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    Clinical Trial Results:
    A randomised Phase III trial to evaluate the efficacy of chemoimmunotherapy with the monoclonal antibody Campath-1H (Alemtuzumab) given in combination with 2-weekly CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) versus 2-weekly CHOP alone in elderly patients with previously untreated systemic T- cell Lymphoma Short Title: A-CHOP-14 (elderly)

    Summary
    EudraCT number
    		 2007-000821-23
    Trial protocol
    		 DE   DK   AT   NL   FR   BE   SE  
    Global end of trial date
    31 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2020
    First version publication date
    30 Nov 2020
    Other versions
    Summary report(s)
    		 a Statement about non-SAEs

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DSHNHL2006-1B/ACT-2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsmedizin der Georg-August-Universität Göttingen
    Sponsor organisation address
    Robert-Koch-Straße 40, Göttingen, Germany, 37075
    Public contact
    Rainer Bredenkamp, Georg-August-Universität, Universitätsmedizin Göttingen Robert-Koch-Straße 40, 37075 Göttingen, +49 55139171347, sz-umg.sponsor-qm@med.uni-goettingen.de
    Scientific contact
    Rainer Bredenkamp, Georg-August-Universität, Universitätsmedizin Göttingen Robert-Koch-Straße 40, 37075 Göttingen, +49 55139171347, sz-umg.sponsor-qm@med.uni-goettingen.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
    14 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Improvement of the efficacy of chemotherapy with CHOP-14 by the additional use of the CD52 monoclonal antibody alemtuzumab measured on the basis of Event-free Survival
    Protection of trial subjects
    Before launching the trial, it was mentioned in the protocol that patients aged 71 - 80 years will be treated in a separate stratum because the tolerability of chemotherapy is poorer in patients of advanced age. Special safety criteria will apply to patients >70 years of age which will include an extensive toxicity analysis during the interim restaging. In case of a clinically symptomatic CMV disease, both alemtuzumab and CHOP-therapy are stopped and an intravenous therapy with ganciclovir (10 mg/kg BW) initiated. The diagnosis of CMV-disease has to be made on clinical grounds, based on typical organ involvement (pneumonia, retinitis, enterocolitis) and detection of the virus in the blood (pp65, PCR) or in a biopsy of the organ involved. Neutropenia is a common side-effect of ganciclovir and valganciclovir. Monitoring of neutrophil counts is an effective and sensitive safety parameter during treatment. Likewise, regular monitoring of creatinine clearance for dose adaptation of ganciclovir or valganciclovir in case of renal insufficiency is essential. In cases of asymptomatic EBV reactivation detected by quantitative PCR, alemtuzumab is stopped. When peripheral blood leukocytes are above the threshold of 2.500/µl, CHOP chemotherapy should be applied without delay. Alemtuzumab treatment should be restarted as soon as EBV-monitoring is negative again, and the alemtuzumab doses omitted should be added to the treatment schedule in two-week intervals at the end of therapy to ensure the full cumulative alemtuzumab dose to be applied. In cases of symptomatic EBV disease, immunochemotherapy should be stopped, and the trial office be consulted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Oct 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    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
    Netherlands: 23
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 53
    Worldwide total number of subjects
    116
    EEA total number of subjects
    116
    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)
    0
    From 65 to 84 years
    116
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 recruitment was planned for a period of 4 years. Based on the experience of significant patient accrual delay in the first year due to center activation, the recruitment was extended to 6 years in amendment 2 (26.04.2010). There was temporary trial hold in recruitment (waiting for the safety analysis results): 08.04.2010 - 02.06.2010

    Pre-assignment
    Screening details
    		 It was planned in the protocol to recruit 274 patients between 61 - 80 years old. 116 patients from 52 hospitals were eligible to paticipate in the study. 58 patients in each group. 40 patients from the Standard arm were recruited after the protocol amendment (28.04.2010), while 37 patients from the Experimental arm recruited after that amendment.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 standard arm
    Arm description
    		 After the prephase treatment completion; patients recieve six cycles of chemotherapy (CT) (CHOP-14): cyclophosphamide (750 mg/m^2 - IV), doxorubicin (50 mg/m^2 - IV), vincristine (1,4 mg/ m^2, with maximum of 2 mg - IV) and prednisone ()100mg absolute p.o.) with G-CSF support. All CT started from day 1 & prednisolone from day 1 - 5. CHOP-14 is to be repeated on day 15. Prerequisites for the continuation of this therapy are: 1. Patient has passed the leukocyte and platelet nadir. 2. Leukocyte count >2500/mm^3 (or neutrophil count >= 1x10^9/l) on day 15 after discontinuation of G-CSF & 3. Platelet count >80 000/mm^3/l) on day 15 4. No active infection 5. No serious organ or other toxicity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    as part of the CHOP-14 regimn: Vincristine 1,4 mg/ m2, with a i.v. maximum of 2 mg day 1

    Investigational medicinal product name
    prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As part of the CHOP-14 regimn: Prednisone 100 mg (absolute) p.o. day 1 – 5. Tapering of prednisone: Prompt discontinuation of prednisone can result in marked fatigue, particularly in elderly patients. We recommend a gradual reduction of the prednisone dose, with administration of 50 mg on day 6, 25 mg on day 7 and 12.5 mg on day 8.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    As part of the CHOP-14 regimn: Doxorubicin 50 mg/m2 i.v. day 1

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    As part of the CHOP-14 regimn: Cyclophosphamide 750 mg/m2 i.v. day 1

    Arm title
    		 Experimental arm
    Arm description
    		 After the completion of the perphase treatment; patents recieve six cycles of chemotherapy (CHOP-14): cyclophosphamide, doxorubicin, vincristine and prednisone with G-CSF support. In addition to the standard arm, patientes recieve six doses of the monoclonal CD52 antibody alemtuzumab 30 mg s.c. on day 1 of CHOP each at 14-day intervals. If the thresholds (leukocytes >2500/mm^3 and platelets >80000/mm^3) are still not reached after a 1-week postponement of therapy (by day 22 after CHOP-14), further treatment should be delayed, with checks of blood counts every 3 days, until these values are reached.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    as part of the CHOP-14 regimn: Vincristine 1,4 mg/ m2, with a i.v. maximum of 2 mg day 1

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As part of the CHOP-14 regimn: Prednisone 100 mg (absolute) p.o. day 1 – 5 Tapering of prednisone: Prompt discontinuation of prednisone can result in marked fatigue, particularly in elderly patients. We recommend a gradual reduction of the prednisone dose, with administration of 50 mg on day 6, 25 mg on day 7 and 12.5 mg on day 8.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    As part of the CHOP-14 regimn: Cyclophosphamide 750 mg/m2 i.v. day 1

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    As part of the CHOP-14 regimn: Doxorubicin 50 mg/m2 i.v. day 1

    Investigational medicinal product name
    alemtuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg s.c. in the thighs on day 1 of CHOP. In course 1 of A-CHOP, the 1st dose of alemtuzumab may be split into 10 mg on day 1 & 20 mg on day 2 to minimize drug reactions. For s.c. admin. the content of an alemtuzumab ampoule is 30 mg per ml (taken up into a 2 ml syringe). One syringe filled with 1 ml alemtuzumab solution is injected into the left or right thigh, with care being taken to avoid repeated use of exactly the same injection site. At the start of treatment, local reactions can be experienced, such as mild swelling and reddening of the skin, sometimes painful; such reactions decrease during continued therapy. Prior to the initial administration, patients are to be given paracetamol 1g & 50-100 mg diphenhydramine hydrochloride or clemastine 2 mg 30 minutes prior to the s.c. injection. If the thresholds (leukocytes >2500/mm^3 and platelets >80 000/mm^3) are still not reached after 1-week postponement of therapy (by day 22 after CHOP-14) further treatment should be delayed.

    Number of subjects in period 1
    		standard arm Experimental arm
    Started
    58
    58
    Completed
    55
    54
    Not completed
    3
    4
         Consent withdrawn by subject
    -
    1
         Protocol deviation
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    standard arm
    Reporting group description
    		 After the prephase treatment completion; patients recieve six cycles of chemotherapy (CT) (CHOP-14): cyclophosphamide (750 mg/m^2 - IV), doxorubicin (50 mg/m^2 - IV), vincristine (1,4 mg/ m^2, with maximum of 2 mg - IV) and prednisone ()100mg absolute p.o.) with G-CSF support. All CT started from day 1 & prednisolone from day 1 - 5. CHOP-14 is to be repeated on day 15. Prerequisites for the continuation of this therapy are: 1. Patient has passed the leukocyte and platelet nadir. 2. Leukocyte count >2500/mm^3 (or neutrophil count >= 1x10^9/l) on day 15 after discontinuation of G-CSF & 3. Platelet count >80 000/mm^3/l) on day 15 4. No active infection 5. No serious organ or other toxicity.

    Reporting group title
    Experimental arm
    Reporting group description
    		 After the completion of the perphase treatment; patents recieve six cycles of chemotherapy (CHOP-14): cyclophosphamide, doxorubicin, vincristine and prednisone with G-CSF support. In addition to the standard arm, patientes recieve six doses of the monoclonal CD52 antibody alemtuzumab 30 mg s.c. on day 1 of CHOP each at 14-day intervals. If the thresholds (leukocytes >2500/mm^3 and platelets >80000/mm^3) are still not reached after a 1-week postponement of therapy (by day 22 after CHOP-14), further treatment should be delayed, with checks of blood counts every 3 days, until these values are reached.

    Reporting group values
    		 standard arm Experimental arm Total
    Number of subjects
    		 58 58 116
    Age categorical
    (<=70 years) versus (>70 years)
    Units: Subjects
        From 60 - 70 years
    		 39 37 76
        from 71 - 80 years
    		 19 21 40
    Age continuous
    Units: years
        median (full range (min-max))
    		 69 (61 to 80) 69 (60 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 29 20 49
        Male
    		 29 38 67
    Value of serum LDH
    Value for serum LDH (LDH ≤UNV vs. LDH>UNV)
    Units: Subjects
        LDH > UNV
    		 29 27 56
        LDH =< UNV
    		 29 31 60
    International prognostic IPI
    on the basis of the number of risk factors determined during examination, the patient will be allocated to one of the four risk groups using the "International Prognostic (IPI) as follows: 1. low risk group, 2. low-intermediate risk group, 3. intermediate-high risk group, 4. High-risk group.
    Units: Subjects
        IPI 0, 1
    		 8 7 15
        IPI 2
    		 15 21 36
        IPI 3
    		 22 15 37
        IPI 4, 5
    		 13 15 28
    primary pathology (T-cell)
    Units: Subjects
        T-cell lymphoma
    		 3 5 8
        Peripheral T-cell lymphoma, unspecified (PTCL-NOS)
    		 22 23 45
        Lennert‘s lymphoma
    		 0 0 0
        T-zone lymphoma
    		 0 0 0
        T-immunoblastic variant
    		 1 0 1
        Perifollicular variant
    		 0 1 1
        Follicular variant
    		 0 0 0
        T-cell lymphoma of the AIL type
    		 23 25 48
        Anaplastic large cell lymphoma ALK-neg
    		 5 2 7
        Extranodal NK/T-cell lymphoma, nasal type
    		 1 0 1
        Intestinal T/NK-cell lymphoma (± enteropathy)
    		 3 2 5
        Hepatosplenic T-cell lymphoma
    		 0 0 0
        Subcutaneous panniculitis-like PTCL
    		 0 0 0
    primary pathology 1
    With and without reference pathology (technical sufficient material)
    Units: Subjects
        With reference pathology
    		 55 53 108
        Without reference pathology
    		 3 5 8
    Reference pathology II (T-cell)
    Anaplastic large cell lymphoma ALK-neg was excluded after protocol amendment 2. PTCL, was unclassifiable with standard arm. gamma/delta T-cell lymphoma, was unclassifiable with the experimental arm
    Units: Subjects
        T-cell lymphoma
    		 3 1 4
        Peripheral T-cell lymphoma, unspecified (PTCL-NOS)
    		 13 17 30
        Lennert‘s lymphoma
    		 0 0 0
        T-zone lymphoma
    		 0 3 3
        T-immunoblastic variant
    		 0 0 0
        Perifollicular variant
    		 2 1 3
        Follicular variant
    		 1 1 2
        T-cell lymphoma of the AIL type
    		 25 24 49
        Anaplastic large cell lymphoma ALK-neg
    		 4 3 7
        Extranodal NK/T-cell lymphoma, nasal type
    		 1 0 1
        Intestinal T/NK-cell lymphoma (± enteropathy)
    		 3 2 5
        Hepatosplenic T-cell lymphoma
    		 0 0 0
        Subcutaneous panniculitis-like PTCL
    		 0 0 0
        other T-cell
    		 1 1 2
        no T-cell
    		 2 0 2
        without reference pathology
    		 3 5 8
    ECOG
    Performance status (ECOG = 0-1 vs. ECOG > 1)
    Units: Subjects
        ECOG = 0-1
    		 47 46 93
        ECOG > 1
    		 11 12 23
    Bulky disease
    Units: Subjects
        yes
    		 6 5 11
        no
    		 52 53 105
    stage of disease
    Stage (I, II vs. III, IV) stage of disease in accordance with the International Prognostic Index
    Units: Subjects
        I, II
    		 10 10 20
        III, IV
    		 48 48 96
    Number of extranodal involvements
    Number of extranodal involvements (0-1 vs. >1) in accordance with the International Prognostic Index.
    Units: Subjects
        0 - 1
    		 45 46 91
        >1
    		 13 12 25
    Subject analysis sets

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all randomized patients with study treatment n=58 (6 x CHOP-14) n=58 (6 x CHOP-14 + A)

    Subject analysis set title
    Per protocol set 1 (PPS1)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    all patients FAS with fulfilled inclusion criteria; patients randomized in arm B without any alemtuzumab therapy excluded. n=55 (6 x CHOP-14) n=54 (6 x CHOP-14 + A)

    Subject analysis set title
    Per protocol set 2 (PPS2)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    all patients PPS1 with confirmed reference pathology) n=50 (6 x CHOP-14) n=49 (6 x CHOP-14 + A) (for 8 patients no reference pathology available, 2 patients with non confirmed T-cell pathology)

    Subject analysis sets values
    		 Full analysis set (FAS) Per protocol set 1 (PPS1) Per protocol set 2 (PPS2)
    Number of subjects
    116
    109
    99
    Age categorical
    (<=70 years) versus (>70 years)
    Units: Subjects
        From 60 - 70 years
    76
    72
    65
        from 71 - 80 years
    40
    37
    34
    Age continuous
    Units: years
        median (full range (min-max))
    69 (60 to 80)
    69 (61 to 80)
    69 (61 to 80)
    Gender categorical
    Units: Subjects
        Female
    49
    45
    42
        Male
    67
    64
    57
    Value of serum LDH
    Value for serum LDH (LDH ≤UNV vs. LDH>UNV)
    Units: Subjects
        LDH > UNV
    56
    52
    48
        LDH =< UNV
    60
    57
    51
    International prognostic IPI
    on the basis of the number of risk factors determined during examination, the patient will be allocated to one of the four risk groups using the "International Prognostic (IPI) as follows: 1. low risk group, 2. low-intermediate risk group, 3. intermediate-high risk group, 4. High-risk group.
    Units: Subjects
        IPI 0, 1
    15
    15
    12
        IPI 2
    36
    33
    31
        IPI 3
    37
    36
    35
        IPI 4, 5
    28
    25
    21
    primary pathology (T-cell)
    Units: Subjects
        T-cell lymphoma
    8
    8
    7
        Peripheral T-cell lymphoma, unspecified (PTCL-NOS)
    45
    41
    36
        Lennert‘s lymphoma
    0
    0
    0
        T-zone lymphoma
    0
    0
    0
        T-immunoblastic variant
    1
    1
    1
        Perifollicular variant
    1
    1
    1
        Follicular variant
    0
    0
    0
        T-cell lymphoma of the AIL type
    48
    46
    42
        Anaplastic large cell lymphoma ALK-neg
    7
    7
    7
        Extranodal NK/T-cell lymphoma, nasal type
    1
    1
    1
        Intestinal T/NK-cell lymphoma (± enteropathy)
    5
    4
    4
        Hepatosplenic T-cell lymphoma
    0
    0
    0
        Subcutaneous panniculitis-like PTCL
    0
    0
    0
    primary pathology 1
    With and without reference pathology (technical sufficient material)
    Units: Subjects
        With reference pathology
    108
    101
    91
        Without reference pathology
    8
    8
    8
    Reference pathology II (T-cell)
    Anaplastic large cell lymphoma ALK-neg was excluded after protocol amendment 2. PTCL, was unclassifiable with standard arm. gamma/delta T-cell lymphoma, was unclassifiable with the experimental arm
    Units: Subjects
        T-cell lymphoma
    4
    4
    4
        Peripheral T-cell lymphoma, unspecified (PTCL-NOS)
    30
    26
    26
        Lennert‘s lymphoma
    0
    0
    0
        T-zone lymphoma
    3
    3
    3
        T-immunoblastic variant
    0
    0
    0
        Perifollicular variant
    3
    3
    3
        Follicular variant
    2
    2
    2
        T-cell lymphoma of the AIL type
    49
    47
    47
        Anaplastic large cell lymphoma ALK-neg
    7
    7
    7
        Extranodal NK/T-cell lymphoma, nasal type
    1
    1
    1
        Intestinal T/NK-cell lymphoma (± enteropathy)
    5
    4
    4
        Hepatosplenic T-cell lymphoma
    0
    0
    0
        Subcutaneous panniculitis-like PTCL
    0
    0
    0
        other T-cell
    2
    2
    2
        no T-cell
    2
    2
    0
        without reference pathology
    8
    8
    0
    ECOG
    Performance status (ECOG = 0-1 vs. ECOG > 1)
    Units: Subjects
        ECOG = 0-1
    93
    87
    80
        ECOG > 1
    23
    22
    19
    Bulky disease
    Units: Subjects
        yes
    11
    9
    8
        no
    105
    100
    91
    stage of disease
    Stage (I, II vs. III, IV) stage of disease in accordance with the International Prognostic Index
    Units: Subjects
        I, II
    20
    20
    17
        III, IV
    96
    89
    82
    Number of extranodal involvements
    Number of extranodal involvements (0-1 vs. >1) in accordance with the International Prognostic Index.
    Units: Subjects
        0 - 1
    91
    87
    80
        >1
    25
    22
    19

    End points

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    End points reporting groups
    Reporting group title
    standard arm
    Reporting group description
    		 After the prephase treatment completion; patients recieve six cycles of chemotherapy (CT) (CHOP-14): cyclophosphamide (750 mg/m^2 - IV), doxorubicin (50 mg/m^2 - IV), vincristine (1,4 mg/ m^2, with maximum of 2 mg - IV) and prednisone ()100mg absolute p.o.) with G-CSF support. All CT started from day 1 & prednisolone from day 1 - 5. CHOP-14 is to be repeated on day 15. Prerequisites for the continuation of this therapy are: 1. Patient has passed the leukocyte and platelet nadir. 2. Leukocyte count >2500/mm^3 (or neutrophil count >= 1x10^9/l) on day 15 after discontinuation of G-CSF & 3. Platelet count >80 000/mm^3/l) on day 15 4. No active infection 5. No serious organ or other toxicity.

    Reporting group title
    Experimental arm
    Reporting group description
    		 After the completion of the perphase treatment; patents recieve six cycles of chemotherapy (CHOP-14): cyclophosphamide, doxorubicin, vincristine and prednisone with G-CSF support. In addition to the standard arm, patientes recieve six doses of the monoclonal CD52 antibody alemtuzumab 30 mg s.c. on day 1 of CHOP each at 14-day intervals. If the thresholds (leukocytes >2500/mm^3 and platelets >80000/mm^3) are still not reached after a 1-week postponement of therapy (by day 22 after CHOP-14), further treatment should be delayed, with checks of blood counts every 3 days, until these values are reached.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all randomized patients with study treatment n=58 (6 x CHOP-14) n=58 (6 x CHOP-14 + A)

    Subject analysis set title
    Per protocol set 1 (PPS1)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    all patients FAS with fulfilled inclusion criteria; patients randomized in arm B without any alemtuzumab therapy excluded. n=55 (6 x CHOP-14) n=54 (6 x CHOP-14 + A)

    Subject analysis set title
    Per protocol set 2 (PPS2)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    all patients PPS1 with confirmed reference pathology) n=50 (6 x CHOP-14) n=49 (6 x CHOP-14 + A) (for 8 patients no reference pathology available, 2 patients with non confirmed T-cell pathology)

    Primary: EFS (Event-Free Survival)

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    End point title
    		 EFS (Event-Free Survival)
    End point description
    It includes: - PD - PR (treated), NC, unknown at the end of study therapy - Relapse after CR/CRu - CR/ CRu and additional treatment - Death of any cause
    End point type
    Primary
    End point timeframe
    It was calculated as the time from randomization to the date of the first reported event. Patients with no reported event at the time of analysis were censored at the most recent assessment date. It was analyzed for all treatment arms at 3, 4, and 5 years
    End point values
    		 standard arm Experimental arm Full analysis set (FAS) Per protocol set 1 (PPS1) Per protocol set 2 (PPS2)
    Number of subjects analysed
    58 [1]
    58 [2]
    116 [3]
    109 [4]
    99 [5]
    Units: percentage
        36 months
    24
    27
    25
    26
    26
        48 months
    18
    21
    20
    20
    20
        60 months
    10
    21
    16
    17
    16
    Notes
    [1] - 95% CI
    [2] - 95% CI
    [3] - 95% CI
    [4] - 95% CI
    [5] - 95% CI
    Statistical analysis title
    		 per protocol
    Statistical analysis description
    T-cell, PPS1 (n=109) EFS according to treatment arm
    Comparison groups
    Experimental arm v standard arm v Per protocol set 1 (PPS1) v Full analysis set (FAS) v Per protocol set 2 (PPS2)
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.143 [6]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [6] - T-cell, EFS according to treatment arm: P=0.248 FAS (n=116). P=0.143 PPS1 (n=109). P=0.386 PPS2 (n=99).

    Secondary: PFS (Progression-Free Survival)

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    End point title
    		 PFS (Progression-Free Survival)
    End point description
    it includes: - PD - Progression after PR, NC (untreated), unknown (untreated) at the end of study therapy - treated NC, treated unknown at the end of study therapy - Relapse after CR/CRu - Death of any cause
    End point type
    Secondary
    End point timeframe
    It was calculated as the time from randomization to the date of the first reported event. Patients with no reported event at the time of analysis were censored at the most recent assessment date. It was analyzed for all treatment arms at 3, 4, and 5 years
    End point values
    		 standard arm Experimental arm Full analysis set (FAS) Per protocol set 1 (PPS1) Per protocol set 2 (PPS2)
    Number of subjects analysed
    58 [7]
    58 [8]
    116 [9]
    109 [10]
    99 [11]
    Units: percentage
        36 months
    29
    28
    28
    30
    29
        48 months
    24
    22
    23
    24
    23
        60 months
    13
    22
    18
    18
    16
    Notes
    [7] - 95% CI
    [8] - 95% CI
    [9] - 95% CI
    [10] - 95% CI
    [11] - 95% CI
    No statistical analyses for this end point

    Secondary: OS (Overall Survival)

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    End point title
    		 OS (Overall Survival)
    End point description
    - Death of any cause
    End point type
    Secondary
    End point timeframe
    It was calculated as the time from randomization to the date of the first reported event. Patients with no reported event at the time of analysis were censored at the most recent assessment date. It was analyzed for all treatment arms at 3, 4, and 5 years
    End point values
    		 standard arm Experimental arm Full analysis set (FAS) Per protocol set 1 (PPS1) Per protocol set 2 (PPS2)
    Number of subjects analysed
    58 [12]
    58 [13]
    116 [14]
    109 [15]
    99 [16]
    Units: percentage
        36 months
    56
    37
    47
    50
    47
        48 months
    56
    25
    42
    44
    41
        60 months
    39
    25
    33
    35
    31
    Notes
    [12] - 95% CI
    [13] - 95% CI
    [14] - 95% CI
    [15] - 95% CI
    [16] - 95% CI
    No statistical analyses for this end point

    Secondary: complete remission rate (CR rate)

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    End point title
    		 complete remission rate (CR rate)
    End point description
    End point type
    Secondary
    End point timeframe
    at the end of the therpay according to treatment's arm
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58 [17]
    58 [18]
    116 [19]
    Units: percentage
    43
    60
    52
    Notes
    [17] - 25 / 58 (43%) 95% CI: 30%; 57%
    [18] - 35 / 58 (60%) 95% CI: 47%; 73%
    [19] - 60 / 116 (52%) 95% CI: 42%; 61%
    No statistical analyses for this end point

    Secondary: Number of given chemotherapy cycles

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    End point title
    		 Number of given chemotherapy cycles
    End point description
    End point type
    Secondary
    End point timeframe
    at the end of the therpay according to treatment's arm
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58
    58
    116
    Units: cycles
        1 cycle
    5
    2
    7
        2 cycles
    3
    0
    3
        3 cycles
    0
    4
    4
        4 cycles
    2
    4
    6
        5 cycles
    2
    5
    7
        6 cycles
    46
    43
    89
    Attachments
    		 Duration of chemotherapy cycles
    No statistical analyses for this end point

    Secondary: Overall response (OR)

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    End point title
    		 Overall response (OR)
    End point description
    Number of complete remissions, unconfirmed complete remissions and partial remissions (including CR/Cru, PR in patients after early discontinuation) divided by the number of patients
    End point type
    Secondary
    End point timeframe
    at the end of the therpay according to treatment's arm
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58 [20]
    58 [21]
    116 [22]
    Units: percentage
    60
    72
    66
    Notes
    [20] - 35/58 (60%) 95% CI: (47%; 73%)
    [21] - 42/58 (72%) 95% CI: (59%; 83%)
    [22] - 77/116 (66%) 95% CI: (57%; 75%)
    No statistical analyses for this end point

    Secondary: Leukocytopenia

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    End point title
    		 Leukocytopenia
    End point description
    to follow the Possible side effects of the protocol-conformable treatment. The results represent the percentage of cycles per each treatment arm that affected with Leukocytopenia. CTC results are withen nadir interval: day 8 - 10
    End point type
    Secondary
    End point timeframe
    over all treatment cycles
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58
    58
    116
    Units: percentage
        CTC= 0 (>=4*10^3/mm^3)
    19
    11
    14
        CTC=1 (<4*10^3/mm^3)
    5
    9
    7
        CTC=2 (<3*10^3/mm^3)
    11
    9
    10
        CTC=3 (<2*10^3/mm^3)
    20
    20
    20
        CTC=4 (<1*10^3/mm^3)
    44
    49
    49
    No statistical analyses for this end point

    Secondary: Thrombocytopenia

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    End point title
    		 Thrombocytopenia
    End point description
    The results represent the percentage of cycles per each treatment arm that affected with Thrombocytopenia. CTC results are withen nadir interval: day 8 - 10
    End point type
    Secondary
    End point timeframe
    over all treatment cycles
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58
    58
    116
    Units: percentage
        CTC= 0 (>=4*10^3/mm^3)
    62
    55
    58
        CTC=1 (<4*10^3/mm^3)
    14
    23
    19
        CTC=2 (<3*10^3/mm^3)
    14
    10
    11
        CTC=3 (<2*10^3/mm^3)
    4
    11
    8
        CTC=4 (<1*10^3/mm^3)
    5
    2
    4
    No statistical analyses for this end point

    Secondary: Anaemia

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    End point title
    		 Anaemia
    End point description
    The results represent the percentage of cycles per each treatment arm that affected with anaemia.
    End point type
    Secondary
    End point timeframe
    over all treatment cycles
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58
    58
    116
    Units: percentage
        CTC= 0 (>=4*10^3/mm^3)
    34
    32
    33
        CTC=1 (<4*10^3/mm^3)
    22
    22
    22
        CTC=2 (<3*10^3/mm^3)
    40
    39
    39
        CTC=3 (<2*10^3/mm^3)
    4
    8
    6
        CTC=4 (<1*10^3/mm^3)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Haematological toxicity per patient

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    End point title
    		 Haematological toxicity per patient
    End point description
    The results represent the percentage of patients per each treatment arm. the number of laboratory values within nadir interval for Thrombocytopenia (CTC) is small!
    End point type
    Secondary
    End point timeframe
    over all treatment cycles per patient
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58
    58
    116
    Units: percentage
        Leukocytopenia CTC= 4
    54
    70
    63
        Thrombocytopenia CTC= 3, 4
    13
    19
    17
        Anaemia CTC= 3, 4
    19
    29
    24
    No statistical analyses for this end point

    Secondary: Adverse events during chemotherapy per patient

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    End point title
    		 Adverse events during chemotherapy per patient
    End point description
    The results represent the number of cycles with CTC grade 3 - 5 / number of documented cycles
    End point type
    Secondary
    End point timeframe
    during chemotherapy over all cycles per patient
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58
    58
    116
    Units: percentage
        Nausea
    5
    3
    4
        Vomiting
    3
    2
    3
        Diarrhoea
    3
    9
    6
        Constipation
    0
    3
    2
        Mucositis/ stomatitis
    0
    5
    3
        Cardiac arrhythmia
    0
    2
    1
        Cardiac general
    2
    7
    4
        Haemorrhage/ bleeding
    2
    2
    2
        Renal/ genitourinary
    9
    5
    7
        Neuropathy sensory
    70
    9
    8
        Mood alteration
    0
    2
    1
        Allergic reaction/ hypersensitivity
    0
    2
    1
        Infection
    21
    40
    30
    No statistical analyses for this end point

    Secondary: Types of infections

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    End point title
    		 Types of infections
    End point description
    (grade 3-5). several types of infections can be specified for one infection
    End point type
    Secondary
    End point timeframe
    during chemotherapy
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58 [23]
    58 [24]
    116 [25]
    Units: percentage
        Bacterial
    59
    32
    40
        Fungal
    6
    10
    9
        Viral
    0
    50
    34
    Notes
    [23] - Total no. of infection (n=17)
    [24] - total no. of infection (n=38)
    [25] - total no. of infection (n=55)
    No statistical analyses for this end point

    Secondary: Therapeutic intervention during chemotherapy / Cycles

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    End point title
    		 Therapeutic intervention during chemotherapy / Cycles
    End point description
    results represent the percentage of cycles
    End point type
    Secondary
    End point timeframe
    over all chemotherapy cycles
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58 [26]
    58 [27]
    116 [28]
    Units: percentage
        Red blood cell transfusions
    14
    21
    17
        Platelet transfusions
    1
    2
    2
    Notes
    [26] - n= 300
    [27] - n=313
    [28] - n=613
    No statistical analyses for this end point

    Secondary: Therapeutic intervention during chemotherapy / Patients

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    End point title
    		 Therapeutic intervention during chemotherapy / Patients
    End point description
    the results represent the percentage of patients
    End point type
    Secondary
    End point timeframe
    over all chemotherapy cycles
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58
    58
    116
    Units: percentage
        Red blood cell transfusions
    40
    62
    51
        Platelet transfusions
    7
    10
    9
    No statistical analyses for this end point

    Secondary: cause of death 1

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    End point title
    		 cause of death 1
    End point description
    Several causes of death can be specified for one patient. The result of (other) is defined as 1 pat. accident, 1 pat. hemiparesis. Every case of death occurring within the first 2 months after final restaging is considered treatment related, if there is no clear evidence of disease related death. In cases of death later than 2 months after final restaging, the treating physician has to decide whether it was caused by therapy (primary or salvage), by lymphoma (or both) or by an intercurrent disease. If in doubt death should be reported as therapy related. Every case of death to has to be reported to the trial office within one working day by fax if classified as an SAE.
    End point type
    Secondary
    End point timeframe
    until completion pf the study (treatment and follow-up period)
    End point values
    		 standard arm Experimental arm Full analysis set (FAS) Per protocol set 1 (PPS1) Per protocol set 2 (PPS2)
    Number of subjects analysed
    58 [29]
    58 [30]
    116
    109
    99
    Units: percentage
        Tumour related
    70
    62
    65
    62
    64
        Therapy related
    10
    15
    13
    13
    12
        Concomitant diseases
    10
    13
    12
    11
    10
        Secondary neoplasia
    7
    8
    7
    8
    8
        Other
    7
    0
    3
    3
    3
        Unknown
    3
    8
    6
    6
    7
    Notes
    [29] - intent-to-treat principle
    [30] - intent-to-treat principle
    No statistical analyses for this end point

    Secondary: Cause of death 2

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    End point title
    		 Cause of death 2
    End point description
    these results show the patients who faced one main cause of death (single). The results of (other) are defined as 1 pat. accident, 1 pat. hemiparesis
    End point type
    Secondary
    End point timeframe
    treatment and follow-up period
    End point values
    		 standard arm Experimental arm Full analysis set (FAS) Per protocol set 1 (PPS1) Per protocol set 2 (PPS2)
    Number of subjects analysed
    58
    58
    116
    109
    99
    Units: no. of patients
        only tumour
    19
    22
    41
    37
    37
        Only therapy
    2
    5
    7
    7
    6
        Concomitant disease
    2
    4
    6
    6
    5
        Secondary neoplasia
    2
    3
    5
    5
    5
        Other
    2
    0
    2
    2
    2
        Unknown
    1
    3
    4
    4
    4
    No statistical analyses for this end point

    Secondary: Prephase treatment

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    End point title
    		 Prephase treatment
    End point description
    All patients in both arms were to receive prephase treatment prior to initiation of therapy. The purpose of the prephase treatment is to prevent tumour lysis syndrome in patients with extensive tumours, to improve the performance status of the patient and to reduce the toxicity of the first chemotherapy cycle. This treatment consists of: Vincristine: 1 mg i.v. day -6 (single dose), where day 1 = day 1 of CHOP therapy. Prednisolone: 100 mg p.o. day -6 through day zero, where day 1 = day 1 of CHOP therapy. The main therapy phase (CHOP and CHOP + alemtuzumab, respectively), must not be initiated before randomisation, and must directly follow the prephase treatment.
    End point type
    Secondary
    End point timeframe
    a 1-week course, preceding the main phase therapy of CHOP-14 with / without alemtuzumab.
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    58
    58
    116
    Units: no. of patients
    54
    55
    109
    No statistical analyses for this end point

    Secondary: Vincristine as prephase treatment

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    End point title
    		 Vincristine as prephase treatment
    End point description
    Vincristine: 1 mg i.v. day -6 (single dose), where day 1 = day 1 of CHOP therapy.
    End point type
    Secondary
    End point timeframe
    a 1-week course, preceding the main phase therapy of CHOP-14 with / without alemtuzumab.
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    54
    55
    109
    Units: percentage
        0 mg given
    9
    16
    13
        1 mg given
    85
    76
    81
        2 mg given
    6
    7
    7
    No statistical analyses for this end point

    Secondary: prednisolone as prephase treatment

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    End point title
    		 prednisolone as prephase treatment
    End point description
    Prednisolone: 100 mg p.o. day -6 through day zero, where day 1 = day 1 of CHOP therapy.
    End point type
    Secondary
    End point timeframe
    a 1-week course, preceding the main phase therapy of CHOP-14 with / without alemtuzumab.
    End point values
    		 standard arm Experimental arm Full analysis set (FAS)
    Number of subjects analysed
    54
    55
    109
    Units: mg
        median (full range (min-max))
    700 (300 to 1300)
    700 (280 to 1400)
    700 (280 to 1400)
    No statistical analyses for this end point

    Post-hoc: EFS per gender (Female)

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    End point title
    		 EFS per gender (Female)
    End point description
    End point type
    Post-hoc
    End point timeframe
    It was calculated as the time from randomization to the date of the first reported event. Patients with no reported event at the time of analysis were censored at the most recent assessment date. It was analyzed for all treatment arms at 3, 4, and 5 years
    End point values
    		 standard arm Experimental arm
    Number of subjects analysed
    29
    20
    Units: percentage
        3 years
    31
    49
        4 years
    31
    49
        5 years
    12
    49
    Statistical analysis title
    		 full set
    Comparison groups
    standard arm v Experimental arm
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.095
    Method
    		 Regression, Cox
    Confidence interval

    Post-hoc: EFS per gender (male)

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    End point title
    		 EFS per gender (male)
    End point description
    End point type
    Post-hoc
    End point timeframe
    It was calculated as the time from randomization to the date of the first reported event. Patients with no reported event at the time of analysis were censored at the most recent assessment date. It was analyzed for all treatment arms at 3, 4, and 5 years
    End point values
    		 standard arm Experimental arm
    Number of subjects analysed
    32
    35
    Units: percentage
        3 years
    17
    15
        4 years
    6
    8
        5 years
    0
    0
    Statistical analysis title
    		 full set
    Comparison groups
    standard arm v Experimental arm
    Number of subjects included in analysis
    67
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.301
    Method
    		 Regression, Cox
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The reported adverse events represent the period of the chemotherapy over all cycles and the first 3 months until first follow-up.
    Adverse event reporting additional description
    it is based on a full-set analysis (n=116)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    standard arm
    Reporting group description
    		 After the prephase treatment completion; patients recieve six cycles of chemotherapy (CT) (CHOP-14): cyclophosphamide (750 mg/m^2 - IV), doxorubicin (50 mg/m^2 - IV), vincristine (1,4 mg/ m^2, with maximum of 2 mg - IV) and prednisone ()100mg absolute p.o.) with G-CSF support. All CT started from day 1 & prednisolone from day 1 - 5. CHOP-14 is to be repeated on day 15. Prerequisites for the continuation of this therapy are: 1. Patient has passed the leukocyte and platelet nadir. 2. Leukocyte count >2500/mm^3 (or neutrophil count >= 1x10^9/l) on day 15 after discontinuation of G-CSF & 3. Platelet count >80 000/mm^3/l) on day 15 4. No active infection 5. No serious organ or other toxicity.

    Reporting group title
    Experimental arm
    Reporting group description
    		 After the completion of the perphase treatment; patients recieve six cycles of chemotherapy (CHOP-14): cyclophosphamide, doxorubicin, vincristine and prednisone with G-CSF support. In addition to the standard arm, patientes recieve six doses of the monoclonal CD52 antibody alemtuzumab 30 mg s.c. on day 1 of CHOP each at 14-day intervals. If the thresholds (leukocytes >2500/mm^3 and platelets >80000/mm^3) are still not reached after a 1-week postponement of therapy (by day 22 after CHOP-14), further treatment should be delayed, with checks of blood counts every 3 days, until these values are reached.

    Serious adverse events
    		 standard arm Experimental arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 58 (46.55%)
    38 / 58 (65.52%)
         number of deaths (all causes)
    30
    39
         number of deaths resulting from adverse events
    6
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Refractory anaemia with an excess of blast
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 58 (8.62%)
    6 / 58 (10.34%)
         occurrences causally related to treatment / all
    7 / 7
    10 / 10
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         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 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    ataxia
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    7 / 58 (12.07%)
    5 / 58 (8.62%)
         occurrences causally related to treatment / all
    9 / 9
    6 / 6
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Histiocytosis haematophagic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland disorder
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BK virus infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 58 (0.00%)
    7 / 58 (12.07%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia fungal
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (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 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viraemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 standard arm Experimental arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 58 (51.72%)
    52 / 58 (89.66%)
    Cardiac disorders
    Arrhythmia
    Additional description: Cardiac arrhythmia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    cardiac general
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 58 (6.90%)
         occurrences all number
    1
    4
    Nervous system disorders
    neuropathy sensory
         subjects affected / exposed
    4 / 58 (6.90%)
    5 / 58 (8.62%)
         occurrences all number
    5
    6
    Blood and lymphatic system disorders
    Haemorrhage
    Additional description: Haemorrhage/ bleeding
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 58 (1.72%)
         occurrences all number
    1
    1
    Immune system disorders
    allergic reaction
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 58 (1.72%)
         occurrences all number
    6
    1
    Nausea
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 58 (3.45%)
         occurrences all number
    7
    2
    Diarrhoea
         subjects affected / exposed
    2 / 58 (3.45%)
    5 / 58 (8.62%)
         occurrences all number
    2
    7
    Constipation
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    2
    Stomatitis
    Additional description: Mucositis/ stomatitis
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    5
    Renal and urinary disorders
    genitourinary
    Additional description: Renal/ genitourinary
         subjects affected / exposed
    5 / 58 (8.62%)
    3 / 58 (5.17%)
         occurrences all number
    5
    3
    Psychiatric disorders
    Mood alteration
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    1
    Infections and infestations
    Infection
    Additional description: p-value = 0.026
         subjects affected / exposed
    12 / 58 (20.69%)
    23 / 58 (39.66%)
         occurrences all number
    17
    38

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2010
    Based on the experiences in in the ACT-1 trial, in which an increased rate of opportunistic infections had been observed, an extraordinary safety analysis was performed as soon as the 30th patient had completed the full treatment course in the ACT-2 trial. This safety analysis was discussed with the DSMB and the trial steering group, leading to a temporary hold of recruitment communicated to the trial centers on 08 April 2010. An amendment reducing the dose of alemtuzumab was prepared and submitted to EC as well as the competent authorities. As of 26 May 2010 and 02 June 2010, respectively the German national authority (PEI) and the lead EC in Goettingen approved the amendment of the trial, with the exclusion of anaplastic large cell from this trial and the reduction of alemtuzumab to 30 mg per cycle in the first 4 cycles of the experimental A-CHOP arm of the trial. There was another previous amendment to the protocol on January 26, 2009. As per initial protocol of the trial, recruitment into the trial was planned for a period of 4 years. Based on the experience of significant patient accrual delay in the first year of the trial due to center activation, the time period for recruitment was extended to 6 years in the 2nd amendment, as 26 April 2010.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Apr 2010
    emporary trial hold: 08 April 2010 through 02 June 2010: Based on the experiences in in the ACT-1 trial, in which an increased rate of opportunistic infections had been observed, an extraordinary safety analysis was performed as soon as the 30th patient had completed the full treatment course in the ACT-2 trial. This safety analysis was discussed with the DSMB and the trial steering group, leading to a temporary hold of recruitment communicated to the trial centers on 08 April 2010.
    02 Jun 2010

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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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