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    Clinical Trial Results:
    A placebo controlled double blind randomised controlled proof of concept study of zolpidem for the treatment of motor and cognitive deficits in late-stage Parkinson’s

    Summary
    EudraCT number
    		 2017-004297-34
    Trial protocol
    		 GB  
    Global end of trial date
    31 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Sep 2020
    First version publication date
    26 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    236252
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03621046
    WHO universal trial number (UTN)
    		 U1111-1204-4692
    Sponsors
    Sponsor organisation name
    Aston University
    Sponsor organisation address
    Aston Triangle, Birmingham, United Kingdom, B4 7ET
    Public contact
    Research and Knowledge Exchange, Aston University, 44 01212043000, research_governance@aston.ac.uk
    Scientific contact
    Professor Ian Stanford, Aston University, 44 01212044015, i.m.stanford@aston.ac.uk
    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
    08 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if a 5 mg dose of zolpidem is beneficial in reducing motor symptoms and cognitive deficits in late-stage Parkinson’s.
    Protection of trial subjects
    Screening measures were used. Participants were recruited from Secondary Care Parkinson’s Disease Clinic at the Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust and permitted to continue concomitant care during their participation in the trial.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    12 Sep 2018
    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
    United Kingdom: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was from a single centre (Queen Elizabeth Hospital, Birmingham). All participants were recruited by the Clinical Lead (Dr Benjamin Wright) from Neurology clinics held at Queen Elizabeth Hospital, UK.

    Pre-assignment
    Screening details
    		 Diagnosis of idiopathic Parkinson’s and Hoehn and Yahr score of 2.5 or more; Willing to participate and refrain from driving whist taking zolpidem/placebo; Within age range 40 to 80 years.

    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
    Packaging was undertaken by the drug supplier. The placebo was over encapsulated to ensure that zolpidem and placebo capsules appeared identical. Sharp Clinical Services (UK) Ltd provided 28 containers each with a randomised label. Each container contained either 4 zolpidem or 4 placebo capsules. In addition they provided 2 sets of code breaks. On administering to patient each Participant was given a Unique Participant Identification Number (UPIN).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zolpidem 5mg
    Arm description
    		 Single dose capsule of 5 mg zolpidem for 4 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    zolpidem tartrate
    Investigational medicinal product code
    Other name
    stillnoct,
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    5mg daily for 4 days.

    Arm title
    		 Placebo
    Arm description
    		 Placebo 5mg daily for 4 days
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Zolpidem 5mg Placebo
    Started
    14
    14
    Completed
    14
    13
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zolpidem 5mg
    Reporting group description
    		 Single dose capsule of 5 mg zolpidem for 4 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 5mg daily for 4 days

    Reporting group values
    		 Zolpidem 5mg Placebo Total
    Number of subjects
    		 14 14 28
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 4 3 7
        From 65-84 years
    		 10 11 21
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 6 10 16
        Male
    		 8 4 12

    End points

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    End points reporting groups
    Reporting group title
    Zolpidem 5mg
    Reporting group description
    		 Single dose capsule of 5 mg zolpidem for 4 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 5mg daily for 4 days

    Primary: Change in UPDRS III

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    End point title
    		 Change in UPDRS III
    End point description
    A UPDRS motor Examination (Part III) was undertaken as part of the initial clinical assessment in the clinic on day 1. Following this, zolpidem or placebo was administered and the UPDRS III was repeated a minimum of 1 hour later. Post-hoc analysis confirmed a significant symptomatic improvements following administration of zolpidem (UPDRS III reduction -7.2 ± 2.37, p < 0.0001). Following administration of placebo, there was a significant reduction in UPDRS III (-8.43 ± 2.03, p < 0.0001) which was not significantly different from that found in zolpidem, p = 0.7).
    End point type
    Primary
    End point timeframe
    Duration of study
    End point values
    		 Zolpidem 5mg Placebo
    Number of subjects analysed
    14
    14
    Units: Change in UPDRS III
        arithmetic mean (standard deviation)
    -7.21 ( 8.88 )
    -8.43 ( 7.59 )
    Attachments
    		 MeanUPDRSscore
    Statistical analysis title
    		 unpaired t-test
    Comparison groups
    Zolpidem 5mg v Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.7 [1]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - No significant difference between zolpidem and placebo with regard to changes in UPDRS III

    Primary: Correlation analysis

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    End point title
    		 Correlation analysis
    End point description
    Correlation analysis showed that the greatest reductions in UPDRS III were found in those patients who had exhibited the greatest deficits. Thus, the largest reduction in UPDRS III was significantly correlated, not only with initial total UPDRS (p < 0.001) but also with initial UPDRS III (p < 0.01). However, unlike the zolpidem data, no significant correlations were found in UPDRS III improvement with either initial total UPDRS or initial UPDRS III.
    End point type
    Primary
    End point timeframe
    Duration of trial
    End point values
    		 Zolpidem 5mg Placebo
    Number of subjects analysed
    14
    14
    Units: Correlation analysis
        number (not applicable)
    14
    14
    Attachments
    		 Untitled (Filename: Correlations.pdf)
    Statistical analysis title
    		 Correlation
    Statistical analysis description
    A comparision of UPDRS total and UPDRS III against the change in UPDRS III in Zolpidem
    Comparison groups
    Zolpidem 5mg v Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 ≤ 0.001 [2]
    Method
    		 Regression, Linear
    Parameter type
    		 Slope
    Confidence interval
    Notes
    [2] - The largest reduction in UPDRS III was significantly correlated, not only with initial total UPDRS (p < 0.001) but also with initial UPDRS III (p < 0.01).

    Post-hoc: Category naming test

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    End point title
    		 Category naming test
    End point description
    Following administration of zolpidem, three patients showed an improved performance and nine patients showed a decline in performance with one patient showed no change (mean -2.14 ± 1.47). For placebo, five patients showed improvements and nine patients a decline and one patient no change (mean = -0.58 ± 0.89). Overall, there was no significant difference between placebo or zolpidem in the category naming test. The decline in performance after administration of zolpidem is difficult to reconcile but may be due to residual drowsiness or may just be attributable to tiredness over the course of a long day.
    End point type
    Post-hoc
    End point timeframe
    Duration of study
    End point values
    		 Zolpidem 5mg Placebo
    Number of subjects analysed
    14
    14
    Units: Change in category naming
        arithmetic mean (standard deviation)
    -2.14 ( 5.51 )
    -.58 ( 3.33 )
    Attachments
    		 Untitled (Filename: Category naming sheet.pdf)
    Untitled (Filename: Letter Fluency Test and Category Naming Test Raw Data.pdf)
    No statistical analyses for this end point

    Post-hoc: Letter Fluency Test

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    End point title
    		 Letter Fluency Test
    End point description
    Following administration of zolpidem, five patients showed improvement and nine patients showed a decline (mean = -1.39 ± 0.86). For placebo, nine patients showed improvements, three patient showed a decline and two patients no change. Overall, there was an improvement in letter fluency following placebo (1.61 ± 0.74). This is a surprising result and may indicate a learning effect or simply that the patients are more at ease upon repeating the test.
    End point type
    Post-hoc
    End point timeframe
    Overall study
    End point values
    		 Zolpidem 5mg Placebo
    Number of subjects analysed
    14
    14
    Units: Change in letter fluency
        arithmetic mean (standard deviation)
    -1.39 ( 3.20 )
    1.66 ( 2.78 )
    Attachments
    		 Untitled (Filename: Letter Fluency Test and Category Naming Test Raw Data.pdf)
    Untitled (Filename: Letter fluency sheet.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 24 hours of the investigator’s knowledge of occurrence
    Adverse event reporting additional description
    Adverse effects (AEs) were assessed in the clinic (day 1) and also during telephone conversions which took place on days 2, 6 and 8
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Zolpidem 5mg
    Reporting group description
    		 Single dose capsule of 5 mg zolpidem for 4 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 5mg daily for 4 days

    Serious adverse events
    		 Zolpidem 5mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Zolpidem 5mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 14 (85.71%)
    1 / 14 (7.14%)
    Social circumstances
    Anxiety
    Additional description: Anxiety related to using the Smartphone
    alternative dictionary used: Sponsor definition 1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Product issues
    Transient effects
    Additional description: Sleeping, tiredness drowsiness (usually <1hr in duration) and/or vivid dreaming
    alternative dictionary used: Sponsor's definition 1
         subjects affected / exposed
    12 / 14 (85.71%)
    0 / 14 (0.00%)
         occurrences all number
    26
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2019
    Baseline blood pressure assessment added.
    04 Sep 2019
    Change of Chief Investigator.

    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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