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    Clinical Trial Results:
    A Placebo-Controlled, Double-Blind, Randomized Trial to Compare the Effect of Treatment on Plaque Burden as Determined by Intravascular Ultrasound and to Evaluate the Efficacy, Pharmacokinetics, Safety, and Tolerability of MDCO-216 Given as Multiple Weekly Infusions in Subjects With a Recent Acute Coronary Syndrome.

    Summary
    EudraCT number
    		 2015-000826-13
    Trial protocol
    		 CZ   HU   NL   PL  
    Global end of trial date
    26 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Aug 2017
    First version publication date
    02 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MDCO-APO-15-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02678923
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Medicines Company
    Sponsor organisation address
    8 Sylvan Way, Parsippany, United States, 07054
    Public contact
    Global Health Science Center, The Medicines Company, 001 8889776326, medical.information@themedco.com
    Scientific contact
    Global Health Science Center, The Medicines Company, 001 8889776326, medical.information@themedco.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
    26 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was a proof-of-concept, placebo-controlled, double-blind, randomized trial in participants with a recent acute coronary syndrome (ACS) to evaluate the efficacy, pharmacokinetics, safety, tolerability, disease progression measures by intravascular ultrasound (IVUS), and pharmacodynamics of MDCO-216 infusion. Eligible participants were randomized to receive 5 infusions of MDCO-216 20 milligrams/kilogram (mg/kg) or placebo in a 1:1 ratio.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 2015
    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
    Canada: 7
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Poland: 83
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    Hungary: 14
    Worldwide total number of subjects
    126
    EEA total number of subjects
    119
    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)
    78
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening procedures were performed up to 14 days prior to the first dose of study drug. All screening procedures were completed prior to randomization and the first dose of study drug.

    Period 1
    Period 1 title
    MDCO-216 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    The site pharmacist and/or qualified designee was the only team member at the site level who was unblinded to treatment assignment to allow for preparation of study drug. The study drug supply was not blinded. The Sponsor and Sponsor’s designee involved in monitoring the pharmacy data were also unblinded. The infusion bag containing the study medication was identified with the participant’s identification number, but did not identify the specific drug product.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MDCO-216
    Arm description
    		 20 mg/kg of MDCO-216 administered intravenously (IV) as a 360 milliliters (mL) infusion over 2 hours on Days 1, 8, 15, 22, and 29.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MDCO-216
    Investigational medicinal product code
    Other name
    Recombinant Apo A-I Milano (rApoA-IM)
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants randomized to the MDCO-216 group received MDCO-216 20 mg/kg infused IV over 2 hours in a 360 mL volume on Days 1, 8, 15, 22, and 29.

    Arm title
    		 Placebo
    Arm description
    		 360 mL of placebo (0.9% sodium chloride [NaCl] solution) infusion, IV, over 2 hours on Days 1, 8, 15, 22, and 29.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    NaCl Solution
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants randomized to the placebo group received 360 mL normal saline (0.9% w/v sodium chloride) infused IV over 2 hours on Days 1, 8, 15, 22, and 29.

    Number of subjects in period 1 [1]
    		MDCO-216 Placebo
    Started
    58
    64
    Received 1 Dose of Study Drug
    58
    64
    Completed
    53
    62
    Not completed
    5
    2
         Did Not Return for Study Visits
    1
    -
         Consent withdrawn by subject
    3
    2
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Four randomized participants had protocol deviations and were discontinued before receiving any study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MDCO-216
    Reporting group description
    		 20 mg/kg of MDCO-216 administered intravenously (IV) as a 360 milliliters (mL) infusion over 2 hours on Days 1, 8, 15, 22, and 29.

    Reporting group title
    Placebo
    Reporting group description
    		 360 mL of placebo (0.9% sodium chloride [NaCl] solution) infusion, IV, over 2 hours on Days 1, 8, 15, 22, and 29.

    Reporting group values
    		 MDCO-216 Placebo Total
    Number of subjects
    		 58 64 122
    Age categorical
    Safety population included all participants who received at least one infusion of study drug.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 36 39 75
        From 65-84 years
    		 22 25 47
        85 years and over
    		 0 0 0
    Gender categorical
    Safety population included all participants who received at least one infusion of study drug.
    Units: Subjects
        Female
    		 13 16 29
        Male
    		 45 48 93
    Region of Enrollment
    Units: Subjects
        Canada
    		 3 3 6
        Czech Republic
    		 3 2 5
        Hungary
    		 6 8 14
        Netherlands
    		 8 8 16
        Poland
    		 38 43 81

    End points

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    End points reporting groups
    Reporting group title
    MDCO-216
    Reporting group description
    		 20 mg/kg of MDCO-216 administered intravenously (IV) as a 360 milliliters (mL) infusion over 2 hours on Days 1, 8, 15, 22, and 29.

    Reporting group title
    Placebo
    Reporting group description
    		 360 mL of placebo (0.9% sodium chloride [NaCl] solution) infusion, IV, over 2 hours on Days 1, 8, 15, 22, and 29.

    Subject analysis set title
    MDCO-216
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified intent-to-treat (mITT) population included all participants who were screened, enrolled, randomized, received at least one infusion of study drug, and who had an evaluable Baseline and Follow-up IVUS assessment.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT population included all participants who were screened, enrolled, randomized, received at least one infusion of study drug and who had an evaluable Baseline and Follow-up IVUS assessment.

    Primary: Change From Baseline In Percent Atheroma Volume (PAV) At Day 36

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    End point title
    		 Change From Baseline In Percent Atheroma Volume (PAV) At Day 36
    End point description
    Change from Baseline to Day 36 post-randomization in PAV in a targeted (imaged) coronary artery for all anatomically comparable slices, as determined by IVUS. The change is calculated by subtracting the value at Baseline from the value at Day 36, with positive numbers to represent increases and negative numbers to represent decreases. Change in PAV was analyzed using an analysis of covariance (ANCOVA) model that included Baseline PAV as a covariate and treatment group as factor. Least Squares (LS) mean was adjusted for stratification factors of country and prior statin use.
    End point type
    Primary
    End point timeframe
    Baseline, Day 36
    End point values
    		 MDCO-216 Placebo
    Number of subjects analysed
    52
    61
    Units: change in percent
        least squares mean (standard error)
    -0.21 ( 0.386 )
    -0.94 ( 0.382 )
    Statistical analysis title
    		 Change From Baseline In PAV At Day 36
    Statistical analysis description
    Change in PAV was analyzed using an analysis of covariance (ANCOVA) model that included baseline PAV as a covariate and treatment group as factor. Least Squares (LS) mean was adjusted for stratification factors of country and prior statin use.
    Comparison groups
    MDCO-216 v Placebo
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0738 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 1.52
    Notes
    [1] - Baseline parameter value as a covariate and treatment group as factor, adjusting for country and prior statin use.

    Secondary: Change From Baseline In Total Atheroma Volume (TAV) At Day 36

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    End point title
    		 Change From Baseline In Total Atheroma Volume (TAV) At Day 36
    End point description
    Change from Baseline to Day 36 post-randomization in normalized TAV in a targeted (imaged) coronary artery for all anatomically comparable slices, as determined by IVUS. The change is calculated by subtracting the value at Baseline from the value at Day 36, with positive numbers to represent increases and negative numbers to represent decreases. Change in TAV was analyzed using an analysis of covariance (ANCOVA) model that included Baseline TAV as a covariate and treatment group as factor. LS mean was adjusted for stratification factors of country and prior statin use.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 36
    End point values
    		 MDCO-216 Placebo
    Number of subjects analysed
    52
    61
    Units: cubic millimeter (mm^3)
        least squares mean (standard error)
    -6.33 ( 3.425 )
    -7.89 ( 3.354 )
    No statistical analyses for this end point

    Secondary: Change From Baseline In TAV For The 10 Millimeters (mm) Subsegment With The Greatest Disease Burden At Day 36

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    End point title
    		 Change From Baseline In TAV For The 10 Millimeters (mm) Subsegment With The Greatest Disease Burden At Day 36
    End point description
    Change in TAV from Baseline to Day 36 post-randomization of the most diseased 10-mm subsegment, as determined by IVUS. The change is calculated by subtracting the value at Baseline from the value at Day 36, with positive numbers to represent increases and negative numbers to represent decreases. Change in TAV was analyzed using an analysis of covariance (ANCOVA) model that included Baseline TAV for the most diseased 10-mm subsegment as a covariate and treatment group as factor. LS mean was adjusted for stratification factors of country and prior statin use.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 36
    End point values
    		 MDCO-216 Placebo
    Number of subjects analysed
    52
    61
    Units: mm^3
        least squares mean (standard error)
    -2.16 ( 1.809 )
    -1.74 ( 1.908 )
    No statistical analyses for this end point

    Secondary: Participants With Regression Of Coronary Atherosclerosis As Measured By A PAV Change Greater Than 2 Standard Deviations Of Test-Retest Measurement Variability

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    End point title
    		 Participants With Regression Of Coronary Atherosclerosis As Measured By A PAV Change Greater Than 2 Standard Deviations Of Test-Retest Measurement Variability
    End point description
    The number of participants with regression of coronary atherosclerosis is presented. For this Outcome Measure, the regression of coronary atherosclerosis is defined as a reduction in PAV from Baseline to Day 36 of greater than 2 standard deviations of the test-retest variability.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 36
    End point values
    		 MDCO-216 Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Participants
    Notes
    [2] - Test-retest requires IVUS to be done twice at the same time point and retest IVUS was not done.
    [3] - Test-retest requires IVUS to be done twice at the same time point and retest IVUS was not done.
    No statistical analyses for this end point

    Secondary: Participants With Regression Of Coronary Atherosclerosis As Measured By A PAV Change <0

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    End point title
    		 Participants With Regression Of Coronary Atherosclerosis As Measured By A PAV Change <0
    End point description
    The number of participants with regression of coronary atherosclerosis is presented. For this Outcome Measure, the regression of coronary atherosclerosis is defined as a change in PAV from Baseline to Day 36 of less than zero.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 36
    End point values
    		 MDCO-216 Placebo
    Number of subjects analysed
    52
    61
    Units: participants
    29
    41
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 59 days (±2 days) post randomization
    Adverse event reporting additional description
    Safety population included all participants who received at least one infusion of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    MDCO-216
    Reporting group description
    		 20 mg/kg administered IV as a 360 mL infusion over 2 hours on Days 1, 8, 15, 22, and 29.

    Reporting group title
    Placebo
    Reporting group description
    		 360 mL (0.9% NaCl solution) infusion, IV, over 2 hours on Days 1, 8, 15, 22, and 29.

    Serious adverse events
    		 MDCO-216 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 58 (17.24%)
    7 / 64 (10.94%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Echocardiogram abnormal
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Coronary artery restenosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystole
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vessel puncture site haemorrhage
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 64 (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: 3%
    Non-serious adverse events
    		 MDCO-216 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 58 (41.38%)
    12 / 64 (18.75%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 64 (3.13%)
         occurrences all number
    2
    2
    Blood creatine phosphokinase
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 64 (3.13%)
         occurrences all number
    2
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 64 (1.56%)
         occurrences all number
    4
    1
    Headache
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 64 (1.56%)
         occurrences all number
    5
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 64 (6.25%)
         occurrences all number
    3
    4
    General disorders and administration site conditions
    Vessel puncture site haematoma
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 64 (3.13%)
         occurrences all number
    4
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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