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    Clinical Trial Results:
    A Phase 4, Randomized-withdrawal, Double-blind, Placebo controlled, Parallel-group Study to Investigate the Clinical Benefit of Midodrine Hydrochloride in Male and Female Subjects with Symptomatic Orthostatic Hypotension

    Summary
    EudraCT number
    2012-005760-99
    Trial protocol
    SK   CZ   PL  
    Global end of trial date
    11 Nov 2013

    Results information
    Results version number
    v1
    This version publication date
    28 Aug 2018
    First version publication date
    25 Jan 2015
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD426-405
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01515865
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Development LLC
    Sponsor organisation address
    725 Chesterbrook Boulevard, Wayne, United States, 19087
    Public contact
    Medical Communications, Shire Pharmaceuticals Limited, 44 8000556614, medinfoglobal@shire.com
    Scientific contact
    Medical Communications, Shire Pharmaceuticals Limited, 44 8000556614, medinfoglobal@shire.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
    11 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the clinical benefit of midodrine hydrochloride (HCl) in subjects with symptomatic orthostatic hypotension (SOH) as determined by the proportion of subjects who fail to maintain an adequate response to treatment following randomized withdrawal of treatment (placebo) as compared to subjects remaining on active treatment (midodrine HCl).
    Protection of trial subjects
    This study was conducted in accordance with ICH Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements. A data monitoring committee monitored safety data generated by the study at regular intervals for the duration of the study. Their role was to protect the interests of subjects in the study and of those still to be entered, by review of accumulating safety and tolerability data generated in this study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 May 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 90
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Poland: 5
    Worldwide total number of subjects
    98
    EEA total number of subjects
    8
    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)
    84
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This was a double-blind, placebo-controlled, randomized-withdrawal, parallel-group multicenter study conducted at 12 sites in the United States and 2 sites in the European Union (1 site in Poland and 1 site in Slovakia) to investigate the clinical benefit of midodrine HCl in male and female subjects with SOH.

    Pre-assignment
    Screening details
    Screening procedures were completed within 28 days prior to Day -1, while subjects were on their current midodrine HCl dose schedule. All screening assessments and procedures were performed by the principal investigator or a qualified designee.

    Period 1
    Period 1 title
    Withdrawal
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Midodrine HCL - Open-label Withdrawal
    Arm description
    On the morning of Day -1, subjects took their usual morning dose of midodrine HCl, using their own midodrine HCl supplies at approximately the same time before rising that they would normally take their morning dose. On the morning of Day 1, subjects had their usual morning dose of midodrine HCl withheld.
    Arm type
    Experimental

    Investigational medicinal product name
    Midodrine Hydrochloride (HCL)
    Investigational medicinal product code
    Other name
    ProAmatine
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 and 10 mg tablets (United States) or 2.5 mg tablets (European Union), at the subject's current dose level.

    Number of subjects in period 1
    Midodrine HCL - Open-label Withdrawal
    Started
    98
    Completed
    95
    Not completed
    3
         Not Specified
    3
    Period 2
    Period 2 title
    Dose-stabilization
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Midodrine HCL - Open-label
    Arm description
    On Day 2, all eligible subjects continued on their midodrine HCl dose regimen over at least 14 days, using study-supplied investigational product.
    Arm type
    Experimental

    Investigational medicinal product name
    Midodrine Hydrochloride (HCL)
    Investigational medicinal product code
    Other name
    ProAmatine
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 and 10 mg tablets (United States) or 2.5 mg tablets (European Union), at the subject's current dose level.

    Number of subjects in period 2 [1]
    Midodrine HCL - Open-label
    Started
    71
    Completed
    69
    Not completed
    2
         Withdrawal by Subject
    1
         Not Specified
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Twenty-four subjects from the Open-label Withdrawal phase did not meet the criteria required to be enrolled into the Dose-stabilization phase.
    Period 3
    Period 3 title
    Double-blind, Randomized-withdrawal
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor
    Blinding implementation details
    The investigator designated a blinded qualified individual to administer the dose to the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Midodrine HCl - Randomized
    Arm description
    On Day 16 subjects received overencapsulated midodrine HCl tablets (equivalent to their previously prescribed dose).
    Arm type
    Experimental

    Investigational medicinal product name
    Midodrine Hydrochloride (HCL)
    Investigational medicinal product code
    Other name
    ProAmatine
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 and 10 mg overencapsulated tablets (United States) or 2.5 mg overencapsulated tablets (European Union), at the subject's current dose level.

    Arm title
    Placebo - Randomized
    Arm description
    On Day 16 subjects received matching placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of matching placebo.

    Number of subjects in period 3 [2]
    Midodrine HCl - Randomized Placebo - Randomized
    Started
    33
    34
    Completed
    33
    34
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Two subjects from the Dose-stabilization phase did not meet the criteria required to be enrolled into the Double-blind, Randomized-withdrawal phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Withdrawal
    Reporting group description
    -

    Reporting group values
    Withdrawal Total
    Number of subjects
    98 98
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    45.5 ± 17.45 -
    Gender categorical
    Units: Subjects
        Female
    76 76
        Male
    22 22
    Region of enrollment
    Units: Subjects
        United States
    90 90
        Slovakia
    3 3
        Poland
    5 5

    End points

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    End points reporting groups
    Reporting group title
    Midodrine HCL - Open-label Withdrawal
    Reporting group description
    On the morning of Day -1, subjects took their usual morning dose of midodrine HCl, using their own midodrine HCl supplies at approximately the same time before rising that they would normally take their morning dose. On the morning of Day 1, subjects had their usual morning dose of midodrine HCl withheld.
    Reporting group title
    Midodrine HCL - Open-label
    Reporting group description
    On Day 2, all eligible subjects continued on their midodrine HCl dose regimen over at least 14 days, using study-supplied investigational product.
    Reporting group title
    Midodrine HCl - Randomized
    Reporting group description
    On Day 16 subjects received overencapsulated midodrine HCl tablets (equivalent to their previously prescribed dose).

    Reporting group title
    Placebo - Randomized
    Reporting group description
    On Day 16 subjects received matching placebo.

    Primary: Percent of Subjects Who Failed to Maintain a Response

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    End point title
    Percent of Subjects Who Failed to Maintain a Response
    End point description
    Failure to maintain a response was defined as any randomized subject that met both criterion 1 and criterion 2 below on Day 16: 1. The Orthostatic Hypotension Symptom Assessment (OHSA) Item 1 score increased by >=4 points compared to baseline. OHSA Item 1 is a dizziness scale that is scored on a range from 0 (no dizziness) to 10 (severe dizziness). A lower score indicates less severe symptoms. 2. There was an increase in the number of syncopal/near syncopal events or severity of events within 15 minutes of standing compared to those observed at baseline. Syncope was defined as a loss of consciousness, and near syncope was defined as a feeling (e.g., dizziness, lightheadedness, feeling faint, feeling as though one would black out) that, without intervention, would lead to a loss of consciousness. This end point used the Full Analysis Set, defined as all randomized subjects who received at least 1 dose of double-blind investigational product and had data available.
    End point type
    Primary
    End point timeframe
    30 minutes post-dose on Day 16
    End point values
    Midodrine HCl - Randomized Placebo - Randomized
    Number of subjects analysed
    33
    34
    Units: percentage of subjects
        number (not applicable)
    30.3
    44.1
    Statistical analysis title
    Failure to maintain a response
    Comparison groups
    Placebo - Randomized v Midodrine HCl - Randomized
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3145
    Method
    Fisher exact
    Parameter type
    Mean difference (final values)
    Point estimate
    -13.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.6
         upper limit
    9.8

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 Days
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo - Randomized Safety Analysis Set (Part C)
    Reporting group description
    -

    Reporting group title
    Midodrine HCl - Randomized Safety Analysis Set (Part C)
    Reporting group description
    -

    Reporting group title
    Midodrine HCl - Open-label Withdrawal (Part A)
    Reporting group description
    -

    Reporting group title
    Midodrine HCl - Open-label (Part B)
    Reporting group description
    -

    Serious adverse events
    Placebo - Randomized Safety Analysis Set (Part C) Midodrine HCl - Randomized Safety Analysis Set (Part C) Midodrine HCl - Open-label Withdrawal (Part A) Midodrine HCl - Open-label (Part B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 98 (0.00%)
    0 / 71 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo - Randomized Safety Analysis Set (Part C) Midodrine HCl - Randomized Safety Analysis Set (Part C) Midodrine HCl - Open-label Withdrawal (Part A) Midodrine HCl - Open-label (Part B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
    5 / 98 (5.10%)
    2 / 71 (2.82%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    5 / 98 (5.10%)
    2 / 71 (2.82%)
         occurrences all number
    0
    0
    5
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Sep 2012
    This amendment included the following changes. 1-Dates of the planned study period were updated to match agreement with the Food and Drug Administration (FDA): a-The definition of Part A (Withdrawal phase) was changed from 1 day (Day 1) to 2 days duration (Day -1 to Day 1); b-Discharge was on Day 17; and c-Follow-up was 5-7 days after discharge rather than 5-7 days after last dose of study drug. 2-In order to better reflect the general patient population, qualification criteria for advancing from Part B to C (Dose-stabilization and Double-blind Randomized-withdrawal phases, respectively) were modified to indicate that the changes in orthostatic blood pressure should have been comparable at baseline and Part B, and that some subjects may not have exhibited a change. 3-Methodology sections were amended to clarify that procedures for qualification of subjects into the study, including Parts A and B, may have been repeated once if necessary. 4-Physical examination was removed as a safety assessment and secondary endpoint, since findings were to be included in the adverse events section. 5-Exclusion criteria were modified. 6-Sections detailing administration of investigational product were updated to address concerns expressed by the FDA. 7-The timing of screening procedures was changed to within 28 days prior to Day -1, rather than 28 days prior to receiving the first dose of investigational product. 8-Additional guidelines were added to address FDA recommendations concerning blood pressure measurements. 9-Definitions of syncopal and near syncopal events were added.
    15 Jan 2013
    This amendment included the following changes. 1-Text was added to include that in the European Union only the 2.5 mg dose strength was used. 2-Text was added to clarify that a subject was eligible to enter Part B of the study if he was unable to stand for the assessments to be conducted, which meant either to start the assessments or to complete the entire assessment period. 3-Text was added to clarify that the subject number and randomization number used in the SPD426-406 study could not be used in Study SPD426-405. 4-Text was added to clarify that the capsules were to be swallowed whole and not opened, crushed, chewed, or cut. 5-Text was updated to clarify that the physical examination was performed in Europe by a qualified registered physician.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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