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    Clinical Trial Results:
    A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLINDED, ASCENDING MULTIPLE DOSE STUDY OF THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF XMAB®5871 IN PATIENTS WITH RHEUMATOID ARTHRITIS

    Summary
    EudraCT number
    		 2012-003057-29
    Trial protocol
    		 CZ   SK   HU  
    Global end of trial date
    30 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Nov 2016
    First version publication date
    12 Nov 2016
    Other versions
    Summary report(s)
    		 XmAb5871-02 Study Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    XmAb5871-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Xencor, Inc.
    Sponsor organisation address
    111 West Lemon Avenue, Monrovia, United States, CA 91016
    Public contact
    Chief Medical Officer, Xencor Inc, 1 8584803890, pfoster@xencor.com
    Scientific contact
    Chief Medical Officer, Xencor Inc, 1 8584803890, pfoster@xencor.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
    30 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety and tolerability profile of multiple-dose, every 14-day, intravenous (iv) administration of XmAb5871 in patients with RA
    Protection of trial subjects
    In Part A, a sentinel dosing strategy was used for the first dose of Cohort 1. The first 2 patients in Cohort 1 were randomized such that 1 patient received XmAb5871 and 1 patient received placebo. This sentinel pair were dosed first and were observed for 48 – 72 hours before study drug was administered to the remainder of the cohort. For all remaining cohorts, no more than 3 patients were infused on any given day. Dose escalation to the next cohort occurred after review by the Dose Escalation Safety Committee (DESC) of safety data up to at least Day15 for all patients in a cohort. Progression to the next higher dose only occurred if the previous dose level was deemed to be safe and well tolerated by the DESC.
    Background therapy
    		 Currently taking methotrexate (MTX) consecutively for ≥ 12 weeks and on a stable dose of oral or subcutaneous MTX at 7.5-25 mg weekly for ≥ 4 weeks at randomisation visit. A lower MTX dose was accepted if it was the highest tolerated dose; however, toxicity documentation by the Investigator was required. All patients were to take folic acid to minimize toxicity, according to local guidelines.
    Evidence for comparator
    		 Not applicable - comparator was standard of care for the disease plus placebo.
    Actual start date of recruitment
    19 Dec 2012
    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
    Poland: 27
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Hungary: 22
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    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)
    46
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were enrolled from 3 countries: Poland, Czech Republic and Hungary. Screening of patients in to Part A lasted from 19 Dec 2012 to 16 Jul 2013. Screening of patients in to Part B began on 02 Sept 2013 and ended on 07 Apr 2014. The last patient was randomised in to the study 15 Apr 2014.

    Pre-assignment
    Screening details
    		 Subjects dropping-out or withdrawing, for any reason, without completing all screening evaluations successfully, were considered as “screening failures“. Such subjects did not receive a subject number, and no data were collected in the eCRFs. The Investigator kept a screening log of all subjects screened.

    Period 1
    Period 1 title
    Part A (Cohorts 1-4)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    30 patients in Part A (23 XmAb5871, 7 placebo)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A (Active)
    Arm description
    		 Patients treated with active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    XmAb5871
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    XmAb5871 at one of 4 doses (0.3, 1.0, 3.0, 10.0 mg/kg) was administered as an iv infusion over 2 hours every 14 days for 6 doses. XmAb5871 drug product was a liquid product supplied in single-use glass vials.

    Arm title
    		 Part A (Placebo)
    Arm description
    		 Patients treated with placebo treatment
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo of equal volume to match XmAb5871 was administered by iv infusion over 2 hours. The placebo solution was a vehicle control (10 mM sodium phosphate, 150 mM sodium chloride with 0.01% (w/v) polysorbate 20, pH 7.2)

    Number of subjects in period 1 [1]
    		Part A (Active) Part A (Placebo)
    Started
    22
    7
    Completed
    21
    7
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The patient enrollment in to Part A does not correspond with enrollment in to Part B. Part B was an expansion Cohort and included the enrollment of a different group of patients, in accordance with the protocol.
    Period 2
    Period 2 title
    Part B (Cohort 5)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    27 patients in Part B (18 XmAb5871, 9 placebo)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part B (Placebo)
    Arm description
    		 Patients treated with placebo treatment
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo of equal volume to match XmAb5871 was administered by iv infusion over 2 hours. The placebo solution was a vehicle control (10 mM sodium phosphate, 150 mM sodium chloride with 0.01% (w/v) polysorbate 20, pH 7.2)

    Arm title
    		 Part B (Active)
    Arm description
    		 Patients treated with active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    XmAb5871
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    XmAb5871 administered to an expansion cohort (Cohort 5), to further investigate one of the doses previously studied in Part A (10 mg/kg), administered as an iv infusion over 2 hours every 14 days for 6 doses. XmAb5871 drug product was a liquid product supplied in single-use glass vials.

    Number of subjects in period 2 [2]
    		Part B (Placebo) Part B (Active)
    Started
    9
    18
    Completed
    8
    15
    Not completed
    1
    3
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    -
    2
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The patient enrollment in to Part A does not correspond with enrollment in to Part B. Part B was an expansion Cohort and included the enrollment of a different group of patients, in accordance with the protocol.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A (Active)
    Reporting group description
    		 Patients treated with active treatment

    Reporting group title
    Part A (Placebo)
    Reporting group description
    		 Patients treated with placebo treatment

    Reporting group values
    		 Part A (Active) Part A (Placebo) Total
    Number of subjects
    		 22 7 29
    Age categorical
    Patient Age was collected at patient enrollment
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Patient Age at enroollment
    Units: years
        median (full range (min-max))
    		 59 (45 to 65) 61 (48 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 19 6 25
        Male
    		 3 1 4
    Subject analysis sets

    Subject analysis set title
    Pharmacokinetic Coh 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 2 receiving 1.0 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 1 receiving 0.3 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 3
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 3 receiving 3.0 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 4 and 5
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohorts 4 and 5 receiving 10.0 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 4
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 4 receiving 10.0 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 5
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 5 receiving 10.0 mg/kg XmAb5871

    Subject analysis sets values
    		 Pharmacokinetic Coh 2 Pharmacokinetic Coh 1 Pharmacokinetic Coh 3 Pharmacokinetic Coh 4 and 5 Pharmacokinetic Coh 4 Pharmacokinetic Coh 5
    Number of subjects
    6
    3
    6
    25
    7
    18
    Age categorical
    Patient Age was collected at patient enrollment
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Patient Age at enroollment
    Units: years
        median (full range (min-max))
    59 (53 to 65)
    58 (52 to 63)
    60.5 (52 to 64)
    60 (25 to 69)
    59 (45 to 63)
    60.5 (25 to 69)
    Gender categorical
    Units: Subjects
        Female
    5
    3
    5
    21
    6
    15
        Male
    1
    0
    1
    4
    1
    3

    End points

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    End points reporting groups
    Reporting group title
    Part A (Active)
    Reporting group description
    		 Patients treated with active treatment

    Reporting group title
    Part A (Placebo)
    Reporting group description
    		 Patients treated with placebo treatment
    Reporting group title
    Part B (Placebo)
    Reporting group description
    		 Patients treated with placebo treatment

    Reporting group title
    Part B (Active)
    Reporting group description
    		 Patients treated with active treatment

    Subject analysis set title
    Pharmacokinetic Coh 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 2 receiving 1.0 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 1 receiving 0.3 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 3
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 3 receiving 3.0 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 4 and 5
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohorts 4 and 5 receiving 10.0 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 4
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 4 receiving 10.0 mg/kg XmAb5871

    Subject analysis set title
    Pharmacokinetic Coh 5
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    PK data for patients in Cohort 5 receiving 10.0 mg/kg XmAb5871

    Primary: Safety and Tolerability

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    End point title
    		 Safety and Tolerability [1]
    End point description
    Safety and tolerability assessments consisted of AEs, vital signs, electrocardiogram (ECG), clinical laboratory, immunogenicity and physical examination. Assessments were performed according to the time points defined in the schedules of assessments. Data presented is number of patients with Treatment Emergent AEs (TEAEs) and number of patients confirmed as positive for anti-XmAb5871 antibodies (ADA).
    End point type
    Primary
    End point timeframe
    From Randomisation (Day -1) to Day 169
    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: For this explorative study, no prospective calculations of statistical power were made. The sample size was selected to provide information on safety, tolerability, PK, efficacy and PD following single and multiple doses of XmAb5871. Descriptive statistics were provided for selected demographic, safety, PK, PD, and biomarker data by cohort. Descriptive statistics on continuous data includes means, medians, SDs and ranges, while categorical data may be summarized using frequency counts and %s.
    End point values
    		 Pharmacokinetic Coh 2 Pharmacokinetic Coh 1 Pharmacokinetic Coh 3 Pharmacokinetic Coh 4 and 5
    Number of subjects analysed
    6
    3
    6
    25
    Units: Number of patients
        Number of patients with TEAE
    3
    3
    5
    19
        Patients with +ve anti-XmAb5871 (ADA)
    0
    0
    0
    7
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (Plasma Concn)

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    End point title
    		 Pharmacokinetics (Plasma Concn)
    End point description
    To characterize the PK of multiple-dose, intravenously administered XmAb5871 in patients with RA. All figures presented are averages across the Cohorts
    End point type
    Secondary
    End point timeframe
    After final dose
    End point values
    		 Pharmacokinetic Coh 2 Pharmacokinetic Coh 1 Pharmacokinetic Coh 3 Pharmacokinetic Coh 4 and 5
    Number of subjects analysed
    6
    3
    6
    25
    Units: Plasma XmAb5871 concentrations
    number (not applicable)
        Trough concentrations on Day 85 (ng/mL)
    382
    89.3
    1639
    4297
    No statistical analyses for this end point

    Secondary: Efficacy

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    End point title
    		 Efficacy
    End point description
    Efficacy assessments were measured according to the time points defined in the Protocol
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 169
    End point values
    		 Part A (Active) Part A (Placebo) Part B (Placebo) Part B (Active)
    Number of subjects analysed
    21
    7
    8
    15
    Units: Efficacy Measurements
    median (full range (min-max))
        ACR Hybrid Score on Day 85
    39.4 (-23.1 to 70.9)
    10.1 (1.4 to 59.7)
    27.6 (-52.4 to 61)
    50 (-14.3 to 86.9)
        DAS28-CRP Score on Day 85
    3.2 (1.8 to 5.9)
    4.6 (2.1 to 5.7)
    4.2 (3.4 to 6.1)
    4.1 (1.7 to 5.9)
    No statistical analyses for this end point

    Secondary: Efficacy (EULAR)

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    End point title
    		 Efficacy (EULAR)
    End point description
    Number of patients achieving a specific EULAR score (No, Moderate or Good) at Day 85
    End point type
    Secondary
    End point timeframe
    Day 85
    End point values
    		 Part A (Active) Part A (Placebo) Part B (Placebo) Part B (Active)
    Number of subjects analysed
    21
    7
    8
    15
    Units: Number of patients
        No
    3
    5
    2
    2
        Moderate
    9
    1
    6
    8
        Good
    9
    1
    0
    5
    No statistical analyses for this end point

    Secondary: Efficacy (ACR Score)

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    End point title
    		 Efficacy (ACR Score)
    End point description
    Number of patients achieving an ACR score of ACR20, ACR50 or ACR70.
    End point type
    Secondary
    End point timeframe
    Day 85
    End point values
    		 Part A (Active) Part A (Placebo) Part B (Placebo) Part B (Active)
    Number of subjects analysed
    21
    7
    8
    15
    Units: Number of patients
        ACR20
    15
    2
    5
    13
        ACR50
    6
    1
    1
    6
        ACR70
    2
    0
    0
    3
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (Cmax after final dose)

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    End point title
    		 Pharmacokinetics (Cmax after final dose)
    End point description
    Cmax - Maximal observed serum concentration.
    End point type
    Secondary
    End point timeframe
    After final dose
    End point values
    		 Pharmacokinetic Coh 2 Pharmacokinetic Coh 1 Pharmacokinetic Coh 3 Pharmacokinetic Coh 4 Pharmacokinetic Coh 5
    Number of subjects analysed
    6
    3
    6
    7
    18
    Units: ng/mL
    number (not applicable)
        Cmax after final dose
    21287
    4943
    59913
    257015
    272832
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (Clearance after final dose)

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    End point title
    		 Pharmacokinetics (Clearance after final dose)
    End point description
    To characterize the PK of multiple-dose, intravenously administered XmAb5871 in patients with RA. All figures presented are averages across the Cohort. Clearance of drug from the body, CL = Dose/AUCinf
    End point type
    Secondary
    End point timeframe
    After final dose
    End point values
    		 Pharmacokinetic Coh 2 Pharmacokinetic Coh 1 Pharmacokinetic Coh 3 Pharmacokinetic Coh 4 Pharmacokinetic Coh 5
    Number of subjects analysed
    6
    3
    6
    7
    18
    Units: mL/day/kg
    number (not applicable)
        Clearance after final dose
    15.27
    15.82
    16.95
    16.29
    13.83
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (Half-life)

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    End point title
    		 Pharmacokinetics (Half-life)
    End point description
    To characterize the PK of multiple-dose, intravenously administered XmAb5871 in patients with RA. All figures presented are averages across the Cohort. Terminal half-life computed over the terminal portion of the concentration versus time profile. Computed as Half-life = ln(2)/Lambda, where Lambda is the slope of the regression line through the terminal portion of the plot of natural log of concentration vs. time
    End point type
    Secondary
    End point timeframe
    After final dose
    End point values
    		 Pharmacokinetic Coh 2 Pharmacokinetic Coh 1 Pharmacokinetic Coh 3 Pharmacokinetic Coh 4 Pharmacokinetic Coh 5
    Number of subjects analysed
    6
    3
    6
    7
    18
    Units: Hours
    number (not applicable)
        Half-life
    62.39
    65.8
    79.09
    98.4
    93.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded at each clinic visit from signing of the Informed Consent Form until completion of the End of Study visit.
    Adverse event reporting additional description
    At every patient visit, patients were asked non-leading questions to determine the occurrence of AEs. In addition, all AEs reported spontaneously during the course of the clinical study were recorded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Part A (Active)
    Reporting group description
    		 Patients receiving active treatment (XmAb5871) during Part A (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg or 10 mg/kg)

    Reporting group title
    Part A (Placebo)
    Reporting group description
    		 Patients receiving placebo treatment (placebo) during Part A.

    Reporting group title
    Part B (Active)
    Reporting group description
    		 Patients receiving active treatment (XmAb5871) during Part B (10 mg/kg)

    Reporting group title
    Part B (Placebo)
    Reporting group description
    		 Patients receiving placebo treatment (placebo) during Part B.

    Serious adverse events
    		 Part A (Active) Part A (Placebo) Part B (Active) Part B (Placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    1 / 18 (5.56%)
    2 / 9 (22.22%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Venous thrombosis
    Additional description: 1 patient receiving XmAb5871 10 mg/kg had a phlebothrombosis of the right lower limb of moderate intensity, considered to be possibly related to the study drug. SAE occurred 22 days after the final infusion. Sponsor classified relationship unlikely.
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Post herpetic neuralgia
    Additional description: 1 patient receiving placebo had post-herpetic neuralgia of moderate intensity, considered to be possibly related to the study drug, 2 days after final infusion.
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Infusion related reaction
    Additional description: 1 patient receiving XmAb5871 10 mg/kg had an infusion-related reaction with hypotension of severe intensity, considered to be definitely related to the study drug. The patient was permanently withdrawn from study drug; patient fully recovered.
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Herpes zoster
    Additional description: 1 patient receiving placebo had an abdominal herpes zoster of moderate intensity, considered to be possibly related to the study drug, 2 days after final infusion.
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
    Additional description: 1 patient receiving placebo had a bacterial respiratory tract infection of mild intensity, considered not to be related to the study drug.
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3.5%
    Non-serious adverse events
    		 Part A (Active) Part A (Placebo) Part B (Active) Part B (Placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 22 (77.27%)
    4 / 7 (57.14%)
    13 / 18 (72.22%)
    7 / 9 (77.78%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Body temperature increased
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 7 (14.29%)
    4 / 18 (22.22%)
    0 / 9 (0.00%)
         occurrences all number
    3
    1
    4
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Infusion related reaction
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vessel puncture site bruise
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    1 / 18 (5.56%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    1
    Influenza like illness
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 7 (14.29%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    4 / 18 (22.22%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    4
    0
    Nausea
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    2 / 18 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    4
    0
    2
    1
    Diarrhoea
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 7 (0.00%)
    3 / 18 (16.67%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 7 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 7 (0.00%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 7 (28.57%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 7 (14.29%)
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    0
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 7 (14.29%)
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Bronchitis
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Tracheitis
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 7 (0.00%)
    0 / 18 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2012
    Amendment 1 applied to the Czech Republic only. The CSP was amended on 29 October 2012, primarily to comply with the recommendations received from Competent Authority Statni Ustav Pro Kontrolu Leciv (State Institute for Drug Control) in Czech Republic. However, Amendment 1 was not formally approved because the Sponsor withdrew submission on 07 November 2012. The changes implemented in Amendment 1 were as follows: 1. The upper limit of the age of the participating subjects in Part A of the clinical study was reduced from 70 to 65 years 2. The subjects were to follow-up for 72 hours post end of infusion for first dosing and 24 hours for the subsequent dosings; as a result, all outpatient visits up to the last dosing were changed from outpatient into inpatient visits 3. The subjects with known residential exposure to an individual with tuberculosis prior to or during screening (if not treated with appropriate chemoprophylaxis) or positive Quantiferon test at screening were excluded
    15 Jan 2013
    The Clinical Study Protocol was amended primarily to enhance subjects’ safety, to increase scientific validity, to improve feasibility of the clinical study, and to correct mistakes and inconsistencies detected in Protocol Version 1.0 dated 31 July 2012. Amendment 2, dated 15 January 2013, applied for Hungary, Poland, Romania and the Slovak Republic only. A separate protocol amendment was prepared for the Czech Republic in compliance with recommendations received from the Czech Competent Authority. The major changes implemented in the present Amendment 2 were as follows: 1. Exclusion of subjects with positive Quantiferon test at screening. 2. Assessment of some additional safety laboratory parameters. 3. Adding of time point for vital signs assessment at 15 minutes after end of infusion; clarification of time points for vital signs assessment on dosing days and on non dosing days. 4. Prolongation of fasting period for the subjects before dosing, and waiving of obligation to fast before blood sampling except screening and Day –1. 5. Change of time points for blood sampling for PK on non-dosing days. 6. Collecting an additional blood sample for Biomarker Development. 7. Clarification of consequences following occurrence of significant safety events with respect to interruption of dose escalation. 8. Correction of criteria given for ACR classification of functional capacity.
    19 Jan 2013
    Amendment 3 applied to the Czech Republic only. The CSP was amended on 19 January 2013, primarily to enhance subjects’ safety, to increase scientific validity, to improve feasibility of the clinical study, and to correct mistakes and inconsistencies detected in Clinical Study Protocol Version 2.0, dated 29 October 2012. A part of the changes that were addressed in this amendment were already implemented in Amendment 1. The major changes implemented in Amendment 3, dated 19 January 2013 were as follows: 1. Assessment of some additional safety laboratory parameters. 2. Adding of time point for vital signs assessment at 15 minutes after end of infusion; clarification of time points for vital signs assessment on dosing days and on non dosing days. 3. Prolongation of fasting period for the subjects before dosing, and waiving of obligation to fast before blood sampling except screening and Day –1. 4. Change of time points for blood sampling for PK on non-dosing days. 5. Collection of an additional blood sample for Biomarker Development. 6. Clarification of consequences following occurrence of significant safety events with respect to interruption of dose escalation. 7. Correction of criteria given for ACR classification of functional capacity. A separate amendment was prepared for Hungary, Romania, Poland and the Slovak Republic (Amendment 2, dated 15 January 2013) implementing the same changes as listed in Amendment 3.
    26 Aug 2013
    Amendment 4, dated 26 Aug 2013, applied to the Czech Republic only. It was prepared to define the dose of the study drug XmAb5871 for the expansion cohort (Cohort 5) as recommended by the DESC. During the DESC meeting on 16 August 2013 the safety data of Cohort 4 through at least Day 15 were discussed and all available cumulative safety data from the previous cohorts were reviewed to assess the presence of any cumulative toxicity. The maximum dose of 10.0 mg/kg was considered safe and well tolerated to be used in the expansion cohort. The updated safety information for XmAb5871 was implemented in the protocol. The number of countries was updated as the clinical study was withdrawn in Romania.
    23 Oct 2013
    Amendment 5 dated 23 October 2013 was prepared in order to modify the Inclusion Criterion No 6/b. The required hsCRP value was reduced from greater than or equal to 10.0 mg/L to 6 mg/L, in order allow inclusion of a greater proportion of rheumatoid arthritis patients with active disease on stable non-biologic DMARD therapy in Part B of this clinical study. Separate amendments were prepared for the Czech Republic (Amendment 5 dated 23 October 2013) and for Hungary, Poland and the Slovak Republic (Amendment 6 dated 23 October 2013) implementing the same changes.
    23 Oct 2013
    Amendment 6 dated 23 October 2013 was prepared in order to modify the Inclusion Criterion No 6/b. The required hsCRP value was reduced from greater than or equal to 10.0 mg/L to 6 mg/L, in order allow inclusion of a greater proportion of rheumatoid arthritis patients with active disease on stable non-biologic DMARD therapy in Part B of this clinical study. Separate amendments were prepared for the Czech Republic (Amendment 5 dated 23 October 2013) and for Hungary, Poland and the Slovak Republic (Amendment 6 dated 23 October 2013) implementing the same 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
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