ID

41682

Beschreibung

Study ID: 110106 Clinical Study ID: 110106 Study Title: A single centre, randomized, double-blind, dose ascending, placebo-controlled study, in two parts, to evaluate the safety, tolerability and pharmacokinetics of escalating single and repeat inhaled doses of GSK573719 and placebo formulated with the excipient magnesium stearate, in healthy subjects and in a healthy population of Cytochrome P450 Isoenzyme 2D6 poor metabolisers. Patient Level Data: Study Listed on ClinicalStudyDataRequest.com Clinicaltrials.gov Identifier: NCT00803673 Sponsor: GlaxoSmithKline Phase: Phase 1 Study Recruitment Status: Completed Generic Name: GSK573719, Placebo Study Indication: Pulmonary Disease, Chronic Obstructive

Stichworte

  1. 13.12.20 13.12.20 -
Rechteinhaber

GlaxoSmithKline

Hochgeladen am

13. Dezember 2020

DOI

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    Safety, tolerability and pharmacokinetics of GSK573719 and placebo formulated with the excipient magnesium stearate NCT00803673

    Logs and Repeats - Pharmacokinetics Blood; Local Laboratory; Summary Holter; Holter Abnormalities

    Pharmacokinetics Blood
    Beschreibung

    Pharmacokinetics Blood

    Alias
    UMLS CUI-1
    C0031328
    UMLS CUI-2
    C0005767
    Actual date/time
    Beschreibung

    Actual date/time

    Datentyp

    datetime

    Alias
    UMLS CUI [1]
    C1264639
    Pulmonary Function Tests
    Beschreibung

    Pulmonary Function Tests

    Alias
    UMLS CUI-1
    C0024119
    Date/time of test
    Beschreibung

    Date/time of test

    Datentyp

    datetime

    Alias
    UMLS CUI [1,1]
    C0024119
    UMLS CUI [1,2]
    C0011008
    UMLS CUI [1,3]
    C0040223
    FEV1 (3 readings) - 1
    Beschreibung

    FEV1 (3 readings) - 1

    Datentyp

    integer

    Maßeinheiten
    • L
    Alias
    UMLS CUI [1]
    C0748133
    L
    FEV1 (3 readings) - 2
    Beschreibung

    FEV1 (3 readings) - 2

    Datentyp

    integer

    Maßeinheiten
    • L
    Alias
    UMLS CUI [1]
    C0748133
    L
    FEV1 (3 readings) - 3
    Beschreibung

    FEV1 (3 readings) - 3

    Datentyp

    integer

    Maßeinheiten
    • L
    Alias
    UMLS CUI [1]
    C0748133
    L
    FVC (3 readings) - 1
    Beschreibung

    FVC (3 readings) - 1

    Datentyp

    integer

    Maßeinheiten
    • L
    Alias
    UMLS CUI [1]
    C1287681
    L
    FVC (3 readings) - 2
    Beschreibung

    FVC (3 readings) - 2

    Datentyp

    integer

    Maßeinheiten
    • L
    Alias
    UMLS CUI [1]
    C1287681
    L
    FVC (3 readings) - 3
    Beschreibung

    FVC (3 readings) - 3

    Datentyp

    integer

    Maßeinheiten
    • L
    Alias
    UMLS CUI [1]
    C1287681
    L
    Local Laboratory
    Beschreibung

    Local Laboratory

    Alias
    UMLS CUI-1
    C0022885
    Date and time sample taken
    Beschreibung

    Date and time sample taken

    Datentyp

    datetime

    Alias
    UMLS CUI [1,1]
    C0011008
    UMLS CUI [1,2]
    C0040223
    UMLS CUI [1,3]
    C0200345
    Has the subject fasted?
    Beschreibung

    Has the subject fasted?

    Datentyp

    boolean

    Alias
    UMLS CUI [1]
    C0015663
    Laboratory Test - Clinical Chemistry
    Beschreibung

    Laboratory Test - Clinical Chemistry

    Datentyp

    integer

    Alias
    UMLS CUI [1,1]
    C0022885
    UMLS CUI [1,2]
    C0008000
    Laboratory Test - Haematology
    Beschreibung

    Laboratory Test - Haematology

    Datentyp

    integer

    Alias
    UMLS CUI [1,1]
    C0022885
    UMLS CUI [1,2]
    C0018941
    Laboratory Test Result - Numeric
    Beschreibung

    Laboratory Test Result - Numeric

    Datentyp

    integer

    Alias
    UMLS CUI [1,1]
    C0587081
    UMLS CUI [1,2]
    C2347373
    Laboratory result - Character result
    Beschreibung

    Laboratory result - Character result

    Datentyp

    text

    Alias
    UMLS CUI [1,1]
    C0587081
    UMLS CUI [1,2]
    C2350015
    Laboratory - No result
    Beschreibung

    Laboratory - No result

    Datentyp

    integer

    Alias
    UMLS CUI [1]
    C0587081
    Summary Holter
    Beschreibung

    Summary Holter

    Alias
    UMLS CUI-1
    C0013801
    UMLS CUI-2
    C0242482
    Start Date and Time of Holter
    Beschreibung

    Start Date and Time of Holter

    Datentyp

    datetime

    Alias
    UMLS CUI [1,1]
    C0013801
    UMLS CUI [1,2]
    C0808070
    UMLS CUI [2,1]
    C0013801
    UMLS CUI [2,2]
    C1301880
    Stop Date and Time of Holter
    Beschreibung

    Stop Date and Time of Holter

    Datentyp

    datetime

    Alias
    UMLS CUI [1,1]
    C0013801
    UMLS CUI [1,2]
    C0806020
    UMLS CUI [2,1]
    C0013801
    UMLS CUI [2,2]
    C1522314
    MInimum heart rate
    Beschreibung

    MInimum heart rate

    Datentyp

    integer

    Maßeinheiten
    • beats/min
    Alias
    UMLS CUI [1,1]
    C0018810
    UMLS CUI [1,2]
    C1524031
    beats/min
    Maximum heart rate
    Beschreibung

    Maximum heart rate

    Datentyp

    integer

    Maßeinheiten
    • beats/min
    Alias
    UMLS CUI [1,1]
    C0018810
    UMLS CUI [1,2]
    C0806909
    beats/min
    Mean heart rate
    Beschreibung

    Mean heart rate

    Datentyp

    integer

    Maßeinheiten
    • beats/min
    Alias
    UMLS CUI [1]
    C1881634
    beats/min
    Number of ventricular runs
    Beschreibung

    Number of ventricular runs

    Datentyp

    integer

    Alias
    UMLS CUI [1]
    C2189285
    Number of ventricular runs - Not done, specify reason
    Beschreibung

    Number of ventricular runs - Not done, specify reason

    Datentyp

    text

    Alias
    UMLS CUI [1,1]
    C2189285
    UMLS CUI [1,2]
    C2826287
    Number of ventricular runs - Not applicable
    Beschreibung

    Number of ventricular runs - Not applicable

    Datentyp

    integer

    Alias
    UMLS CUI [1]
    C2189285
    Number of supraventricular runs
    Beschreibung

    Number of supraventricular runs

    Datentyp

    integer

    Alias
    UMLS CUI [1,1]
    C0039240
    UMLS CUI [1,2]
    C0237753
    Supraventricular runs - Not done, specify reason
    Beschreibung

    Supraventricular runs - Not done, specify reason

    Datentyp

    text

    Alias
    UMLS CUI [1,1]
    C0039240
    UMLS CUI [1,2]
    C2826287
    Supraventricular runs - Not applicable
    Beschreibung

    Supraventricular runs - Not applicable

    Datentyp

    integer

    Alias
    UMLS CUI [1]
    C0039240
    Interpretation of Holter
    Beschreibung

    Interpretation of Holter

    Datentyp

    integer

    Alias
    UMLS CUI [1,1]
    C0013801
    UMLS CUI [1,2]
    C4086187
    Holter Abnormalities
    Beschreibung

    Holter Abnormalities

    Alias
    UMLS CUI-1
    C0013801
    UMLS CUI-2
    C1704258
    Start Date and Time of Holter
    Beschreibung

    Start Date and Time of Holter

    Datentyp

    datetime

    Alias
    UMLS CUI [1,1]
    C0013801
    UMLS CUI [1,2]
    C0808070
    UMLS CUI [2,1]
    C0013801
    UMLS CUI [2,2]
    C1301880
    Stop Date and Time of Holter
    Beschreibung

    Stop Date and Time of Holter

    Datentyp

    datetime

    Alias
    UMLS CUI [1,1]
    C0013801
    UMLS CUI [1,2]
    C0806020
    UMLS CUI [2,1]
    C0013801
    UMLS CUI [2,2]
    C1522314
    Holter Abnormalities
    Beschreibung

    Holter Abnormalities

    Alias
    UMLS CUI-1
    C0013801
    UMLS CUI-2
    C1704258
    Holter abnormality
    Beschreibung

    Holter abnormality

    Datentyp

    text

    Alias
    UMLS CUI [1,1]
    C0013801
    UMLS CUI [1,2]
    C1704258
    Other abnormal rhythm, specify
    Beschreibung

    Other abnormal rhythm, specify

    Datentyp

    text

    Alias
    UMLS CUI [1,1]
    C0199556
    UMLS CUI [1,2]
    C0205161
    UMLS CUI [1,3]
    C0205394
    UMLS CUI [2]
    C2348235
    Other morphology, specify
    Beschreibung

    Other morphology, specify

    Datentyp

    text

    Alias
    UMLS CUI [1,1]
    C0332437
    UMLS CUI [1,2]
    C0205394
    UMLS CUI [2]
    C2348235
    Other conduction, specify
    Beschreibung

    Other conduction, specify

    Datentyp

    text

    Alias
    UMLS CUI [1]
    C0340494
    UMLS CUI [2]
    C2348235
    Other myocardial infarction, specify
    Beschreibung

    Other myocardial infarction, specify

    Datentyp

    text

    Alias
    UMLS CUI [1,1]
    C0027051
    UMLS CUI [1,2]
    C0205394
    UMLS CUI [2]
    C2348235
    Other depolarisation/repolrisation, specify
    Beschreibung

    Other depolarisation/repolrisation, specify

    Datentyp

    text

    Alias
    UMLS CUI [1,1]
    C0948857
    UMLS CUI [1,2]
    C0205394
    UMLS CUI [2]
    C2348235
    Other abnormality/ Cardiologist comments
    Beschreibung

    Other abnormality/ Cardiologist comments

    Datentyp

    text

    Alias
    UMLS CUI [1,1]
    C1704258
    UMLS CUI [1,2]
    C0205394
    UMLS CUI [2,1]
    C0175906
    UMLS CUI [2,2]
    C0947611
    Holter monitoring method
    Beschreibung

    integer

    Datentyp

    integer

    Alias
    UMLS CUI [1,1]
    C0013801
    UMLS CUI [1,2]
    C0871511

    Ähnliche Modelle

    Logs and Repeats - Pharmacokinetics Blood; Local Laboratory; Summary Holter; Holter Abnormalities

    Name
    Typ
    Description | Question | Decode (Coded Value)
    Datentyp
    Alias
    Item Group
    Pharmacokinetics Blood
    C0031328 (UMLS CUI-1)
    C0005767 (UMLS CUI-2)
    Actual date/time
    Item
    Actual date/time
    datetime
    C1264639 (UMLS CUI [1])
    Item Group
    Pulmonary Function Tests
    C0024119 (UMLS CUI-1)
    Date/time of test
    Item
    Date/time of test
    datetime
    C0024119 (UMLS CUI [1,1])
    C0011008 (UMLS CUI [1,2])
    C0040223 (UMLS CUI [1,3])
    FEV1 (3 readings) - 1
    Item
    FEV1 (3 readings) - 1
    integer
    C0748133 (UMLS CUI [1])
    FEV1 (3 readings) - 2
    Item
    FEV1 (3 readings) - 2
    integer
    C0748133 (UMLS CUI [1])
    FEV1 (3 readings) - 3
    Item
    FEV1 (3 readings) - 3
    integer
    C0748133 (UMLS CUI [1])
    FVC (3 readings) - 1
    Item
    FVC (3 readings) - 1
    integer
    C1287681 (UMLS CUI [1])
    FVC (3 readings) - 2
    Item
    FVC (3 readings) - 2
    integer
    C1287681 (UMLS CUI [1])
    FVC (3 readings) - 3
    Item
    FVC (3 readings) - 3
    integer
    C1287681 (UMLS CUI [1])
    Item Group
    Local Laboratory
    C0022885 (UMLS CUI-1)
    Date and time sample taken
    Item
    Date and time sample taken
    datetime
    C0011008 (UMLS CUI [1,1])
    C0040223 (UMLS CUI [1,2])
    C0200345 (UMLS CUI [1,3])
    Has the subject fasted?
    Item
    Has the subject fasted?
    boolean
    C0015663 (UMLS CUI [1])
    Item
    Laboratory Test - Clinical Chemistry
    integer
    C0022885 (UMLS CUI [1,1])
    C0008000 (UMLS CUI [1,2])
    Code List
    Laboratory Test - Clinical Chemistry
    CL Item
    Albumin (1)
    CL Item
    Alkaline Phosphatse (2)
    CL Item
    ALT (3)
    CL Item
    AST (4)
    CL Item
    Calcium (5)
    CL Item
    Creatinine (6)
    CL Item
    Direct Bilirubin (7)
    CL Item
    GGT (8)
    CL Item
    Glucose (9)
    CL Item
    Potassium (10)
    CL Item
    Sodium (11)
    CL Item
    Total Bilirubin (12)
    CL Item
    Total Protein (13)
    CL Item
    Urea (14)
    CL Item
    Uric Acid (15)
    Item
    Laboratory Test - Haematology
    integer
    C0022885 (UMLS CUI [1,1])
    C0018941 (UMLS CUI [1,2])
    Code List
    Laboratory Test - Haematology
    CL Item
    Basophils (1)
    CL Item
    Eosinophils (2)
    CL Item
    Haemoglobin (3)
    CL Item
    Haematocrit (4)
    CL Item
    Lymphocytes (5)
    CL Item
    MCH (6)
    CL Item
    MCHC (7)
    CL Item
    MCV (8)
    CL Item
    Monocytes (9)
    CL Item
    Neutrophils (10)
    CL Item
    RBC (11)
    CL Item
    WBC (12)
    Laboratory Test Result - Numeric
    Item
    Laboratory Test Result - Numeric
    integer
    C0587081 (UMLS CUI [1,1])
    C2347373 (UMLS CUI [1,2])
    Laboratory result - Character result
    Item
    Laboratory result - Character result
    text
    C0587081 (UMLS CUI [1,1])
    C2350015 (UMLS CUI [1,2])
    Item
    Laboratory - No result
    integer
    C0587081 (UMLS CUI [1])
    Code List
    Laboratory - No result
    CL Item
    No result (1)
    Item Group
    Summary Holter
    C0013801 (UMLS CUI-1)
    C0242482 (UMLS CUI-2)
    Start Date and Time of Holter
    Item
    Start Date and Time of Holter
    datetime
    C0013801 (UMLS CUI [1,1])
    C0808070 (UMLS CUI [1,2])
    C0013801 (UMLS CUI [2,1])
    C1301880 (UMLS CUI [2,2])
    Stop Date and Time of Holter
    Item
    Stop Date and Time of Holter
    datetime
    C0013801 (UMLS CUI [1,1])
    C0806020 (UMLS CUI [1,2])
    C0013801 (UMLS CUI [2,1])
    C1522314 (UMLS CUI [2,2])
    MInimum heart rate
    Item
    MInimum heart rate
    integer
    C0018810 (UMLS CUI [1,1])
    C1524031 (UMLS CUI [1,2])
    Maximum heart rate
    Item
    Maximum heart rate
    integer
    C0018810 (UMLS CUI [1,1])
    C0806909 (UMLS CUI [1,2])
    Mean heart rate
    Item
    Mean heart rate
    integer
    C1881634 (UMLS CUI [1])
    Number of ventricular runs
    Item
    Number of ventricular runs
    integer
    C2189285 (UMLS CUI [1])
    Number of ventricular runs - Not done, specify reason
    Item
    Number of ventricular runs - Not done, specify reason
    text
    C2189285 (UMLS CUI [1,1])
    C2826287 (UMLS CUI [1,2])
    Item
    Number of ventricular runs - Not applicable
    integer
    C2189285 (UMLS CUI [1])
    Code List
    Number of ventricular runs - Not applicable
    CL Item
    Not applicable (1)
    Number of supraventricular runs
    Item
    Number of supraventricular runs
    integer
    C0039240 (UMLS CUI [1,1])
    C0237753 (UMLS CUI [1,2])
    Supraventricular runs - Not done, specify reason
    Item
    Supraventricular runs - Not done, specify reason
    text
    C0039240 (UMLS CUI [1,1])
    C2826287 (UMLS CUI [1,2])
    Item
    Supraventricular runs - Not applicable
    integer
    C0039240 (UMLS CUI [1])
    Code List
    Supraventricular runs - Not applicable
    CL Item
    Not applicable (1)
    Item
    Interpretation of Holter
    integer
    C0013801 (UMLS CUI [1,1])
    C4086187 (UMLS CUI [1,2])
    Code List
    Interpretation of Holter
    CL Item
    Normal (1)
    CL Item
    Abnormal - Not clinically significant (2)
    CL Item
    Abnormal - Clinically significant (3)
    CL Item
    No result (4)
    CL Item
    Unable to evaluate (8)
    Item Group
    Holter Abnormalities
    C0013801 (UMLS CUI-1)
    C1704258 (UMLS CUI-2)
    Start Date and Time of Holter
    Item
    Start Date and Time of Holter
    datetime
    C0013801 (UMLS CUI [1,1])
    C0808070 (UMLS CUI [1,2])
    C0013801 (UMLS CUI [2,1])
    C1301880 (UMLS CUI [2,2])
    Stop Date and Time of Holter
    Item
    Stop Date and Time of Holter
    datetime
    C0013801 (UMLS CUI [1,1])
    C0806020 (UMLS CUI [1,2])
    C0013801 (UMLS CUI [2,1])
    C1522314 (UMLS CUI [2,2])
    Item Group
    Holter Abnormalities
    C0013801 (UMLS CUI-1)
    C1704258 (UMLS CUI-2)
    Item
    Holter abnormality
    text
    C0013801 (UMLS CUI [1,1])
    C1704258 (UMLS CUI [1,2])
    Code List
    Holter abnormality
    CL Item
    Electrical alternans (A21)
    CL Item
    R on T phenomenon (A22)
    CL Item
    Ventricular fibrillation (A23)
    CL Item
    Trigeminy (A20)
    CL Item
    Ventricular premature depolarisation (A17)
    CL Item
    Sustained ventricular tachycardia (>100 beats/min, >30 beats) (A26)
    CL Item
    Non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats) (A25)
    CL Item
    Idioventricular rhythm (<= beats/min, defined by wide QRS complex) (A24)
    CL Item
    Sustained supraventricular tachycardia (>100 beats/min, >30 beats) (A12)
    CL Item
    Atrial flutter (A13)
    CL Item
    Monomorphic non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats) (A28)
    CL Item
    Atrial fibrillation (A14)
    CL Item
    Monomorphic sustained ventricular tachycardia (>100 beats/min, >30 beats) (A29)
    CL Item
    Ventricular couplets (A18)
    CL Item
    Bigeminy (A19)
    CL Item
    Multifocal atrial tachycardia (wandering atrial pacemaker w/rate >100 beats/min) (A10)
    CL Item
    Non-sustained supraventricular tachycardia (>100 beats/min, 3-30 beats) (A11)
    CL Item
    Torsade de Pointes (TdP) (A32)
    CL Item
    Pacemaker (A33)
    CL Item
    Wide QRS tachycardia (diagnosis unknown) (A27)
    CL Item
    Polymorphic non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats) (A30)
    CL Item
    Junctional rhythm (<=100 beats/min, defined by narrow QRS complex) (A15)
    CL Item
    Polymorphic sustained ventricular tachycardia (>100 beats/min, >30 beats) (A31)
    CL Item
    Junctional tachycardia (>100 beats/min) (A16)
    CL Item
    Short PR Interval (A35)
    CL Item
    No abnormalities (A00)
    CL Item
    Sinus bradycardia (50-59 beats/min) (A01)
    CL Item
    Sinus bradycardia (40-49 beats/min) (A02)
    CL Item
    Sinus bradycardia (30-39 beats/min) (A03)
    CL Item
    Sinus bradycardia (<30 beats/min) (A04)
    CL Item
    Sinus pause (A05)
    CL Item
    Sinus tachycardia (>100 beats/min) (A06)
    CL Item
    Ectopic supraventricular beats (A07)
    CL Item
    Ectopic supraventricular rhythm (A08)
    CL Item
    Wandering atrial pacemaker (A09)
    CL Item
    First degree AV block (PR Interval >200msec) (A34)
    CL Item
    Second degree AV block (Mobitz type 1) (A36)
    CL Item
    Second degree AV block (Mobitz type 2) (A37)
    CL Item
    2:1 AV block (A38)
    CL Item
    Third degree AV block (A39)
    CL Item
    Left axis deviation (QRS axis more negative thant -30 degrees) (A40)
    CL Item
    Right axis deviation (QRS axis more positive than +110 degrees) (A41)
    CL Item
    Incomplete right bundle branch block (A42)
    CL Item
    Incomplete left bundle branch block (A43)
    CL Item
    Right bundle branch block (A44)
    CL Item
    Left anterior hemiblock (A45)
    CL Item
    Left posterior hemiblock (A46)
    CL Item
    Left bundle branch block (A47)
    CL Item
    Bifascicular block (A48)
    CL Item
    Non-specific intraventricular conduction delay (QRS >=120 msec) (A49)
    CL Item
    Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-levine) (A50)
    CL Item
    QTc prolongation >=500 msec (A51)
    CL Item
    AV dissociation (A52)
    CL Item
    Myocardial Infarction, old (A53)
    CL Item
    Myocardial Infarction, non Q-wave (A54)
    CL Item
    Non-specific ST-T changes (A55)
    CL Item
    J point elevation (A56)
    CL Item
    ST elevation (A57)
    CL Item
    ST depression (A58)
    CL Item
    St segment abnormality (A59)
    CL Item
    U waves (A60)
    CL Item
    T wave Inversion (A61)
    CL Item
    T wave peaked (A62)
    CL Item
    T waves biphasic (A63)
    CL Item
    T waves flat (A64)
    CL Item
    Notched T-waves (A65)
    CL Item
    Low QRS voltage (A66)
    CL Item
    T wave abnormality (A67)
    CL Item
    Other abnormal rhythm (A94)
    CL Item
    Other morphology (A95)
    CL Item
    Other conduction (A96)
    CL Item
    Other myocardial infarction (A97)
    CL Item
    Other depolarisation/repolarisation (A98)
    CL Item
    Other abnormality/Cardiologist comments (A99)
    Other abnormal rhythm, specify
    Item
    Other abnormal rhythm, specify
    text
    C0199556 (UMLS CUI [1,1])
    C0205161 (UMLS CUI [1,2])
    C0205394 (UMLS CUI [1,3])
    C2348235 (UMLS CUI [2])
    Other morphology, specify
    Item
    Other morphology, specify
    text
    C0332437 (UMLS CUI [1,1])
    C0205394 (UMLS CUI [1,2])
    C2348235 (UMLS CUI [2])
    Other conduction, specify
    Item
    Other conduction, specify
    text
    C0340494 (UMLS CUI [1])
    C2348235 (UMLS CUI [2])
    Other myocardial infarction, specify
    Item
    Other myocardial infarction, specify
    text
    C0027051 (UMLS CUI [1,1])
    C0205394 (UMLS CUI [1,2])
    C2348235 (UMLS CUI [2])
    Other depolarisation/repolrisation, specify
    Item
    Other depolarisation/repolrisation, specify
    text
    C0948857 (UMLS CUI [1,1])
    C0205394 (UMLS CUI [1,2])
    C2348235 (UMLS CUI [2])
    Other abnormality/ Cardiologist comments
    Item
    Other abnormality/ Cardiologist comments
    text
    C1704258 (UMLS CUI [1,1])
    C0205394 (UMLS CUI [1,2])
    C0175906 (UMLS CUI [2,1])
    C0947611 (UMLS CUI [2,2])
    Item
    Holter monitoring method
    integer
    C0013801 (UMLS CUI [1,1])
    C0871511 (UMLS CUI [1,2])
    Code List
    Holter monitoring method
    CL Item
    12 Lead 1000Hz  (1)
    CL Item
    12 Lead 180Hz  (2)
    CL Item
    3 Lead 180Hz  (3)
    CL Item
    3 Lead 512Hz (4)

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