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    Clinical Trial Results:
    INTRAMYOCARDIAL TRANSPLANTATION OF BONE MARROW STEM CELLS FOR IMPROVEMENT OF POST-INFARCT MYOCARDIAL REGENERATION IN ADDITION TO CABG SURGERY: a controlled prospective, randomized, double blinded multicenter trial

    Summary
    EudraCT number
    		 2006-006404-11
    Trial protocol
    		 DE  
    Global end of trial date
    04 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Aug 2018
    First version publication date
    26 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PERFECT001(M-2006-144)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00950274
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 German Clinical Trials Register: DRKS00000213
    Sponsors
    Sponsor organisation name
    Miltenyi Biotec GmbH
    Sponsor organisation address
    Friedrich-Ebert-Straße 68, Bergisch Gladbach, Germany, 51429
    Public contact
    Clinical Trials Information, Miltenyi Biotec GmbH, petrah@miltenyibiotec.de
    Scientific contact
    Clinical Trials Information, Miltenyi Biotec GmbH, petrah@miltenyibiotec.de
    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
    04 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Determine whether injection of autologously derived bone marrow stem cells yielded a functional benefit in addition to the coronary artery bypass graft (CABG) operation as determined by left ventricular heart function (left ventricular ejection fraction [LVEF] determined with magnetic resonance imaging [MRI]).
    Protection of trial subjects
    1. Recording of AEs 2. Assessment of Major adverse cardiovascular events (cardiac death, myocardial infarction, secondary intervention/reoperation, ventricular arrhythmia) and tachycardial supraventricular arrhythmia >160 bpm (Holter ECG). 3. Laboratory tests (post-operative check and specific tests for cell preparation) 4. Unwanted tissue changes (tumors) will be monitored by MRI and/or echocardiography 5. Vital signs (blood pressure and pulse) 6. Physical examination, 12-lead ECG
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 82
    Worldwide total number of subjects
    82
    EEA total number of subjects
    82
    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)
    46
    From 65 to 84 years
    36
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 119 [1]
    Number of subjects completed
    		 82

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Adverse event, serious fatal: 1
    Reason: Number of subjects
    		 not eligible for enrolment: 35
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 119 patients were screened but only 82 patients were randomized to active treatment or placebo.
    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 placebo group
    Arm description
    		 saline and serum injected intramyocardially during CABG surgery
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intracardiac use
    Dosage and administration details
    The placebo consisted in 5 mL of physiological saline and 10% of autologous serum. The placebo was injected intramyocardially (divided in 15 injections or more) during coronary artery bypass graft (CABG) surgery.

    Arm title
    		 CD133+ treatment group
    Arm description
    		 CD133+ cells injected intramyocardially during CABG surgery
    Arm type
    		 Experimental

    Investigational medicinal product name
    CD133+ autologous bone marrow stem cells
    Investigational medicinal product code
    Other name
    CD133+ enriched bone marrow stem cells
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intracardiac use
    Dosage and administration details
    The CD133+ cell preparation consisted in 5 mL of CD133+ cells (500,000-5,000,000 cells) suspended in physiological saline and 10% of autologous serum. The product (CD133+ cells ) was injected intramyocardially (divided in 15 injections or more) during coronary artery bypass graft (CABG) surgery.

    Number of subjects in period 1
    		placebo group CD133+ treatment group
    Started
    40
    42
    Completed
    36
    32
    Not completed
    4
    10
         Consent withdrawn by subject
    -
    2
         Adverse event, non-fatal
    -
    5
         Body size does not alow MRI anymore
    1
    -
         Pacemaker implantation
    1
    -
         Cell preparation not eligible for treatment
    -
    3
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    placebo group
    Reporting group description
    		 saline and serum injected intramyocardially during CABG surgery

    Reporting group title
    CD133+ treatment group
    Reporting group description
    		 CD133+ cells injected intramyocardially during CABG surgery

    Reporting group values
    		 placebo group CD133+ treatment group Total
    Number of subjects
    		 40 42 82
    Age categorical
    18 years ≤ Age < 80 years
    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)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Adults/Seniors (18-85 years)
    		 0 0 0
        18 years ≤ Age < 80 years
    		 40 42 82
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.9 ( 8.49 ) 63 ( 8.72 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 5 11
        Male
    		 34 37 71
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS/ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    A full analysis set (FAS) following the principle of intent-to-treat (ITT) had to include every patient randomized and compare the patients per group to which they were randomly allocated, regardless of patients' compliance, or withdrawal from the study. Confirmatory analyses on primary efficacy end-point was to be performed on the FAS patients. This ITT analysis was to be considered as the primary one.

    Subject analysis set title
    Safety Analysis Set (SAS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population had to comprise all patients randomized into the study and treated. Safety evaluations were to be performed on the safety population (SAS). All comparisons were to be executed per the group, to which the patients were randomized.

    Subject analysis set title
    Per Protocol Set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol set (PPS) was defined as a subset of the FAS/ITT patients who were compliant with the study protocol. The PPS sample had to consist of all patients from the FAS/ITT group without any major protocol violation. A secondary efficacy analysis of the primary endpoint had to be performed based upon the PPS, to assess the sensitivity of the analysis to the choice of analysis population.

    Subject analysis set title
    Safety Analysis Set II (SASII)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In case treatment application violations were regarded as major violations during the blinded review meeting, and it was decided to analyse safety issues separately, two additional safety analysis sets SASII and SASIII which were not foreseen in the protocol were to be created. SASII had to consist of all patients who were treated correctly with 15 injections.

    Subject analysis set title
    Safety Analysis Set III (SASIII)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In case treatment application violations were regarded as major violations during the blinded review meeting, and it was decided to analyse safety issues separately, two additional safety analysis sets SASII and SASIII which were not foreseen in the protocol were to be created. SASIII had to consist of all patients who were treated with more than 15 injections.

    Subject analysis set title
    Insufficient CD 133+ Analysis Set (I-cd133+-AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who received the cellular product or Placebo but were excluded from per protocol analysis set post-hoc because of cell count insufficiency were to be evaluated separately. This “Insufficient CD133+ Analysis Set”-Population (silent drop-outs) had to include every patient with a randomization number and a CD133+ cell count from 0.5x106> CD133+ cell count ≥ 0.1x106. All comparisons in the I-CD133+- AS Population were to be executed per the group, to which the patients were randomized.

    Subject analysis sets values
    		 Full Analysis Set (FAS/ITT) Safety Analysis Set (SAS) Per Protocol Set (PPS) Safety Analysis Set II (SASII) Safety Analysis Set III (SASIII) Insufficient CD 133+ Analysis Set (I-cd133+-AS)
    Number of subjects
    82
    77
    58
    42
    35
    3
    Age categorical
    18 years ≤ Age < 80 years
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
        Adults/Seniors (18-85 years)
        18 years ≤ Age < 80 years
    82
    77
    58
    42
    35
    3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    placebo group
    Reporting group description
    		 saline and serum injected intramyocardially during CABG surgery

    Reporting group title
    CD133+ treatment group
    Reporting group description
    		 CD133+ cells injected intramyocardially during CABG surgery

    Subject analysis set title
    Full Analysis Set (FAS/ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    A full analysis set (FAS) following the principle of intent-to-treat (ITT) had to include every patient randomized and compare the patients per group to which they were randomly allocated, regardless of patients' compliance, or withdrawal from the study. Confirmatory analyses on primary efficacy end-point was to be performed on the FAS patients. This ITT analysis was to be considered as the primary one.

    Subject analysis set title
    Safety Analysis Set (SAS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population had to comprise all patients randomized into the study and treated. Safety evaluations were to be performed on the safety population (SAS). All comparisons were to be executed per the group, to which the patients were randomized.

    Subject analysis set title
    Per Protocol Set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol set (PPS) was defined as a subset of the FAS/ITT patients who were compliant with the study protocol. The PPS sample had to consist of all patients from the FAS/ITT group without any major protocol violation. A secondary efficacy analysis of the primary endpoint had to be performed based upon the PPS, to assess the sensitivity of the analysis to the choice of analysis population.

    Subject analysis set title
    Safety Analysis Set II (SASII)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In case treatment application violations were regarded as major violations during the blinded review meeting, and it was decided to analyse safety issues separately, two additional safety analysis sets SASII and SASIII which were not foreseen in the protocol were to be created. SASII had to consist of all patients who were treated correctly with 15 injections.

    Subject analysis set title
    Safety Analysis Set III (SASIII)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In case treatment application violations were regarded as major violations during the blinded review meeting, and it was decided to analyse safety issues separately, two additional safety analysis sets SASII and SASIII which were not foreseen in the protocol were to be created. SASIII had to consist of all patients who were treated with more than 15 injections.

    Subject analysis set title
    Insufficient CD 133+ Analysis Set (I-cd133+-AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who received the cellular product or Placebo but were excluded from per protocol analysis set post-hoc because of cell count insufficiency were to be evaluated separately. This “Insufficient CD133+ Analysis Set”-Population (silent drop-outs) had to include every patient with a randomization number and a CD133+ cell count from 0.5x106> CD133+ cell count ≥ 0.1x106. All comparisons in the I-CD133+- AS Population were to be executed per the group, to which the patients were randomized.

    Primary: LVEF at 6 months post-OP, measured by MRI at rest

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    End point title
    		 LVEF at 6 months post-OP, measured by MRI at rest
    End point description
    LVEF (left ventricular ejection fraction) at 6 months postoperatively, measured by MRI (magnetic resonance imaging) at rest and change in LVEF at 6 months post-OP compared with preoperatively (screening) and early postoperatively (discharge) as assessed by MRI. Cardiac MRI was established as the gold standard for determination of LV function (LVEF and LV volumes).
    End point type
    Primary
    End point timeframe
    6 months postoperatively
    End point values
    		 placebo group CD133+ treatment group
    Number of subjects analysed
    34 [1]
    30 [2]
    Units: Percentage of LVEF
        arithmetic mean (standard error)
    42.5 ( 9.65 )
    44.1 ( 13.78 )
    Notes
    [1] - arithmetic mean calculated out of 34 subjects
    [2] - arithmetic mean calculated out of 30 subjects
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    exploratory analysis of covariance (ANCOVA) adjusting for the covariates treatment, study sites and baseline LVEF.
    Comparison groups
    placebo group v CD133+ treatment group
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8581 [3]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - =0.2855 (center) =0.0205 (LVEF at baseline) =0.7366 (Treatment*Center) =0.8182 (treatment*LVEF at baseline) =0.2760 (Center*LVEF at baseline) =0.6660 (Treatment*Center*LVEF at baseline)
    Statistical analysis title
    		 Additional Analysis
    Statistical analysis description
    mixed model analysis for repeat measures approach (MMRM) in order to compensate possible artefacts due to incomplete data groups
    Comparison groups
    placebo group v CD133+ treatment group
    Number of subjects included in analysis
    64
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.4454
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Change in LVEF at 6 month post-OP compared with preoperatively (screening) assessed by cardiac MRI scans

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    End point title
    		 Change in LVEF at 6 month post-OP compared with preoperatively (screening) assessed by cardiac MRI scans
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months post OP
    End point values
    		 placebo group CD133+ treatment group
    Number of subjects analysed
    34
    30
    Units: Percentage of LVEF
        arithmetic mean (standard error)
    8.0 ( 8.71 )
    11.4 ( 13.52 )
    No statistical analyses for this end point

    Secondary: Change in LVEF at 6 month post-OP compared with preoperatively (screening) assessed by echocardiography

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    End point title
    		 Change in LVEF at 6 month post-OP compared with preoperatively (screening) assessed by echocardiography
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months post OP
    End point values
    		 placebo group CD133+ treatment group
    Number of subjects analysed
    32
    31
    Units: Percentage of LVEF
        arithmetic mean (standard error)
    5.1 ( 10.73 )
    6.0 ( 7.48 )
    No statistical analyses for this end point

    Secondary: Change in LVEF at 6 month post-OP compared with early postoperatively (discharge) assessed by cardiac MRI scans

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    End point title
    		 Change in LVEF at 6 month post-OP compared with early postoperatively (discharge) assessed by cardiac MRI scans
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months post OP
    End point values
    		 placebo group CD133+ treatment group
    Number of subjects analysed
    16
    14
    Units: Percentage of LVEF
        arithmetic mean (standard error)
    4.1 ( 8.57 )
    8.8 ( 6.38 )
    No statistical analyses for this end point

    Secondary: Change in LVEF at 6 month post-OP compared with early postoperatively (discharge) assessed by echocardiography

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    End point title
    		 Change in LVEF at 6 month post-OP compared with early postoperatively (discharge) assessed by echocardiography
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months post OP
    End point values
    		 placebo group CD133+ treatment group
    Number of subjects analysed
    28
    30
    Units: Percentage of LVEF
        arithmetic mean (standard error)
    4.5 ( 9.70 )
    4.3 ( 5.82 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events collected between start of screening and end of main trial phase
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    CD133+
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 CD133+ Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 37 (51.35%)
    15 / 40 (37.50%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Implantable defibrillator insertion
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (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
    Impaired healing
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Epididymitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (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
    In-stent coronary artery restenosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative thoracic procedure complication
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin haemorrhage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diabetic foot infection
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 40 (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: 5%
    Non-serious adverse events
    		 CD133+ Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 37 (97.30%)
    40 / 40 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Hypertension
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 40 (10.00%)
         occurrences all number
    3
    5
    Hypertensive crisis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Thrombophlebitis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Chest pain
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 40 (5.00%)
         occurrences all number
    5
    2
    Impaired healing
         subjects affected / exposed
    4 / 37 (10.81%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    Oedema
         subjects affected / exposed
    8 / 37 (21.62%)
    12 / 40 (30.00%)
         occurrences all number
    10
    15
    Oedema peripheral
         subjects affected / exposed
    10 / 37 (27.03%)
    14 / 40 (35.00%)
         occurrences all number
    12
    16
    Pain
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    Cough
         subjects affected / exposed
    9 / 37 (24.32%)
    7 / 40 (17.50%)
         occurrences all number
    10
    7
    Dyspnoea
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Dyspnoea exertional
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 40 (7.50%)
         occurrences all number
    3
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Pleural effusion
         subjects affected / exposed
    19 / 37 (51.35%)
    20 / 40 (50.00%)
         occurrences all number
    20
    21
    Pneumothorax
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 37 (13.51%)
    5 / 40 (12.50%)
         occurrences all number
    6
    5
    Sleep disorder
         subjects affected / exposed
    4 / 37 (10.81%)
    5 / 40 (12.50%)
         occurrences all number
    4
    5
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    4
    C-reactive protein increased
         subjects affected / exposed
    5 / 37 (13.51%)
    3 / 40 (7.50%)
         occurrences all number
    5
    4
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Haemoglobin decreased
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 40 (2.50%)
         occurrences all number
    3
    2
    Troponin T increased
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Urine output decreased
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    8 / 37 (21.62%)
    9 / 40 (22.50%)
         occurrences all number
    9
    9
    Procedural pain
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Wound secretion
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Arrhythmia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Atrial fibrillation
         subjects affected / exposed
    7 / 37 (18.92%)
    9 / 40 (22.50%)
         occurrences all number
    9
    9
    Atrioventricular block
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Atrioventricular block first degree
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Bradycardia
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 40 (12.50%)
         occurrences all number
    0
    6
    Bundle branch block left
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Pericardial effusion
         subjects affected / exposed
    6 / 37 (16.22%)
    7 / 40 (17.50%)
         occurrences all number
    6
    7
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Supraventricular tachyarrhythmia
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 40 (5.00%)
         occurrences all number
    5
    3
    Supraventricular tachycardia
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Tachycardia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Ventricular arrhythmia
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Ventricular extrasystoles
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    Ventricular tachycardia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 37 (18.92%)
    6 / 40 (15.00%)
         occurrences all number
    8
    6
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 37 (16.22%)
    7 / 40 (17.50%)
         occurrences all number
    6
    7
    Nausea
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    Vomiting
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Scar pain
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 40 (2.50%)
         occurrences all number
    3
    2
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Renal failure
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 40 (2.50%)
         occurrences all number
    4
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 37 (2.70%)
    6 / 40 (15.00%)
         occurrences all number
    1
    6
    Joint effusion
         subjects affected / exposed
    2 / 37 (5.41%)
    5 / 40 (12.50%)
         occurrences all number
    2
    5
    Muscle tightness
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    Neck pain
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Pain in extremity
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Infections and infestations
    Device related infection
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Lung infection
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Pneumonia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Hypokalaemia
         subjects affected / exposed
    5 / 37 (13.51%)
    3 / 40 (7.50%)
         occurrences all number
    6
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jul 2009
    Chnage of Sponsorship; change of Stem Cell Maufacturer/Central Laboratory Cell Processing; IMP: range of the amount of cells applied was expanded from 5-10x106 CD133+ cells to 1-10x106 CD133+ in order to be in accordance with the range applied in the preceding phase I/II trials; moderate revision to Inclusion and exclusion criteria, Revision of AE Section: Start of documentation changed from Assessment IIa to the date of IC (Assessment I); IC: Text regarding time given to patients for considerations changed
    18 Dec 2009
    Medical Director at sponsor changed; LVEF for inclusion changed from ≤ 35% to 25% ≤ LVEF ≤ 40%
    20 Dec 2010
    Restart of recruitment; Threshold for cell number changed to 0.5 Mio -5 Mio; EQ-5D questionnaire implemented
    09 Jun 2011
    New sites; Change of Coordinating Investigator
    18 Nov 2011
    LVEF threshold rised to ≤ 50%; prolongation of recruitment time from 2 to 3 years, totalstudy duration increased to 3.5 years
    17 Aug 2012
    Interimanalyis after 70 patients completed 6-Months follow up; study duriation extended by 1 year
    27 Apr 2016
    Recruitment Stop 12Nov2015 due to decrease in availability of eligible patients; sponsor study responsible physician changed; Core lab responsibility changed

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Sep 2010
    Voluntary hold of recruitment: Cell number of at least 1 Mio CD 133+ cells not reached in two patients. Root cause analysis done
    20 Dec 2010

    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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