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    Clinical Trial Results:
    A Phase 1, Multicenter, Open-Label, Single-Arm, Multiple Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Natalizumab in Pediatric Subjects with Relapsing Remitting Multiple Sclerosis

    Summary
    EudraCT number
    2012-005082-13
    Trial protocol
    IT  
    Global end of trial date
    24 Sep 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Feb 2016
    First version publication date
    04 Apr 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    101MS328
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01884935
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen Idec
    Sponsor organisation address
    225 Binney Street , Cambridge, United States, 02142
    Public contact
    Biogen Idec Study Medical Director, Biogen Idec, Clinicaltrials@biogenidec.com
    Scientific contact
    Biogen Idec Study Medical Director, Biogen Idec, Clinicaltrials@biogenidec.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001095-PIP02-12
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine the pharmacokinetic (PK) profile of multiple doses of natalizumab in pediatric subjects with relapsing remitting multiple sclerosis (RRMS).
    Protection of trial subjects
    Parents or legal guardians must provide written, informed consent, and subjects may provide written assent (if appropriate), before any screening tests or assessments are performed. Subjects must remain in the clinic for 1 hour after the infusion of study treatment is complete for observation and for collection of samples for PK and pharmacodynamic (PD) analyses (if applicable). Epinephrine for subcutaneous injection, diphenhydramine for intravenous (IV) injection, and any other medications and resuscitation equipment for the emergency management of anaphylactic reactions must be available in the room where the infusions are being performed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Jul 2013
    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
    Italy: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    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)
    1
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects were screened for a maximum of 4 weeks prior to first study infusion.

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

    Arms
    Arm title
    Natalizumab
    Arm description
    300 mg IV natalizumab every 4 weeks for 16 weeks (a total of 5 doses)
    Arm type
    Experimental

    Investigational medicinal product name
    natalizumab
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Natalizumab is supplied as a sterile liquid in vials containing 300 mg natalizumab per vial (15 mL of a 20 mg/mL solution). One vial of natalizumab contains a sufficient volume for a single IV infusion following dilution in 100 mL 0.9% sodium chloride for injection.

    Number of subjects in period 1
    Natalizumab
    Started
    13
    Completed
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    300 mg intravenous (IV) natalizumab every 4 weeks for 16 weeks (a total of 5 doses)

    Reporting group values
    Natalizumab Total
    Number of subjects
    13 13
    Age categorical
    Units: Subjects
        10 to 11 Years
    1 1
        12 to 13 Years
    1 1
        14 to 15 Years
    4 4
        16 Years
    5 5
        17 Years
    2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    15.2 ± 1.77 -
    Gender categorical
    Units: Subjects
        Female
    10 10
        Male
    3 3

    End points

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    End points reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    300 mg IV natalizumab every 4 weeks for 16 weeks (a total of 5 doses)

    Subject analysis set title
    PK Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The PK population is defined as all subjects who received at least 1 dose of natalizumab and have at least 1 post-baseline measurement of natalizumab concentration.

    Subject analysis set title
    PD Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The PD population is defined as all subjects who received at least 1 dose of natalizumab and have at least 1 post-baseline measurement of the PD parameter being assessed.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety population was defined as all subjects who received at least 1 dose of natalizumab and had at least 1 post-baseline assessment of the safety parameter being analyzed.

    Primary: Maximum Plasma Concentration (Cmax)

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    End point title
    Maximum Plasma Concentration (Cmax) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
    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: Summary statistics for each PK parameter are presented in the data table.
    End point values
    PK Population
    Number of subjects analysed
    13
    Units: µg/mL
        geometric mean (confidence interval 95%)
    142.9 (127.9 to 159.6)
    No statistical analyses for this end point

    Primary: Predose (Trough) Concentrations (Cpredose) From Multiple Dosing

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    End point title
    Predose (Trough) Concentrations (Cpredose) From Multiple Dosing [2]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
    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: Summary statistics for each PK parameter are presented in the data table.
    End point values
    PK Population
    Number of subjects analysed
    13
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Week 4
    24.8 (16.79 to 36.62)
        Week 8
    22.53 (10.34 to 49.12)
        Week 12
    26.59 (12.25 to 57.73)
        Week 16
    34.04 (20.51 to 56.5)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration Curve From Time of First to Last Dose (AUClast)

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    End point title
    Area Under the Plasma Concentration Curve From Time of First to Last Dose (AUClast) [3]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
    Notes
    [3] - 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: Summary statistics for each PK parameter are presented in the data table.
    End point values
    PK Population
    Number of subjects analysed
    13
    Units: hr*µg/mL
        geometric mean (confidence interval 95%)
    47389.4 (40399 to 55589.4)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration Curve From Time of First Dose to Infinity (AUC0-inf)

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    End point title
    Area Under the Plasma Concentration Curve From Time of First Dose to Infinity (AUC0-inf) [4]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
    Notes
    [4] - 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: Summary statistics for each PK parameter are presented in the data table.
    End point values
    PK Population
    Number of subjects analysed
    9 [5]
    Units: hr*µg/mL
        geometric mean (confidence interval 95%)
    48970.4 (39912.5 to 60083.8)
    Notes
    [5] - 4 subjects were excluded as their terminal phase could not be adequately characterized.
    No statistical analyses for this end point

    Primary: Time to Maximum Plasma Concentration (Tmax)

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    End point title
    Time to Maximum Plasma Concentration (Tmax) [6]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
    Notes
    [6] - 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: Summary statistics for each PK parameter are presented in the data table.
    End point values
    PK Population
    Number of subjects analysed
    13
    Units: hours
        geometric mean (confidence interval 95%)
    7.874 (2.996 to 20.692)
    No statistical analyses for this end point

    Primary: Clearance (Cl)

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    End point title
    Clearance (Cl) [7]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
    Notes
    [7] - 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: Summary statistics for each PK parameter are presented in the data table.
    End point values
    PK Population
    Number of subjects analysed
    9 [8]
    Units: L/week
        geometric mean (confidence interval 95%)
    1.029 (0.839 to 1.263)
    Notes
    [8] - 4 subjects were excluded as their terminal phase could not be adequately characterized.
    No statistical analyses for this end point

    Primary: Volume of Distribution

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    End point title
    Volume of Distribution [9]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
    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: Summary statistics for each PK parameter are presented in the data table.
    End point values
    PK Population
    Number of subjects analysed
    9 [10]
    Units: Liters
        geometric mean (confidence interval 95%)
    1.902 (1.427 to 2.536)
    Notes
    [10] - 4 subjects were excluded as their terminal phase could not be adequately characterized.
    No statistical analyses for this end point

    Primary: Elimination Half-life (t1/2)

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    End point title
    Elimination Half-life (t1/2) [11]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1: within 4 hours prior to start of infusion, within 15 minutes after end of infusion; Day 2: 24 hours (±4 hours) after end of infusion; Day 8; Day 15 (±2 days); Day 22 (±2 days); Weeks 4, 8, 12, and 16: within 4 hours prior to start of infusion
    Notes
    [11] - 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: Summary statistics for each PK parameter are presented in the data table.
    End point values
    PK Population
    Number of subjects analysed
    9 [12]
    Units: hours
        geometric mean (confidence interval 95%)
    215.1 (159.7 to 289.7)
    Notes
    [12] - 4 subjects were excluded as their terminal phase could not be adequately characterized.
    No statistical analyses for this end point

    Secondary: Summary of Alpha4 Integrin Saturation Values

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    End point title
    Summary of Alpha4 Integrin Saturation Values
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline; 15 minutes post-dose; Days 2, 8, 15, and 22; Weeks 4, 8, 12, and 16
    End point values
    PD Population
    Number of subjects analysed
    13 [13]
    Units: percent
    geometric mean (confidence interval 95%)
        Baseline; n=13
    3.4 (2.6 to 4.4)
        15 Minutes Post-dose; n=12
    96 (89.9 to 102.6)
        Day 2; n=13
    94.6 (91.5 to 97.7)
        Day 8; n=13
    92.7 (91 to 94.4)
        Day 15; n=13
    84 (78.8 to 89.5)
        Day 22; n=13
    82.6 (76.9 to 88.6)
        Week 4; n=12
    77.2 (67.4 to 88.5)
        Week 8; n=12
    56.3 (29.9 to 106.1)
        Week 12; n=12
    64.8 (38.6 to 108.9)
        Week 16; n=12
    79.5 (71.2 to 88.7)
    Notes
    [13] - n=subjects with an assessment at given time point.
    No statistical analyses for this end point

    Secondary: Overall Summary of Adverse Events (AEs)

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    End point title
    Overall Summary of Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a subject administered study drug and that does not necessarily have a causal relationship with this treatment. A serious AE is any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the subject at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital anomaly or birth defect; any other medically important event that, in the opinion of the Investigator, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above. AEs were categorized as related or not related to study drug; severity was categorized as mild, moderate, or severe.
    End point type
    Secondary
    End point timeframe
    From first infusion of study treatment through Week 16 (or 12 [±2] weeks after the last infusion)
    End point values
    Safety Population
    Number of subjects analysed
    13
    Units: subjects
        Any AE
    10
        Moderate or Severe AE
    2
        Severe AE
    0
        Related AE
    3
        Serious AE
    1
        Related Serious AE
    0
        Discontinuations Due to an AE
    0
        Withdrawals From Study Due to an AE
    0
    No statistical analyses for this end point

    Secondary: Number of Infusion Reactions and Acute Infusion-related Hypersensitivity Reactions

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    End point title
    Number of Infusion Reactions and Acute Infusion-related Hypersensitivity Reactions
    End point description
    Infusion reactions were defined as those AEs occurring within 2 hours after the start of natalizumab infusion. If the start time of an AE or infusion was missing, but the AE occurred on the same day as the infusion, it was to be assumed to be an infusion reaction. Acute infusion-related hypersensitivity reactions were defined as hypersensitivity reactions that occurred within 2 hours after the start of natalizumab infusion with preferred terms of: hypersensitivity not otherwise specified (NOS), anaphylactic reaction, anaphylactoid reaction, dermatitis allergic, drug hypersensitivity, urticaria NOS, vasoconstriction, urticaria generalized, and erythema multiforme.
    End point type
    Secondary
    End point timeframe
    From first infusion of study treatment through Week 16 (or 12 [±2] weeks after the last infusion)
    End point values
    Safety Population
    Number of subjects analysed
    13 [14]
    Units: reactions
        Infusion Reactions
    2
        Acute Infusion-related Hypersensitivity Reactions
    0
    Notes
    [14] - number of subjects with a reaction=1
    No statistical analyses for this end point

    Secondary: Anti-natalizumab Antibody Summary

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    End point title
    Anti-natalizumab Antibody Summary
    End point description
    Number of subjects with positive and negative anti-natalizumab antibody tests at Day 1 and Week 16.
    End point type
    Secondary
    End point timeframe
    Day 1 through Week 16
    End point values
    Safety Population
    Number of subjects analysed
    13
    Units: subjects
        Day 1: Positive
    0
        Day 1: Negative
    13
        Week 16: Positive
    0
        Week 16: Negative
    13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first infusion of study treatment through Week 16 (or 12 [±2] weeks after the last infusion)
    Adverse event reporting additional description
    Overall summary for treatment-emergent adverse events (TEAEs) is presented. A TEAE was defined as any AE that had onset on or after the first infusion of study treatment, or any pre-existing condition that had worsened after the first infusion of study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    300 mg IV natalizumab every 4 weeks for 16 weeks (a total of 5 doses)

    Serious adverse events
    Natalizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
         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
    Natalizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 13 (76.92%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Cardiac disorders
    Extrasystoles
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Dizziness
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Tension
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Bronchitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 13 (7.69%)
         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
    05 Mar 2013
    • Included a more restrictive criterion regarding eligibility for treatment with natalizumab in accordance with the clinical requirements, as outlined in the Italian Tysabri Registry. • Clarified that all blood samples and magnetic resonance imaging scans collected from the subjects are to be stored for 15 years and destroyed thereafter. • Clarified that, although the 24-hour sampling period was expected to provide the Cmax and Tmax data for most if not all of the study subjects, the assessments of Cmax and Tmax included samples from the entire sampling schedule as specified in the Schedule of Events. The Cmax and Tmax values presented are representative of the entire sampling schedule and not just of the 24 hour sampling period. • Removed the measurement of serum concentration of soluble vascular adhesion molecule 1 (sVCAM-1). Soluble VCAM-1 was found to be suppressed after administration of natalizumab and was thought to provide an alternative measurement to α4 integrin saturation. However, a consistent relationship between sVCAM-1 serum concentration and α4 integrin saturation could not be established. Therefore, PD assessments in this study were limited to well understood markers of natalizumab therapy.

    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
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