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    Clinical Trial Results:
    Randomised, Double-Blind, Placebo-Controlled, Phase IIa Study in Healthy Volunteers to Evaluate the Protective Efficacy and Safety of CR8020 in an Influenza Challenge Model

    Summary
    EudraCT number
    		 2013-002185-39
    Trial protocol
    		 GB  
    Global end of trial date
    22 Jan 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 May 2016
    First version publication date
    03 Jun 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

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    Trial identification
    Sponsor protocol code
    CR8020FLZ2002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01938352
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Crucell Holland B.V
    Sponsor organisation address
    Newtonweg 1, Leiden, Netherlands, 2333 CP
    Public contact
    Clinical Registry Group, Crucell Vaccine Institute, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Crucell Vaccine Institute, ClinicalTrialsEU@its.jnj.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
    22 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the reduction in AUC of virus load from the nasal mucosa in the CR8020 treatment group compared to placebo, post influenza virus challenge.
    Protection of trial subjects
    The safety assessments included laboratory measurements (for example hematology, urinalysis, pregnancy test on females of childbearing potential); vital sign measurements; electrocardiograms (ECGs), and physical examination. Adverse events and vital signs were monitored throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Aug 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
    United Kingdom: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    22
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 22 participants were enrolled in this study. All 22 participants were included in the safety analysis set and 19 participants were included in the efficacy analysis set during this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CR8020 Group
    Arm description
    		 Participants received a single dose of 15 milligram per kilogram (mg/kg) of CR8020 administered as an intravenous infusion over 2 hours on Day -2. On Day 0, participants were intranasally inoculated with the challenge virus.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CR8020
    Investigational medicinal product code
    CR8020/JNJ-54235051
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CR8020 15 mg/kg, administered by intravenous infusion.

    Arm title
    		 Placebo Group
    Arm description
    		 Participants received a single dose of Placebo [5 percent (%) dextrose in water] administered by intravenous infusion over 2 hours on Day -2. On Day 0, participants were intranasally inoculated with the challenge virus.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (5% dextrose in water), given as an intravenous infusion.

    Number of subjects in period 1
    		CR8020 Group Placebo Group
    Started
    11
    11
    Completed
    11
    10
    Not completed
    0
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CR8020 Group
    Reporting group description
    		 Participants received a single dose of 15 milligram per kilogram (mg/kg) of CR8020 administered as an intravenous infusion over 2 hours on Day -2. On Day 0, participants were intranasally inoculated with the challenge virus.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Participants received a single dose of Placebo [5 percent (%) dextrose in water] administered by intravenous infusion over 2 hours on Day -2. On Day 0, participants were intranasally inoculated with the challenge virus.

    Reporting group values
    		 CR8020 Group Placebo Group Total
    Number of subjects
    		 11 11 22
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 11 11 22
        From 65 to 84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 27.7 ( 5.98 ) 24.8 ( 5.46 ) -
    Title for Gender
    Units: subjects
        Female
    		 3 3 6
        Male
    		 8 8 16

    End points

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    End points reporting groups
    Reporting group title
    CR8020 Group
    Reporting group description
    		 Participants received a single dose of 15 milligram per kilogram (mg/kg) of CR8020 administered as an intravenous infusion over 2 hours on Day -2. On Day 0, participants were intranasally inoculated with the challenge virus.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Participants received a single dose of Placebo [5 percent (%) dextrose in water] administered by intravenous infusion over 2 hours on Day -2. On Day 0, participants were intranasally inoculated with the challenge virus.

    Subject analysis set title
    Efficacy Analysis Set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Efficacy analysis set (N=19) included all randomized participants inoculated with challenge virus.

    Subject analysis set title
    Pharmacokinetic Analysis Set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Pharmacokinetic analysis set included all participants (N=11) who received CR8020 and who did not have any important events or protocol deviations that would affect the integrity of the pharmacokinetic (PK) data or too few serum concentration data points to allow accurate assessment of the derived PK parameters.

    Primary: Area under the curve (AUC) of viral load

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    End point title
    		 Area under the curve (AUC) of viral load
    End point description
    The AUC was calculated based on quantitative polymerase chain reaction (qPCR) results for nasopharyngeal (NP) swabs collected thrice daily post-viral challenge up to the start of oseltamivir treatment on Day 6.
    End point type
    Primary
    End point timeframe
    During the 7 days following influenza virus challenge
    End point values
    		 CR8020 Group Placebo Group
    Number of subjects analysed
    11 [1]
    8 [2]
    Units: units on a standard curve
        arithmetic mean (standard deviation)
    73112.74 ( 155588.9 )
    27.5 ( 78 )
    Notes
    [1] - Efficacy Analysis Set
    [2] - Efficacy Analysis Set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Null hypothesis: AUC Viral Load is not greater in CR8020 group than placebo group.
    Comparison groups
    CR8020 Group v Placebo Group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.028 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - Placebo controlled
    [4] - P-value was based on the 1-sided Wilcoxon Rank Sum test at 5% significance level.

    Secondary: Percentage of participants with detected and quantitative influenza infection rate

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    End point title
    		 Percentage of participants with detected and quantitative influenza infection rate
    End point description
    Detected influenza infection rate was defined as greater than or equal to (≥4) qPCR positive NP swabs post-viral challenge, including all samples up to discharge from the quarantine. All values above the detection limit (non-negative values) were considered positive. Quantitative influenza infection rate was defined as ≥4 qPCR positive NP swabs post-viral challenge, including all samples up to discharge from the quarantine. All values above the quantification limit (quantitative values) were considered positive.
    End point type
    Secondary
    End point timeframe
    Up to 7 days following influenza virus challenge
    End point values
    		 CR8020 Group Placebo Group
    Number of subjects analysed
    11 [5]
    8 [6]
    Units: Percentage of participants
        number (not applicable)
    54.5
    0
    Notes
    [5] - Efficacy analysis set
    [6] - Efficacy analysis set
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    CR8020 Group v Placebo Group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.018 [8]
    Method
    		 Fisher exact
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 16.9
         upper limit
    		 81.57
    Notes
    [7] - Placebo controlled
    [8] - P-value was based on the 2-sided Fisher exact test at 5% significance level.

    Secondary: AUC of influenza composite symptoms

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    End point title
    		 AUC of influenza composite symptoms
    End point description
    AUC of influenza composite symptoms was calculated based on the sum of the individual scores (0 to 3) on each of the 10 pre-defined clinical influenza symptoms as recorded by the participants post viral challenge up to the start of oseltamivir treatment on Day 6.
    End point type
    Secondary
    End point timeframe
    Up to 7 days following influenza virus challenge
    End point values
    		 CR8020 Group Placebo Group
    Number of subjects analysed
    11 [9]
    8 [10]
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.03 ( 7.985 )
    2.25 ( 3.69 )
    Notes
    [9] - Efficacy analysis set
    [10] - Efficacy analysis set
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Null hypothesis: AUC influenza composite symptoms is not greater in CR8020 group than placebo.
    Comparison groups
    CR8020 Group v Placebo Group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.02 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - Placebo controlled
    [12] - P-value was based on the 1-sided Wilcoxon Rank Sum test at 5% significance level.

    Secondary: Maximum serum concentration (Cmax) of CR8020

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    End point title
    		 Maximum serum concentration (Cmax) of CR8020 [13]
    End point description
    Cmax following a single 2-hour intravenous infusion of 15 mg/kg of CR8020. This pharmacokinetic parameter was calculated in 11 participants in the CR8020 group who received a complete dose of CR8020.
    End point type
    Secondary
    End point timeframe
    Day -2 (pre- and post-dose), Day -1, Day 0 (pre-challenge) and on Days 1, 2, 5, 28 and 96.
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be reported for the specific arms only
    End point values
    		 CR8020 Group
    Number of subjects analysed
    11 [14]
    Units: microgram per milliliter (μg/mL)
        arithmetic mean (standard deviation)
    330.16 ( 63.643 )
    Notes
    [14] - Pharmacokinetics Analysis Set
    No statistical analyses for this end point

    Secondary: Area under the serum concentration- time curve [AUC(0-t) and AUC(0-7d)] of CR8020

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    End point title
    		 Area under the serum concentration- time curve [AUC(0-t) and AUC(0-7d)] of CR8020 [15]
    End point description
    AUC(0-t) was defined as area under the serum concentration-time curve from 0 to the time of the last measurable concentration. AUC(0-7d) was defined as area under the serum concentration-time curve from time 0 to Day 7. This pharmacokinetic parameter was calculated in 11 participants in the CR8020 group who received a complete dose of CR8020.
    End point type
    Secondary
    End point timeframe
    Day -2 (pre- and post-dose), Day -1, Day 0 (pre-challenge) and on Days 1, 2, 5, 28 and 96.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be reported for the specific arms only
    End point values
    		 CR8020 Group
    Number of subjects analysed
    11 [16]
    Units: microgram day per milliliter (μg∙day/mL)
    arithmetic mean (standard deviation)
        AUC(0-t)
    5460.5 ( 991.37 )
        AUC(0-7d)
    1319.8 ( 250.04 )
    Notes
    [16] - Pharmacokinetics Analysis Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 96
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    CR8020 Group
    Reporting group description
    		 Participants received a single dose of 15 milligram per kilogram (mg/kg) of CR8020 administered as an intravenous infusion over 2 hours on Day -2. On Day 0, participants were intranasally inoculated with the challenge virus.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Participants received a single dose of Placebo (5% dextrose in water) administered by intravenous infusion over 2 hours on Day -2. On Day 0, participants were intranasally inoculated with the challenge virus.

    Serious adverse events
    		 CR8020 Group Placebo Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Electrocardiogram t wave inversion
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 CR8020 Group Placebo Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 11 (81.82%)
    6 / 11 (54.55%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    3
    Amylase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    2
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Scratch
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Catheter site bruise
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    Nasal congestion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 11 (9.09%)
         occurrences all number
    3
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    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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