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    Clinical Trial Results:
    An Open-label, Randomized, Active Comparator-Controlled, Adaptive Parallel-group Phase 2 Study to Assess the Safety and Efficacy of Multiple Doses of ISIS 416858 Administered Subcutaneously to Patients Undergoing Total Knee Arthroplasty

    Summary
    EudraCT number
    		 2012-001836-72
    Trial protocol
    		 LV   BG  
    Global end of trial date
    14 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jul 2019
    First version publication date
    27 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS416858-CS3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01713361
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, United States, CA 92010
    Public contact
    Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 800-679-4747, patients@ionisph.com
    Scientific contact
    Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 800-679-4747, patients@ionisph.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 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To assess the safety and efficacy profile of ISIS 416858, including incidence of bleeding and Venous thromboembolism (VTE), in subjects undergoing total knee arthroplasty • To compare the efficacy and safety profile of ISIS 416858 in subjects who achieve </= 0.2 units per millilitre (U/mL) factor XI (FXI) activity levels to that of enoxaparin
    Protection of trial subjects
    Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Oct 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 22
    Country: Number of subjects enrolled
    Latvia: 36
    Country: Number of subjects enrolled
    Canada: 36
    Country: Number of subjects enrolled
    Russian Federation: 109
    Country: Number of subjects enrolled
    Ukraine: 111
    Worldwide total number of subjects
    314
    EEA total number of subjects
    58
    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)
    178
    From 65 to 84 years
    136
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were randomised to 19 study centres in 5 countries (Bulgaria, Canada, Latvia, Russian Federation and Ukraine).

    Pre-assignment
    Screening details
    		 14 subjects were randomised under the original protocol in the treatment arms ISIS 416858 100 mg (n=3), ISIS 416858 200 mg (n=4), ISIS 416858 300 mg (n=4), and enoxaparin 40 mg (n=3). Of these 14 subjects, 12 received study treatment. After amendment, 300 subjects were randomised in the ISIS 416858 200mg, 300mg and enoxaparin 40 mg arm groups.

    Pre-assignment period milestones
    Number of subjects started
    		 314
    Number of subjects completed
    		 293

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Subject not analysed per protocol amendment: 14
    Reason: Number of subjects
    		 Did not receive study treatment: 7
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Enoxaparin 40 mg
    Arm description
    		 Enoxaparin 40 mg was administered subcutaneously (SC) the evening prior to surgery (optional), 6 to 8 hours after surgery followed by daily injections for at least 8 additional days post surgery.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enoxaparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg Enoxaparin was administered SC evening prior to surgery (optional), 6 to 8 hours after surgery followed by daily injections for at least 8 additional days post surgery.

    Arm title
    		 ISIS 416858 200 mg
    Arm description
    		 Subjects received SC doses of ISIS 416858 200 mg 7 times prior to total knee arthroplasty (TKA), and 2 times after surgery (6 hours and 3 days after surgery).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 416858
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ISIS 416858 200 mg SC was administered 7 times prior to TKA, and 2 times after surgery (6 hours and 3 days after surgery ).

    Arm title
    		 ISIS 416858 300 mg
    Arm description
    		 Subjects received SC doses of ISIS 416858 300 mg 7 times prior to TKA, and 2 times after surgery (6 hours and 3 days after surgery).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 416858
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ISIS 416858 300 mg SC was administered 7 times prior to TKA, and 2 times after surgery (6 hours and 3 days after surgery ).

    Number of subjects in period 1 [1]
    		Enoxaparin 40 mg ISIS 416858 200 mg ISIS 416858 300 mg
    Started
    72
    144
    77
    Completed
    71
    141
    73
    Not completed
    1
    3
    4
         Adverse Event or SAE
    1
    1
    -
         Voluntary withdrawal
    -
    2
    4
    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 number of subjects reported in the baseline period is for the safety population of the amended protocol. The subjects in the trial information are the total subjects enrolled worldwide.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enoxaparin 40 mg
    Reporting group description
    		 Enoxaparin 40 mg was administered subcutaneously (SC) the evening prior to surgery (optional), 6 to 8 hours after surgery followed by daily injections for at least 8 additional days post surgery.

    Reporting group title
    ISIS 416858 200 mg
    Reporting group description
    		 Subjects received SC doses of ISIS 416858 200 mg 7 times prior to total knee arthroplasty (TKA), and 2 times after surgery (6 hours and 3 days after surgery).

    Reporting group title
    ISIS 416858 300 mg
    Reporting group description
    		 Subjects received SC doses of ISIS 416858 300 mg 7 times prior to TKA, and 2 times after surgery (6 hours and 3 days after surgery).

    Reporting group values
    		 Enoxaparin 40 mg ISIS 416858 200 mg ISIS 416858 300 mg Total
    Number of subjects
    		 72 144 77 293
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64 ± 9 63 ± 9 63 ± 8 -
    Gender categorical
    Units: Subjects
        Female
    		 60 118 60 238
        Male
    		 12 26 17 55

    End points

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    End points reporting groups
    Reporting group title
    Enoxaparin 40 mg
    Reporting group description
    		 Enoxaparin 40 mg was administered subcutaneously (SC) the evening prior to surgery (optional), 6 to 8 hours after surgery followed by daily injections for at least 8 additional days post surgery.

    Reporting group title
    ISIS 416858 200 mg
    Reporting group description
    		 Subjects received SC doses of ISIS 416858 200 mg 7 times prior to total knee arthroplasty (TKA), and 2 times after surgery (6 hours and 3 days after surgery).

    Reporting group title
    ISIS 416858 300 mg
    Reporting group description
    		 Subjects received SC doses of ISIS 416858 300 mg 7 times prior to TKA, and 2 times after surgery (6 hours and 3 days after surgery).

    Primary: Percentage of Subjects with Venous Thromboembolism (VTE)

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    End point title
    		 Percentage of Subjects with Venous Thromboembolism (VTE)
    End point description
    Total VTE includes asymptomatic DVT, adjudicated symptomatic VTE (includes symptomatic DVT and symptomatic pulmonary embolism [PE]), and adjudicated fatal PE or unexplained death for which PE cannot be ruled out. The Per-Protocol Set (PPS) consists of amendment protocol subjects as a subset of the Safety Set who had the scheduled surgery and were evaluable for efficacy. Subjects in the enoxaparin group who did not follow the enoxaparin dose regimen for at least 5 consecutive days after surgery were not included in the PPS.
    End point type
    Primary
    End point timeframe
    Up to 10 days post surgery (46 days)
    End point values
    		 Enoxaparin 40 mg ISIS 416858 200 mg ISIS 416858 300 mg
    Number of subjects analysed
    69
    134
    71
    Units: percentage of subjects
        number (confidence interval 95%)
    30 (20 to 43)
    27 (20 to 35)
    4 (1 to 12)
    Statistical analysis title
    		 VTE: Enoxaparin 40 mg v ISIS 416858 200 mg
    Statistical analysis description
    A superiority test was evaluated using the chi-square test to assess the difference between subjects in the ISIS 416858 group and enoxaparin group.
    Comparison groups
    Enoxaparin 40 mg v ISIS 416858 200 mg
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 8
    Statistical analysis title
    		 VTE: Enoxaparin 40 mg v ISIS 416858 300 mg
    Statistical analysis description
    A superiority test was evaluated using the chi-square test to assess the difference between subjects in the ISIS 416858 group and enoxaparin group.
    Comparison groups
    ISIS 416858 300 mg v Enoxaparin 40 mg
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -26
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -16

    Secondary: Percentage of Subjects with all Proximal Deep Vein Thrombosis (DVTs), all Distal-Only DVTs and non-Fatal and Fatal Pulmonary Embolism (PEs)

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    End point title
    		 Percentage of Subjects with all Proximal Deep Vein Thrombosis (DVTs), all Distal-Only DVTs and non-Fatal and Fatal Pulmonary Embolism (PEs)
    End point description
    PPS consists of amendment protocol subjects as a subset of the Safety Set who had the scheduled surgery and were evaluable for efficacy. Subjects in the enoxaparin group who did not follow the enoxaparin dose regimen for at least 5 consecutive days after surgery were not included in the PPS.
    End point type
    Secondary
    End point timeframe
    From first study drug administration up to 4 weeks after mandatory bilateral venography (up to 74 days)
    End point values
    		 Enoxaparin 40 mg ISIS 416858 200 mg ISIS 416858 300 mg
    Number of subjects analysed
    69
    134
    71
    Units: percentage of subjects
    number (confidence interval 95%)
        Proximal DVTs
    5.8 (1.602 to 14.183)
    5.2 (2.126 to 10.467)
    1.4 (0.036 to 7.599)
        Distal-Only DVTs
    24.6 (15.055 to 36.490)
    21.6 (14.998 to 29.580)
    2.8 (0.343 to 9.808)
        Non-Fatal PE
    0.0 (0.000 to 5.206)
    0.0 (0.000 to 2.715)
    0.0 (0.000 to 5.063)
        Fatal PE
    0.0 (0.000 to 5.206)
    0.0 (0.000 to 2.715)
    0.0 (0.000 to 5.063)
    Statistical analysis title
    		 Proximal DVT for ISIS 416858 200 mg
    Comparison groups
    Enoxaparin 40 mg v ISIS 416858 200 mg
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 5
    Statistical analysis title
    		 Proximal DVT for ISIS 416858 300 mg
    Comparison groups
    Enoxaparin 40 mg v ISIS 416858 300 mg
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.205
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.8
    Statistical analysis title
    		 Distal-Only DVTs for ISIS 416858 200 mg
    Comparison groups
    Enoxaparin 40 mg v ISIS 416858 200 mg
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.629
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 7.4
    Statistical analysis title
    		 Distal-Only DVTs for ISIS 416858 300 mg
    Comparison groups
    Enoxaparin 40 mg v ISIS 416858 300 mg
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -21.8
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -12.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 22 months
    Adverse event reporting additional description
    The safety set population included all subjects who were enrolled under the protocol amendment and received at least 1 dose of trial medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Enoxaparin 40 mg
    Reporting group description
    		 Enoxaparin 40 mg was administered subcutaneously (SC) the evening prior to surgery (optional), 6 to 8 hours after surgery followed by daily injections for at least 8 additional days post surgery.

    Reporting group title
    ISIS 416858 200 mg
    Reporting group description
    		 Subjects received SC doses of ISIS 416858 200 milligrams (mg) 7 times prior to total knee arthroplasty (TKA), and 2 times after surgery (6 hours and 3 days after surgery).

    Reporting group title
    ISIS 416858 300 mg
    Reporting group description
    		 Subjects received SC doses of ISIS 416858 300 mg 7 times prior to TKA, and 2 times after surgery (6 hours and 3 days after surgery).

    Serious adverse events
    		 Enoxaparin 40 mg ISIS 416858 200 mg ISIS 416858 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 144 (2.08%)
    1 / 77 (1.30%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Post procedural fistula
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 144 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 144 (0.69%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 144 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Enoxaparin 40 mg ISIS 416858 200 mg ISIS 416858 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 72 (65.28%)
    114 / 144 (79.17%)
    62 / 77 (80.52%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    19 / 72 (26.39%)
    46 / 144 (31.94%)
    18 / 77 (23.38%)
         occurrences all number
    19
    46
    18
    Anaemia postoperative
         subjects affected / exposed
    9 / 72 (12.50%)
    16 / 144 (11.11%)
    13 / 77 (16.88%)
         occurrences all number
    9
    16
    13
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    18 / 72 (25.00%)
    30 / 144 (20.83%)
    3 / 77 (3.90%)
         occurrences all number
    18
    31
    3
    Haematoma
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 144 (2.08%)
    2 / 77 (2.60%)
         occurrences all number
    4
    3
    4
    Hypertension
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 144 (1.39%)
    5 / 77 (6.49%)
         occurrences all number
    1
    2
    5
    General disorders and administration site conditions
    Hyperthermia
         subjects affected / exposed
    4 / 72 (5.56%)
    5 / 144 (3.47%)
    6 / 77 (7.79%)
         occurrences all number
    6
    5
    6
    Injection site erythema
         subjects affected / exposed
    0 / 72 (0.00%)
    26 / 144 (18.06%)
    23 / 77 (29.87%)
         occurrences all number
    0
    61
    73
    Injection site haematoma
         subjects affected / exposed
    2 / 72 (2.78%)
    7 / 144 (4.86%)
    9 / 77 (11.69%)
         occurrences all number
    10
    9
    21
    Injection site pain
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 144 (2.08%)
    7 / 77 (9.09%)
         occurrences all number
    0
    10
    9
    Injection site pruritus
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 144 (1.39%)
    8 / 77 (10.39%)
         occurrences all number
    0
    2
    26
    Injection site swelling
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 144 (0.69%)
    6 / 77 (7.79%)
         occurrences all number
    0
    5
    29
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 72 (5.56%)
    7 / 144 (4.86%)
    6 / 77 (7.79%)
         occurrences all number
    4
    7
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 144 (0.69%)
    4 / 77 (5.19%)
         occurrences all number
    0
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2013
    • Extended the ISIS 416858 treatment period in order to achieve reduction in Factor XI (FXI) activity to levels ≤0.2 U/mL. • Extended the duration of treatment with ISIS 416858 to include two additional doses prior to surgery and one additional dose after surgery compared with the original protocol dosing regimen. • Eliminated the lowest dose cohort (100 mg). • Modified the primary and secondary objectives/endpoints to better reflect the importance of assessing antithrombotic efficacy of ISIS 416858 as a function of FXI activity reduction, especially in subjects who achieve the targeted level of FXI activity (≤0.2 U/mL). • Modified the timing of TKA surgery and venography with respect to Study Day 1, and extended the screening period in order to make it easier to get all test results back prior to treatment assignment. • Modified the reporting of serious adverse events (SAEs) to better discriminate between SAEs associated with the study drug and those associated with the surgical procedure. • Clarified the exclusion criteria; Added more lab tests to the schedule of procedures; and included additional follow-up for subjects with FXI activity ≤0.3 U/mL at the end of the follow-up period.

    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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    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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