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    Clinical Trial Results:
    A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure

    Summary
    EudraCT number
    2018-003941-41
    Trial protocol
    GB   EE   PL   ES   AT   DK   BG   HU   PT   IT  
    Global end of trial date
    10 Nov 2021

    Results information
    Results version number
    v2(current)
    This version publication date
    23 Feb 2023
    First version publication date
    15 Dec 2022
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Edits to the primary endpoint description.

    Trial information

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    Trial identification
    Sponsor protocol code
    0170
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03829657
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Theravance Biopharma Ireland Limited
    Sponsor organisation address
    Ten Earlsfort Terrace, Dublin, Ireland, D02 T380
    Public contact
    Brett Haumann, Theravance Biopharma Ireland Limited, 00 35315394800, bhaumann@theravance.com
    Scientific contact
    Brett Haumann, Theravance Biopharma Ireland Limited, 00 35315394800, bhaumann@theravance.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 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the durability of effect of ampreloxetine in participants with symptomatic neurogenic orthostatic hypotension (symptomatic nOH) due to multiple system atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) compared with placebo over a double-blind, randomized withdrawal (RW) period of 6 weeks following an open label (OL) treatment of 16 weeks. To evaluate the safety and tolerability of ampreloxetine when taken for up to 22 weeks.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Harmonised Tripartite Guideline.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Feb 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
    Austria: 1
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    United States: 50
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Ukraine: 21
    Country: Number of subjects enrolled
    United Kingdom: 18
    Worldwide total number of subjects
    203
    EEA total number of subjects
    81
    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)
    203
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled from February 2019 to November 2021.

    Pre-assignment
    Screening details
    203 participants were enrolled in the OL treatment period and 128 participants who completed the OL treatment period continued in the RW treatment period.

    Period 1
    Period 1 title
    OL Treatment Period
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    OL Treatment Period: 0169 Placebo Rollover
    Arm description
    Participants who received the placebo in study 0169, received 10 mg oral ampreloxetine once a day (QD) for up to 16 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Ampreloxetine
    Investigational medicinal product code
    Other name
    TD-9855
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 10 mg QD for up to 16 weeks.

    Arm title
    OL Treatment Period: 0169 Ampreloxetine
    Arm description
    Participants who received ampreloxetine in study 0169, received 10 mg oral ampreloxetine QD for up to 16 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Ampreloxetine
    Investigational medicinal product code
    Other name
    TD-9855
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 10 mg QD for up to 16 weeks.

    Arm title
    OL Treatment Period: De Novo
    Arm description
    Participants with symptomatic neurogenic orthostatic hypotension (nOH) who met all applicable study inclusion criteria and none of the applicable exclusion criteria, received 10 mg oral ampreloxetine QD for up to 16 weeks. These participants did not roll over from the 0169 study.
    Arm type
    Experimental

    Investigational medicinal product name
    Ampreloxetine
    Investigational medicinal product code
    Other name
    TD-9855
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 10 mg QD for up to 16 weeks.

    Number of subjects in period 1
    OL Treatment Period: 0169 Placebo Rollover OL Treatment Period: 0169 Ampreloxetine OL Treatment Period: De Novo
    Started
    85
    85
    33
    Completed
    52
    64
    12
    Not completed
    33
    21
    21
         Consent withdrawn by subject
    6
    7
    5
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    12
    4
    2
         Miscellaneous
    3
    1
    1
         Failure to Meet Day 29 Continuation Criterion
    10
    6
    4
         Study Terminated by Sponsor
    1
    3
    9
    Period 2
    Period 2 title
    RW Treatment Period (Week 16 to Week 24)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    RW Treatment Period: Placebo
    Arm description
    Participants who completed the OL treatment period and were randomized to receive oral placebo QD for a further 6 weeks in the RW treatment period.
    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
    Participants received the placebo QD for a further 6 weeks.

    Arm title
    RW Treatment Period: Ampreloxetine
    Arm description
    Participants who completed the OL treatment period and were randomized to receive 10 mg oral ampreloxetine QD for a further 6 weeks in the RW treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Ampreloxetine
    Investigational medicinal product code
    Other name
    TD-9855
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 10 mg QD for a further 6 weeks.

    Number of subjects in period 2
    RW Treatment Period: Placebo RW Treatment Period: Ampreloxetine
    Started
    64
    64
    Completed
    61
    58
    Not completed
    3
    6
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    -
    1
         Miscellaneous
    -
    1
         Study Terminated by Sponsor
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OL Treatment Period: 0169 Placebo Rollover
    Reporting group description
    Participants who received the placebo in study 0169, received 10 mg oral ampreloxetine once a day (QD) for up to 16 weeks.

    Reporting group title
    OL Treatment Period: 0169 Ampreloxetine
    Reporting group description
    Participants who received ampreloxetine in study 0169, received 10 mg oral ampreloxetine QD for up to 16 weeks.

    Reporting group title
    OL Treatment Period: De Novo
    Reporting group description
    Participants with symptomatic neurogenic orthostatic hypotension (nOH) who met all applicable study inclusion criteria and none of the applicable exclusion criteria, received 10 mg oral ampreloxetine QD for up to 16 weeks. These participants did not roll over from the 0169 study.

    Reporting group values
    OL Treatment Period: 0169 Placebo Rollover OL Treatment Period: 0169 Ampreloxetine OL Treatment Period: De Novo Total
    Number of subjects
    85 85 33 203
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    OL Treatment Period Safety Analysis Set: all enrolled participants who received at least 1 dose of ampreloxetine during the OL period. 3 participants are not included in the analysis and the N value = 200. 0169 Placebo Rollover N = 83 0169 Ampreloxetine Rollover N = 85 De Novo N = 32
    Units: years
        arithmetic mean (standard deviation)
    68.2 ( 9.35 ) 68.2 ( 9.00 ) 69.0 ( 7.97 ) -
    Gender categorical
    Units: Subjects
        Female
    22 30 8 60
        Male
    61 55 24 140
        Not Reported
    2 0 1 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2 4 0 6
        Not Hispanic or Latino
    77 76 32 185
        Unknown or Not Reported
    6 5 1 12
    Race/Ethnicity
    Units: Subjects
        White
    80 83 31 194
        Black or African American
    0 1 1 2
        Asian
    2 1 0 3
        Other
    1 0 0 1
        Not Reported
    2 0 1 3

    End points

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    End points reporting groups
    Reporting group title
    OL Treatment Period: 0169 Placebo Rollover
    Reporting group description
    Participants who received the placebo in study 0169, received 10 mg oral ampreloxetine once a day (QD) for up to 16 weeks.

    Reporting group title
    OL Treatment Period: 0169 Ampreloxetine
    Reporting group description
    Participants who received ampreloxetine in study 0169, received 10 mg oral ampreloxetine QD for up to 16 weeks.

    Reporting group title
    OL Treatment Period: De Novo
    Reporting group description
    Participants with symptomatic neurogenic orthostatic hypotension (nOH) who met all applicable study inclusion criteria and none of the applicable exclusion criteria, received 10 mg oral ampreloxetine QD for up to 16 weeks. These participants did not roll over from the 0169 study.
    Reporting group title
    RW Treatment Period: Placebo
    Reporting group description
    Participants who completed the OL treatment period and were randomized to receive oral placebo QD for a further 6 weeks in the RW treatment period.

    Reporting group title
    RW Treatment Period: Ampreloxetine
    Reporting group description
    Participants who completed the OL treatment period and were randomized to receive 10 mg oral ampreloxetine QD for a further 6 weeks in the RW treatment period.

    Primary: Proportion of Treatment Failure at Week 6 of RW Treatment Period

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    End point title
    Proportion of Treatment Failure at Week 6 of RW Treatment Period
    End point description
    Treatment failure was defined as proportion of participants who met the following criteria at Week 6 following randomization: Change (worsening) from baseline in Question 1 of the Orthostatic Hypotension Symptom Assessment (OHSA#1) score of 1.0 point and worsening of disease severity as assessed by a 1-point change in Patient Global Impression of Severity (PGI-S). OHSA Question #1 assessed dizziness, lightheadedness, feeling faint, or feeling like you might blackout. PGI-S assessed patient's impression of disease severity. Least squares mean is the model-based proportion of participants with treatment failure using logistic regression. RW Treatment Period Full Analysis Set: all randomized participants who received at least 1 dose of study medication (ampreloxetine or placebo) following randomization.
    End point type
    Primary
    End point timeframe
    6-week randomized withdrawal period (Week 16 to Week 22)
    End point values
    RW Treatment Period: Placebo RW Treatment Period: Ampreloxetine
    Number of subjects analysed
    64
    64
    Units: Proportion of treatment failure
        least squares mean (standard error)
    0.42 ( 0.068 )
    0.30 ( 0.065 )
    Statistical analysis title
    Placebo vs Ampreloxetine
    Comparison groups
    RW Treatment Period: Placebo v RW Treatment Period: Ampreloxetine
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.196
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    1.29

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    OL Treatment Period: Day 1 to Week 16 (plus a 2 week follow-up period); RW Treatment Period: Week 16 to Week 24 (plus a 2 week follow-up period)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    OL Treatment Period
    Reporting group description
    Includes all participants in the OL treatment period. Participants received 10 mg oral ampreloxetine once a day (QD) for up to 16 weeks.

    Reporting group title
    RW Treatment Period: Placebo
    Reporting group description
    Participants who completed the OL treatment period and were randomized to receive oral placebo QD for a further 6 weeks in the RW treatment period.

    Reporting group title
    RW Treatment Period: Ampreloxetine
    Reporting group description
    Participants who completed the OL treatment period and were randomized to receive 10 mg oral ampreloxetine QD for a further 6 weeks in the RW treatment period.

    Serious adverse events
    OL Treatment Period RW Treatment Period: Placebo RW Treatment Period: Ampreloxetine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 200 (8.00%)
    2 / 64 (3.13%)
    4 / 64 (6.25%)
         number of deaths (all causes)
    5
    0
    2
         number of deaths resulting from adverse events
    0
    0
    1
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Bulbar palsy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Subcapsular renal haematoma
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    OL Treatment Period RW Treatment Period: Placebo RW Treatment Period: Ampreloxetine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 200 (52.50%)
    16 / 64 (25.00%)
    17 / 64 (26.56%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Diastolic hypertension
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Flushing
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Supine hypertension
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    White coat hypertension
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Discomfort
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    2
    0
    2
    Gait disturbance
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperthermia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Malaise
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Immune system disorders
    Allergy to vaccine
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Social circumstances
    Walking disability
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Gynaecomastia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Ovarian cyst
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Priapism
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Uterine enlargement
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Epistaxis
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Anxiety
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Bruxism
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Confusional state
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Hallucination
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Hallucination, visual
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hypomania
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    0
    Mental status changes
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Panic attack
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Sleep disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Investigations
    Post procedural discomfort
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    2
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Blood urea increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Colonoscopy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Cystoscopy
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    Glomerular filtration rate abnormal
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Haematocrit decreased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Troponin increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Back injury
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    0
    Fall
         subjects affected / exposed
    3 / 200 (1.50%)
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    1
    Hand fracture
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    Skin laceration
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Soft tissue injury
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Bundle branch block left
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Myocardial infarction
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    2
    0
    Tachycardia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Burning sensation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    7 / 200 (3.50%)
    1 / 64 (1.56%)
    2 / 64 (3.13%)
         occurrences all number
    13
    1
    2
    Dizziness exertional
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness postural
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    7
    0
    0
    Dyskinesia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    8 / 200 (4.00%)
    2 / 64 (3.13%)
    0 / 64 (0.00%)
         occurrences all number
    14
    6
    0
    Hypokinesia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Loss of consciousness
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Memory impairment
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Migraine with aura
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Multiple system atrophy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    On and off phenomenon
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Oromandibular dystonia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Parkinson's disease
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    1
    0
    1
    Radial nerve palsy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Radiculopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Spasmodic dysphonia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Speech disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    1
    0
    Syncope
         subjects affected / exposed
    4 / 200 (2.00%)
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    4
    0
    2
    Tremor
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Bulbar palsy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Anaemia vitamin B12 deficiency
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphopenia
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Diplopia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hypermetropia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Open angle glaucoma
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Vitreous floaters
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 200 (3.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    6
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    1
    0
    1
    Dry mouth
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    1
    0
    1
    Inguinal hernia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Large intestine polyp
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    7 / 200 (3.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    7
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    Retching
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Toothache
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hair growth rate abnormal
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hand dermatitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    4 / 200 (2.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    4
    0
    1
    Palmar erythema
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Rash
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Rash pruritic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    Calculus urinary
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Nocturia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary hesitation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Back pain
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Groin pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Mobility decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Neck pain
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    1
    0
    Osteoporosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Tendonitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    1
    COVID-19
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    12 / 200 (6.00%)
    3 / 64 (4.69%)
    2 / 64 (3.13%)
         occurrences all number
    17
    3
    3
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 64 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2019
    • Added the new drug name • Updated the number of countries • Increased the screening window to allow adequate time for NE sample processing • Updated the number of days in the screening period from 14 days (2 weeks) to 21 days (3 weeks) to allow adequate time for norepinephrine (NE) sample processing • Clarified and defined “sustained” in regard to systolic blood pressure (SBP) for at least 4 hours after 3 minutes of standing or after 5 minutes in the sitting position • Added ‘becoming pregnant’ as one of the stopping rules • Included a detailed description of highly acceptable methods of contraception including definition of sexual abstinence • Correction made in regard to diagnostic criteria • Made the wording concise in exclusion criteria • Removed specific OH medications • Removed the requirement that study medication must be taken “prior to breakfast” • Removed the requirement to contact the Sponsor prior to unblinding a participant's treatment • Clarified and defined acceptable contraception methods • Limited potential weight variations due to external factors like type of clothing etc. • Allowed fludrocortisone and cannabinoids • Prohibited the use of NE reuptake inhibitor (NRIs), NSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and psychostimulants • Updated the PGI-S to a 5-category scale • Removed reference to specific device (Kinesia 360) • Made language around assessments more generic • Allowed for possibility that some countries could not import the device
    04 Dec 2019
    • Added study name • Changed personnel • Added additional sites and countries • Provided clarification that, apart from primary and key secondary objectives, other objectives were now classified explicitly as exploratory • Increased screening period to allow sufficient time for conduct of screening procedures • Removed requirement of discussion with Sponsor’s medical monitor • Extended screening window to 4 weeks, other corresponding changes • Clarified diagnosis of PAF • Allowed enrollment of participant's with controlled diabetes mellitus • Droxidopa was not available in all countries where the trial was conducted; thus, only if applicable • Excluded participants with hypersensitivity to ampreloxetine • Added continuation criteria to synopsis • Prohibited alpha blockers • Clarified efficacy endpoints • Clarified the statistical testing procedure as discussed in detail in statistical analysis plan (SAP) • Improved wording • Provided clearer instructions on conduct of corresponding study procedures • Added terms for completeness • Clarified Study 0145 was completed and results were presented in protocol • Clarified the optimal time(s) protocol procedures should conducted • Allowed for a confirmation if there was doubt per Investigator’s opinion • Clarification procedure conduct • Clarified the need for additional testing if the participant had diabetes mellitus • Provide clarification of the chemistry panel • Removed involvement of Sponsor should the Investigator decide to withdraw a participant from the study
    20 Mar 2020
    • Additional electrocardiogram (ECG) added as a safety measure • Provided clarification on ECG completion duration • Clarified language and updated text to reflect internal standards
    05 Aug 2020
    • Added study and drug name and name of the new Clinical Study Director • References to “snOH” changed to “symptomatic nOH” to clearly define disease under study and consistency throughout the document • Clarified references for consistency throughout the document to differentiate those that had signed study informed consent form • Clarified that Study 0145 was completed and results were presented in the protocol • Stated reasoning for update in study design, which was the implementation of the Decentralized Platform in response to the COVID-19 pandemic • Clarified the screening visit must be performed in clinic • Clarified the role of the Engineering Steering Committee and their decision-making process • Added exclusion for SARS-CoV-2 infection due to COVID-19 pandemic • Clarity added, and order revised for consistency across the document, and to reflect the removal of smoking status subgroups in the SAP • Added baseline NE subgroups • Changed the postbaseline blood sample collection time point for pharmacodynamic markers (NR and dihydroxyphenylglycol) from Day 29 to Day 57 • To the planned analyses of standing SBP at 3 minutes and at 10 minutes during the orthostatic standing test, addition of similar analyses of standing heart rate at 3 minutes and at 10 minutes.

    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.
    De Novo participants in the OL treatment period had limited follow-up due to early termination of the study.
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