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    Clinical Trial Results:
    The use of Peroxisome Proliferator Activator Receptor Agonists in the management of Androgen Independent Prostate Cancer

    Summary
    EudraCT number
    		 2006-001398-44
    Trial protocol
    		 GB  
    Global end of trial date
    24 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Dec 2016
    First version publication date
    10 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PR 2006-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Barts Health NHS Trust
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    Dr Jonathan Shamash, Centre for Experimental Cancer Medicine, Charterhouse Square, London, EC1M 6BQ, +44 2078828493, bci-ppar@qmul.ac.uk
    Scientific contact
    Dr Jonathan Shamash, Centre for Experimental Cancer Medicine, Charterhouse Square, London, EC1M 6BQ, +44 02078828493, bci-ppar@qmul.ac.uk
    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
    20 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective for this study is PSA doubling time. The secondary objectives are to find PSA response, symptomatic progression, restoration of androgen sensitivity, quality of life (using the EORTC QLQ-C30 and EORTC QLQ-PR25 quality of life assessments) and time to progression.
    Protection of trial subjects
    Side effects were closely monitored during and after the study. Patients were required to attend regular clinic appointments whilst they were on study medication and adverse events were recorded. The patient information sheet included details on expected adverse events for patients to look out for and also detailed that unexpected events may occur. The Trial Management Group for the trial was in place throughout to closely assess the side effects of the drugs on a regular basis to make sure there were no excess risks to patients. On-site monitoring was performed throughout the study to provide real time review of source data to allow for early detection of signals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2007
    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
    United Kingdom: 49
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    0
    From 65 to 84 years
    44
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 1/2/2007, 49 patients out of an intended 67 were recruited by two hospitals within the UK only. Trial was terminated early in November 2015 due to slow recruitment.

    Pre-assignment
    Screening details
    		 Inclusion criteria allowed patients with androgen independent prostate cancer defined as rising PSA in the presence of MAB who were asymptomatic (ECOG 0-2).

    Pre-assignment period milestones
    Number of subjects started
    		 49
    Number of subjects completed
    		 49

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Overall trial
    Arm description
    		 Single arm: Rosiglitazone/Pioglitazone followed by addition of fenofibrate, followed by addition of calcitriol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pioglitazone
    Investigational medicinal product code
    EU/1/00/150/011-015
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg once daily, orally

    Investigational medicinal product name
    Fenofibrate
    Investigational medicinal product code
    PL 00512/0391
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    267mg daily

    Investigational medicinal product name
    Calcitriol
    Investigational medicinal product code
    PL00031/0123
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    500 mcg daily

    Investigational medicinal product name
    Rosiglitazone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4mg BD for a minimum of 6 weeks orally

    Number of subjects in period 1
    		Overall trial
    Started
    49
    Rosiglitazone cohort
    31 [1]
    Pioglitazone cohort
    18 [2]
    Completed
    47
    Not completed
    2
         Consent withdrawn by subject
    1
         Protocol deviation
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Pioglitazone replaced the drug Rosiglitazone after recruiting 31 patients. Two patients were excluded from analysis. 18 patients were recruited to Pioglitazone. Therefor two cohorts of patients.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Pioglitazone replaced the drug Rosiglitazone after recruiting 31 patients. Two patients were excluded from analysis. 18 patients were recruited to Pioglitazone. Therefor two cohorts of patients.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Single arm: Rosiglitazone/Pioglitazone followed by addition of fenofibrate, followed by addition of calcitriol.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 49 49
    Age categorical
    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
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 75 (70 to 82) -
    Gender categorical
    All subjects were male.
    Units: Subjects
        Female
    		 0 0
        Male
    		 49 49
    Gleason score
    Units: Subjects
        <7
    		 5 5
        >=7
    		 33 33
        missing
    		 11 11
    Lower urinary tract symptoms
    Units: Subjects
        Yes
    		 7 7
        No
    		 39 39
        Missing
    		 3 3
    Cardian history
    Units: Subjects
        Yes
    		 10 10
        No
    		 35 35
        Missing
    		 4 4
    Respiratory
    Units: Subjects
        Yes
    		 4 4
        No
    		 42 42
        Missing
    		 3 3
    Diagnosis method
    Units: Subjects
        Biopsy
    		 38 38
        TURP
    		 4 4
        Other
    		 2 2
        Missing
    		 5 5
    Has a TURP been performed?
    Units: Subjects
        Yes
    		 8 8
        No
    		 33 33
        Missing
    		 8 8
    Clinical T category (1997)
    Units: Subjects
        T0
    		 1 1
        T1
    		 1 1
        T2
    		 4 4
        T3
    		 15 15
        T4
    		 7 7
        TX
    		 5 5
        Missing
    		 16 16
    Prior radical prostechtomy
    Units: Subjects
        Yes
    		 1 1
        No
    		 43 43
        Missing
    		 5 5
    Prior radical RT
    Units: Subjects
        Yes
    		 10 10
        No
    		 34 34
        Missing
    		 5 5
    Metastases at study entry
    Units: Subjects
        Yes
    		 15 15
        No
    		 25 25
        Missing
    		 9 9
    Metastases at diagnosis
    Units: Subjects
        Yes
    		 15 15
        No
    		 23 23
        Mising
    		 11 11
    GnRH analogues?
    Units: Subjects
        Yes
    		 34 34
        No
    		 2 2
        Missing
    		 13 13
    Maximum androgen blockage
    Units: Subjects
        Yes
    		 41 41
        No
    		 1 1
        Missing
    		 7 7
    Bilateral orchidectomy
    Units: Subjects
        Yes
    		 1 1
        No
    		 7 7
        Missing
    		 41 41
    Subject analysis sets

    Subject analysis set title
    Overall trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All consented patients took part in observational (pre-treatment) phase and/or received any medication

    Subject analysis sets values
    		 Overall trial
    Number of subjects
    47
    Age categorical
    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
    Units: years
        median (inter-quartile range (Q1-Q3))
    75 (70 to 82)
    Gender categorical
    All subjects were male.
    Units: Subjects
        Female
    0
        Male
    47
    Gleason score
    Units: Subjects
        <7
    5
        >=7
    33
        missing
    9
    Lower urinary tract symptoms
    Units: Subjects
        Yes
    7
        No
    39
        Missing
    1
    Cardian history
    Units: Subjects
        Yes
    10
        No
    35
        Missing
    2
    Respiratory
    Units: Subjects
        Yes
    4
        No
    42
        Missing
    1
    Diagnosis method
    Units: Subjects
        Biopsy
    38
        TURP
    4
        Other
    2
        Missing
    3
    Has a TURP been performed?
    Units: Subjects
        Yes
    8
        No
    33
        Missing
    6
    Clinical T category (1997)
    Units: Subjects
        T0
    1
        T1
    1
        T2
    4
        T3
    15
        T4
    7
        TX
    5
        Missing
    14
    Prior radical prostechtomy
    Units: Subjects
        Yes
    1
        No
    43
        Missing
    3
    Prior radical RT
    Units: Subjects
        Yes
    10
        No
    34
        Missing
    3
    Metastases at study entry
    Units: Subjects
        Yes
    15
        No
    25
        Missing
    7
    Metastases at diagnosis
    Units: Subjects
        Yes
    15
        No
    23
        Mising
    9
    GnRH analogues?
    Units: Subjects
        Yes
    34
        No
    2
        Missing
    11
    Maximum androgen blockage
    Units: Subjects
        Yes
    41
        No
    1
        Missing
    5
    Bilateral orchidectomy
    Units: Subjects
        Yes
    1
        No
    7
        Missing
    39

    End points

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    End points reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Single arm: Rosiglitazone/Pioglitazone followed by addition of fenofibrate, followed by addition of calcitriol.

    Subject analysis set title
    Overall trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All consented patients took part in observational (pre-treatment) phase and/or received any medication

    Primary: PSA doubling time

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    End point title
    		 PSA doubling time
    End point description
    Time to PSA progression is defined as the time from start of treatment to when PSA progression is initially seen. PSA progression is defined by the PCWG2 criteria: - Decline from baseline: Time from start of therapy to first PSA increase that is ≥25% and ≥2ng/mL above the nadir, and which is confirmed by a 2nd value 3 or more weeks later. - No decline from baseline: PSA progression ≥25% and ≥2ng/mL after 12 weeks.
    End point type
    Primary
    End point timeframe
    baseline to disease progression (PSA progression)
    End point values
    		 Overall trial Overall trial
    Number of subjects analysed
    47
    47
    Units: week
        median (inter-quartile range (Q1-Q3))
    35 (17.5 to 144.1)
    35 (17.5 to 144.1)
    Statistical analysis title
    		 Wilcoxon sign rank sum test
    Statistical analysis description
    Wilcoxon sign rank sum test comparing PSADT during the monitoring phase and treatment phases for the same patients.
    Comparison groups
    Overall trial v Overall trial
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.001
    Method
    		 Wilcoxon sign rank sum test
    Confidence interval
    Notes
    [1] - Subject in this analysis is 47. Wilcoxon sign rank sum test compares PSADT between monitoring phase and treatment phases for the same patients.

    Secondary: Restoration of androgen sensitivity

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    End point title
    		 Restoration of androgen sensitivity
    End point description
    PSA levels down from end of trial - after reintroduction of bicalutamide
    End point type
    Secondary
    End point timeframe
    From end of trial - after reintroduction of bicalutamide
    End point values
    		 Overall trial
    Number of subjects analysed
    11
    Units: Number
    2
    No statistical analyses for this end point

    Secondary: PSA response

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    End point title
    		 PSA response
    End point description
    At least 50% reduction is PSA
    End point type
    Secondary
    End point timeframe
    From start of treatment to progression/end of trial
    End point values
    		 Overall trial
    Number of subjects analysed
    47
    Units: Number
    1
    No statistical analyses for this end point

    Secondary: Symptomatic progression

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    End point title
    		 Symptomatic progression
    End point description
    If patients had noted pain or a new symptom
    End point type
    Secondary
    End point timeframe
    From start of treatment to progression
    End point values
    		 Overall trial Overall trial
    Number of subjects analysed
    47
    47
    Units: Number
    8
    8
    Statistical analysis title
    		 Proportion
    Comparison groups
    Overall trial v Overall trial
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    		 Proportion with CI
    Parameter type
    		 Proportion
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0764
         upper limit
    		 0.3081
    Notes
    [2] - The symptomatic proportion is base on 47 patients.

    Secondary: Time to progression

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    End point title
    		 Time to progression
    End point description
    End point type
    Secondary
    End point timeframe
    From study entry to progression/end of study
    End point values
    		 Overall trial Overall trial
    Number of subjects analysed
    47
    47
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    23.7 (18 to 37)
    23.7 (18 to 37)
    Attachments
    		 K-M for Time to Progression
    Statistical analysis title
    		 K-M curve and Log-rank test
    Statistical analysis description
    Log-rank test for the difference in progression free survival between patients who received Rosiglitazone and who received Pioglitazone.
    Comparison groups
    Overall trial v Overall trial
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0053 [4]
    Method
    		 Logrank
    Confidence interval
    Notes
    [3] - Pioglitazone replaced the drug Rosiglitazone and hence this analysis. This analysis is based on 47 patients: Rosiglitazone (29) and Pioglitazone (18).
    [4] - P-value from the Log-rank test.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From trial consent to 30 days after last dose of IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 all patients that took part in the trial

    Serious adverse events
    		 overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 47 (23.40%)
         number of deaths (all causes)
    32
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Aortic valve replacement
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Pancreatitis
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    3 / 47 (6.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hydronephrosis
         subjects affected / exposed
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 47 (100.00%)
    Investigations
    Weight gain
         subjects affected / exposed
    16 / 47 (34.04%)
         occurrences all number
    25
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 47 (12.77%)
         occurrences all number
    7
    Neuropathy peripheral
         subjects affected / exposed
    7 / 47 (14.89%)
         occurrences all number
    9
    Dysgeusia
         subjects affected / exposed
    9 / 47 (19.15%)
         occurrences all number
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    36 / 47 (76.60%)
         occurrences all number
    105
    Oedema
         subjects affected / exposed
    24 / 47 (51.06%)
         occurrences all number
    45
    Pain
         subjects affected / exposed
    32 / 47 (68.09%)
         occurrences all number
    65
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 47 (6.38%)
         occurrences all number
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    18 / 47 (38.30%)
         occurrences all number
    38
    Diarrhoea
         subjects affected / exposed
    9 / 47 (19.15%)
         occurrences all number
    13
    Flatulence
         subjects affected / exposed
    11 / 47 (23.40%)
         occurrences all number
    20
    Nausea
         subjects affected / exposed
    14 / 47 (29.79%)
         occurrences all number
    20
    Vomiting
         subjects affected / exposed
    9 / 47 (19.15%)
         occurrences all number
    13
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    12 / 47 (25.53%)
         occurrences all number
    28
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    7 / 47 (14.89%)
         occurrences all number
    13
    Urticaria
         subjects affected / exposed
    2 / 47 (4.26%)
         occurrences all number
    2
    Infections and infestations
    Stomatitis
         subjects affected / exposed
    43 / 47 (91.49%)
         occurrences all number
    213
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    17 / 47 (36.17%)
         occurrences all number
    26
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2008
    Reduction of minimum entry age to 16 years. Clarification of SUSAR reporting requirements.
    24 Sep 2009
    Introduction of weekly calcitriol monitoring
    19 Apr 2011
    Addition of Pioglitazone following withdrawal of Avandia.
    23 Nov 2011
    Updates to PIS following a Drug Safety Notification from MHRA for Pioglitazone.
    29 May 2012
    Update to Sponsor name due to institutional mergers.
    24 Jan 2013
    Inclusion criteria amended to allow pain in patients with previous chemotherapy if this is controlled with simple analgesics or codeine phosphate.

    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
    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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