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    Clinical Trial Results:
    PEntoxifylline in Anaemia Resistant to erythropoietin (PEAR)

    Summary
    EudraCT number
    2011-006168-30
    Trial protocol
    GB  
    Global end of trial date
    20 Sep 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Apr 2019
    First version publication date
    21 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RLH_Pentoxifylline_Dec2011
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Barts Health NHS Trust
    Sponsor organisation address
    Whitechapel, London, United Kingdom, E1 1BB
    Public contact
    Dr Stanley FAN, Barts and The London NHS Trust, 44 2073777480, s.fan@qmul.ac.uk
    Scientific contact
    Dr Stanley FAN, Barts and The London NHS Trust, 44 2073777480, s.fan@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 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study the effects Pentoxifylline in ESA resistant ESRD patients on haemodialysis. The primary study endpoints is the ESA requirement relative to the Hb level (is there a difference in a randomised placebo controlled cross-over study)?
    Protection of trial subjects
    But we had a safety committee comprised of other renal consultants who were not involved with the study
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Apr 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
    United Kingdom: 84
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    55
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    2 week screening run-in period. Subjects will attend their Dialysis Unit (run by BHT )for their standard hemodialysis on Day 1 (visit 1).Subjects will be entered in a run-in period for 2 weeks where biochemistry and haematology will be measure weekly (+/-3 days) to establish baseline. All blood tests will be taken prior to a dialysis session.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pentoxy
    Arm description
    Trental 400
    Arm type
    Experimental

    Investigational medicinal product name
    Pentoxyphylline
    Investigational medicinal product code
    Pentoxyphylline
    Other name
    Trental 400
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule per day (overencapsulated Trental 400)

    Arm title
    Placebo
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    Pentoxy Placebo
    Started
    30
    39
    Completed
    28
    39
    Not completed
    2
    0
         Consent withdrawn by subject
    2
    -
    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: 84 patients consented to the study. However, this study included a run-in period (before randomisation) and during this time, some patients withdrew. Hence the baseline numbers total 69 and not the initial "full" 84

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pentoxy
    Reporting group description
    Trental 400

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Pentoxy Placebo Total
    Number of subjects
    30 39 69
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.5 ± 13.2 56.1 ± 14.1 -
    Gender categorical
    Units: Subjects
        Female
    5 10 15
        Male
    25 29 54
        Not recorded
    0 0 0
    Baseline Hb
    Units: g/dl
        arithmetic mean (standard deviation)
    11.3 ± 0.9 10.7 ± 0.9 -

    End points

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    End points reporting groups
    Reporting group title
    Pentoxy
    Reporting group description
    Trental 400

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: ESA dose in iu / Hb in g/dl

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    End point title
    ESA dose in iu / Hb in g/dl
    End point description
    End point type
    Primary
    End point timeframe
    6 months with last result carried forward
    End point values
    Pentoxy Placebo
    Number of subjects analysed
    28
    38
    Units: iu/g/dl
        arithmetic mean (standard deviation)
    3.98 ± 3.09
    4.91 ± 3.49
    Attachments
    Untitled (Filename: Outcome_ESA-Hb_1.pdf)
    Statistical analysis title
    Primary ESA/Hb analysis
    Statistical analysis description
    Primary end point was compared as difference in mean of ESA dose relative to haemoglobin between first two readings during run in period and last two readings during follow up period in experimental and placebo groups using unpaired student t-test. P values of < 0.05 will be considered statistically significant
    Comparison groups
    Pentoxy v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    6 months
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Own specified list
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    IMP arm
    Reporting group description
    -

    Serious adverse events
    Placebo IMP arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 39 (30.77%)
    5 / 30 (16.67%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    cvs excluding fluid overload
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 30 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    overload
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    stroke
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    pychosomatic muscle weakness
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    bleed
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdo Pain
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Elective bariatric surgery
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    elective surgery
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    glucose abnormalities
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Dialysis Access infection
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    foot infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo IMP arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 39 (100.00%)
    29 / 30 (96.67%)
    Vascular disorders
    Dialysis access- non infective
         subjects affected / exposed
    32 / 39 (82.05%)
    19 / 30 (63.33%)
         occurrences all number
    63
    58
    Dialysis Access infections
         subjects affected / exposed
    7 / 39 (17.95%)
    2 / 30 (6.67%)
         occurrences all number
    10
    5
    Investigations
    medication changes
         subjects affected / exposed
    26 / 39 (66.67%)
    15 / 30 (50.00%)
         occurrences all number
    65
    40
    Cardiac disorders
    cvs excluding fluid overload
         subjects affected / exposed
    30 / 39 (76.92%)
    17 / 30 (56.67%)
         occurrences all number
    83
    55
    fluid overload
         subjects affected / exposed
    26 / 39 (66.67%)
    14 / 30 (46.67%)
         occurrences all number
    44
    29
    Respiratory, thoracic and mediastinal disorders
    respiratory disorders
         subjects affected / exposed
    12 / 39 (30.77%)
    8 / 30 (26.67%)
         occurrences all number
    20
    11
    Nervous system disorders
    Neuro or eye issues
         subjects affected / exposed
    2 / 39 (5.13%)
    5 / 30 (16.67%)
         occurrences all number
    2
    11
    Gastrointestinal disorders
    GI disturbance
         subjects affected / exposed
    16 / 39 (41.03%)
    7 / 30 (23.33%)
         occurrences all number
    20
    8
    Renal and urinary disorders
    Genitourinary symptom
         subjects affected / exposed
    4 / 39 (10.26%)
    3 / 30 (10.00%)
         occurrences all number
    8
    3
    Skin and subcutaneous tissue disorders
    Skin disorder
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 30 (13.33%)
         occurrences all number
    1
    4
    Musculoskeletal and connective tissue disorders
    Bone Mineral Metabolism
         subjects affected / exposed
    20 / 39 (51.28%)
    8 / 30 (26.67%)
         occurrences all number
    29
    9
    Endocrine disorders
    Endocrine disorder
         subjects affected / exposed
    3 / 39 (7.69%)
    8 / 30 (26.67%)
         occurrences all number
    5
    10

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Feb 2013
    We applying for the substantial amendment because in the original application the Active IMP, pentoxifylline 400mg prolonged release tablets (Trental), was to be sourced from Germany. Since then, our IMP supplier has informed us that the German product has become unavailable for export, so the IMP is now to be sourced from Portugal. Trental as marketed in Portugal has the Marketing Authorisation (registration) number 4600284 (packs of 60)
    20 Mar 2013
    After careful consideration of the recent literature and the funding situation, we should like to remove the “experimental end-points” in the protocol. However, we shall still be consenting patients to have bloods stored for future research. For this reason, we will not change the number, volume or the frequency of the blood tests. As per original protocol, blood will be stored in a HTA approved tissue bank. If we decide to analysis of these stored blood samples at a future date, we shall submit a new study protocol and seek ethical approval prior to any analysis. We believe that there would be potential ethical issues if we were performed tests on patients that are no longer relevant given the current literature. We believe the scientific validity of the study will not be compromised as we are seeking consent for blood to be stored. These can be analysed for experimental end-points at a future date (subject to a different study protocol/ethic submission). Because the frequency and the amount of blood / intervention is unchanged, we have not felt it necessary to amend the Patient Information Sheet (remaining version 4-1 27th Nov 2012).
    01 Nov 2013
    1. Changes to the inclusion crieteria: a. Removal of CRP > 5 as one of the inclusion crieteria b. Erythropoietin stimulating agent (ESA) dose has been changed to erythropoietin dose greater than or equal to 6000 iu equivalent of EPO (erythropoietin) per week or if ESA resistance index is greater than or equal to 6.5 iu /kg/wk/g Hb for equivalent EPO dose to maintain stable haemoglobin levels. This dose is similar to median ESA requirement for haemodialysis patients with arterio venous fistula as dialysis access in our unit. 2. Changes to FDG - PET / CT scan protocol : Following the review of initial 5 scans research team has changed the FDG-PET / CT protocol. The new protocol will provide sufficient data for secondary end point analysis. The duration of dynamic imaging for the PET scan has been changed from 0 to 50 minutes to 0 to 60 minutes. The initial protocol of whole body imaging at 60 min and 160 min has now been changed to single whole body imaging at 90 min. The number of venous blood samples during the dynamic imaging has also been reduced to total 11 samples ( total blood volume 33 mls per scan) from total 21 blood samples (total blood volume 63mls per scan). This change in imaging protocol had to be implemented before formal approval because there is better patient experience during the scan visit and reduced radiation exposure to patients with no compromise to the quality of data obtained. 3. Patient information sheet has also been modified based in view of change in FDG-PET/CT protocol. Total imaging time for FDG-PET/CT scan has been reduced to 2 hrs compared to 4 hrs previously.

    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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