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    Clinical Trial Results:
    Efficacy and Safety of Bone Marrow-Derived Mesenchymal Cardiopoietic Cells (C3BS-CQR-1) for the Treatment of Chronic Advanced Ischemic Heart Failure

    Summary
    EudraCT number
    		 2011-001117-13
    Trial protocol
    		 BE   GB   HU   PL   SE   ES   IE   BG   LT   EE   HR  
    Global end of trial date
    10 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2020
    First version publication date
    07 Oct 2020
    Other versions
    Summary report(s)
    		 Results of CHART-1 primary endpoint in the European Journal of Heart Failure

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    C3BS-C-11-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01768702
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celyad Oncology SA
    Sponsor organisation address
    2 rue Edouard Belin, Mont Saint Guibert, Belgium, 1435
    Public contact
    Clinical Trial Information, Celyad Onclogy SA, 2472192739 +32472192739, shalleux@celyad.com
    Scientific contact
    Clinical Trial Information, Celyad Onclogy SA, 2472192739 +32472192739, shalleux@celyad.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
    15 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the efficacy of C3BS-CQR-1 by comparing the overall response to C3BS-CQR-1 relative to a sham procedure using a composite outcome of mortality, morbidity, changes in quality of life , six-minute walk distance, and left ventricular structure and function at 39 weeks (9 months) post-procedure.
    Protection of trial subjects
    The study was conducted in compliance with the requirements of governmental regulatory bodies and ethics committees of each participating centre
    Background therapy
    		 Standard of care
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Dec 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
    Poland: 42
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Hungary: 97
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Serbia: 95
    Country: Number of subjects enrolled
    Switzerland: 2
    Worldwide total number of subjects
    290
    EEA total number of subjects
    175
    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)
    158
    From 65 to 84 years
    132
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Eligible patients gave written informed consent prior to any study-related procedures. Patients were not compensated for participation except for travel expenses. Patients were >18 to < 80 years with left ventricular ejection fraction (LVEF)<35%, NYHA 2 and 3 and ischaemic heart failure.

    Pre-assignment
    Screening details
    		 Patients were randomized 1:1 to cardiopoietic cell injection or a sham control procedure after confirmation by the central production facility that > 24 million MSCs were achieved according to pre-specified release criteria. An Interactive Web Randomization Service was used according to a central randomization scheme stratified by study centre.

    Pre-assignment period milestones
    Number of subjects started
    		 315 [1]
    Intermediate milestone: Number of subjects
    Had one intervention: 290
    Number of subjects completed
    		 271

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Deaths: 16
    Reason: Number of subjects
    		 manufacturing failure: 18
    Reason: Number of subjects
    		 Physician decision: 7
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    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: As explained 315 were randomized but 19 could not get one of the procedure, as 16 died and 3 withdrew consent. Therefore, the number of patients enrolled in the trial were finally 290.
    Period 1
    Period 1 title
    Injection to 2y follow up (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    This was a patient- and evaluator-blinded study. To keep the blind, 2 teams were formed at each site, i.e., an Interventional Team that was unblinded to treatment (Team A), and a blinded Evaluator Team (Team B). Members of the unblinded team were clinical site investigators and operators involved in the index procedure (e.g., the reception and unpacking of the drug product and the preparation of the drug product prior to injection; the injection or sham procedure; and the patient’s follow-up).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 C3BS-CQR-1 treated
    Arm description
    		 Injection of the C3BS-CQR-1 using the C-Cath injection catheter. C3BS-CQR-1 is an autologous stem cell-based bio-therapeutic. The active ingredients of C3BS-CQR-1 are cardiopoietic cells derived from the patient’s bone marrow mesenchymal stem cells. A target volume of 65 mL to 85 mL of anti-coagulated bone marrow will be harvested from the iliac crest of the patient at the hospital. The fresh bone marrow sample will be processed and frozen in order to allow its storage until the initiation of the manufacturing process. After thawing, BMMSCs will be isolated, cultured in the presence of a proprietary combination of factors to guide them towards the cardiovascular lineage (thereby called cardiopoietic cells), and expanded. The manufacture process and release of the drug product takes about 7-15 weeks after thawing of the bone marrow sample. This commitment process of MSCs is based on the cell treatment with a protein-based mixture and excludes genetic manipulation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    C3BS-CQR-1
    Investigational medicinal product code
    C3BS-CQR-1
    Other name
    C-CURE
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intracardiac use
    Dosage and administration details
    Cryopreserved cardiopoietic cell batches meeting release criteria (C3BS-CQR-1 manufactured by Celyad, Mont-Saint-Guibert, Belgium) were shipped frozen to sites and reconstituted within 6 h before injection. Cardiopoietic cells were delivered using standard cardiac catheterization procedures and a cell retention-enhanced injection catheter (C-Cathez TM; Celyad, Mont-Saint-Guibert, Belgium).17 Intramyocardial injections (0.5mL each, 1 cm apart) were made into left ventricle areas with wall thickness >_ 8mm, avoiding the apex and segments adjacent to the mitral or aortic valves. Target zones were mapped using biplane left ventricular angiography integrating preceding echocardiography information regarding wall thickness.

    Arm title
    		 Sham, no injection
    Arm description
    		 Patients randomized to the control group received sham injection. An introducer sheath was inserted into the right or left femoral artery using standard procedures for percutaneous interventions, and a mock injection procedure was performed over a period of 30 to 60 minutes. No waiting time was required in case the patient was sedated per local practice. The sheath was removed at the end of the mock procedure.
    Arm type
    		 Sham procedure

    Investigational medicinal product name
    Sham
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intracardiac use
    Dosage and administration details
    In fact, the operator mimicked intra cadiac injections but did not inject any substances

    Investigational medicinal product name
    Sham
    Investigational medicinal product code
    Sham
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intracardiac use
    Dosage and administration details
    Patients randomized to the control group received sham injection. An introducer sheath was inserted into the right or left femoral artery using standard procedures for percutaneous interventions, and a mock injection procedure was performed over a period of 30 to 60 minutes. No waiting time was required in case the patient was sedated per local practice. The sheath was removed at the end of the mock procedure.

    Number of subjects in period 1 [2]
    		C3BS-CQR-1 treated Sham, no injection
    Started
    120
    151
    39 weeks efficacy
    108
    135
    52 weeks safety
    104
    133
    Completed
    92
    109
    Not completed
    28
    42
         Deaths
    25
    38
         Lost to follow-up
    3
    4
    Notes
    [2] - 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: 315 were randomized However, due to time to get autologous manufacturing (3 weeks) , only 290 were really enrolled to one of the two procedures, and in the end, only 271 received the procedure as planned This is explained in the CONSORT diagram in the EHJ article. Out of the 315, 19 could not get one of the procedure, as 16 died and 3 withdrew consent. Out of the 290, another 19 did not get the CDR-1 procedure as product was out of specs for 18, and 1 was withdrawn by the PI

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    C3BS-CQR-1 treated
    Reporting group description
    		 Injection of the C3BS-CQR-1 using the C-Cath injection catheter. C3BS-CQR-1 is an autologous stem cell-based bio-therapeutic. The active ingredients of C3BS-CQR-1 are cardiopoietic cells derived from the patient’s bone marrow mesenchymal stem cells. A target volume of 65 mL to 85 mL of anti-coagulated bone marrow will be harvested from the iliac crest of the patient at the hospital. The fresh bone marrow sample will be processed and frozen in order to allow its storage until the initiation of the manufacturing process. After thawing, BMMSCs will be isolated, cultured in the presence of a proprietary combination of factors to guide them towards the cardiovascular lineage (thereby called cardiopoietic cells), and expanded. The manufacture process and release of the drug product takes about 7-15 weeks after thawing of the bone marrow sample. This commitment process of MSCs is based on the cell treatment with a protein-based mixture and excludes genetic manipulation.

    Reporting group title
    Sham, no injection
    Reporting group description
    		 Patients randomized to the control group received sham injection. An introducer sheath was inserted into the right or left femoral artery using standard procedures for percutaneous interventions, and a mock injection procedure was performed over a period of 30 to 60 minutes. No waiting time was required in case the patient was sedated per local practice. The sheath was removed at the end of the mock procedure.

    Reporting group values
    		 C3BS-CQR-1 treated Sham, no injection Total
    Number of subjects
    		 120 151 271
    Age categorical
    Patients were selected if they were more than 18 and less than 80
    Units: Subjects
        18 and more, less than 80
    		 120 151 271
    Gender categorical
    Units: Subjects
        Female
    		 13 15 28
        Male
    		 107 136 243
    NYHA Class
    Units: Subjects
        NYHA 1
    		 0 0 0
        NYHA 2
    		 23 36 59
        NYHA 3
    		 96 114 210
        NYHA 4
    		 1 1 2
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 28.2 ( 3.7 ) 28.6 ( 4.4 ) -
    Time from heart failure diagnosis to screening
    Units: months
        median (full range (min-max))
    		 44.1 (12.3 to 100.1) 46.3 (16 to 97.7) -
    Subject analysis sets

    Subject analysis set title
    Per protocol efficacy
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects randomized according to pre specified arm and administered as randomized

    Subject analysis sets values
    		 Per protocol efficacy
    Number of subjects
    271
    Age categorical
    Patients were selected if they were more than 18 and less than 80
    Units: Subjects
        18 and more, less than 80
    271
    Age continuous
    Age at inclusion step
    Units: years
        arithmetic mean (standard deviation)
    62,01 ( 8,6 )
    Gender categorical
    Units: Subjects
        Female
        Male
    NYHA Class
    Units: Subjects
        NYHA 1
    0
        NYHA 2
    59
        NYHA 3
    210
        NYHA 4
    2
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    ( )
    Time from heart failure diagnosis to screening
    Units: months
        median (full range (min-max))

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    C3BS-CQR-1 treated
    Reporting group description
    		 Injection of the C3BS-CQR-1 using the C-Cath injection catheter. C3BS-CQR-1 is an autologous stem cell-based bio-therapeutic. The active ingredients of C3BS-CQR-1 are cardiopoietic cells derived from the patient’s bone marrow mesenchymal stem cells. A target volume of 65 mL to 85 mL of anti-coagulated bone marrow will be harvested from the iliac crest of the patient at the hospital. The fresh bone marrow sample will be processed and frozen in order to allow its storage until the initiation of the manufacturing process. After thawing, BMMSCs will be isolated, cultured in the presence of a proprietary combination of factors to guide them towards the cardiovascular lineage (thereby called cardiopoietic cells), and expanded. The manufacture process and release of the drug product takes about 7-15 weeks after thawing of the bone marrow sample. This commitment process of MSCs is based on the cell treatment with a protein-based mixture and excludes genetic manipulation.

    Reporting group title
    Sham, no injection
    Reporting group description
    		 Patients randomized to the control group received sham injection. An introducer sheath was inserted into the right or left femoral artery using standard procedures for percutaneous interventions, and a mock injection procedure was performed over a period of 30 to 60 minutes. No waiting time was required in case the patient was sedated per local practice. The sheath was removed at the end of the mock procedure.

    Subject analysis set title
    Per protocol efficacy
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects randomized according to pre specified arm and administered as randomized

    Primary: Effiicacy

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    End point title
    		 Effiicacy
    End point description
    It is a hierarchical composite outcome, that was evaluated using a Finkelstein-Schoenfeld's test. This test is an extension of the generalized Wilcoxon rank sum test based on a hierarchy of the endpoints and compared every patient to every other patient in a pairwise manner, thereby assigning +1, 0, or -1 dependent on whether the patient in the pair did better, the same, or worse than the other patient. Each pair of patients was compared with respect to the following endpoints in the order given: (1) Mortality; (2) Number of WHF events: 0, 1, or ≥2: (3) MLWHFQ ≥10 point improvement, ≥10 point deterioration, no meaningful change; (4) 6MWT ≥40 m improvement, ≥40 m deterioration, no meaningful change; (5) LVESV ≥15 mL improvement, ≥15 mL deterioration, no meaningful change, and (6) LVEF ≥4% absolute improvement, ≥4% absolute deterioration, no meaningful change. The net scores for each patient were summed and then ranked.
    End point type
    Primary
    End point timeframe
    39 weeks
    End point values
    		 C3BS-CQR-1 treated Sham, no injection
    Number of subjects analysed
    120
    151
    Units: 18120
    10404
    0
    Attachments
    		 Primay endpoint results
    Statistical analysis title
    		 Composite efficacy endpoint in the treated set
    Statistical analysis description
    Treatment arm sample size of 120 patients per group was estimated to provide 87% power to detect a treatment effect corresponding to a Mann–Whitney estimator (the probability of a better response in the active treatment group plus half the probability of a tie) of 0.61 (values> 0.5 favour active treatment).
    Comparison groups
    C3BS-CQR-1 treated v Sham, no injection
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 > 0.01
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.61
    Variability estimate
    Standard deviation
    Dispersion value
    0.24
    Notes
    [1] - The treatment arm sample size of 120 patients per group was estimated to provide 87% power to detect a treatment effect corresponding to a Mann–Whitney estimator (the probability of a better response in the active treatment group plus half the probability of a tie) of 0.61 (values> 0.5 favour active treatment).

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    104 weeks, end of study
    Adverse event reporting additional description
    Below are the numbers that are part of the Clinical Study Report. The number of patients for which there are non serious events is not specified. The threshold of 5% was applied to Adverse Events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    C3BS-CQR-1 treated
    Reporting group description
    		 All patients treated with the experimental product

    Reporting group title
    Sham control group
    Reporting group description
    		 Group composed of 151 patients that were randomized to receive the Sham procedure and 19 patients that were randomized to receive the experimental product but could not for the following reasons: 18 as the product could not be manufactured within specs and 1 as the procedure was contra indicated by the physician

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There are no non-serious AEs with a reporting rate above the 5 % threshold.
    Serious adverse events
    		 C3BS-CQR-1 treated Sham control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    78 / 120 (65.00%)
    100 / 170 (58.82%)
         number of deaths (all causes)
    26
    45
         number of deaths resulting from adverse events
    26
    45
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 120 (0.83%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular fibrillation
         subjects affected / exposed
    7 / 120 (5.83%)
    5 / 170 (2.94%)
         occurrences causally related to treatment / all
    3 / 15
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute myocardial infarction
         subjects affected / exposed
    3 / 120 (2.50%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    1 / 120 (0.83%)
    4 / 170 (2.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    4 / 120 (3.33%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 120 (0.00%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    4 / 120 (3.33%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 120 (0.83%)
    5 / 170 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    1 / 4
    Cardiac failure
         subjects affected / exposed
    35 / 120 (29.17%)
    44 / 170 (25.88%)
         occurrences causally related to treatment / all
    2 / 62
    0 / 84
         deaths causally related to treatment / all
    0 / 8
    0 / 14
    Cardiac failure chronic
         subjects affected / exposed
    4 / 120 (3.33%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    5 / 120 (4.17%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 120 (0.00%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 120 (0.00%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    2 / 120 (1.67%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    6 / 120 (5.00%)
    15 / 170 (8.82%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Cardiac pacemaker insertion
         subjects affected / exposed
    2 / 120 (1.67%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implantable defibrillator insertion
         subjects affected / exposed
    8 / 120 (6.67%)
    5 / 170 (2.94%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 120 (0.00%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 120 (0.00%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    3 / 120 (2.50%)
    9 / 170 (5.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 3
    0 / 9
    Sudden death
         subjects affected / exposed
    3 / 120 (2.50%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    5 / 120 (4.17%)
    6 / 170 (3.53%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 120 (5.00%)
    5 / 170 (2.94%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 120 (0.00%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 120 (0.00%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 C3BS-CQR-1 treated Sham control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 170 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2014
    Extension of shelf-life
    19 Aug 2015
    Modification of secondary efficacy endpoint.
    03 Feb 2016
    Change of Reference Safety Information in the IB.

    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.
    Efficacy data shown at 39 weeks, which were not fundamentally changed at 52 weeks. On going analysis at 104 weeks. A sub population of responders was identified in a post hoc analysis, which is explained in the EHJ enclosed paper, to be confirmed.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28025189
    http://www.ncbi.nlm.nih.gov/pubmed/28560782
    http://www.ncbi.nlm.nih.gov/pubmed/26662998
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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