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    Clinical Trial Results:
    Title: A phase 3, twelve-week, multi-center, multinational, randomized, double-blind, double-dummy, parallel group study to determine the efficacy, safety and tolerability of P2B001 once daily compared to its individual components in subjects with early Parkinson’s Disease and to a calibration arm of pramipexole ER. Methodology: This was a randomised, placebo-controlled, double-blind, double-dummy study design with a 12-week treatment period. Eligible subjects with Parkinson’s disease (PD) of less than 3 years’ duration participated in a titration phase of up to 6 weeks, followed by a maintenance phase. Subjects were randomised 2:2:2:1 into 1 of 4 treatment groups: P2B001 (a fixed low dose combination of pramipexole 0.6 mg [PPX] and rasagiline 0.75 mg [RAS]), PPX, RAS, or PramiER (the currently marketed version of pramipexole, extended release formulation). Treatments were taken once daily: 1 capsule (P2B001, PPX, RAS, or placebo) plus 1-3 tablets (PramiER or placebo). The study was conducted to evaluate the efficacy of the combined product P2B001 in comparison with its individual components (PPX and RAS) and to compare safety and efficacy with therapeutic doses of PramiER.

    Summary
    EudraCT number
    		 2017-001420-21
    Trial protocol
    		 DE   ES  
    Global end of trial date
    24 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2022
    First version publication date
    09 Sep 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    P2B001/003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03329508
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharma Two B Ltd
    Sponsor organisation address
    3 Pekeris St., Weizmann Science Park, Rehovot, Israel, 7670203
    Public contact
    Irit Aish, Pharma Two B Ltd, 00972 89472672, irita@Pharma2b.com
    Scientific contact
    Hadas Friedmann, Pharma Two B Ltd, 00972 89472672, hadas@pharma2b.com
    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
    10 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Aug 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the superiority of P2B001 0.6/0.75 mg as compared to its individual components (PPX 0.6 mg and RAS 0.75 mg) in the change from Baseline to End of Week 12 Visit in the Total Unified Parkinson's Disease Rating Scale (UPDRS) Score (sum of Parts II + III). This scale is the standard measurement of Parkinson’s symptoms and is well recognised as reliable, accurate, and valid.
    Protection of trial subjects
    The study and any amendments were reviewed and approved by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB). The study was monitored by an IDMC. The study was conducted according to the protocol, the laws, regulations and administrative provisions relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use, as applicable by national legislation and directives, including Directive 2001/20/EC of the European Parliament and the Council of the European Union and US 21 CFR Part 11, 50, 54, 56 and 312. The principles of informed consent, according to Declaration of Helsinki 1964 and all its updates, the International Conference on Harmonization (ICH) step 5 guidelines on Good Clinical Practice (GCP), 21 CFR part 50 of the FDA Regulations and/or EU Directives, were followed. The subjects were properly informed, given time to contemplate participation, and freely gave their consent by signing and dating the EC/IRB-approved informed consent form. The consent form and any other documents relevant to the consent process were submitted to the IEC/IRB together with the protocol and approved prior to study start. No rescue therapy was allowed during the treatment phase and for 2 weeks afterwards (until the safety follow-up visit), except in an emergency situation. If needed by the subject for adequate treatment of subject’s Parkinson's symptoms and according to the Investigator’s judgment, the study medication was discontinued and a rescue medication was administered. A Data and Safety Monitoring Board (DSMB) periodically reviewed, in an unblinded fashion, safety data accumulated in the study. The data that the DSMB received included adverse events (AEs), vital signs, and ECGs of subjects experiencing AEs.
    Background therapy
    		 All concomitant medication that the subject took from the Screening visit, plus any changes in concomitant medication or new medications, were recorded. Subjects were not permitted to receive concomitant therapy with any of the medications listed below for longer than 4 weeks or within the previous 1-3 months prior to baseline visit: •Other investigational therapy (washout period 30 days prior to study entry, Baseline Visit). •Previous monoamine oxidase (MAO)-B inhibitors •Previous levodopa or dopamine agonists •Previous anticholinergic drugs for PD •Subjects were permitted to take peripheral anticholinergic drugs if they were stable on low dose for at least 4 weeks prior to study entry. Once enrolled into the study, use of new peripheral anticholinergic drugs was prohibited •Non-selective MAO inhibitors •Dopamine antagonists •Ciprofloxacin or other CYP1A2 inhibitors that may affect RAS plasma concentrations •Antitussive agent dextromethorphan: co-administration with RAS may lead to psychosis •Analgesic agents such as tramadol, methadone, meperidine and propoxyphene due to risk of serotonin syndrome •St. John's Wort or cyclobenzaprine •Marijuana or previous exposure to marijuana during the last 30 days Care was taken to avoid or minimize use of sympathomimetic medications, including nasal, oral and ophthalmic decongestants and cold remedies due to possible hypertensive reactions. Care was taken when study drugs were given with sedating medications (e.g., diphenhydramine, doxylamine succinate and other first-generation antihistamines) due to possible additive sedative effects with pramipexole. Fifty-three subjects took antidepressant drugs concomitantly with the study medication. The subjects were closely followed up by site PI for signs of serotonin syndrome.
    Evidence for comparator
    		 Pramipexole and rasagiline are both approved drugs and routinely used in standard therapy for the treatment of individuals with PD. They have different mechanisms and there is reason to believe that their combined activity will be better than each individual drug as monotherapy, and that lower doses of each could be used without losing the therapeutic effect, while avoiding the side effects associated with higher doses of both drugs when taken as monotherapy.
    Actual start date of recruitment
    19 Jan 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
    Germany: 103
    Country: Number of subjects enrolled
    United States: 380
    Country: Number of subjects enrolled
    Spain: 59
    Country: Number of subjects enrolled
    Canada: 2
    Worldwide total number of subjects
    544
    EEA total number of subjects
    162
    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)
    268
    From 65 to 84 years
    276
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Subjects were recruited from 70 sites in North America and Europe. A total of 544 subjects were recruited to allow for close to 525 eligible subjects. The safety analysis set (519 subjects) included treated subjects.

    Pre-assignment
    Screening details
    		 Eligibility was evaluated as per the inclusion/exclusion Criteria. Personal interviews included medical history, physical and neurological examinations, and evaluation for trial eligibility by clinical staff and an external eligibility monitoring committee (EMC).

    Period 1
    Period 1 title
    Treatment period (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
    To preserve blinding, capsules of P2B001 0.6/0.75 mg, PPX 0.6 mg, RAS 0.75 mg, and placebo were visually identical. Tablets of PramiER and their placebos were visually identical. Blinding was maintained throughout the study. All personnel involved in subject assessment, monitoring, analysis and data management were blinded to the subject assignment. Specific, independent, unblinded study personnel from the CRO were available to provide the DSMB with periodic reports.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 P2B001
    Arm description
    		 P2B001: a fixed-dose combination extended-release (ER) capsule containing 0.6 mg pramipexole and 0.75 mg rasagiline; plus PramiER placebo tablets.
    Arm type
    		 Experimental

    Investigational medicinal product name
    P2B001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were instructed to take 1 capsule by mouth with a glass of water (240 mL), with or without food, and at about the same time each day.

    Investigational medicinal product name
    Placebo tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were instructed to take up to 3 PramiER placebo tablets (depending on dose 1.5-4.5 mg following titration phase) by mouth with a glass of water (240 mL), with or without food, and at about the same time each day.

    Arm title
    		 PPX 0.6
    Arm description
    		 Pramipexole: ER capsule containing 0.6 mg pramipexole; plus PramiER placebo tablets.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pramipexole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were instructed to take 1 capsule by mouth with a glass of water (240 mL), with or without food, and at about the same time each day.

    Investigational medicinal product name
    Placebo Tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were instructed to take up to 3 PramiER placebo tablets (depending on dose 1.5-4.5 mg following titration phase) by mouth with a glass of water (240 mL), with or without food, and at about the same time each day.

    Arm title
    		 RAS 0.75
    Arm description
    		 Rasagiline: ER capsule containing 0.75 mg Rasagiline; plus PramiER placebo tablets.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rasagiline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were instructed to take 1 capsule by mouth with a glass of water (240 mL), with or without food, and at about the same time each day.

    Investigational medicinal product name
    Placebo Tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were instructed to take up to 3 PramiER placebo tablets (depending on dose 1.5-4.5 mg following titration phase) by mouth with a glass of water (240 mL), with or without food, and at about the same time each day.

    Arm title
    		 PramiER
    Arm description
    		 PramiER: currently marketed ER tablets; plus placebo capsules (matching the experimental arms).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PramiER
    Investigational medicinal product code
    Other name
    Pramipexole extended-release
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose of PramiER was 0.375 mg given once per day. Based on efficacy and tolerability, dosages were increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 and 1.5 mg increments up to a maximum recommended dose of 4.5 mg per day. E Subjects were instructed to take up to 3 PramiER placebo tablets (depending on dose 1.5-4.5 mg following titration phase) by mouth with a glass of water (240 mL), with or without food, and at about the same time each day.

    Investigational medicinal product name
    Placebo Capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were instructed to take placebo capsules by mouth with a glass of water (240 mL), with or without food, at about the same time every day.

    Number of subjects in period 1
    		P2B001 PPX 0.6 RAS 0.75 PramiER
    Started
    157
    156
    154
    77
    Completed
    137
    137
    134
    67
    Not completed
    20
    19
    20
    10
         Request of primary care physician or investigator
    1
    -
    -
    -
         Unable to achieve minimum dose of PramiER (1.5 mg)
    -
    1
    -
    -
         Adverse event, non-fatal
    8
    6
    4
    5
         Other
    1
    2
    1
    1
         Adverse event (prior to treatment)
    -
    -
    1
    -
         Other reason (prior to first dose)
    -
    -
    -
    1
         Additional non-protocol related therapy required
    1
    -
    -
    -
         Withdrew consent prior to first dose
    7
    4
    6
    2
         Erroneously randomised
    -
    4
    -
    -
         Lack of efficacy
    2
    2
    8
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    P2B001
    Reporting group description
    		 P2B001: a fixed-dose combination extended-release (ER) capsule containing 0.6 mg pramipexole and 0.75 mg rasagiline; plus PramiER placebo tablets.

    Reporting group title
    PPX 0.6
    Reporting group description
    		 Pramipexole: ER capsule containing 0.6 mg pramipexole; plus PramiER placebo tablets.

    Reporting group title
    RAS 0.75
    Reporting group description
    		 Rasagiline: ER capsule containing 0.75 mg Rasagiline; plus PramiER placebo tablets.

    Reporting group title
    PramiER
    Reporting group description
    		 PramiER: currently marketed ER tablets; plus placebo capsules (matching the experimental arms).

    Reporting group values
    		 P2B001 PPX 0.6 RAS 0.75 PramiER Total
    Number of subjects
    		 157 156 154 77 544
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.9 ( 9.4 ) 64.9 ( 8.4 ) 65.1 ( 9.5 ) 63.9 ( 8.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 51 52 48 24 175
        Male
    		 106 104 106 53 369
    Baseline Total UPDRS Scores (Parts II+III)
    Unified Parkinson's Disease Rating Scale (UPDRS) defined as sum of Parts II + III (scores 0-160). This scale is the standard measurement of Parkinson’s symptoms and is well recognized as reliable, accurate, and valid.
    Units: UPDRS Scores (Parts II+III)
        arithmetic mean (standard deviation)
    		 30.7 ( 9.9 ) 31.3 ( 11.0 ) 31.3 ( 10.2 ) 28.8 ( 10.0 ) -
    Baseline Total UPDRS II ADL
    UPDRS II - a self-evaluation of the activities of daily life (ADLs) including speech, swallowing, handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food.
    Units: UPDRS II Score
        arithmetic mean (standard deviation)
    		 8.1 ( 3.7 ) 8.1 ( 4.3 ) 8.2 ( 3.8 ) 7.9 ( 4.5 ) -
    Baseline Total UPDRS III Motor
    UPDRS III - a clinician-scored monitored motor evaluation.
    Units: UPDRS III Score
        arithmetic mean (standard deviation)
    		 22.6 ( 7.5 ) 23.3 ( 8.0 ) 22.9 ( 7.7 ) 20.9 ( 6.9 ) -
    Baseline Total MMSE Score
    Mini mental state examination (MMSE) is a commonly used set of questions for screening cognitive function.
    Units: MMSE Score
        arithmetic mean (standard deviation)
    		 29.0 ( 1.1 ) 29.0 ( 1.1 ) 29.1 ( 1.0 ) 29.1 ( 1.1 ) -
    Baseline Total ESS Score
    The Epworth Sleepiness Scale (ESS) is a questionnaire to check a person’s sleepiness during the day.
    Units: ESS Score
        arithmetic mean (standard deviation)
    		 5.5 ( 4.0 ) 6.2 ( 4.0 ) 5.7 ( 4.3 ) 6.1 ( 4.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    P2B001
    Reporting group description
    		 P2B001: a fixed-dose combination extended-release (ER) capsule containing 0.6 mg pramipexole and 0.75 mg rasagiline; plus PramiER placebo tablets.

    Reporting group title
    PPX 0.6
    Reporting group description
    		 Pramipexole: ER capsule containing 0.6 mg pramipexole; plus PramiER placebo tablets.

    Reporting group title
    RAS 0.75
    Reporting group description
    		 Rasagiline: ER capsule containing 0.75 mg Rasagiline; plus PramiER placebo tablets.

    Reporting group title
    PramiER
    Reporting group description
    		 PramiER: currently marketed ER tablets; plus placebo capsules (matching the experimental arms).

    Primary: Total UPDRS score changes from baseline to Week 12

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    End point title
    		 Total UPDRS score changes from baseline to Week 12
    End point description
    The primary efficacy endpoint for this study was the change from Baseline to Week 12 Visit in Total UPDRS score (defined as sum of Parts II + III, scores 0-160). The data is presented as a model adjusted LSM of the change from baseline in the mITT population.
    End point type
    Primary
    End point timeframe
    From baseline to the end of Week 12.
    End point values
    		 P2B001 PPX 0.6 RAS 0.75 PramiER
    Number of subjects analysed
    147
    144
    144
    72
    Units: UPDRS Score
        least squares mean (standard error)
    -7.98 ( 0.60 )
    -5.32 ( 0.61 )
    -4.69 ( 0.61 )
    -8.35 ( 0.86 )
    Statistical analysis title
    		 P2B001 vs PPX
    Statistical analysis description
    A mixed model repeated measures (MMRM) analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PPX 0.6
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -2.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.33
         upper limit
    		 -1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85
    Statistical analysis title
    		 P2B001 vs RAS
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    RAS 0.75 v P2B001
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.96
         upper limit
    		 -1.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85
    Statistical analysis title
    		 P2B001 vs PramiER
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PramiER
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.7197
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.67
         upper limit
    		 2.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.04
    Notes
    [1] - Exploratory
    Statistical analysis title
    		 P2B001 vs PramiER - Non-inferiority
    Statistical analysis description
    P2B001 was not statistically significantly different from a marketed dose of PramiER for the Total UPDRS (titrated to an optimal dose for each individual subject; 1.5-4.5 mg with mean = 3.2 mg). A post-hoc non-inferiority analysis was conducted and showed that P2B001 is not inferior to PramiER using a 3-point threshold margin.
    Comparison groups
    P2B001 v PramiER
    Number of subjects included in analysis
    219
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0052
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 2.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.96

    Secondary: Total ESS score changes from baseline to Week 12

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    End point title
    		 Total ESS score changes from baseline to Week 12
    End point description
    The first secondary endpoint was the change from baseline to end of Week 12 in total Epworth Sleepiness Scale (ESS) score. The data are presented as a model adjusted LSM of the change from baseline in the mITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to end of Week 12.
    End point values
    		 P2B001 PPX 0.6 RAS 0.75 PramiER
    Number of subjects analysed
    147
    144
    144
    72
    Units: ESS Score
        least squares mean (standard error)
    -0.33 ( 0.25 )
    0.39 ( 0.25 )
    -0.81 ( 0.26 )
    2.33 ( 0.36 )
    Statistical analysis title
    		 P2B001 vs PPX
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PPX 0.6
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0399
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.41
         upper limit
    		 -0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [2] - Exploratory
    Statistical analysis title
    		 P2B001 vs RAS
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v RAS 0.75
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.1756
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 1.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [3] - Exploratory
    Statistical analysis title
    		 P2B001 vs PramiER
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PramiER
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -2.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 -1.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.43

    Secondary: Total UPDRS III Motor changes from baseline to Week 12

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    End point title
    		 Total UPDRS III Motor changes from baseline to Week 12
    End point description
    The second secondary endpoint was the change from baseline to end of Week 12 in total UPDRS III Motor score. The data is presented as a model adjusted LSM of the change from baseline in the mITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to end of Week 12.
    End point values
    		 P2B001 PPX 0.6 RAS 0.75 PramiER
    Number of subjects analysed
    147
    144
    144
    72
    Units: UPDRS Score
        least squares mean (standard error)
    -5.82 ( 0.47 )
    -4.30 ( 0.48 )
    -4.07 ( 0.48 )
    -6.38 ( 0.68 )
    Statistical analysis title
    		 P2B001 vs PPX
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PPX 0.6
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0231
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.84
         upper limit
    		 -0.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.67
    Notes
    [4] - Exploratory
    Statistical analysis title
    		 P2B001 vs RAS
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v RAS 0.75
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0092
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.06
         upper limit
    		 -0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.67
    Notes
    [5] - Exploratory
    Statistical analysis title
    		 P2B001 vs PramiER
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PramiER
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.5093
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.07
         upper limit
    		 2.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.82
    Notes
    [6] - Exploratory

    Secondary: Total UPDRS II ADL changes from baseline to Week 12

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    End point title
    		 Total UPDRS II ADL changes from baseline to Week 12
    End point description
    The third secondary endpoint was the change from baseline to end of Week 12 in total UPDRS II ADL score. The data is presented as a model adjusted LSM of the change from baseline in the mITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to end of Week 12.
    End point values
    		 P2B001 PPX 0.6 RAS 0.75 PramiER
    Number of subjects analysed
    147
    144
    144
    72
    Units: UPDRS Score
        least squares mean (standard error)
    -2.14 ( 0.22 )
    -0.97 ( 0.22 )
    -0.62 ( 0.22 )
    -2.02 ( 0.31 )
    Statistical analysis title
    		 P2B001 vs PPX
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PPX 0.6
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.77
         upper limit
    		 -0.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Notes
    [7] - Exploratory
    Statistical analysis title
    		 P2B001 vs RAS
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v RAS 0.75
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.13
         upper limit
    		 -0.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Notes
    [8] - Exploratory
    Statistical analysis title
    		 P2B001 vs PramiER
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PramiER
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.7367
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 0.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38
    Notes
    [9] - Exploratory

    Secondary: Change in ADL subscale score of PDQ39 from baseline to Week 12

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    End point title
    		 Change in ADL subscale score of PDQ39 from baseline to Week 12
    End point description
    The fourth secondary endpoint was the change from baseline to end of Week 12 in ADL subscale score of PDQ39. The data is presented as a model adjusted LSM of the change from baseline in the mITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to end of Week 12.
    End point values
    		 P2B001 PPX 0.6 RAS 0.75 PramiER
    Number of subjects analysed
    147
    144
    144
    72
    Units: PDQ39 score
        least squares mean (standard error)
    -5.30 ( 0.89 )
    -3.40 ( 0.90 )
    -2.04 ( 0.92 )
    -3.12 ( 1.27 )
    Statistical analysis title
    		 P2B001 vs PPX
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PPX 0.6
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.1299
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.36
         upper limit
    		 0.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.25
    Notes
    [10] - Exploratory
    Statistical analysis title
    		 P2B001 vs RAS
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v RAS 0.75
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0099
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -3.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.73
         upper limit
    		 -0.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.26
    Notes
    [11] - Exploratory
    Statistical analysis title
    		 P2B001 vs PramiER
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PramiER
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.1589
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -2.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.21
         upper limit
    		 0.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.54
    Notes
    [12] - Exploratory

    Secondary: Total PDQ39 score changes from baseline to Week 12

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    End point title
    		 Total PDQ39 score changes from baseline to Week 12
    End point description
    The fifth secondary endpoint was the change from baseline to end of Week 12 in total PDQ39 score. The data is presented as a model adjusted LSM of the change from baseline in the mITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to end of Week 12.
    End point values
    		 P2B001 PPX 0.6 RAS 0.75 PramiER
    Number of subjects analysed
    147
    144
    144
    72
    Units: PDQ39 score
        least squares mean (standard error)
    -2.58 ( 0.55 )
    -1.56 ( 0.55 )
    -1.33 ( 0.57 )
    -0.73 ( 0.78 )
    Statistical analysis title
    		 P2B001 vs PPX
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PPX 0.6
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.1789
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.53
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.76
    Notes
    [13] - Exploratory
    Statistical analysis title
    		 P2B001 vs RAS
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v RAS 0.75
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.1047
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.78
         upper limit
    		 0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.77
    Notes
    [14] - Exploratory
    Statistical analysis title
    		 P2B001 vs PramiER
    Statistical analysis description
    A MMRM analysis included fixed effects: categorical scheduled week by treatment interaction, CGR1 and baseline total UPDRS score. Unstructured covariance was used, and REML estimation method and degrees of freedom adjusted using the Kenward-Roger method. Data from all 3 scheduled changes from Baseline (derived) to post-Baseline visits (Weeks 5, 8 and 12) were used as response and differences between the treatments at Week 12 were estimated using contrasts.
    Comparison groups
    P2B001 v PramiER
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.0494
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -1.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.94
    Notes
    [15] - Exploratory

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to end of Week 12.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    P2B001
    Reporting group description
    		 P2B001: a fixed-dose combination ER capsule containing 0.6 mg pramipexole and 0.75 mg rasagiline; plus PramiER placebo tablets.

    Reporting group title
    PPX 0.6
    Reporting group description
    		 Pramipexole: ER capsule containing 0.6 mg pramipexole; plus PramiER placebo tablets.

    Reporting group title
    RAS 0.75
    Reporting group description
    		 Rasagiline: ER capsule containing 0.75 mg Rasagiline; plus PramiER placebo tablets.

    Reporting group title
    PramiER
    Reporting group description
    		 PramiER: currently marketed ER tablets; plus placebo capsules (matching the experimental arms).

    Serious adverse events
    		 P2B001 PPX 0.6 RAS 0.75 PramiER
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 150 (2.00%)
    3 / 148 (2.03%)
    2 / 147 (1.36%)
    0 / 74 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 148 (0.00%)
    1 / 147 (0.68%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle haemorrhage
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 148 (0.00%)
    1 / 147 (0.68%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 148 (0.00%)
    1 / 147 (0.68%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 P2B001 PPX 0.6 RAS 0.75 PramiER
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 150 (52.00%)
    86 / 148 (58.11%)
    52 / 147 (35.37%)
    54 / 74 (72.97%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 150 (4.00%)
    8 / 148 (5.41%)
    5 / 147 (3.40%)
    1 / 74 (1.35%)
         occurrences all number
    6
    10
    12
    2
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    4 / 150 (2.67%)
    5 / 148 (3.38%)
    4 / 147 (2.72%)
    9 / 74 (12.16%)
         occurrences all number
    4
    6
    4
    9
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    22 / 150 (14.67%)
    27 / 148 (18.24%)
    7 / 147 (4.76%)
    23 / 74 (31.08%)
         occurrences all number
    25
    32
    7
    29
    Dizziness
         subjects affected / exposed
    16 / 150 (10.67%)
    14 / 148 (9.46%)
    19 / 147 (12.93%)
    7 / 74 (9.46%)
         occurrences all number
    18
    15
    21
    7
    Headache
         subjects affected / exposed
    9 / 150 (6.00%)
    14 / 148 (9.46%)
    9 / 147 (6.12%)
    5 / 74 (6.76%)
         occurrences all number
    14
    15
    12
    5
    Memory impairment
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 148 (0.00%)
    1 / 147 (0.68%)
    4 / 74 (5.41%)
         occurrences all number
    0
    0
    1
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    23 / 150 (15.33%)
    22 / 148 (14.86%)
    2 / 147 (1.36%)
    13 / 74 (17.57%)
         occurrences all number
    27
    25
    2
    14
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    28 / 150 (18.67%)
    24 / 148 (16.22%)
    10 / 147 (6.80%)
    17 / 74 (22.97%)
         occurrences all number
    33
    29
    10
    22
    Constipation
         subjects affected / exposed
    6 / 150 (4.00%)
    11 / 148 (7.43%)
    9 / 147 (6.12%)
    7 / 74 (9.46%)
         occurrences all number
    6
    12
    9
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 150 (8.67%)
    9 / 148 (6.08%)
    4 / 147 (2.72%)
    7 / 74 (9.46%)
         occurrences all number
    14
    9
    4
    8
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 150 (1.33%)
    10 / 148 (6.76%)
    2 / 147 (1.36%)
    4 / 74 (5.41%)
         occurrences all number
    2
    11
    2
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 150 (2.00%)
    2 / 148 (1.35%)
    2 / 147 (1.36%)
    4 / 74 (5.41%)
         occurrences all number
    4
    2
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jul 2018
    • Revised text of inclusion criteria presented below: 3. Subject is male or female ≥35.0 years of age to ≤80.0 years of age at the time of enrollment. 5. Subject with disease duration less than 3 years since diagnosis. 8. Women of child-bearing potential (WOCBP)* must use a reliable method of contraception (e.g., oral contraceptive or long-term injectable or implantable hormonal contraceptive, double-barrier methods [such as condom plus diaphragm, condom plus spermicide foam, condom plus sponge], or intra-uterine devices) for the entire study duration, and must have a negative serum pregnancy test at Screening and negative urine pregnancy at baseline visit. *WOCBP are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopaused. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause. • Exclusion criteria 23 deleted • Change to Overall study design and plan description Text added: Down-titration phase: a 7 day gradual down titration of pramipexole ER or matching placebo. The down titration should be done by reducing the dose every two days by half (except for subjects taking 4.5 mg, these should reduce the dose to 3.0 mg and then continue to reduce by half every two days). There is no treatment with once daily P2B001/RAS 0.75/PPX0.6/Placebo capsules during this period. • Change to Section 5.2 Revised text: Subject loses their kit of study medication and a replacement kit is requested, in this situation the PI should request an emergency shipment to alert the distributor to ship the replacement kit urgently).
    16 Jul 2018
    Continued from above: • Change to Section 7.5 Text added: o Early Study Termination(EST) o A subject who requests to stop study participation for any reason before the end of week 12, including study treatment and study scheduled activities, will be requested to undergo a study termination visit as described in section 9.2.11 o The reasons for withdrawal could include the following: o Subject withdrawal of consent and refusal to continue participation in study o Pregnancy o Adverse Event/Experience o Loss to follow-up/failure to return o Death • Change to Section 8.3.5 Revised text in section 8.3.5: Concomitant medication logs will be completed at the Screening visit and will be updated at each subsequent visit. The logs will include the medication taken by the subject over the past 3 months. A separate log will record anti-PD medications that were previously used. • Change to Section 10 Revised text in section 10: All concomitant medication that the subject is taking from the screening visit should be recorded on the concomitant medications log. In addition, any changes in concomitant medication or new medications added, including as a result of an inter-current illness must be recorded in the case report forms. A separate log will record anti-PD medications taken prior to enrollment.
    16 Jul 2018
    Continued from above: • Change to Section 8.3.9 Revised text in section 8.3.9: Columbia Suicide Severity Rating Scale (CSSRS, see Appendix VIII) will be used. Baseline / screening version of the CSSRS will be used at screening visit. This version assesses suicidality in a patient’s lifetime and during the past six months. The Since Last Visit (SLV) version of the CSSRS will be used at all consequent visits. This version assesses suicidality since the patient’s last visit. Efforts must be made to ensure that the same trained team member completes this questionnaire for each subject. A subject with any suicidal ideation that answered YES to questions 4 or 5 in the CSSRS questionnaire will be referred to a mental health professional. CSSRS-SLV will be used on the baseline visit and at end of weeks 3, 5, 8, 12/Treatment Termination visit and end of week 14 (visits 3, 4, 5, 6 and 7). • Change to Section 9.2.3 Revised text in section 9.2.3: CSSRS-SLV • Change to Section 8.4.1 UPDRS Revised text: The UPDRS part II will be completed by a trained neurologist or other trained research staff member as delegated by the Site PI. For consistency efforts must be made to ensure that the same trained research staff member will do the UPDRS part II at all required visits for all subjects.
    16 Jul 2018
    Continued from above: • Change to Section 9.2.2 Revised text in section 9.2.2: After completion of all the testing for the assessment of eligibility, it will be decided by the Investigator whether the subject is eligible for the study. For a subject to be eligible all the inclusion criteria must be met and none of the exclusion criteria must apply. Therefore, all the results from the screening procedures must be available before determining a subject’s eligibility. Subjects found eligible will be further reviewed by a central eligibility monitoring committee (see 16.4.2). The maximal interval between the screening and baseline visits is 28 days that can be extended up to 35 days, however, additional Sponsor approval will be required. . Subjects that were screen failures may rescreen for the study. If the rescreening visit is within 28 days (or 35 days with sponsor approval) of the original blood testing, the screening number remains the same and the blood draw does not need to be repeated, unless it is the reason for the screening failure. Subjects complying with inclusion/exclusion criteria will be randomly assigned to one of the four treatment groups by a central website based computer program using Randomization Trial Supply Management (RTSM). A randomization form must be completed via the RTSM as soon as possible after subject eligibility was confirmed in order to trigger shipment of investigational product for this subject.
    16 Jul 2018
    Continued from above: • Change to Section 9.2.3 Revised text in section 9.2.3: The time between visit 1 (screening), and visit 2 (baseline), will be no less than 24 hours and no more than 28 days (or 35 days with sponsor approval). In this visit a medication kit will be dispensed to him/her together with a leaflet of instructions for use. The subject will be given an emergency contact card with 24 hour contact numbers. The subject will be instructed to keep the contact card with him/her at all times. The following activities will be performed: - Dispensation of study medication kit • Change to Section 12.2 Revised text in section 12.2: All subjects will be assigned a unique subject number at the screening visit (visit 1). The subjects found to be eligible for the study by both PI and the EMC will be randomized as soon as possible in order to trigger shipment of investigational medication to the subject. • Change to Section 22.1 appendix I; schedule of activities Revised text below table: ** The maximal interval between the screening and baseline visits can be extended to 35 days; however, additional Sponsor approval will be required. • Change to Section 12.6 Revised text in section 12.6: Subjects will be instructed to bring the last medication box used (open and unopened bottles) with them to visits 4, 5, 6 and 7 for compliance and accountability checks. During each study visits, (visits 4-7), the Investigator and/or site coordinator will assess the subject’s compliance with the prescribed regimen for the study medication.
    16 Jul 2018
    Continued from above: • Change to Section 12.7 Revised text in section 12.7: For study drug accountability, the subject will be requested to bring for visit 4-7, all empty, partially used or unused bottles from the box used during the previous month. • Change to Section 21 Investigator Agreements Deleted text: Place to add sponsor representative name and signature was deleted. • Change to Section 22.9 Appendix IX: UPDRS Deleted text: “half point scores are allowed for Part III questions)”
    18 Nov 2020
    • Change sponsor representative details on title page • Change to details on eligible subjects in each arm Revised text: Up to 525 eligible subjects with early untreated PD, who are not early terminated from the study during screening or baseline visits and are randomized to treatment with P2B001 0.6/0.75 or pramipexole 0.6 mg once daily, or rasagiline 0.75 mg once daily, or pramipexole ER titrated to optimal dose (1.5, 3.0 or 4.5mg) using a randomization scheme of 2:2:2:1, respectively. • Change to Section 15.3 Revised text: Subjects will be randomized to treatment with P2B001 0.6/0.75 (approximately 150 subjects), or pramipexole 0.6 mg once daily (approximately 150 subjects), or rasagiline 0.75 mg once daily (approximately 150 subjects), or pramipexole ER titrated to therapeutic optimal dose (approximately 75 subjects) using a randomization scheme of 2:2:2:1, respectively, stratified by region. • Text added to Section 7.5 Early Discontinuation Subjects Text added on Early Treatment Termination (ETT): The reasons for withdrawal could include the following: - Subject withdrawal of consent to be treated with study medication(s) but still consenting to participate in study visits and activities - Request of the Investigator for any medical or other reason - Request of the primary care physician via the Investigator - Pregnancy - Non-compliance - Subject who cannot achieve the minimum therapeutic dose of pramipexole ER (or placebo) of 1.5 mg per day. - Major protocol violation - Adverse Event/Experience - Lack of Efficacy - Subjects who, according to the Investigator, need additional therapy that is excluded in the protocol for the treatment of the disease. - Any other reason relating to the patient's safety or integrity of the study data.
    18 Nov 2020
    Continued from above: • Text added to Section 7.5 Early Discontinuation Subjects Text added on Early Study Termination (ETT): A subject who requests to stop study participation for any reason before the end of week 12, including study treatment and study scheduled activities, will be requested to undergo a study termination visit as described in section 9.2.11, unless erroneously randomized or withdrew consent prior to first dose. The reasons for EST could include the following: - Pregnancy - Adverse Event/Experience - Subject withdrawal of consent and refusal to continue participation in study due to lack of efficacy or due to other reasons - Lost to follow-up/failure to return - Death - Erroneously randomized - Withdrew consent prior to first dose • Change to Section 9.2.2 Added text in section 9.2.2: Extension beyond 35 days and up to 90 days may be approved but will require a new collection of screening laboratory samples at an unscheduled visit prior to baseline. • Change to Section 9.2.3 Revised text in section 9.2.3: The time between visit 1 (screening), and visit 2 (baseline), will be no less than 24 hours and no more than 28 days (or up to 90 days with sponsor approval).
    18 Nov 2020
    Continued from above: • Change to Appendix I Added text below table of activities Appendix I: 35 – 90 days may be approved but a new collection of screening laboratory samples will be required to verify eligibility prior to baseline. • Change to Section 9.2.11 Revised text in section 9.2.11 Early Treatment/Study Termination Visit: Subjects who terminate treatment/study early (following first dose and prior to visit 6) according to criteria in section 7.5 will be requested to undergo a treatment/study termination visit. • Change to definition of ITT analyses set in Section 15.4 Revised text: Intention-to-Treat Analysis Set (ITT): The ITT Analysis Set will include all eligible and randomized subjects who are not early terminated from the study during screening or baseline visits according to the treatment group to which they are originally randomized to. • Change to definition of mITT analyses set in Section 15.4 Revised text: Modified Intention-to-Treat Analysis Set (mITT): The mITT Analyses Set is a subset of the ITT Analysis Set including subjects who have at least one post-baseline UPDRS assessment and have taken at least one study drug dose according to the treatment group to which they are originally randomized to. • Change to Synopsis and Section 15.3 Added text: If ever there is a discrepancy in the between the Protocol and the Statistical Analysis Plan, the methods defined in the SAP will have precedence.
    23 Aug 2021
    Changes in the planned analysis prior to unblinding: The mITT analysis set in the original statistical analysis plan (SAP) (pre-SAP addendum) included only subjects who were randomised, took at least one dose of study drug, and had at least one post-baseline UPDRS (parts II + III) score at the planned scheduled visits. This definition excluded 13 subjects who terminated treatment or the study before the first post baseline scheduled visit at the end of Week 5, but completed a post-baseline UPDRS (parts II+III) measurement at an unscheduled visit. A change in the definition of mITT analysis set was submitted to the FDA prior to the unblinding of the study in an addendum to the SAP in which these subjects were included. The mITT analysis set according to the SAP addendum included subjects that were randomised, took at least one dose of study drug and had at least one post-baseline (UPDRS Parts II + III) score at the planned scheduled visits or at an unscheduled early termination visit. A sensitivity analysis to the principal analysis of the primary endpoint with the pre-SAP addendum analysis set was done to test the impact of this change.

    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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