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    Clinical Trial Results:
    Open Label Phase II Evaluation of Pharmacokinetics, Efficacy, and Safety of Kedrion Human Plasma-derived Antihaemophilic Double Virus inactivated and Nanofiltered Factor IX Administered to Previously Treated Severe or Moderately Severe Hemophilia B Patients

    Summary
    EudraCT number
    2005-006186-14
    Trial protocol
    IT  
    Global end of trial date
    06 Jan 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    KB037
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Kedrion SpA
    Sponsor organisation address
    Località Ai Conti, Barga/Lucca, Italy, 55051
    Public contact
    Chiara Guarnieri/Roberta Macchia Kedrion SpA, Kedrion SpA, +39 0583767326, r.macchia@kedrion.com
    Scientific contact
    Chiara Guarnieri/Roberta Macchia Kedrion SpA, Kedrion SpA, +39 0583767320, c.guarnieri@kedrion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Pharmacokinetics (PK) evaluation in vivo incremental recovery; area under the curve (AUC);area under the moment curve (AUMC); plasma half-life (tœ),determination of the time necessary to reach the peak plasma concentration (Tmax),clearance (CL), mean permanence time (MRT),distribution volume at steady state (Vdss),peak plasma concentration (Cmax) Efficacy and Safety evaluation Efficacy: 1) Evaluation of the haemostatic efficacy of Kedrion human plasma-derived double virus inactivated and nanofiltered factor IX (henceforth: Investigational Medicinal Product- IMP) in the management of acute bleeding events. Safety: 1) Assessment of the risk of inhibitor (neutralizing anti factor IX antibodies) development in conjunction with infusion of the IMP throughout the study period 2) Assessment of thrombogenicity of the IMP 3) Assessment of the short and medium term safety of the IMP, when administered to severe/moderately severe Previously Treated Patients
    Protection of trial subjects
    Subjects may withdraw their consent for participation in the study at any time without prejudice. Additionally, the Investigator may withdraw a subject if, in his/her clinical judgment, it is in the best interest of the subject or if the subject cannot comply with the protocol. Wherever possible, the tests and evaluations listed for the termination visit should be carried out. The sponsor should be notified of all study withdrawals within 24 hours.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Jun 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Romania: 9
    Worldwide total number of subjects
    16
    EEA total number of subjects
    15
    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)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    16
    Number of subjects completed
    16

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

    Arms
    Arm title
    single arm
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Nanofiltered Factor IX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pharmacokinetic: 50 + 5 IU/Kg BW Prophylactic regimen: The frequency of FIX was twice/week. The IMP was administered iv at a maximum infusion rate of 10 ml/min. The dose administered was 30-40 IU/kg BW with the exact dose determined by the Investigator and rounded up to the nearest whole vial. Once the prophylactic dose and regimen have been established, every effort had to be made to maintain that regimen throughout the study period. Changes in the dosing regimen might have been made at the Investigator’s discretion. On-Demand regimen In the event that the subject experienced a bleed that requires infusion of FIX, the subjects had to be treated exclusively with the IMP, administered iv at a maximum infusion rate of 10 mL/min. The dose and time intervals between doses used to treat the bleed will be at the discretion of the Investigator. The required initial dosage may eventually be determined using the following formula: BW (kg) x desired Factor IX increase% x 1.2

    Number of subjects in period 1
    single arm
    Started
    16
    Completed
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial (overall period)
    Reporting group description
    -

    Reporting group values
    overall trial (overall period) Total
    Number of subjects
    16 16
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    1 1
        Adults (18-64 years)
    15 15
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    40.5 (17 to 69) -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    16 16
    Subject analysis sets

    Subject analysis set title
    full population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    -All enrolled patients population: all enrolled subjects in the trial (16) -Efficacy population: all enrolled subjects, who received at least one infusion of IMP, completing the planned minimum 6 months exposure days, plus additional 6 months or 50 exposure days (whichever comes first) (14) -Per Protocol population: all Efficacy population subjects with no major protocol violations (14) -PK population: all enrolled subjects who received at least one infusion of IMP and participated in the PK phase (two PK determinations, once at the study entry and the second one after 6 months) (14) -Safety population: all enrolled subjects who received at least one infusion of IMP. An early termination does not result in the exclusion of patients from this population (16)

    Subject analysis sets values
    full population
    Number of subjects
    16
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    1
        Adults (18-64 years)
    15
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    40.5 (17 to 69)
    Gender categorical
    Units: Subjects
        Female
    0
        Male
    16

    End points

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    End points reporting groups
    Reporting group title
    single arm
    Reporting group description
    -

    Subject analysis set title
    full population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    -All enrolled patients population: all enrolled subjects in the trial (16) -Efficacy population: all enrolled subjects, who received at least one infusion of IMP, completing the planned minimum 6 months exposure days, plus additional 6 months or 50 exposure days (whichever comes first) (14) -Per Protocol population: all Efficacy population subjects with no major protocol violations (14) -PK population: all enrolled subjects who received at least one infusion of IMP and participated in the PK phase (two PK determinations, once at the study entry and the second one after 6 months) (14) -Safety population: all enrolled subjects who received at least one infusion of IMP. An early termination does not result in the exclusion of patients from this population (16)

    Primary: FIX concentration at 6 months (6 h post infusion)

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    End point title
    FIX concentration at 6 months (6 h post infusion) [1]
    End point description
    End point type
    Primary
    End point timeframe
    First PK at Time 0 Second PK after 6 months
    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: Pharmacokinetic Analyses: PK parameters were evaluated using a non-compartmental model. Different types of paramenters were estimated: Slope, Rate constant, Elinination rate constant, α and β half life, Cmax, Tmax, AUC, AUMC and MRT, Vdss, Vd, Cl Each parameter was summarized by mean and SD of the mean. The differences of means (baseline vs 6 months) will be evaluated using paired T test. All PK concentrations were summarized by means of summary statistics for each timepoint
    End point values
    single arm
    Number of subjects analysed
    14
    Units: UI/dl
        arithmetic mean (standard deviation)
    52.4 ± 15.28
    No statistical analyses for this end point

    Primary: Efficacy endpoint(mean of bleed/month)

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    End point title
    Efficacy endpoint(mean of bleed/month) [2]
    End point description
    End point type
    Primary
    End point timeframe
    mean number of new bleeds per month (both the total number and those secondary to trauma) during the all study period
    Notes
    [2] - 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: Efficacy Analysis: Efficacy data reported on the CRF and on the patient diary was combined and evaluated by analyzing: - the number of new bleeds per month during the study, total or those secondary to trauma. These parameters were summarized by means and 95% confidence interval of mean
    End point values
    single arm
    Number of subjects analysed
    14
    Units: Number of bleed/Month
        median (full range (min-max))
    0.1 (0 to 3.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reported for all the study period
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    All patients who received at least 1 infusion with IMP

    Serious adverse events
    Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    Chest pain
    Additional description: Chest wall pain
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.44%
    Non-serious adverse events
    Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 16 (37.50%)
    Vascular disorders
    Hypertension
    Additional description: Arterial hypertension
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Surgical and medical procedures
    dental operation
    Additional description: Dental procedure
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
    Additional description: ALT increase
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Nervous system disorders
    Headache
    Additional description: Headache
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Paresthesia
    Additional description: Bilateral paresthesia left hand second third and fourth finger
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    General disorders and administration site conditions
    asthenia
    Additional description: Mild asthenia due to mild liver failure post surgery
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Teething
    Additional description: Teeth pain
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    erythema facial
    Additional description: Facial and neck erythema
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
    Additional description: Muscles cramps
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Infections and infestations
    Upper respiratory tract infection
    Additional description: Acute upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    2
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Dec 2009
    Amendment 1 main changes: 1. Monitoring and Quality activities were outsourced to the CRO Sintesi Research S.r.l. 2. Number of patients updated from “not less than 20” to “at least 20” according to CPMP/BPWG/198/95 rev. 1 Guideline 3. Exclusion of adolescent patients from 12 to 18 years, and consequently deletion of the inclusion criteria “weight>35 Kg” 4. PK evaluations: wash-out period changed from “4-7 days” to “at least 4 (7 if possible)”, according to the reference Guideline. 5. Safety: Inhibitors evaluations: IgE, IgG1, IgG2, IgG3 ed IgG4 dosage against FIX was added in case of patients who develop anaphylaxis and/or inhibitors according to CPMP/BPWG/198/95 rev. 1 “Note for Guidance on the Clinical Investigation of Human Plasma Derived Factor VIII and IX Products”
    27 Feb 2012
    Amendment 2 main changes: Only administrative changes

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Jan 2016
    Serious delays on the enrollment timelines in all the countries involved in the trial (Italy, Turkey and Romania), have had a negative impact on the IMP stocks dedicated to the study, and in some cases the IMP expired before its use. In order to guarantee the IMP delivery, the available IMP at that time was used to treat patients already enrolled, waiting for a new production of the product. After that the study was temporarily suspended waiting for the availability of new IMP. Unfortunately no new production of nanofiltered FIX was done and the final decision was to close definitely the study, with only 16 enrolled patients (Protocol required 20 patients)
    -

    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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