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    Clinical Trial Results:
    Therapy for chronic cold agglutinin disease: A prospective, non-randomized international multicenter trial on the safety and efficacy of bendamustine and rituximab combination therapy.

    Summary
    EudraCT number
    		 2011-004835-30
    Trial protocol
    		 NO   DK   FI  
    Global end of trial date
    22 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Feb 2021
    First version publication date
    22 Feb 2021
    Other versions
    Summary report(s)
    		 Berentsen et al_Blood 2017

    Trial information

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    Trial identification
    Sponsor protocol code
    CAD5
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02689986
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Haugesund Hospital, Helse Fonna
    Sponsor organisation address
    Karmsundgata 128, Haugeusnd, Norway, 5504
    Public contact
    Sigbjorn Berentsen, Department of Medicine, 47 52732000, sigbjorn.berentsen@haugnett.no
    Scientific contact
    Sigbjorn Berentsen, Department of Research and Innovation, 47 52732000, sigbjorn.berentsen@haugnett.no
    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
    22 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Rate of complete and partial responses, respectively.
    Protection of trial subjects
    Trial including protection of trial subjects was performed in accordance with REK (Regional Committee for Medical and Health Research Ethichs) approval, NoMi (Norwegian Medicines Agency) approval, and the Declaration of Helsinki.
    Background therapy
    		 None.
    Evidence for comparator
    		 No comparator(s).
    Actual start date of recruitment
    01 Aug 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety, Scientific research
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 38
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Finland: 5
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    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)
    19
    From 65 to 84 years
    23
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients had to be diagnosed with CAD and require therapy. Criteria for CAD: hemolysis combined, CA titer>64, DAT + for C3d, confirmation of bone marrow clonal B-cell lymphoproliferative disorder. Exclusion criteria as per protocol.

    Pre-assignment
    Screening details
    		 History, clinical examination, blood trests and bone marrow examination as per protocol See protocol chapter 4.2-4.4 or attached publication.

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

    Arms
    Arm title
    		 All patients
    Arm description
    		 All patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/sqm /1 hr infusion days 1-2 for 4 cycles at 20 d interval. Dose reduction allowed as per protocol. Administered as combination therapy which also includes rituximab 375 mg/sqm day 1 at the same intevals.

    Number of subjects in period 1
    		All patients
    Started
    45
    Completed
    45
    Period 2
    Period 2 title
    End of trial
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Non-randomized trial

    Arms
    Arm title
    		 All patients
    Arm description
    		 All patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/sqm /1 hr infusion days 1-2 for 4 cycles at 20 d interval. Dose reduction allowed as per protocol. Administered as combination therapy which also includes rituximab 375 mg/sqm day 1 at the same intevals.

    Number of subjects in period 2
    		All patients
    Started
    45
    Completed
    45

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 All patients at baseline

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 45 45
    Age categorical
    Adults 18-64 years: 19 From 65-84 years: 23 85 years and over: 3
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 19 19
        From 65-84 years
    		 23 23
        85 years and over
    		 3 3
    Age continuous
    Units: years
        median (full range (min-max))
    		 74 (48 to 86) -
    Gender categorical
    Males and females, respectively.
    Units: Subjects
        Female
    		 25 25
        Male
    		 20 20
    All patients
    Units: Subjects
        All
    		 45 45
    All patients
    All patients
    Units: Subjects
        All
    		 45 45
        Not recorded
    		 0 0
    Subject analysis sets

    Subject analysis set title
    Basline characteristics
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Baseline characteristics

    Subject analysis set title
    End of trial
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who completed the trial

    Subject analysis sets values
    		 Basline characteristics End of trial
    Number of subjects
    45
    45
    Age categorical
    Adults 18-64 years: 19 From 65-84 years: 23 85 years and over: 3
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    19
        From 65-84 years
    23
        85 years and over
    3
    Age continuous
    Units: years
        median (full range (min-max))
    74 (48 to 86)
    Gender categorical
    Males and females, respectively.
    Units: Subjects
        Female
    25
        Male
    20
    All patients
    Units: Subjects
        All
    45
    All patients
    All patients
    Units: Subjects
        All
    45
        Not recorded
    0

    End points

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    End points reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 All patients
    Reporting group title
    All patients
    Reporting group description
    		 All patients

    Subject analysis set title
    Basline characteristics
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Baseline characteristics

    Subject analysis set title
    End of trial
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who completed the trial

    Primary: Complete + partial responses (CR + PR)

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    End point title
    		 Complete + partial responses (CR + PR)
    End point description
    Complete and partial responses, repectively, as define per protocol.
    End point type
    Primary
    End point timeframe
    Any
    End point values
    		 All patients Basline characteristics End of trial
    Number of subjects analysed
    45
    45
    45
    Units: patients
        Complete responses (CR)
    18
    0
    18
        Partial responses (PR)
    14
    0
    14
    Statistical analysis title
    		 Not relevant
    Statistical analysis description
    Not relevant
    Comparison groups
    Basline characteristics v End of trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 90
         upper limit
    		 99
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Not relevant
    Comparison groups
    Basline characteristics v End of trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 90
         upper limit
    		 99
    Variability estimate
    Standard error of the mean

    Secondary: Hemoglobin increase

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    End point title
    		 Hemoglobin increase
    End point description
    Increase in hemoglobin level at response or at the end of study.
    End point type
    Secondary
    End point timeframe
    Any
    End point values
    		 All patients All patients Basline characteristics End of trial
    Number of subjects analysed
    45
    0 [1]
    45
    45
    Units: g/dL
    median (full range (min-max))
        CR
    4.4 (0.1 to 11.8)
    ( to )
    0 (0 to 0)
    4.4 (0.1 to 11.8)
        PR
    3.9 (0 to 7.6)
    ( to )
    0 (0 to 0)
    3.9 (0 to 7.6)
        All patients
    3.6 (0 to 11.8)
    ( to )
    0 (0 to 0)
    3.6 (0 to 11.8)
    Notes
    [1] - Only one reporting group
    Statistical analysis title
    		 Not relevant
    Statistical analysis description
    Not relevant
    Comparison groups
    All patients v End of trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.05 [3]
    Method
    		 Not relevant
    Parameter type
    		 Not relevant
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Notes
    [2] - No comparison
    [3] - Not relevant; single-armed trial
    Statistical analysis title
    		 Not relevant
    Comparison groups
    Basline characteristics v End of trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 90
         upper limit
    		 99
    Variability estimate
    Standard error of the mean
    Notes
    [4] - Non-randomized study

    Secondary: Time to response (TTR)

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    End point title
    		 Time to response (TTR)
    End point description
    Time from start of treatment to achievement of any degree of response.
    End point type
    Secondary
    End point timeframe
    Any
    End point values
    		 All patients Basline characteristics
    Number of subjects analysed
    45
    45 [5]
    Units: months
        median (full range (min-max))
    1.9 (0.25 to 12)
    1.9 (0.25 to 12)
    Notes
    [5] - All responders
    Statistical analysis title
    		 Not relevant
    Statistical analysis description
    Not relevant
    Comparison groups
    All patients v Basline characteristics
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 90
         upper limit
    		 99
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Whole study period
    Adverse event reporting additional description
    As per observations during follow-up according to protocol.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 All patients

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 45 (11.11%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    1
    Blood and lymphatic system disorders
    Neutropenia requiring hospitalization
    Additional description: Neutropenia requiring hospitalization
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Generalized weakness and hypothermia
    Additional description: An 80 year-old man died 3 weeks after developing generalized weakness and hypothermia immediately after administration of rituximab. We considered his death related to rituximab (standard therapy) but not bendamustine (study drug).
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 45 (37.78%)
    General disorders and administration site conditions
    Non-hematologic AEs
    Additional description: Gastrointestinal discomfort (mostly mild nausea) (5 events), rash (4), non-neutropenic infection (2), atrial fibrillation (1). Manageable in all cases.
         subjects affected / exposed
    17 / 45 (37.78%)
         occurrences all number
    17

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28533306
    http://www.ncbi.nlm.nih.gov/pubmed/32374875
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