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    Clinical Trial Results:
    A Multi-Centre, Open-Label, Non-Controlled Trial on Safety and Efficacy of N8 (turoctocog alfa) in Prevention and Treatment of Bleeds in Previously Treated Subjects with Haemophilia A Sub-Trial: Safety and Efficacy of N8 (turoctocog alfa) in Prevention and Treatment of Bleeding during Surgical Procedures in Subjects with Haemophilia A

    Summary
    EudraCT number
    2008-003960-20
    Trial protocol
    DE   GB   ES   IT   DK  
    Global end of trial date
    21 Sep 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7008-3543
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00840086
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000428-PIP01-08
    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
    08 Feb 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part A and Part B: To evaluate the efficacy of N8 in bleeding prevention in subjects with haemophilia A. To evaluate the efficacy of N8 in on-demand treatment of bleeding episodes in subjects with haemophilia A. Additional Objective for Part A To describe the steady-state PK profile of N8 in the subjects who participated in the phase 1 trial NN7008-3522, 3 months after initial dose of N8. Part C: To evaluate the efficacy of N8 in bleeding prevention during surgical procedures in subjects with haemophilia A. To evaluate the haemostatic effect of N8 during surgical procedures and in the early postoperative period (Day 1 to Day 6) for subjects with haemophilia A.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki(2008) and ICH Good Clinical Practice (1996).
    Background therapy
    In accordance with the EMA guidelines on development of new FVIII products the clinical programme for turoctocog alfa was initiated with a pharmacokinetic trial (NN7008-3522) to document the essential pharmacokinetic characteristics of the product and to achieve initial safety information. The initial pharmacokinetic trial was designed as a comparative trial to the rFVIII product, Advate which is one of the commercially available rFVIII products. The pharmacokinetic parameters were based on FVIII coagulation activity measurements. This parameter is known to correlate to clinical efficacy of FVIII products. In the present trial, a pharmacokinetic session was performed 3-6 months after the first pharmacokinetic session with turoctocog alfa in NN7008-3522 using the same dose as the first pharmacokinetic session with turoctocog alfa, which is in accordance with the EMA guideline on development of new FVIII products. The main purpose of the second pharmacokinetic assessment was to evaluate changes in pharmacokinetic parameters as indicators of inhibitor information. This pharmacokinetic session was included in the present trial (NN7008-3543) for patients who completed the pharmacokinetic trial (NN7008-3522) mentioned above. The present trial consisted of three parts (part A, part B and part C). The only difference between part A and part B is the above described pharmacokinetic session. In the surgery sub-trial part C, the patients had the option to undergo surgery. The surgery part was also designed in accordance with the EMA guideline on development of new FVIII products.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    07 Apr 2009
    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
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Croatia: 11
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Japan: 9
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Serbia: 19
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    United States: 29
    Country: Number of subjects enrolled
    Brazil: 16
    Worldwide total number of subjects
    150
    EEA total number of subjects
    35
    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)
    24
    Adults (18-64 years)
    126
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited at 48 sites in 15 countries: Brazil (2 sites), Croatia (2 sites), Germany (4 sites), Israel (1 site), Italy (2 sites), Japan (8 sites), Malaysia (1 site), Russian Federation (1 site), Republic of Serbia (5 sites), Spain (2 sites), Switzerland (1 site), Taiwan (1 site), Turkey (5 sites), the UK (3 sites) and US (10 sites).

    Pre-assignment
    Screening details
    Not applicable

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

    Arms
    Arm title
    All Subjects treated with turoctocog alfa
    Arm description
    All subjects participating in the study (Part A + Part B + Part C).
    Arm type
    Experimental

    Investigational medicinal product name
    N8
    Investigational medicinal product code
    NN7008
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive bleeding preventive treatment (home treatment with self-injection i.v.) with turoctocog alfa at a dose of 20-40 IU/kg body weight every second day or 20-50 IU/kg body weight three times per week at the investigator's discretion

    Number of subjects in period 1
    All Subjects treated with turoctocog alfa
    Started
    150
    Completed
    146
    Not completed
    4
         Protocol violation
    2
         Adverse event
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Subjects treated with turoctocog alfa
    Reporting group description
    All subjects participating in the study (Part A + Part B + Part C).

    Reporting group values
    All Subjects treated with turoctocog alfa Total
    Number of subjects
    150 150
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    28 ± 11.79 -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    150 150
    Region of Enrollment
    Units: Subjects
        Brazil
    16 16
        Croatia
    11 11
        Germany
    10 10
        Israel
    12 12
        Italy
    7 7
        Japan
    9 9
        Malaysia
    5 5
        Russia
    5 5
        Serbia
    19 19
        Spain
    4 4
        Switzerland
    5 5
        Taiwan
    4 4
        Turkey
    11 11
        United Kingdom
    3 3
        United States
    29 29
    Subject analysis sets

    Subject analysis set title
    Total (Part A+ Part B)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Preventive treatment and treatment of bleeds: The doses were individualised based on the trough FVIII activity level. The doses could be adjusted by the investigator. The dose level chosen was 20-40 IU/kg every second day or 20-50 IU/kg three times per week (Part A + Part B). Subjects previously treated with turoctocog alpha were included in Part A.

    Subject analysis set title
    Part C
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Surgery sub-trial: This part of the trial included any of the patients from Part A and Part B that during the course of the trial needed to undergo a major or minor surgical procedure requiring at least 7 days of daily FVIII treatment, including the day of surgery. Patients received a preoperative loading dose of turoctocog alfa immediately prior to the surgical procedure. On the day of surgery and until Day 7 (included) turoctocog alfa was dose adjusted aiming for a trough level above 0.50 IU/mL. Day 8 to last day of the surgical recovery period (if relevant) turoctocog alfa was dosed according to local guidelines

    Subject analysis sets values
    Total (Part A+ Part B) Part C
    Number of subjects
    150
    9
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    28 ± 11.79
    25 ± 6.53
    Gender categorical
    Units: Subjects
        Female
        Male
    Region of Enrollment
    Units: Subjects
        Brazil
        Croatia
        Germany
        Israel
        Italy
        Japan
        Malaysia
        Russia
        Serbia
        Spain
        Switzerland
        Taiwan
        Turkey
        United Kingdom
        United States

    End points

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    End points reporting groups
    Reporting group title
    All Subjects treated with turoctocog alfa
    Reporting group description
    All subjects participating in the study (Part A + Part B + Part C).

    Subject analysis set title
    Total (Part A+ Part B)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Preventive treatment and treatment of bleeds: The doses were individualised based on the trough FVIII activity level. The doses could be adjusted by the investigator. The dose level chosen was 20-40 IU/kg every second day or 20-50 IU/kg three times per week (Part A + Part B). Subjects previously treated with turoctocog alpha were included in Part A.

    Subject analysis set title
    Part C
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Surgery sub-trial: This part of the trial included any of the patients from Part A and Part B that during the course of the trial needed to undergo a major or minor surgical procedure requiring at least 7 days of daily FVIII treatment, including the day of surgery. Patients received a preoperative loading dose of turoctocog alfa immediately prior to the surgical procedure. On the day of surgery and until Day 7 (included) turoctocog alfa was dose adjusted aiming for a trough level above 0.50 IU/mL. Day 8 to last day of the surgical recovery period (if relevant) turoctocog alfa was dosed according to local guidelines

    Primary: The incidence rate of FVIII inhibitors (greater than or equal to 0.6 Bethesda Units (BU))

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    End point title
    The incidence rate of FVIII inhibitors (greater than or equal to 0.6 Bethesda Units (BU)) [1]
    End point description
    The incidence rate of FVIII inhibitors was calculated by having all patients with inhibitors in the nominator and including all patients with a minimum 50 exposure plus any patients with less than 50 exposures but with inhibitors in denominator.
    End point type
    Primary
    End point timeframe
    The adverse events were collected throughout the trial, corresponding to an average of 188 days per subject.
    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: The trial was one-armed, so there were no comparison arms in the trial. The primary endpoint was incidence rate of FVIII inhibitors (≥0.6 BU). No FVIII inhibitors were detected during the trial. Furthermore, the 1-sided 97.5% upper confidence limit for the inhibitor incidence rate of zero was 2.46%, thus the primary test of adequate safety (upper confidence limit below 6.8%) succeeded. No further statistical analysis was done.
    End point values
    All Subjects treated with turoctocog alfa Part C
    Number of subjects analysed
    150
    9
    Units: N with Inhibitors / N with ≥50 EDs
    150
    9
    No statistical analyses for this end point

    Secondary: Frequency of Adverse Events (AEs)

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    End point title
    Frequency of Adverse Events (AEs)
    End point description
    Adverse event was defined as events occurring after administration of trial product. Severe AEs: considerable interference with subject's daily activities, unacceptable. Moderate AEs: Marked symptoms, moderate interference with the patient’s daily activities. Mild AEs: No or transient symptoms, no interference with the patient’s daily activities. Serious AEs: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalization, persistent/significant disability/incapacity/congenital anomaly/birth defect.
    End point type
    Secondary
    End point timeframe
    The adverse events were collected throughout the trial, corresponding to an average of 188 days per subject
    End point values
    All Subjects treated with turoctocog alfa Total (Part A+ Part B) Part C
    Number of subjects analysed
    150 [2]
    150
    9
    Units: events
        All AEs
    225
    222
    3
        Severe AEs
    8
    8
    0
        Moderate AEs
    52
    51
    1
        Mild AEs
    165
    163
    2
        Serious AEs
    9
    9
    0
        Probably or Possibly Related
    17
    17
    0
    Notes
    [2] - Adverse events reported during surgeries are listed in Part C. those outside are reported in A and B
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events were collected throughout the trial, corresponding to an average of 188 days per subject.
    Adverse event reporting additional description
    Safety analysis set includes all subjects who received at least one dose of the investigational product.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    All Subjects Treated With Turoctocog Alfa
    Reporting group description
    All subjects participating in the study (Part A + Part B + Part C).

    Serious adverse events
    All Subjects Treated With Turoctocog Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 150 (4.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Melaena
         subjects affected / exposed
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All Subjects Treated With Turoctocog Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 150 (24.00%)
    Injury, poisoning and procedural complications
    Incorrect dose administered
         subjects affected / exposed
    15 / 150 (10.00%)
         occurrences all number
    19
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 150 (9.33%)
         occurrences all number
    18
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 150 (8.00%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jun 2009
    Substantial amendment 9. The substantial amendment 9 to the NN7008-3543 protocol version 3.0 (dated 28-Aug-2008) and Subject Information/Informed Consent Form version 2.0 dated 28-Aug-2008: The purpose of this amendment is to clarify further the description of the protocol procedures which includes the addition of Appendix D, Surgery Guideline. Also the trial title was updated. This amendment is applicable to all countries.
    02 Feb 2010
    Substantial amendment 14. The current document is a substantial amendment to protocol NN7008-3543 version 3.0 (dated 28-Aug-2008) and Subject Information/Informed Consent Form version 5.0 (dated 18-May-2009). Changes are made to this protocol in response to comments from the FDA dated August 14, 2009 and to harmonize the protocol with EMEA guidelines on investigation of FVIII products, issued July 2009. This amendment is applicable to all countries. The most significant change is revision to the objectives and endpoints where safety (incidence of inhibitor development) is now the primary endpoint, and efficacy is secondary. As part of the new primary endpoint, a new hypothesis test is set, and inhibitor tests are added at visits 5, 6b, and 8 to ensure adequate safety follow-up. The requirement that subjects should be HCV negative and/or lupus anticoagulant negative if no other condition precludes trial participation has been removed in agreement with EMEA guidelines on investigation of FVIII products, issued July 2009. In addition, other minor changes have been made to further improve the clinical protocol. Explanations of the changes are outlined below: • Revision of order of objectives and endpoints: safety (incidence of inhibitor development) is now the primary endpoint, and efficacy endpoints are secondary. In development of FVIII products, PK is an accepted surrogate endpoint for efficacy, and is demonstrated in phase 1. In general, safety is the primary objective to address in phase 3 trials. • Revision of title and re-ordering of sections addressing safety and efficacy, respectively. • Addition of inhibitor tests at visits 5, 6b, and 8 to ensure adequate safety follow-up in accordance with the changed primary endpoint every 4-5 weeks during study participation. • Introduction of hypothesis test for inhibitor development with upper limit of 6.8%, resulting in acceptance of max. 3 inhibitors in the trial. This change is in line with observed inhibitor
    02 Feb 2010
    Substantial amendment 15. The current document is a Substantial amendment to protocol NN7008-3543 version 3.0 (dated 28-Aug-2008) and Subject Information/Informed Consent Form version 5.0 (dated 18-May-2009). Changes are made to this protocol in response to obtained results from the completed phase 1 trial, NN7008-3522, and to accommodate requests and comments from participating investigators. This amendment is applicable to all countries. The most significant changes are an increase of the maximum allowed dose from 100 IU/kg BW to 200 IU/kg BW and the limit of 14 days on maximum dose has been removed. The changes are made to accommodate sufficient haemostasis and to allow for a FVIII level above 0,5 IU/ml during surgery and post surgery. These changes are supported by CMC documentation. Non-planned surgery is now allowed in Part C. Therefore emergency surgery is removed as withdrawal criterion. The required assessments from day 8 to End of Recovery in Part C have been reduced in agreement with EMEA guidelines. Viral safety assessment has been clarified and removed from visit 2b to avoid duplicate blood sampling. For Switzerland Amendment 9 the section about birth control was rewritten excluding a requirement for a medically acceptable birth control. By mistake this was not excluded from the protocol at the same time. This has been corrected now.
    22 Apr 2010
    Substantial amendment 17. This global substantial amendment has primarily been prepared to adjust the definition of inhibitor history. Due to historical laboratory cut-off values ≤ 1BU/mL for inhibitor testing in some countries we have decided to change our inclusion criterion #6 in Section 6.2.2 and Section 8.6.2.2 in order to clarify the inclusion requirement for the sites with above mentioned past practice. Clarification of required registration of data during the Recovery Period has been added. Furthermore, the wording ‘bleeding resolution’ will be changed to ‘stop of bleeding’ to be in alignment with the Case Record Form (CRF) and also minor mistakes will be corrected to be in alignment with the wording introduced with the previous global substantial amendment no.15. Substantial Protocol Amendment no. 17 will be forwarded to Health Authorities and IRBs/Ethics Committees for approval. The consolidated Protocol NN7008-3543 version 11.0 incorporates all changes.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/23647704
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