standard deviation)
        Part 1
    1.58 ± 13.87
        Part 2
    -0.58 ± 3.49
        Part 3
    -1.89 ± 6.88
        Part 4
    -0.16 ± 2.14
        Motor Sum Score
    -2.47 ± 7.88
        Sum Score Part 1 - 3
    -0.89 ± 14.99
    No statistical analyses for this end point

    Secondary: change in other secondary endpoints

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    End point title
    change in other secondary endpoints
    End point description
    End point type
    Secondary
    End point timeframe
    V 1 to V 3, 6 months
    End point values
    Nabilone
    Number of subjects analysed
    19
    Units: points
    arithmetic mean (standard deviation)
        Hoehn and Yahr
    -0.16 ± 0.38
        CGI-I
    -1.16 ± 1.30
        NMSS Total Score
    -4.84 ± 18.08
        KPPS Total Score
    -6.84 ± 15.12
        HADS-A
    -0.16 ± 1.50
        HADS-D
    1 ± 2.08
        PDQ-8 SI
    -2.96 ± 9.11
        ESS
    0.11 ± 2.75
        FSS
    4.26 ± 10.08
        QUIP-RS
    0.11 ± 1.41
    No statistical analyses for this end point

    Secondary: change in scores for cognition

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    End point title
    change in scores for cognition
    End point description
    End point type
    Secondary
    End point timeframe
    variable, scores at the screening visit of the preceeding NMS-Nab1 study were compared to V 3 of this study
    End point values
    Nabilone
    Number of subjects analysed
    19
    Units: points
    arithmetic mean (standard deviation)
        MMSE
    0.42 ± 1.84
        MoCA
    -0.11 ± 1.94
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    V 1 to V 3 = 6 months
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Nabilone
    Reporting group description
    Nabilone, manufactured by AOP Orphan Pharmaceuticals AG (Vienna, Austria), was given orally daily starting with a dose of 0.25 milligrams (mg, one capsule) in the evening after the screening visit. It was titrated in 0.25 mg-increments every one to four days after consultation with the study team during regular telephone calls. Dose adjustments were performed until patients met the responder criterion defined as a patient-based rating of their NMS as “much improved” (CGI-I Rating Scale: 2) or “very much improved” (CGI-I Rating Scale: 1) on the 7-point CGI-I Scale. Patients failing to meet this response criterion at the maximum daily dose of 2 mg or patients with intolerable side effects believed to be related to the study drug were discontinued.

    Serious adverse events
    Nabilone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 22 (18.18%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal cancer
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    worsening of Parkinson´s disease symptoms
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
    Additional description: medication-induced
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
    Additional description: herniated disc in the segment 4/5
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Nabilone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 22 (95.45%)
    Nervous system disorders
    Disturbance in attention
    Additional description: concentration difficulties
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Fall
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Hypoesthesia (face)
    Additional description: transient numbness of the face
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    worsening of Parkinson´s Disease symptoms
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Osteoarthropathy
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Osteopenia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Sep 2018
    (Substantial) Amendment 1: Primary reason for the amendment: The protocol was adapted to reflect changes in EU data protection regulations. A change in the list of prohibited medication was made. Changes in study team members were added. Protocol Version 1.1 Approved by the EC: 25th August 2018 Non-prohibition by the regulatory authorities: 6th September 2018

    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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