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    Clinical Trial Results:
    A Phase 3, 4-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure

    Summary
    EudraCT number
    		 2018-003289-15
    Trial protocol
    		 GB   EE   DE   DK   AT   HU   PL   ES   BG   PT   IT  
    Global end of trial date
    21 Jul 2021

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

    Trial information

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    Trial identification
    Sponsor protocol code
    0169
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03750552
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Theravance Biopharma
    Sponsor organisation address
    Connaught House, 1 Burlington Road, Dublin, Ireland, D04 C5Y6
    Public contact
    Medical Monitor, Theravance Biopharma Inc, +1 855 633 8479, medinfo@theravance.com
    Scientific contact
    Dr. Richard Graham, Theravance Biopharma Inc, +1 650 808 6000, rgraham@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
    21 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of TD-9855 in participants with multiple system atrophy, Parkinson’s disease, or pure autonomic failure experiencing symptomatic neurogenic orthostatic hypotension (nOH) compared with placebo at Week 4, as measured by the change from baseline of the Orthostatic Hypotension Symptom Assessment (OHSA) Question 1 (OHSA#1) score.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the ICH Harmonized Tripartite Guideline.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jun 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
    Russian Federation: 21
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Ukraine: 19
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    United States: 48
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    New Zealand: 1
    Worldwide total number of subjects
    195
    EEA total number of subjects
    78
    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)
    53
    From 65 to 84 years
    140
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 195 participants were enrolled across 76 sites in Australia, Austria, Bulgaria, Canada, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Portugal, Spain, Russia, Ukraine, United Kingdom and the United States.

    Pre-assignment
    Screening details
    		 Overall, 194 randomized participants received at least one dose of study drug. Eight participants from one site were excluded from all analysis sets except the Randomized Analysis Set due to data integrity concerns.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ampreloxetine
    Arm description
    		 Participants received ampreloxetine at a dose of 10 mg once daily (QD) for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ampreloxetine
    Investigational medicinal product code
    TD-9855
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received an oral tablet for ingestion.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo QD for 4 weeks.
    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 an oral tablet for ingestion.

    Number of subjects in period 1
    		Ampreloxetine Placebo
    Started
    98
    97
    Safety Analysis Set
    96
    90 [1]
    Full Analysis Set
    94
    90 [2]
    Completed
    90
    95
    Not completed
    8
    2
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    5
    1
         Not specified
    2
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only participants with valid data were included in this analysis set.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only participants with valid data were included in this analysis set.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ampreloxetine
    Reporting group description
    		 Participants received ampreloxetine at a dose of 10 mg once daily (QD) for 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo QD for 4 weeks.

    Reporting group values
    		 Ampreloxetine Placebo Total
    Number of subjects
    		 98 97 195
    Age categorical
    Units: Subjects
        < 65 years
    		 28 25 53
        ≥ 65 years
    		 70 72 142
    Gender categorical
    Units: Subjects
        Female
    		 37 29 66
        Male
    		 61 68 129
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 3 4
        Not Hispanic or Latino
    		 92 91 183
        Unknown or Not Reported
    		 5 3 8
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 1 2 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 0 1
        White
    		 96 94 190
        More than one race
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Ampreloxetine
    Reporting group description
    		 Participants received ampreloxetine at a dose of 10 mg once daily (QD) for 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo QD for 4 weeks.

    Primary: Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4

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    End point title
    		 Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 Score at Week 4
    End point description
    OHSA is an assessment of the severity of symptoms from low blood pressure. OHSA is a 6 question symptom assessment scale where each question uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. Question #1 assesses dizziness, lightheadedness, feeling faint, or feeling like you might blackout. A mean negative change from baseline indicates a better outcome. Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of OHSA question 1, were included in this analysis.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    		 Ampreloxetine Placebo
    Number of subjects analysed
    94
    90
    Units: Score on a scale
        least squares mean (standard error)
    -1.69 ± 0.290
    -1.45 ± 0.293
    Statistical analysis title
    		 Ampreloxetine versus (v) Placebo
    Comparison groups
    Ampreloxetine v Placebo
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.574
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.05
         upper limit
    		 0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.413

    Secondary: Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4

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    End point title
    		 Change From Baseline in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score at Week 4
    End point description
    OHSA is an assessment of the severity of symptoms from low blood pressure. OHSA is a 6 question symptom assessment scale in which the composite score uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. A mean negative change from baseline indicates a better outcome. Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of OHSA question 1, with a valid composite OHSA score at Week 4 were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    		 Ampreloxetine Placebo
    Number of subjects analysed
    90
    87
    Units: Score on a scale
        least squares mean (standard error)
    -1.32 ± 0.200
    -1.05 ± 0.202
    Statistical analysis title
    		 Ampreloxetine v Placebo
    Comparison groups
    Ampreloxetine v Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.331
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.284

    Secondary: Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at Week 4

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    End point title
    		 Change From Baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) Composite Score at Week 4
    End point description
    OHDAS is an assessment of how low blood pressure symptoms affect daily life. OHDAS is a 4 item assessment in which the composite score uses an 11 point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating the worst possible symptoms/complete interference. A mean negative change from baseline indicates a better outcome. Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of OHSA question 1, with a valid composite OHDAS score at Week 4 were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    		 Ampreloxetine Placebo
    Number of subjects analysed
    87
    85
    Units: Score on a scale
        least squares mean (standard error)
    -1.22 ± 0.265
    -0.95 ± 0.267
    Statistical analysis title
    		 Ampreloxetine v Placebo
    Comparison groups
    Ampreloxetine v Placebo
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.481
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 0.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.376

    Secondary: Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Week 4

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    End point title
    		 Number of Participants Who Experienced an Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Week 4
    End point description
    PGI-C was assessed using a 5-point scale where participants were asked to compare their current condition to their condition at baseline from 1 to 5, with 1 indicating the condition is very much improved and 5 indicating the condition is very much worse. These scores were analyzed in 2 categories: better and no change/worse. Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of Orthostatic Hypotension Symptom Assessment (OHSA) question 1, who have available data were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    		 Ampreloxetine Placebo
    Number of subjects analysed
    91
    87
    Units: participants
    49
    45
    Statistical analysis title
    		 Ampreloxetine v Placebo
    Statistical analysis description
    Cochran-Mantel-Haenszel was stratified by disease type. The assumed common risk difference estimate and standard error are calculated using Mantel-Haenszel stratum weights and the Sato variance estimator. Mantel-Haenszel confidence limits are shown.
    Comparison groups
    Ampreloxetine v Placebo
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.74
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.073

    Secondary: Number of Participants Who Experienced at Least One Fall

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    End point title
    		 Number of Participants Who Experienced at Least One Fall
    End point description
    Participants included in the Full Analysis Set, defined as all randomized participants who received at least one dose of study medication and had at least 1 post-baseline measurement of Orthostatic Hypotension Symptom Assessment (OHSA) question 1, who have available data were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Up to Week 4
    End point values
    		 Ampreloxetine Placebo
    Number of subjects analysed
    93
    90
    Units: participants
    33
    22
    Statistical analysis title
    		 Ampreloxetine v Placebo
    Statistical analysis description
    Cochran-Mantel-Haenszel was stratified by disease type. The assumed common risk difference estimate and standard error are calculated using Mantel-Haenszel stratum weights and the Sato variance estimator. Mantel-Haenszel confidence limits are shown.
    Comparison groups
    Ampreloxetine v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0903
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.064

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 43
    Adverse event reporting additional description
    Participants in the Safety Analysis set, defined as all randomized subjects who received at least 1 dose of study medication, were included in this analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Ampreloxetine
    Reporting group description
    		 Participants received ampreloxetine at a dose of 10 mg QD for 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo QD for 4 weeks.

    Serious adverse events
    		 Ampreloxetine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 96 (4.17%)
    2 / 90 (2.22%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ampreloxetine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 96 (43.75%)
    38 / 90 (42.22%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal cancer
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Vascular disorders
    Supine hypertension
         subjects affected / exposed
    1 / 96 (1.04%)
    3 / 90 (3.33%)
         occurrences all number
    1
    3
    Hypertension
         subjects affected / exposed
    3 / 96 (3.13%)
    0 / 90 (0.00%)
         occurrences all number
    3
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Flushing
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Hot flush
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 96 (3.13%)
    1 / 90 (1.11%)
         occurrences all number
    3
    1
    Asthenia
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Catheter site pain
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Chest discomfort
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Gait disturbance
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Illness
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Injection site pain
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    2
    Temperature regulation disorder
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 96 (3.13%)
    1 / 90 (1.11%)
         occurrences all number
    3
    1
    Anxiety
         subjects affected / exposed
    2 / 96 (2.08%)
    1 / 90 (1.11%)
         occurrences all number
    2
    1
    Abnormal dreams
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Disorientation
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    2
    Investigations
    Blood creatinine phosphokinase increased
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Blood creatine increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Blood urea nitrogen/creatinine ratio increased
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Crystal urine present
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Gastric pH decreased
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Mean cell haemoglobin increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Mean cell volume increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Protein urine
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Eye contusion
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Joint injury
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Skin laceration
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 96 (5.21%)
    3 / 90 (3.33%)
         occurrences all number
    6
    3
    Dizziness
         subjects affected / exposed
    3 / 96 (3.13%)
    0 / 90 (0.00%)
         occurrences all number
    4
    0
    Somnolence
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Amnesia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Balance disorder
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Bulbar palsy
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Dizziness postural
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Loss of consciousness
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 96 (2.08%)
    2 / 90 (2.22%)
         occurrences all number
    3
    2
    Constipation
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Dry mouth
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 90 (1.11%)
         occurrences all number
    2
    1
    Abdominal discomfort
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Duodenitis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Gingival bleeding
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Large intestine polyp
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Salivary hypersecretion
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Bladder pain
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Urinary retention
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Urinary tract inflammation
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Urine flow decreased
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Renal cyst
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    2 / 96 (2.08%)
    1 / 90 (1.11%)
         occurrences all number
    3
    1
    Arthralgia
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Back pain
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 90 (2.22%)
         occurrences all number
    0
    2
    Joint swelling
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Muscular weakness
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 96 (3.13%)
    4 / 90 (4.44%)
         occurrences all number
    3
    4
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 90 (2.22%)
         occurrences all number
    0
    2
    Bacterial disease carrier
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2019
    Changes included: Updates to discontinuation rules, acceptable methods of contraception and unblinding.
    04 Mar 2019
    Changes included: Updates to the number of countries, Screening window, Screening period, clarification of the meaning of "sustained" in regards to systolic blood pressure and stopping rules.
    04 Dec 2019
    Change included: Updates to study name, study objectives, screening period, sponsor medical monitor discussion requirement, PAF diagnosis, enrolment criteria, Droxidopa details, exclusion criteria, prohibition of alpha blockers, Study 0145 results, optimal time(s) protocol procedures should be conducted, to allow for confirmation if there is doubt per investigators opinion, additional test needed for participants with Diabetes Mellitus, chemistry panel, sponsor involvement in participant withdrawal via investigator decision and sample screening visits.
    05 Aug 2020
    Changes included: Updates to Decentralized Platform and operational design due to COVID-19.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    25 Mar 2020
    Recruitment was paused due to COVID-19 on 25Mar2020. Screening was resumed from the 16Apr2020 on a staggered basis based upon the assessment of the COVID-19 situation at a country, regional, and local level.
    16 Apr 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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