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    Clinical Trial Results:
    A randomised, double-blind, placebo controlled trial of pramipexole in addition to mood stabilisers for patients with treatment resistant bipolar depression.

    Summary
    EudraCT number
    		 2018-002869-18
    Trial protocol
    		 GB  
    Global end of trial date
    29 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2024
    First version publication date
    11 Aug 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RES-17-031
    Additional study identifiers
    ISRCTN number
    		 ISRCTN72151939
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Research Ethics Committee: 19/NE/0233, NIHR HTA Funder: 16/154/01
    Sponsors
    Sponsor organisation name
    Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust
    Sponsor organisation address
    Jubilee Road, Gosforth, United Kingdom, NE3 3XT
    Public contact
    Prof R. Hamish McAllister-Williams, Newcastle University, +44 0191 208 1370, hamish.mcallister-williams@ncl.ac.uk
    Scientific contact
    Prof R. Hamish McAllister-Williams, Newcastle University, +44 0191 208 1370, hamish.mcallister-williams@ncl.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
    05 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Oct 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the clinical effectiveness of pramipexole versus placebo alongside standard mood stabilising medication, over 12 weeks, in the management of patients with treatment resistant bipolar depression.
    Protection of trial subjects
    A DMC was convened to undertake independent review. The purpose of this committee was to monitor safety. At the first meeting, the DMC agreed on its charter of operation and how many times the DMC would meet throughout the course of the study. The trial statistician was partially blinded for DMC meetings (treatment arms coded via Group A and Group B until the results reveal meeting which was held at the end of the trial. The senior statistician was fully blinded throughout in line with the rest of the trial management team.
    Background therapy
    		 n/a
    Evidence for comparator
    		 n/a
    Actual start date of recruitment
    28 Nov 2019
    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: 39
    Worldwide total number of subjects
    39
    EEA total number of subjects
    0
    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)
    38
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Potentially eligible participants were either approached in person by a member of the clinical team and asked for verbal consent for a member of the trial team to get in touch or were approached via an invitation letter and summary sent by post or email. Participants were recruited between 28/11/2019 and 26/05/2022.

    Pre-assignment
    Screening details
    		 Patients were identified from secondary care services using patient clinic lists, databases, and research registers. Clinicians were assisted by Clinical Studies Officers or other staff from the Clinical Research Networks where possible. The trial was also advertised to participants directly via posters, trial website and via postal invitations.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Randomisation was carried out using Sealed Envelope (a central, secure, 24-hour web-based system with concealed allocation). Assignment to either arm was blinded to both participants and site staff including the PI. IMPs were manufactured and packaged to ensure participants and staff were blinded. Participants were randomised on a 1:1 basis to receive either pramipexole or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pramipexole
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pramipexole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Arm title
    		 Placebo
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Number of subjects in period 1
    		Pramipexole Placebo
    Started
    18
    21
    Completed
    18
    21
    Period 2
    Period 2 title
    Week 12
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Randomisation was carried out using the Sealed Envelope system (a central, secure, 24-hour web-based randomisation system with concealed allocation). Assignment to either arm was blinded to both participants and site staff including the PI. IMPs were manufactured and packaged to ensure participants and study staff were blinded. Participants were randomised on a 1:1 basis to receive either pramipexole or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pramipexole
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pramipexole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Arm title
    		 Placebo
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Number of subjects in period 2
    		Pramipexole Placebo
    Started
    18
    21
    Completed
    16
    20
    Not completed
    2
    1
         Consent withdrawn by subject
    2
    -
         death likely by suicide
    -
    1
    Period 3
    Period 3 title
    Week 24
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Randomisation was carried out using the Sealed Envelope system (a central, secure, 24-hour web-based randomisation system with concealed allocation). Assignment to either arm was blinded to both participants and site staff including the PI. IMPs were manufactured and packaged to ensure participants and study staff were blinded. Participants were randomised on a 1:1 basis to receive either pramipexole or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pramipexole
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pramipexole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Arm title
    		 Placebo
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Number of subjects in period 3
    		Pramipexole Placebo
    Started
    16
    20
    Completed
    13
    17
    Not completed
    3
    3
         Physician decision
    -
    1
         unknown
    -
    1
         Withdrawn (due to early trial closure)
    3
    1
    Period 4
    Period 4 title
    Week 36
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Randomisation was carried out using the Sealed Envelope system (a central, secure, 24-hour web-based randomisation system with concealed allocation). Assignment to either arm was blinded to both participants and site staff including the PI. IMPs were manufactured and packaged to ensure participants and study staff were blinded. Participants were randomised on a 1:1 basis to receive either pramipexole or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pramipexole
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pramipexole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Arm title
    		 Placebo
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Number of subjects in period 4
    		Pramipexole Placebo
    Started
    13
    17
    Completed
    9
    10
    Not completed
    4
    7
         Physician decision
    1
    -
         Withdrawn (due to early trial closure)
    2
    6
         Lost to follow-up
    1
    -
         moving out of area
    -
    1
    Period 5
    Period 5 title
    Week 48
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Randomisation was carried out using the Sealed Envelope system (a central, secure, 24-hour web-based randomisation system with concealed allocation). Assignment to either arm was blinded to both participants and site staff including the PI. IMPs were manufactured and packaged to ensure participants and study staff were blinded. Participants were randomised on a 1:1 basis to receive either pramipexole or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pramipexole
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pramipexole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Arm title
    		 Placebo
    Arm description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Number of subjects in period 5
    		Pramipexole Placebo
    Started
    9
    10
    Completed
    8
    8
    Not completed
    1
    2
         Withdrawn (due to early trial closure)
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pramipexole
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Reporting group title
    Placebo
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Reporting group values
    		 Pramipexole Placebo Total
    Number of subjects
    		 18 21 39
    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)
    		 18 20 38
        From 65-84 years
    		 0 1 1
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 49 (40 to 57) 49 (36 to 58) -
    Gender categorical
    Units: Subjects
        Female
    		 8 10 18
        Male
    		 10 11 21
    QIDS-SR score
    Units: Subjects
        median (full range (min-max))
    		 15.5 (12 to 19) 18 (16 to 21) -

    End points

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    End points reporting groups
    Reporting group title
    Pramipexole
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Reporting group title
    Placebo
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Reporting group title
    Pramipexole
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Reporting group title
    Placebo
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Reporting group title
    Pramipexole
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Reporting group title
    Placebo
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Reporting group title
    Pramipexole
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Reporting group title
    Placebo
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.
    Reporting group title
    Pramipexole
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Reporting group title
    Placebo
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Primary: QIDS-SR Score at 12 weeks

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    End point title
    		 QIDS-SR Score at 12 weeks
    End point description
    To evaluate the clinical effectiveness of pramipexole versus placebo alongside standard mood stabilising medication, over 12 weeks, in the management of patients with treatment resistant bipolar depression. This was assessed using the Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR) scores for patients randomised to pramipexole compared to those randomised to placebo at 12 weeks, covarying for baseline QIDS-SR score.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Pramipexole Placebo
    Number of subjects analysed
    16
    20
    Units: Subjects
        median (full range (min-max))
    10 (0 to 21)
    16.5 (2 to 24)
    Statistical analysis title
    		 Analysis of covariance (ANCOVA) - 12 weeks
    Statistical analysis description
    This is the primary analysis of the primary outcome measure of the PAX-BD trial, as specified in the protocol. The analysis set is the ITT population. The primary outcome measure is QIDS-SR score after 12 weeks and will be analysed using analysis of covariance (ANCOVA) methods in order to compare the 12 week QIDS-SR scores between the treatment groups while adjusting for QIDS-SR score at the time of randomisation (week 0).
    Comparison groups
    Pramipexole v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0865 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.939
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.445
         upper limit
    		 6.324
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.664
    Notes
    [1] - Analysis of the primary outcome measure of QIDS-SR at week 12 used analysis of covariance (ANCOVA) or related regression methods to examine the difference between the trial arms with adjustment for baseline covariates as far as permitted by the achieved sample size. A two-sided significance level of p<0.05 was used throughout. Unadjusted analysis using the t-test, or related regression or ANCOVA methods adjusting only for trial arm, together with other unadjusted analyses, were also undertaken.
    [2] - The hypothesis to be tested is H0: The average QIDS-SR score at 12 weeks are equal for both arms (Pramipexole v Placebo) with adjustment for baseline QIDS-SR score.

    Secondary: QIDS-SR score at 24, 36 and 48 weeks

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    End point title
    		 QIDS-SR score at 24, 36 and 48 weeks
    End point description
    To examine the impact of pramipexole treatment on mood and anxiety symptoms over 48 weeks. This will be assessed using the Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR). QIDS-SR was collected at the following timepoints during this study: Baseline, Week 12, Week 24, Week 36 and Week 48. Weeks 24, 36 and 48 are reported within this secondary end point section. Baseline is recorded within the Baseline Characteristics section and the week 12 data within the Primary End Point section. This is to save repetition of the same data.
    End point type
    Secondary
    End point timeframe
    Between baseline and 48 weeks.
    End point values
    		 Pramipexole Placebo Pramipexole Placebo Pramipexole Placebo
    Number of subjects analysed
    13 [3]
    17 [4]
    9 [5]
    10 [6]
    8 [7]
    8 [8]
    Units: Subjects
        median (full range (min-max))
    12 (2 to 22)
    16.5 (2 to 26)
    8.5 (0 to 16)
    18 (6 to 27)
    8.5 (1 to 14)
    18.5 (7 to 24)
    Notes
    [3] - at 24 weeks
    [4] - at 24 weeks
    [5] - at 36 weeks
    [6] - at 36 weeks
    [7] - at 48 weeks
    [8] - at 48 weeks
    Statistical analysis title
    		 Analysis of covariance (ANCOVA) - 24 weeks
    Statistical analysis description
    This is the analysis of the secondary objective to examine the impact of pramipexole treatment on mood and anxiety symptoms over 48 weeks as specified in the protocol. The analysis set is the ITT population. The outcome measure was collected via completion of the QIDS-SR score which was completed weekly up to week 48. It was analysed using analysis of covariance (ANCOVA) methods. This analysis covers the week 24 timepoint.
    Comparison groups
    Pramipexole v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.488
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.185
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.275
         upper limit
    		 4.645
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.686
    Notes
    [9] - This is an ad-hoc analysis timepoint. Week 48 was always planned to be analysed, but due to funder decision to close the study early not many participants had reached this planned timepoint. It was therefore considered reasonable to also analyse/present data from weeks 24 and 36 as more participants reached these timepoints.
    Statistical analysis title
    		 Analysis of covariance (ANCOVA) - 36 weeks
    Statistical analysis description
    This is the analysis of the secondary objective to examine the impact of pramipexole treatment on mood and anxiety symptoms over 48 weeks as specified in the protocol. The analysis set is the ITT population. The outcome measure was collected via completion of the QIDS-SR score which was completed weekly up to week 48. It was analysed using analysis of covariance (ANCOVA) methods. This analysis covers the week 36 timepoint.
    Comparison groups
    Pramipexole v Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    6.278
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.85
         upper limit
    		 10.707
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.089
    Statistical analysis title
    		 Analysis of covariance (ANCOVA) - 48 weeks
    Statistical analysis description
    This is the analysis of the secondary objective to examine the impact of pramipexole treatment on mood and anxiety symptoms over 48 weeks as specified in the protocol. The analysis set is the ITT population. The outcome measure was collected via completion of the QIDS-SR score which was completed weekly up to week 48. It was analysed using analysis of covariance (ANCOVA) methods. This analysis covers the week 48 timepoint.
    Comparison groups
    Pramipexole v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.052
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    5.478
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.045
         upper limit
    		 11.002
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.557
    Notes
    [10] - This is an ad-hoc analysis timepoint. Week 48 was always planned to be analysed, but due to funder decision to close the study early not many participants had reached this planned timepoint. It was therefore considered reasonable to also analyse/present data from weeks 24 and 36 as more participants reached these timepoints.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded for all participants from the date of consent until the participant’s final trial assessment or up until the point of withdrawal where this was applicable.
    Adverse event reporting additional description
    290 AEs were reported by 36 of the 39 participants included in the ITT population; 128 reported by 17/18 unique participants in the pramipexole arm and 162 by 19/21 in the placebo arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Pramipexole
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Reporting group title
    Placebo
    Reporting group description
    		 For all participants, initiation of trial treatment followed a 4-week titration schedule starting at 0.25mg/day in a single dose for 3 days. Thereafter the dose was increased by 0.25mg/day every 3 days. The target dose was 2.5mg/day but titration was based on tolerability and response.

    Serious adverse events
    		 Pramipexole Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 21 (14.29%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Foot surgery with overnight stay in hospital
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mania and BAPD Relapse with Psychotic Symptoms
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severe depressive episode with suicidality
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death, likely by suicide
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Pramipexole Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 18 (94.44%)
    19 / 21 (90.48%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    6 / 18 (33.33%)
    6 / 21 (28.57%)
         occurrences all number
    7
    8
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Social circumstances
    Social circumstances
         subjects affected / exposed
    1 / 18 (5.56%)
    4 / 21 (19.05%)
         occurrences all number
    2
    4
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    14 / 18 (77.78%)
    13 / 21 (61.90%)
         occurrences all number
    41
    53
    Investigations
    Investigations
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 21 (14.29%)
         occurrences all number
    1
    3
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    5 / 18 (27.78%)
    7 / 21 (33.33%)
         occurrences all number
    6
    19
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    9 / 18 (50.00%)
    10 / 21 (47.62%)
         occurrences all number
    17
    22
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Eye disorders
    Eye disorders
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    10 / 18 (55.56%)
    12 / 21 (57.14%)
         occurrences all number
    25
    28
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    4 / 18 (22.22%)
    0 / 21 (0.00%)
         occurrences all number
    6
    0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    8 / 18 (44.44%)
    10 / 21 (47.62%)
         occurrences all number
    14
    14
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2019
    Updates made to some eligibility criteria. These updates were made for clarification purposes only and did not change the eligibility criteria itself. This impacted Pre-Randomisation Inclusion Criteria number 5, Pre-Randomisation Exclusion Criteria numbers 5, 10 and 11 and Randomisation Exclusion Criteria number 8 and 9. Full stability data for pramipexole was also available at this stage and this section of the protocol was therefore updated to reflect that there were no specific storage requirements for the trial medication.
    23 Jul 2020
    Protocol updated in response to COVID-19 to allow delivery to continue during government and local restrictions, without compromising participant safety or trial primary outcomes. This included removal of blood pressure and pulse measurements (as agreed by the DMC); allowing for pre-randomisation and randomisation screening activities to also be carried out remotely; ability for pre-randomisation and randomisation stage consent discussions to be conducted via telephone/teleconference or videoconference before the patient attends a shorter face to face clinic visit to complete the consent form; more options regarding collection of urine samples and returning of unused IMP. Pre-Randomisation inclusion criterion number 5 was also updated for clarification purposes only.
    20 Oct 2020
    Updates to allow further flexibility regarding how the participant can initially be approached and to provide sites and participants with a further option regarding collection of unused IMP/empty bottles.
    15 Dec 2020
    Inclusion criteria added to state that participants should be in the pre-randomisation stage for a minimum of 23 days to increase flexibility for those participants who already met the remaining inclusion criteria allowing them to progress to the randomisation stage promptly and not delay their treatment.
    18 Feb 2021
    This amendment included an update to the inclusion and exclusion criteria to allow participants to enter the trial whilst taking certain antipsychotics, which could be adjusted during the pre-randomisation stage to meet the eligibility criteria for Randomisation. This update was made following a meeting with the funder and had the full support of both the PPI group and Trial Steering Committee. The update was approved by the HTA funder committee and their scientific advisers following submission of a written proposal which demonstrated that the co-administration of pramipexole in combination with a limited number of antipsychotics would allow increased recruitment and retention to the trial without comprising clinical effectiveness or safety.
    27 May 2021
    Protocol updated to correct the dose of an antipsychotic that can be used in the trial; to allow researchers to use a wider range of communication methods and to provide greater clarification around the timing and nature of trial procedures. As the trial was paused from March to September 2020 (reducing the amount of time available for the trial to complete the pilot phase), this amendment also outlined that, with the agreement of the funder, the pilot could start again in October 2020 with an end date of October 2021.
    13 May 2022
    This amendment related to the early closure of the PAX-BD trial. The protocol was amended to reflect this change and confirmed that all participants would have the opportunity to be followed up to treatment week 12, including those currently in the pre-randomisation stage of the trial. As well as this there were updates to the inclusion and exclusion criteria to aid sites when randomising the remaining participants to the randomisation stage.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Mar 2020
    Temporary halt implemented due to COVID-19 pandemic. The study was re-started via Substantial Amendment 8 dated 10.08.2020.
    10 Aug 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    n/a
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