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    Clinical Trial Results:
    RIVAROXABAN VERSUS ACENOCUMAROL EN LA PROFILAXIS SECUNDARIA DEL SÍNDROME ANTIFOSFOLÍPIDO:UN ESTUDIO MULTICÉNTRICO, PROSPECTIVO Y RANDOMIZADO.

    Summary
    EudraCT number
    		 2010-019764-36
    Trial protocol
    		 ES  
    Global end of trial date
    31 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Sep 2021
    First version publication date
    16 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SAP-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02926170
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    VHIR
    Sponsor organisation address
    Passeig Vall Hebron 119-129, Barcelona, Spain, 08035
    Public contact
    Joaquin Lopez-Soriano, VHIR, +34 934894779, joaquin.lopez.soriano@vhir.org
    Scientific contact
    Josefina Cortés, VHIR, fina.cortes@vhir.org
    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
    31 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate efficacy and safety of rivaroxaban in patients with antiphospholipid syndrome (APS), and to determine whether rivaroxaban is noninferior to dose-adjusted vitamin K antagonists (VKAs) for thrombotic APS
    Protection of trial subjects
    The local ethics committees approved the study, and all participants provided written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice principles. Adherence in the rivaroxaban group was evaluated by self-reported questionnaire. The study treatment could be discontinued early because of unacceptable serious adverse or thrombotic events, any change in the patient's condition that justified discontinuation, consent withdrawal, pregnancy, or lack of adherence to the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Mar 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
    Spain: 190
    Worldwide total number of subjects
    190
    EEA total number of subjects
    190
    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)
    155
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult patients fulfilling the international consensus criteria for APS were recruited from internal medicine and rheumatology clinics. Eligible patients included those with objectively confirmed arterial or venous thrombosis and a positive result on aPL testing on 2 occasions at least 3 months apart. Testing for aPL was performed locally.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 190
    Number of subjects completed
    		 190

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rivaroxaban
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rivaroxaban (20 mg/d, or 15 mg/d for patients with a creatinine clearance of 30 to 49 mL/min/1.73 m2 Patients were started on low molecular weight heparin (LMWH) (1 mg/kg) administered twice daily. First dose was started on the day of conversion from warfarin to rivaroxaban in the evening and continued for 48 hours. After 48 hours of LMWH, at the 3rd day of conversion, rivaroxaban 15 mg or 20 mg was started in the morning, once daily. Patients receiving 20 mg rivaroxaban once daily could receive 15 mg if creatinine clearance changed to 30-49 mL/min, and in patients receiving 15 mg daily, the dose could be changed to 20 mg if CrCL changed to ≥50 mL/min.

    Arm title
    		 Control
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aldocumar
    Investigational medicinal product code
    Other name
    Sodium warfarin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Adjusted dosage of VKAs s (target INR, 2.0 to 3.0, or 3.1 to 4.0 for those with a history of recurrent thrombosis).

    Number of subjects in period 1
    		Rivaroxaban Control
    Started
    95
    95
    Completed
    84
    86
    Not completed
    11
    9
         Adverse event, serious fatal
    5
    3
         Adverse event, non-fatal
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 190 190
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 155 155
        From 65-84 years
    		 35 35
    Gender categorical
    Units: Subjects
        Female
    		 121 121
        Male
    		 69 69

    End points

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    End points reporting groups
    Reporting group title
    Rivaroxaban
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Primary: New thrombotic events

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    End point title
    		 New thrombotic events
    End point description
    End point type
    Primary
    End point timeframe
    3 years
    End point values
    		 Rivaroxaban Control
    Number of subjects analysed
    95
    95
    Units: percent
        number (not applicable)
    11.6
    6.3
    Statistical analysis title
    		 Recurrent Thrombosis rate
    Comparison groups
    Rivaroxaban v Control
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.21
    Method
    		 Risk Ratio
    Confidence interval

    Secondary: Time to thrombosis

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    End point title
    		 Time to thrombosis
    End point description
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Rivaroxaban Control
    Number of subjects analysed
    95
    95
    Units: units
    11
    6
    Statistical analysis title
    		 Time to thrombotic event
    Comparison groups
    Control v Rivaroxaban
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.19
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 5.24

    Secondary: Type of thrombotic event

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    End point title
    		 Type of thrombotic event
    End point description
    Arterial events
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Rivaroxaban Control
    Number of subjects analysed
    95
    95
    Units: percent
        number (not applicable)
    10.5
    3.2
    No statistical analyses for this end point

    Secondary: Type of thrombotic event

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    End point title
    		 Type of thrombotic event
    End point description
    Venous events
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Rivaroxaban Control
    Number of subjects analysed
    95
    95
    Units: percent
        number (not applicable)
    2.1
    3.2
    Statistical analysis title
    		 Venous events
    Comparison groups
    Rivaroxaban v Control
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.67
    Method
    		 Regression, Cox
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 3.9

    Secondary: Major bleeding

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    End point title
    		 Major bleeding
    End point description
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Rivaroxaban Control
    Number of subjects analysed
    95
    95
    Units: Percent
        number (not applicable)
    6.3
    7.4
    Statistical analysis title
    		 Major bleeding
    Comparison groups
    Rivaroxaban v Control
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.77
    Method
    		 Regression, Cox
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2.46

    Secondary: Nonmajor bleedings

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    End point title
    		 Nonmajor bleedings
    End point description
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Rivaroxaban Control
    Number of subjects analysed
    95
    95
    Units: percent
        number (not applicable)
    9.5
    5.3
    Statistical analysis title
    		 Non major bleeding
    Comparison groups
    Control v Rivaroxaban
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.28
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 5.17

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    3 years
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12
    Reporting groups
    Reporting group title
    Total adverse events
    Reporting group description
    		 -

    Serious adverse events
    		 Total adverse events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 190 (8.42%)
         number of deaths (all causes)
    8
         number of deaths resulting from adverse events
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant conditions
         subjects affected / exposed
    4 / 190 (2.11%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Endocarditis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Systemic lupus erythematosus flare
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Intestinal perforation
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary haemorrhage
    Additional description: Pulmonary Haemorrhage due to capillaritis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Septic shock
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cholecystitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Soft tissue infection
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total adverse events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    99 / 190 (52.11%)
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    4 / 190 (2.11%)
         occurrences all number
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 190 (6.84%)
         occurrences all number
    13
    Dizziness
         subjects affected / exposed
    9 / 190 (4.74%)
         occurrences all number
    9
    Sciatica
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences all number
    3
    Depression
         subjects affected / exposed
    5 / 190 (2.63%)
         occurrences all number
    5
    Immune system disorders
    Systemic lupus erythematosus rash
         subjects affected / exposed
    7 / 190 (3.68%)
         occurrences all number
    7
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    10 / 190 (5.26%)
         occurrences all number
    10
    Respiratory, thoracic and mediastinal disorders
    Chest pain
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences all number
    3
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 190 (8.42%)
         occurrences all number
    16
    Pneumonia
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences all number
    3
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    7 / 190 (3.68%)
         occurrences all number
    7
    Infections and infestations
    Herpes virus infection
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    5 / 190 (2.63%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Iron deficiency anaemia
         subjects affected / exposed
    13 / 190 (6.84%)
         occurrences all number
    13

    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.
    Anticoagulation intensity was not measured, the study was underpowered to detect differences in patient subgroups, and the exploratory nature of post hoc analyses did not allow conclusions to be drawn

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31610549
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