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    Clinical Trial Results:
    A PHASE 2 RANDOMIZED, DOUBLE-BLIND, CROSSOVER, CONTROLLED, MULTI-CENTER, SUBJECT PREFERENCE STUDY OF TIVOZANIB HYDROCHLORIDE VERSUS SUNITINIB IN THE TREATMENT OF SUBJECTS WITH METASTATIC RENAL CELL CARCINOMA

    Summary
    EudraCT number
    		 2012-001730-33
    Trial protocol
    		 BE   IT   GB   ES   DE  
    Global end of trial date
    18 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Aug 2021
    First version publication date
    25 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AV-951-12-205
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01673386
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AVEO Pharmaceuticals, Inc
    Sponsor organisation address
    30 Winter Street, Boston, United States, MA 02108
    Public contact
    Chief Medical Officer, AVEO Pharmaceuticals Inc., 857 400-0101, clinical@aveooncology.com
    Scientific contact
    Chief Medical Officer, AVEO Pharmaceuticals Inc., 857 400-0101, clinical@aveooncology.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
    05 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare subject treatment preference of tivozanib hydrochloride versus sunitinib.
    Protection of trial subjects
    The Investigator submitted this protocol, any protocol modifications, and the subject consent form utilized in this study, to the appropriate IRB or EC for review and approval. All subjects participated in the informed consent process and adequate time was given for each subject to ask questions and make a voluntary decision before enrolling in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Sep 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
    Spain: 8
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    58
    EEA total number of subjects
    34
    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)
    26
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All the subjects were recruited as per the inclusion and exclusion criteria.

    Pre-assignment
    Screening details
    		 All screening assessments were performed within 28 days prior to the first dose of study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tivozanib First, Then Sunitinib
    Arm description
    		 Subject randomized to this arm received 1.5 mg oral tivozanib hydrochloride (drug 1) daily on a 3 weeks on/1 week off schedule for 12 weeks, followed by 50 mg oral sunitinib (drug 2) daily on a 4 weeks on/2 weeks off schedule for 12 weeks. There will be a 1-week washout period, in addition to the planned rest week(s) between the 2 treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tivozanib
    Investigational medicinal product code
    Other name
    Tivozanib Hydrochloride
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Tivozanib hydrochloride was administered orally, 1.5 mg/day beginning on Day 1 of Week 1 for those subjects randomized to Arm 1, and Day 1 of Week 14 for those subjects randomized to Arm 2. Subjects received 1 capsule of tivozanib hydrochloride and 1 capsule of placebo daily for 3 weeks followed by 1 week rest period.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Two capsules of over-encapsulated placebo were administered during the planned rest week(s) in order to maintain the blind.

    Arm title
    		 Sunitinib First, Then Tivosanib
    Arm description
    		 Subject randomized to this arm received 50 mg oral sunitinib (drug 1) daily on a 4 weeks on/2 weeks off schedule for 12 weeks, followed by 1.5 mg oral tivozanib hydrochloride (drug 2) daily on a 3 weeks on/1 week off schedule for 12 weeks. There will be a 1-week washout period, in addition to the planned rest week(s) between the 2 treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sunitinib
    Investigational medicinal product code
    Other name
    Sutent
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sunitinib was administered orally, 50 mg/day beginning on Day 1 of Week 14 for those subjects randomized to Arm 1, and Day 1 of Week 1 for those subjects randomized to Arm 2. Subjects received 2 capsules, each 25 mg, of sunitinib daily for 4 weeks followed by a 2 week rest period.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Two capsules of over-encapsulated placebo were administered during the planned rest week(s) in order to maintain the blind.

    Number of subjects in period 1
    		Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Started
    27
    31
    Completed
    2
    4
    Not completed
    25
    27
         Consent withdrawn by subject
    -
    2
         Adverse event, non-fatal
    5
    2
         Study terminated by sponsor
    16
    22
         Progressive disease
    4
    1

    Baseline characteristics

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

    Reporting group values
    		 Overall Total
    Number of subjects
    		 58 58
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 26 26
        From 65-84 years
    		 32 32
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.6 ( 9.72 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 48 48

    End points

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    End points reporting groups
    Reporting group title
    Tivozanib First, Then Sunitinib
    Reporting group description
    		 Subject randomized to this arm received 1.5 mg oral tivozanib hydrochloride (drug 1) daily on a 3 weeks on/1 week off schedule for 12 weeks, followed by 50 mg oral sunitinib (drug 2) daily on a 4 weeks on/2 weeks off schedule for 12 weeks. There will be a 1-week washout period, in addition to the planned rest week(s) between the 2 treatment periods.

    Reporting group title
    Sunitinib First, Then Tivosanib
    Reporting group description
    		 Subject randomized to this arm received 50 mg oral sunitinib (drug 1) daily on a 4 weeks on/2 weeks off schedule for 12 weeks, followed by 1.5 mg oral tivozanib hydrochloride (drug 2) daily on a 3 weeks on/1 week off schedule for 12 weeks. There will be a 1-week washout period, in addition to the planned rest week(s) between the 2 treatment periods.

    Subject analysis set title
    Tivozanib
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects receiving Tivozanib in Arm 1 and Arm 2

    Subject analysis set title
    Sunitinib
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects receiving Sunitinib in Arm 1 and Arm 2.

    Primary: Proportion of Subjects Who Prefer Tivozanib Hydrochloride or Sunitinib

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    End point title
    		 Proportion of Subjects Who Prefer Tivozanib Hydrochloride or Sunitinib [1]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 25 weeks
    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: The study was terminated prior to completing enrollment; due to low enrollment, no data was collected/analyzed.
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Subjects
    Notes
    [2] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [3] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Number of Subjects With adverse events (AEs) and serious AEs (SAEs)

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    End point title
    		 Number of Subjects With adverse events (AEs) and serious AEs (SAEs)
    End point description
    Number of subjects with serious and non-serious adverse events during the study.
    End point type
    Secondary
    End point timeframe
    Up to 25 weeks
    End point values
    		 Tivozanib Sunitinib
    Number of subjects analysed
    38
    41
    Units: Subjects
    number (not applicable)
        At least one AE
    35
    40
        At least one treatment-related AE
    33
    38
        At least one SAE
    6
    7
        At least one treatment-related SAE
    1
    3
        At least one AE leading to drug withdrawal
    3
    8
        At least one AE with outcome of death
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Dose Reductions

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    End point title
    		 Number of Subjects With Dose Reductions
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 25 weeks
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: subjects
        number (not applicable)
    Notes
    [4] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [5] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Dose Interruptions

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    End point title
    		 Number of Subjects With Dose Interruptions
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 25 weeks
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: subjects
        number (not applicable)
    Notes
    [6] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [7] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Grade 3/4 Hematology Abnormalities

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    End point title
    		 Number of Subjects With Grade 3/4 Hematology Abnormalities
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 25 weeks
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Subjects
        number (not applicable)
    Notes
    [8] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [9] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Grade 3/4 Coagulation Abnormalities

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    End point title
    		 Number of Subjects With Grade 3/4 Coagulation Abnormalities
    End point description
    End point type
    Secondary
    End point timeframe
    Upto 25 weeks
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Subjects
        number (not applicable)
    Notes
    [10] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [11] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Grade 3/4 Urinalysis Abnormalities

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    End point title
    		 Number of Subjects With Grade 3/4 Urinalysis Abnormalities
    End point description
    End point type
    Secondary
    End point timeframe
    Upto 25 weeks
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Subjects
        number (not applicable)
    Notes
    [12] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [13] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Title Number of Subjects With Grade 3/4 Thyroid Function Abnormalities

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    End point title
    		 Title Number of Subjects With Grade 3/4 Thyroid Function Abnormalities
    End point description
    End point type
    Secondary
    End point timeframe
    Upto 25 weeks
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: Subjects
        number (not applicable)
    Notes
    [14] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [15] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)

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    End point title
    		 Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1, 4, 10, 14, 17, 23, and End of Treatment
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: Subjects
        number (not applicable)
    Notes
    [16] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [17] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected
    No statistical analyses for this end point

    Secondary: Change From Baseline in FACT Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS)

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    End point title
    		 Change From Baseline in FACT Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1, 4, 10, 14, 17, 23, and End of Treatment
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: scores on scale
        number (not applicable)
    Notes
    [18] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [19] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Diarrhea (FACT-D)

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    End point title
    		 Change From Baseline in Functional Assessment of Cancer Therapy-Diarrhea (FACT-D)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1, 4, 10, 14, 17, 23, and End of Treatment
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: scores on scale
        number (not applicable)
    Notes
    [20] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [21] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Euro Quality of Life - 5 Dimensions (EQ-5D)

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    End point title
    		 Change From Baseline in Euro Quality of Life - 5 Dimensions (EQ-5D)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1, 4, 10, 14, 17, 23, and End of Treatment
    End point values
    		 Tivozanib First, Then Sunitinib Sunitinib First, Then Tivosanib
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: scores on scale
        number (not applicable)
    Notes
    [22] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    [23] - Study was terminated prior to completing enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of signing the ICF until 30 days after permanent treatment discontinuation at Week 25. The Sponsor terminated Study AV-951-12-205 before enrollment was completed, following the negative decision of the US FDA on the NDA (204408).
    Adverse event reporting additional description
    MedDra v15.0
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Tivozanib
    Reporting group description
    		 Tivozanib hydrochloride 1.5 mg was administered orally to the randomized subjects first in Arm 1 and second in Arm 2.

    Reporting group title
    Sunitinib
    Reporting group description
    		 Sunitinib 50 mg was administered orally to the randomized subjects first in Arm 2 and second in Arm 1.

    Serious adverse events
    		 Tivozanib Sunitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 38 (15.79%)
    7 / 41 (17.07%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    Flank Pain
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Subcutaneous abscess
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Tivozanib Sunitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 38 (92.11%)
    40 / 41 (97.56%)
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Hypertension
         subjects affected / exposed
    19 / 38 (50.00%)
    12 / 41 (29.27%)
         occurrences all number
    34
    20
    Hypotension
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 41 (7.32%)
         occurrences all number
    3
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 38 (13.16%)
    9 / 41 (21.95%)
         occurrences all number
    6
    13
    Chills
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    3
    Fatigue
         subjects affected / exposed
    14 / 38 (36.84%)
    15 / 41 (36.59%)
         occurrences all number
    23
    19
    Oedema Peripheral
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 41 (4.88%)
         occurrences all number
    2
    3
    Peripheral Swelling
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 41 (4.88%)
         occurrences all number
    1
    3
    Pyrexia
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 41 (9.76%)
         occurrences all number
    2
    4
    Tenderness
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 38 (15.79%)
    4 / 41 (9.76%)
         occurrences all number
    6
    4
    Dysphonia
         subjects affected / exposed
    13 / 38 (34.21%)
    5 / 41 (12.20%)
         occurrences all number
    16
    5
    Dyspnoea
         subjects affected / exposed
    4 / 38 (10.53%)
    6 / 41 (14.63%)
         occurrences all number
    5
    8
    Epistaxis
         subjects affected / exposed
    0 / 38 (0.00%)
    6 / 41 (14.63%)
         occurrences all number
    0
    6
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Productive Cough
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    Investigations
    Amylase Increased
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    8
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 41 (7.32%)
         occurrences all number
    1
    4
    Lipase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    5 / 41 (12.20%)
         occurrences all number
    0
    9
    Weight decreased
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 41 (0.00%)
         occurrences all number
    5
    0
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    3
    Platelet Count Decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 41 (7.32%)
         occurrences all number
    3
    3
    Dysgeusia
         subjects affected / exposed
    4 / 38 (10.53%)
    17 / 41 (41.46%)
         occurrences all number
    4
    21
    Headache
         subjects affected / exposed
    5 / 38 (13.16%)
    0 / 41 (0.00%)
         occurrences all number
    6
    0
    Neuropathy Peripheral
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Paraesthesia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 41 (4.88%)
         occurrences all number
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 41 (7.32%)
         occurrences all number
    1
    4
    Neutropenia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    3
    Thrombocytopenia
         subjects affected / exposed
    0 / 38 (0.00%)
    5 / 41 (12.20%)
         occurrences all number
    0
    6
    Eye disorders
    Eyelid Oedema
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 41 (7.32%)
         occurrences all number
    1
    6
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 41 (12.20%)
         occurrences all number
    1
    5
    Constipation
         subjects affected / exposed
    5 / 38 (13.16%)
    3 / 41 (7.32%)
         occurrences all number
    8
    3
    Diarrhoea
         subjects affected / exposed
    17 / 38 (44.74%)
    15 / 41 (36.59%)
         occurrences all number
    22
    19
    Dry Mouth
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 41 (4.88%)
         occurrences all number
    3
    2
    Dyspepsia
         subjects affected / exposed
    2 / 38 (5.26%)
    10 / 41 (24.39%)
         occurrences all number
    2
    10
    Flatulence
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 41 (12.20%)
         occurrences all number
    1
    7
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Gingival Pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    4 / 38 (10.53%)
    12 / 41 (29.27%)
         occurrences all number
    4
    18
    Oral Dysaesthesia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Oral Pain
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Proctalgia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 41 (4.88%)
         occurrences all number
    1
    2
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    4
    Stomatitis
         subjects affected / exposed
    8 / 38 (21.05%)
    10 / 41 (24.39%)
         occurrences all number
    10
    11
    Vomiting
         subjects affected / exposed
    3 / 38 (7.89%)
    7 / 41 (17.07%)
         occurrences all number
    5
    12
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    0
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 41 (7.32%)
         occurrences all number
    1
    3
    Dry Skin
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Hair Colour Changes
         subjects affected / exposed
    1 / 38 (2.63%)
    6 / 41 (14.63%)
         occurrences all number
    1
    7
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    6 / 38 (15.79%)
    10 / 41 (24.39%)
         occurrences all number
    10
    29
    Pruritus
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 41 (4.88%)
         occurrences all number
    3
    2
    Rash
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 41 (9.76%)
         occurrences all number
    3
    6
    Skin Discolouration
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    3
    Yellow skin
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 41 (4.88%)
         occurrences all number
    1
    2
    Proteinuria
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 41 (7.32%)
         occurrences all number
    3
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    4
    0
    Back Pain
         subjects affected / exposed
    3 / 38 (7.89%)
    6 / 41 (14.63%)
         occurrences all number
    5
    6
    Muscle Spasms
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 41 (4.88%)
         occurrences all number
    1
    2
    Musculoskeletal Pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal Stiffness
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    0
    4
    Pain In Extremity
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 41 (4.88%)
         occurrences all number
    1
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Tooth Infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 41 (4.88%)
         occurrences all number
    2
    2
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    7 / 38 (18.42%)
    11 / 41 (26.83%)
         occurrences all number
    12
    14
    Hyponatraemia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jun 2012
    - Tivozanib was changed to tivozanib hydrochloride. - To clarify rest periods during study drug treatment, “off week treatment period” was changed to planned rest week(s) or planned rest period as appropriate. - Text was added for clarity that any subject permanently discontinuing any further study treatment will have a 30-day post treatment safety visit and that this visit is for assessment of delayed effects of study drugs. - The stratification factors were modified to remove number of metastatic sites (0 and 1 vs 2+) and to add histology (clear cell vs. non-clear cell). - The study population was modified to enroll only those subjects with metastatic renal cell carcinoma who did not receive prior systemic therapy for metastatic disease and not to enroll subjects with locally advanced disease. - Inclusion criterion was modified to remove requirement for prior nephrectomy and to allow subjects with or without prior nephrectomy to enroll. - Treatment with full dose oral anticoagulation was permitted.

    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.
    The Sponsor terminated Study AV-951-12-205 before enrollment was completed, following the negative decision of the US FDA on the NDA (204408).
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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