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    Clinical Trial Results:
    A Phase II, open-label, randomised, dose-finding study to compare the efficacy (in terms of clearance of RhD-positive RBCs) and safety of LFB-R593, a monoclonal anti-RhD antibody, vs Rhophylac®, a polyclonal anti-RhD immunoglobulin in healthy RhD negative volunteers.

    Summary
    EudraCT number
    		 2009-011017-24
    Trial protocol
    		 DE  
    Global end of trial date
    11 Jul 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Apr 2017
    First version publication date
    05 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ADNC-0726
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LFB Biotechnologies
    Sponsor organisation address
    3 Avenue des Tropiques BP 40305, COURTABOEUF, France, 91958
    Public contact
    Global Clinical Development Leader, LFB Biotechnologies, 33 1 69 82 56 56,
    Scientific contact
    Global Clinical Development Leader, LFB Biotechnologies, 33 1 69 82 56 56,
    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
    24 Jan 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jul 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are: •To identify the IV effective dose (ED) of LFB-R593 required to effectively clear 15 ml of RhD positive RBCs pre-injected to healthy RhD-negative subjects when compared to Rhophylac® 300 µg IV. •To determine the IM effective dose (ED) of LFB-R593 required to effectively clear 15 ml of RhD positive RBCs pre-injected to healthy RhD-negative subjects when compared to Rhophylac® 300 µg IM.
    Protection of trial subjects
    In order to prevent accidental immunisation of the volunteers in Part I (Groups 1 to 4), a “rescue” dose of 300 µg of Rhophylac® IV was planned to be administered at the latest 240 hours ±8 hours after RBC injection if the RBC clearance rate was under 90% at 165 hours after IMP injection (corresponding to 189 hours following RhD-positive RBCs administration). If the earlier clearance results (time points before 165 hours) strongly suggested that the subject did would not clear 90% of their RBCs at 165 hours (data to be received on an ongoing basis during the study), the Principal Investigator (PI) had to organise the administration of the rescue dose immediately after the sampling at 165 hours, without waiting for the clearance results of this time point. No rescue medication was planned in Part II since each subject received an effective IM dose of Rhophylac® (Groups 6 and 8) or an effective IM dose of LFB-R593 (Groups 5 and 7). The only exception concerned the first 6 subjects in Group 5, who could receive a rescue medication, if the initial LFB-R593 IM dose administered was determined to be “not effective” (see Amendment 2).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Aug 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 78
    Worldwide total number of subjects
    78
    EEA total number of subjects
    78
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    78
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 78 subjects were included in the study between 10/08/2009 and 16/12/2010 (last inclusion) 28 subjects in part I : dose finding IV 50 subjects in part II: dose finding IM

    Pre-assignment
    Screening details
    		 See pre-assignment period.

    Pre-assignment period milestones
    Number of subjects started
    		 159 [1]
    Number of subjects completed
    		 78

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 15
    Reason: Number of subjects
    		 recruitment completed: 15
    Reason: Number of subjects
    		 Protocol deviation: 51
    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: 81 patients screening failure.
    Period 1
    Period 1 title
    Inclusion Visit
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LFB-R593
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    LFB-R593
    Investigational medicinal product code
    ADNC
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Intramuscular use
    Dosage and administration details
    No administration at inclusion visit.

    Arm title
    		 Rhophylac
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rhophylac
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use, Intravenous use
    Dosage and administration details
    No administration at inclusion visit.

    Number of subjects in period 1
    		LFB-R593 Rhophylac
    Started
    43
    35
    Part I Intra Venous
    18 [2]
    10 [3]
    Part II Intra Muscular
    25 [4]
    25 [5]
    Completed
    43
    35
    Notes
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 43 patients (18 IV and 25 IM)
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 35 patients (10 IV and 25 IM)
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 43 patients (18 IV and 25 IM)
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 35 patients (10 IV and 25 IM)
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LFB-R593 100µg IV - Part I
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    LFB-R593
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection of 100µg of LFB-R593 IV 24 hours after RhD-positive RBC injection.

    Arm title
    		 LFB-R593 200µg IV - Part I
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    LFB-R593
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection of 200µg of LFB-R593 IV 24 hours after RhD-positive RBC injection

    Arm title
    		 LFB-R593 300µg IV - Part I
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    LFB-R593
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection of 300µg of LFB-R593 IV 24 hours after RhD-positive RBC injection.

    Arm title
    		 Rhophylac 300µg IV - Part I
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rhophylac
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection of 300µg of Rhophylac IV 24 hours after RhD-positive RBC injection.

    Arm title
    		 LFB-R393 300µg IM - Part II
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    LFB-R593
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Injection of 300µg of LFB-R593 IM 24 hours after RhD-positive RBC injection.

    Arm title
    		 Rhophylac 300µg IM - Part II
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rhophylac
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Injection of 300µg of Rhophylac IM 24 hours after RhD-positive RBC injection.

    Number of subjects in period 2
    		LFB-R593 100µg IV - Part I LFB-R593 200µg IV - Part I LFB-R593 300µg IV - Part I Rhophylac 300µg IV - Part I LFB-R393 300µg IM - Part II Rhophylac 300µg IM - Part II
    Started
    6
    6
    6
    10
    25
    25
    Completed
    6
    6
    6
    10
    25
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Inclusion Visit
    Reporting group description
    		 -

    Reporting group values
    		 Inclusion Visit Total
    Number of subjects
    		 78 78
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 78 78
    Age continuous
    Units: years
        median (full range (min-max))
    		 41 (22 to 60) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 71 71
    Subject analysis sets

    Subject analysis set title
    Part I TTS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total Treated Set part I

    Subject analysis set title
    Part II TTS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Part II Total Treated Set

    Subject analysis sets values
    		 Part I TTS Part II TTS
    Number of subjects
    28
    50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    28
    50
    Age continuous
    Units: years
        median (full range (min-max))
    42 (26 to 60)
    41 (22 to 60)
    Gender categorical
    Units: Subjects
        Female
    1
    6
        Male
    27
    44

    End points

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    End points reporting groups
    Reporting group title
    LFB-R593
    Reporting group description
    		 -

    Reporting group title
    Rhophylac
    Reporting group description
    		 -
    Reporting group title
    LFB-R593 100µg IV - Part I
    Reporting group description
    		 -

    Reporting group title
    LFB-R593 200µg IV - Part I
    Reporting group description
    		 -

    Reporting group title
    LFB-R593 300µg IV - Part I
    Reporting group description
    		 -

    Reporting group title
    Rhophylac 300µg IV - Part I
    Reporting group description
    		 -

    Reporting group title
    LFB-R393 300µg IM - Part II
    Reporting group description
    		 -

    Reporting group title
    Rhophylac 300µg IM - Part II
    Reporting group description
    		 -

    Subject analysis set title
    Part I TTS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total Treated Set part I

    Subject analysis set title
    Part II TTS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Part II Total Treated Set

    Primary: Mean RhD-positive RBC clearance

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    End point title
    		 Mean RhD-positive RBC clearance [1]
    End point description
    End point type
    Primary
    End point timeframe
    Mean RBC clearance after injection in Part I and Part II with time to reach 50% and 90 %
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis
    End point values
    		 LFB-R593 100µg IV - Part I LFB-R593 200µg IV - Part I LFB-R593 300µg IV - Part I Rhophylac 300µg IV - Part I LFB-R393 300µg IM - Part II Rhophylac 300µg IM - Part II
    Number of subjects analysed
    6 [2]
    6 [3]
    6 [4]
    8 [5]
    25 [6]
    25 [7]
    Units: percentage
        > 50 % results
    69
    74
    61
    71
    54
    56
        > 90 % results
    94
    93
    91
    91
    93
    93
    Notes
    [2] - time to RCB clearance : 4h > 50% and 10h >90%
    [3] - time to RCB clearance : 4h > 50% and 10h >90%
    [4] - time to RCB clearance : 2h > 50% and 4h >90%
    [5] - time to RCB clearance : 4h > 50% and 8h >90%
    [6] - Part II (IM) time to RCB clearance : 10h > 50% and 24h >90%
    [7] - Part II (IM) time to RCB clearance : 24h > 50% and 69h >90%
    No statistical analyses for this end point

    Primary: RhD-positive RBC clearance at 165h

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    End point title
    		 RhD-positive RBC clearance at 165h [8]
    End point description
    End point type
    Primary
    End point timeframe
    RhD-positive RBC clearance at 165h after injection
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis
    End point values
    		 LFB-R593 100µg IV - Part I LFB-R593 200µg IV - Part I LFB-R593 300µg IV - Part I Rhophylac 300µg IV - Part I LFB-R393 300µg IM - Part II Rhophylac 300µg IM - Part II
    Number of subjects analysed
    6
    6
    6
    8
    25
    25
    Units: percentage
    99
    100
    100
    98
    99
    99
    No statistical analyses for this end point

    Primary: Elimination half-life of RhD-positive RBCs

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    End point title
    		 Elimination half-life of RhD-positive RBCs [9]
    End point description
    End point type
    Primary
    End point timeframe
    Geometric mean elemination half-live of RhD-positive RBCs after injection of LFB-R593 or Phophylac.
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis
    End point values
    		 LFB-R593 100µg IV - Part I LFB-R593 200µg IV - Part I LFB-R593 300µg IV - Part I Rhophylac 300µg IV - Part I LFB-R393 300µg IM - Part II Rhophylac 300µg IM - Part II
    Number of subjects analysed
    6
    6
    6
    8
    23
    25
    Units: hours
        geometric mean (standard deviation)
    2.36 ( 1.8405 )
    2.504 ( 1.5724 )
    1.285 ( 2.7453 )
    4.354 ( 3.0327 )
    4.028 ( 1.8836 )
    7.366 ( 1.7453 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    overall the study in both parts, (6 months after IMP administration).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Drug-related AEs TTS part I
    Reporting group description
    		 -

    Reporting group title
    Drug related AEs TTS Part II
    Reporting group description
    		 -

    Reporting group title
    Adverse Event TTS TEAEs Part I
    Reporting group description
    		 -

    Reporting group title
    Adverse Event TTS TEAEs Part II
    Reporting group description
    		 -

    Serious adverse events
    		 Drug-related AEs TTS part I Drug related AEs TTS Part II Adverse Event TTS TEAEs Part I Adverse Event TTS TEAEs Part II
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 50 (0.00%)
    1 / 28 (3.57%)
    0 / 50 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Immune system disorders
    Alloimmunisation
    Additional description: RhD Alloimmunisation (Rhophylac)
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 50 (0.00%)
    1 / 28 (3.57%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Drug-related AEs TTS part I Drug related AEs TTS Part II Adverse Event TTS TEAEs Part I Adverse Event TTS TEAEs Part II
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 28 (39.29%)
    5 / 50 (10.00%)
    16 / 28 (57.14%)
    23 / 50 (46.00%)
    Nervous system disorders
    Headache
    Additional description: 8 AEs Part I (IV): 7 AEs group LFB-R593 and 1 AE group Rhophylac 10 AEs Part II (IM): 7 AEs group LFB-R593 and 4 AEs group Rhophylac
         subjects affected / exposed
    7 / 28 (25.00%)
    2 / 50 (4.00%)
    8 / 28 (28.57%)
    6 / 50 (12.00%)
         occurrences all number
    7
    2
    8
    10
    General disorders and administration site conditions
    Chills
    Additional description: 3 AEs group LFB-R593 and 1 AE group Rhophylac
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 50 (0.00%)
    4 / 28 (14.29%)
    0 / 50 (0.00%)
         occurrences all number
    4
    0
    4
    0
    Fatigue
    Additional description: 5 AEs group LFB-R593
         subjects affected / exposed
    5 / 28 (17.86%)
    0 / 50 (0.00%)
    5 / 28 (17.86%)
    0 / 50 (0.00%)
         occurrences all number
    5
    0
    5
    0
    Influenza-like illness
    Additional description: 3 AEs part II (IM), 2 AEs group LFB-R593 and 1 AE group Rhophylac
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 50 (2.00%)
    0 / 28 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
    Additional description: 1 AE part I (IV) group Rhophylac 3 AEs part II (IM) group LFB-R593
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 50 (0.00%)
    1 / 28 (3.57%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    1
    3
    Infections and infestations
    Nasopharyngitis
    Additional description: 3 AEs part I (IV) : 1 group LFB-R593 and 2 group Rhophylac 6 AEs part II (IM): 1 group LFB-R593 and 5 group Rhophylac
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 50 (0.00%)
    3 / 28 (10.71%)
    6 / 50 (12.00%)
         occurrences all number
    0
    0
    3
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2009
    Amendment included additional information requested by the Ethics Comittee of the Land Berlin and the PEI. in addition, some inconsistencies in the protocol were corrected.
    01 Jun 2010
    Changes related to the choice of the 3rd IV dose level and IV effective dose of LFB-R593.
    01 Nov 2010
    Changes related to blood sampling Schedule for determination of RBC clearance. (additional blood samplings for the part II-2)
    15 Mar 2011
    Changes related to expedited notification of adverse events and related to study management.
    20 Jun 2011
    Changes related to the planned interim analyses.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Sep 2009
    Due to the unexpected absence of RhD-positive RBC following 15 mL RBC administration in a healthy volunteer and before administration of the IMP (Rhophylac® 300 µg; reference), DSMB members recommended to halt temporarily the inclusions to investigate the reason of this lack of RhD-positive RBCs. Therefore, the inclusion of further subjects in the study was temporarily stopped on 08 September 2009. This decision was documented in a submission to the PEI on 21 September 2009. This was not related to either the safety or the efficacy of the IMP. A corrective action plan was set up in order to ensure the quality of subsequent RhD-positive preparations. The submission for study restart, dated 16 November 2009, was approved by the IEC on 01 December 2009 and by the PEI on 15 December 2009.
    16 Nov 2009

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