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    Clinical Trial Results:
    Pharmacokinetics and safety of the intravenous human immunoglobulin product Nanogam 100 mg/ml

    Summary
    EudraCT number
    		 2012-005727-32
    Trial protocol
    		 NL  
    Global end of trial date
    09 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Dec 2021
    First version publication date
    05 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MD2012.02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01985373
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Prothya Biosolutions Netherlands B.V. (previously Sanquin Plasma Products B.V.)
    Sponsor organisation address
    Plesmanlaan 125, Amsterdam, Netherlands, 1066CX
    Public contact
    Clinical Operations, Prothya Biosolutions, +31 205123537, ilona.kleinebudde@prothya.com
    Scientific contact
    Clinical Operations, Prothya Biosolutions, +31 205123537, ilona.kleinebudde@prothya.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
    14 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Objective of the study is to show bioequivalency between Nanogam® 50 mg/ml and Nanogam 100 mg/ml by comparing the pharmacokinetics.
    Protection of trial subjects
    Risk minimal. Patients are already stabilised on treatment with Nanogam 50 mg/ml.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jan 2014
    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
    Netherlands: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    18
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment from 08-01-2014 till 07-11-2014. Four clinical sites in the Netherlands.

    Pre-assignment
    Screening details
    		 Primary a- or hypogammaglobulinemia, particularly patients with XLA or CVID, stabilised on treatment with Nanogam 50 mg/ml . A stable clinical situation.

    Period 1
    Period 1 title
    Nanogam 50 mg/ml
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Nanogam 50 mg/ml
    Arm description
    		 One infusion Nanogam 50 mg/ml
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nanogam 50 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Advised dose for Nanogam 50 mg/ml: 0.2-0.8 g/kg every 3-4 weeks. Patients included in current study received one infusion Nanogam 50 mg/ml following their current treatment regimen.

    Number of subjects in period 1
    		Nanogam 50 mg/ml
    Started
    23
    Completed
    23
    Period 2
    Period 2 title
    Nanogam 100 mg/ml
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Nanogam 100 mg/ml
    Arm description
    		 Four infusions Nanogam 100 mg/ml
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nanogam 100 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Advised dose for Nanogam: 0.2-0.8 g/kg every 3-4 weeks. Patients in current study continued treatment with Nanogam 100 mg/ml at the same dose (in grams) and interval as their regular treatment with Nanogam 50 mg/ml.

    Number of subjects in period 2
    		Nanogam 100 mg/ml
    Started
    23
    Completed
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nanogam 50 mg/ml
    Reporting group description
    		 Cross-over

    Reporting group values
    		 Nanogam 50 mg/ml Total
    Number of subjects
    		 23 23
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 18 18
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 51 (20 to 72) -
    Gender categorical
    Units: Subjects
        Female
    		 13 13
        Male
    		 10 10

    End points

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    End points reporting groups
    Reporting group title
    Nanogam 50 mg/ml
    Reporting group description
    		 One infusion Nanogam 50 mg/ml
    Reporting group title
    Nanogam 100 mg/ml
    Reporting group description
    		 Four infusions Nanogam 100 mg/ml

    Primary: C trough

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    End point title
    		 C trough [1]
    End point description
    predose plasma concentration
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after 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: Descriptive statistics were performed.
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    23
    23
    Units: g/L
        arithmetic mean (standard deviation)
    8.9 ± 1.85
    8.7 ± 1.9
    No statistical analyses for this end point

    Primary: t1/2 term

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    End point title
    		 t1/2 term [2]
    End point description
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after 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: Descriptive statistics were performed.
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    22
    17
    Units: hours
        arithmetic mean (standard deviation)
    672.2 ± 226.6
    630.6 ± 129.0
    No statistical analyses for this end point

    Primary: C min

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    End point title
    		 C min
    End point description
    minimum plasma concentration during the dosing interval
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after infusion)
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    23
    23
    Units: g/L
        arithmetic mean (standard deviation)
    8.65 ± 1.88
    8.53 ± 1.88
    Statistical analysis title
    		 Bioequivalence C min
    Statistical analysis description
    Cmin logarithmic scale. All paired observations for test and reference were included in the statistical analysis. The LSmeans and intrasubject variance of the parameters for each treatment group were estimated with a linear mixed effects model, controlling for treatment, sequence and period as fixed effects, and subject as a random effect. A 90% CI were constructed around the difference between the LS means of test and reference. Difference LSmeans/CI were retransformed to the original scale.
    Comparison groups
    Nanogam 50 mg/ml v Nanogam 100 mg/ml
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 LS means ratio
    Point estimate
    98.58
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 96.43
         upper limit
    		 100.77
    Notes
    [3] - Nanogam 100 mg/ml was bioequivalent to Nanogam 50 mg/ml Nanogam if the 90% confidence intervals for IgG Cmin (Test vs Reference) were within 80.00% to 125.00%.

    Primary: C max

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    End point title
    		 C max [4]
    End point description
    Maximum plasma concentration. Cmax is dependent on the rate of infusion, which varied between subjects. Therefore Cmax needs to be interpreted with caution.
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after 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: Descriptive statistics were performed.
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    23
    23
    Units: g/L
        arithmetic mean (standard deviation)
    17.8 ± 4.14
    17.6 ± 4.58
    No statistical analyses for this end point

    Primary: t max

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    End point title
    		 t max [5]
    End point description
    time to reach maximum plasma concentration. tmax is dependent on the rate of infusion and infusion duration which varied between subjects. Therefore tmax needs to be interpreted with caution.
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after infusion
    Notes
    [5] - 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 statistics were performed.
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    23
    23
    Units: hour
        median (full range (min-max))
    2.58 (1.23 to 6.92)
    2.08 (0.62 to 3.75)
    No statistical analyses for this end point

    Primary: AUC lctp

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    End point title
    		 AUC lctp
    End point description
    Area under the plasma concentration time curve from start of infusion up to the last common time point between treatments within one subject; calculated by linear-linear trapezoidal summation.
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after infusion
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    23
    23
    Units: h*g/L
        arithmetic mean (standard deviation)
    5612 ± 1265
    5462 ± 1189
    Statistical analysis title
    		 Bioequivalence AUClctp
    Statistical analysis description
    AUClctp logarithmic scale. All paired observations for test and reference were included in the statistical analysis. The LSmeans and intrasubject variance of the parameters for each treatment group were estimated with a linear mixed effects model, controlling for treatment, sequence and period as fixed effects, and subject as a random effect. A 90% CI were constructed around the difference between the LS means of test and reference. Difference LSmeans/CI were retransformed to the original scale
    Comparison groups
    Nanogam 50 mg/ml v Nanogam 100 mg/ml
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    Method
    Parameter type
    		 LS means ratio
    Point estimate
    97.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 95.02
         upper limit
    		 100.25
    Notes
    [6] - Nanogam 100 mg/ml was bioequivalent to Nanogam 50 mg/ml if the 90% confidence intervals for IgG AUClctp (Test vs Reference) were within 80.00% to 125.00%.

    Primary: C avg

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    End point title
    		 C avg [7]
    End point description
    Average plasma concentration at steady-state over the dosing interval (τ) calculated by AUCτ/τ at steady-state.
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after 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: Descriptive statistics were performed.
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    23
    23
    Units: g/L
        arithmetic mean (standard deviation)
    11.9 ± 2.63
    11.6 ± 2.55
    No statistical analyses for this end point

    Primary: Fluctuation (FI)

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    End point title
    		 Fluctuation (FI) [8]
    End point description
    Fluctuation between the maximum and minimum analyte concentration (FI)
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after infusion
    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 statistics were performed.
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    23
    23
    Units: percentage
        arithmetic mean (standard deviation)
    76.6 ± 17.8
    77.9 ± 22.7
    No statistical analyses for this end point

    Primary: Apparent terminal elimination rate constant (λz)

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    End point title
    		 Apparent terminal elimination rate constant (λz) [9]
    End point description
    Apparent terminal elimination rate constant, determined by linear regression of the terminal points of the ln-linear plasma concentration-time curve
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after 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: Descriptive statistics were performed.
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    22
    17
    Units: 1/hour
        arithmetic mean (standard deviation)
    0.00115 ± 0.00039
    0.00115 ± 0.000280
    No statistical analyses for this end point

    Primary: Vss

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    End point title
    		 Vss [10]
    End point description
    Volume of distribution. Calculations of Vss are reported as approximations, as extrapolations of more than 20.00% of the total AUC and/or R2adj < 0.80 were used for the calculation of AUC∞ (needed for the calculation of Vss).
    End point type
    Primary
    End point timeframe
    PK profiles of total IgG on Visit 1 (Nanogam 5%) and Visit 5 (Nanogam 10%): directly after infusion (within 5 min) and 1 hour, 2 hours, 1, 2, 3, 7, 14 and 21 days after infusion
    Notes
    [10] - 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 statistics were performed.
    End point values
    		 Nanogam 50 mg/ml Nanogam 100 mg/ml
    Number of subjects analysed
    22
    17
    Units: litre(s)
        arithmetic mean (standard deviation)
    4.25 ± 1.06
    4.43 ± 0.747
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period of observation for adverse events extended from the time the patient gave informed consent till the end of the observation period.
    Adverse event reporting additional description
    Safety was monitored by measuring vital signs (blood pressure, heart rate, temperature) and recording all adverse events during and after the infusions with Nanogam. NB All SAEs occured in same patient, who met the exclusion criterion: 'had a known insufficiency of coronary or cerebral circulation', which was considered a major protocol deviation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Nanogam 50 mg/ml (1 infusion)
    Reporting group description
    		 Period between study start and first infusion Nanogam 100 mg/ml. Dosing interval ranged between 13 and 35 days.

    Reporting group title
    Nanogam 100 mg/ml (4 infusions)
    Reporting group description
    		 Period between first dose Nanogam 100 mg/ml and End of Observation (=first regular infusion). Four dosing periods; dosing interval ranged between 13 and 43 days.

    Serious adverse events
    		 Nanogam 50 mg/ml (1 infusion) Nanogam 100 mg/ml (4 infusions)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Cardiac disorders
    Cardiac Arrest
    Additional description: After end of obervation period (29 days after the last infusion). Reported because of seriousness.
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    COPD exacerbation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflamed Salivary Gland
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4.5%
    Non-serious adverse events
    		 Nanogam 50 mg/ml (1 infusion) Nanogam 100 mg/ml (4 infusions)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 23 (21.74%)
    Blood and lymphatic system disorders
    Leukopenia
    Additional description: Without clinical symptoms. No lab performed after Nanogam 5%.
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    4
    General disorders and administration site conditions
    Flu-like illness
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 23 (8.70%)
         occurrences all number
    1
    2
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2

    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
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