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    Clinical Trial Results:
    A Phase II study of Gemcitabine and Bexarotene (GemBex) in the treatment of cutaneous T-cell lymphoma

    Summary
    EudraCT number
    2006-000591-33
    Trial protocol
    GB  
    Global end of trial date
    23 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Oct 2017
    First version publication date
    22 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL/06/009
    Additional study identifiers
    ISRCTN number
    ISRCTN18563749
    US NCT number
    NCT00660231
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    JRO, University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Public contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    Scientific contact
    Scientific contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.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
    17 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary research question is to confirm the feasibility and efficacy of using a combination of Gemcitabine and Bexarotene for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have disease that is no longer controlled by skin-directed therapy and who have had at least one prior systemic therapy.
    Protection of trial subjects
    The risks to the safety of the participants were those generally associated with chemotherapy treatment, including nausea, alopecia, myelotoxicity and potential cardiotoxicity with high dosage. Adverse events were monitored throughout treatment and for 30 days post treatment. Bexarotene is also associated with lipid abnormalities; therefore patients were started on lipid-lowering therapy one week prior to the initiation of Bexarotene therapy and periodic monitoring was mandated to ensure lipid levels were adequate for patients to continue treatment. A corresponding schedule of permitted dose modifications was also provided with the aim of stabilizing lipid levels. Patients were asked to abstain from or minimise alcohol consumption during the course of treatment and to ensure they remained well-hydrated with a view to avoiding pancreatitis; which is an uncommon consequence of hyperlipidaemia. Women who could become pregnant were informed that they must use two effective forms of contraception during the course of the study and for at least six months after stopping treatment; and male patients were informed that they must use barrier contraception throughout and for six months after stopping treatment; because treatment might interfere with normal functioning of the female egg or male sperm.
    Background therapy
    Prophylactic oral fenofibrate 160mg – 200mg daily for 7 days before commencing cycle 1.
    Evidence for comparator
    N/A
    Actual start date of recruitment
    29 Jul 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    19
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    First patient recruited: 29/07/2008 Last patient recruited: 25/03/2011 Recruiting sites: Christie Hospital, Guys and St. Thomas' Hospital, Leicester Royal Infirmary, Nottingham City Hospital, Royal Bournemouth General Hospital, St James's University Hospital, Royal Liverpool University Hospital, Royal Cornwall Hospital, St Bartholomew's Hospital

    Pre-assignment
    Screening details
    Patients were screened for eligibility for inclusion into the study

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

    Arms
    Arm title
    GemBex
    Arm description
    Four cycles of Gemcitabine 1000 mg/m2 (at days 1 and 8 of 21 day cycles) Bexarotene 300 mg/m2 daily concurrently At 12 weeks responding patients maintained on Bexarotene 300 mg/m2 until disease progression or until the drug could no longer be tolerated NB: One patient was registered but found to be ineligible and did not commence trial treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Gemcitabine Hydrochloride
    Investigational medicinal product code
    L01BC05
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m2 intravenously on day 1 and day 8 of 21 day cycles for a maximum of four cycles.

    Investigational medicinal product name
    Bexarotene
    Investigational medicinal product code
    L01XX25
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Given for 14 days orally at 150mg/m2 orally. If tolerated, increased to 300mg/m2 orally daily from days 15-84. At 12 weeks responding patients maintained on 300mg/m2 orally daily until PD or until Bexarotene can no longer be tolerated.

    Number of subjects in period 1
    GemBex
    Started
    36
    Completed
    35
    Not completed
    1
         Patient ineligible; did not start trial treatment
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    - Aged ≥ 18 years - Histologically confirmed diagnosis of CTCL, including mycosis fungoides and Sézary syndrome - CTCL stages Ib, IIa, IIb, III, IVa and IVb. - Failed standard skin-directed therapy and have had at least one course of prior systemic therapy, to which they have either failed to respond or have subsequently progressed - Bexarotene naïve or previous response to single-agent bexarotene, but ≥3 months since last treatment - No treatment for lymphoma in the 4 weeks prior to study entry (except patients on stable low dose steroids; local radiotherapy allowed until 2 weeks prior to study entry) - Life expectancy > 6 months - Written informed consent - ECOG performance status 0-1 - Adequate bone marrow, hepatic & pancreatic function - HIV negative - Not pregnant or breastfeeding - No coexistent or prior malignancy in 5 years prior to study entry

    Reporting group values
    Overall trial (overall period) Total
    Number of subjects
    36 36
    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)
    19 19
        From 65-84 years
    17 17
        85 years and over
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    65 (38 to 83) -
    Gender categorical
    Units: Subjects
        Female
    11 11
        Male
    25 25
    ECOG performance status
    Units: Subjects
        ECOG 0
    20 20
        ECOG 1
    16 16
    Clinical stage at study entry
    Units: Subjects
        Ib
    5 5
        IIa
    2 2
        IIb
    8 8
        III
    8 8
        IVa
    13 13
    T skin
    Units: Subjects
        T1
    1 1
        T2
    7 7
        T3
    11 11
        T4
    17 17
    N lymph nodes
    Units: Subjects
        N0
    14 14
        N1
    9 9
        N2
    2 2
        N3
    11 11
    B peripheral blood
    Units: Subjects
        B0
    18 18
        B1
    17 17
        Missing
    1 1
    M visceral organ involvement
    Units: Subjects
        M0
    36 36
        M1
    0 0
    Lymphadenopathy
    Units: Subjects
        No
    12 12
        Yes
    24 24
    Erythrodermic
    Units: Subjects
        No
    19 19
        Yes
    17 17
    Pruritus
    0-10 continuous scale
    Units: unit(s)
        median (full range (min-max))
    7.5 (0 to 10) -
    mSWAT score
    Modified Severity Weighted Assessment Tool (mSWAT) for Mycosis Fungoides and Sezary Syndrome
    Units: unit(s)
        median (full range (min-max))
    103 (13 to 203) -

    End points

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    End points reporting groups
    Reporting group title
    GemBex
    Reporting group description
    Four cycles of Gemcitabine 1000 mg/m2 (at days 1 and 8 of 21 day cycles) Bexarotene 300 mg/m2 daily concurrently At 12 weeks responding patients maintained on Bexarotene 300 mg/m2 until disease progression or until the drug could no longer be tolerated NB: One patient was registered but found to be ineligible and did not commence trial treatment.

    Primary: Objective Response Rate

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    End point title
    Objective Response Rate [1]
    End point description
    Objective Primary Disease Response Evaluation Criteria (OPDREC) combines the disease response observed in skin, lymph nodes, viscera and blood to a global disease response category. To be defined as CCR, CR or PR, the response must be confirmed with a repeat assessment at least 1 month after the initial assessment.
    End point type
    Primary
    End point timeframe
    The rate of objective response was assessed at 24 weeks, defined as the proportion of patients with confirmed CR, clinical complete response (CCR) or PR, as determined by OPDREC.
    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: Justification: As advised on 23/06/16 by Chersoni Raffaella from the EMA service desk, we can post the result without specifying details of the statistical analyses done because the system currently cannot accommodate one arm studies.
    End point values
    GemBex
    Number of subjects analysed
    35 [2]
    Units: Patients
        Confirmed Complete Response (CR)
    0
        Clinical Complete Response (CCR)
    0
        Partial Response (PR)
    5
        Stable Disease (SD)
    8
        Progressive Disease (PD)
    19
        Not Evaluable (NE)
    3
    Notes
    [2] - All subjects were analysed with only 5 subjects reaching the end point definition
    No statistical analyses for this end point

    Secondary: Reduction change from baseline in mSWAT score

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    End point title
    Reduction change from baseline in mSWAT score
    End point description
    Within 2 weeks of starting treatment, during the initial 12-week combination and subsequently at weeks 13, 17, and 24, and every 8 weeks thereafter, patients underwent various assessments including disease assessment using the modified Severity-Weighted Assessment Tool (mSWAT) score that represents the product of the percentage Total Body Surface Area (%TBSA) involvement of each lesion type multiplied by a weighting factor. The Change from baseline in mSWAT score is defined as the difference in mSWAT score at the assessment time point and the score at baseline. A reduction in mSWAT at week 12 was observed in this group of patients. the data shows the number of patients with reduced mSWAT scores.
    End point type
    Secondary
    End point timeframe
    The modified Severity-Weighted Assessment Tool (mSWAT) scores used for this end point are those assessed at baseline and at week 12, end of combination treatment
    End point values
    GemBex
    Number of subjects analysed
    35
    Units: Patients
    28
    No statistical analyses for this end point

    Secondary: Median Progression Free Survival

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    End point title
    Median Progression Free Survival
    End point description
    Out of the 35 patients that were analysed, 30 had either died (n=15) or were alive with progression (n=15)
    End point type
    Secondary
    End point timeframe
    Progression free survival (PFS) defined as the time from the first date of treatment to the date of first progression or death due to any cause, whichever one comes first.
    End point values
    GemBex
    Number of subjects analysed
    35
    Units: months
        median (full range (min-max))
    5.3 (0 to 21)
    No statistical analyses for this end point

    Secondary: Median Overall Survival

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    End point title
    Median Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall Survival (OS) defined as the time from the first date of treatment to the date of death due to any cause.
    End point values
    GemBex
    Number of subjects analysed
    35
    Units: months
        median (full range (min-max))
    21.2 (0 to 35)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred between informed consent and 28 days post last trial treatment administration had to be reported
    Adverse event reporting additional description
    Trial subjects were assessed for adverse events prior the start of each treatment cycle. All adverse events (AEs) were recorded in the patient notes and the trial CRFs. Those meeting the definition of SAEs were also reported using the trial specific SAE Reporting template.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI - CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    GemBex
    Reporting group description
    Four cycles of Gemcitabine 1000 mg/m2 (at days 1 and 8 of 21 day cycles) Bexarotene 300 mg/m2 daily concurrently At 12 weeks responding patients maintained on Bexarotene 300 mg/m2 until disease progression or until the drug could no longer be tolerated NB: One patient was registered but found to be ineligible and did not commence trial treatment.

    Serious adverse events
    GemBex
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 35 (37.14%)
         number of deaths (all causes)
    15
         number of deaths resulting from adverse events
    2
    Investigations
    Creatinine Increased
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Confusion
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Obstruction, GI
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Obstruction, Small bowel NOS
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 1
    Lung infection
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    GemBex
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 35 (100.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 35 (60.00%)
         occurrences all number
    21
    Pyrexia
         subjects affected / exposed
    8 / 35 (22.86%)
         occurrences all number
    8
    Chills
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    4
    Pain
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    6
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    4
    White blood cell count decreased
         subjects affected / exposed
    18 / 35 (51.43%)
         occurrences all number
    18
    Neutrophil count decreased
         subjects affected / exposed
    23 / 35 (65.71%)
         occurrences all number
    23
    weight loss
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Cardiac disorders
    cardiac disorders other, cardiac
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 35 (74.29%)
         occurrences all number
    26
    Oedema
         subjects affected / exposed
    9 / 35 (25.71%)
         occurrences all number
    9
    Platelet count decreased
         subjects affected / exposed
    8 / 35 (22.86%)
         occurrences all number
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    4
    Headache
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    6
    Diarrhoea
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    4
    Dry mouth
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    6
    Nausea
         subjects affected / exposed
    11 / 35 (31.43%)
         occurrences all number
    11
    Vomiting
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    21 / 35 (60.00%)
         occurrences all number
    21
    Alopecia
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    6
    Rash
         subjects affected / exposed
    7 / 35 (20.00%)
         occurrences all number
    7
    Pigmentation disorder
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Nail disorder
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Pain of skin
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Pain, other - aching muscles and joints
         subjects affected / exposed
    10 / 35 (28.57%)
         occurrences all number
    10
    Bone pain
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    21 / 35 (60.00%)
         occurrences all number
    21
    Metabolism and nutrition disorders
    Cholesterol, serum-High
         subjects affected / exposed
    21 / 35 (60.00%)
         occurrences all number
    21
    Hypertriglyceridaemia
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    4
    Infections and infestations
    Infection
         subjects affected / exposed
    9 / 35 (25.71%)
         occurrences all number
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2007
    The protocol was amended to use a more appropriate method of skin disease assessment known as the Severity Weighted Assessment Tool (SWAT). A Quality of Life Assessment was also added to the study as it is felt that Cutaneous T-Cell Lymphoma has a substantial impact on the quality of life of these patients due to the very nature of the disease.
    10 Aug 2007
    The address of where to send histology specimens was changed in the protocol. Changes were also made to the PIS, Consent form and an additional appendix (addition of skindex). The PIS was updated with additional information regarding patient anonymity when taking photographs of the disease and also included information on the use of photos for publication with consent, a statement was included asking for patient permission. Appendix 8 was been added to incorporate a QOL element to the study given the disease and the impact it's 'visability' can have on a patients physical and/or psychological wellbeing.
    20 Dec 2007
    Several changes were made to the protocol to assist site staff with various aspects of the study including: 1. The assessment of patients using the Severity-Weighted Assessment Tool (SWAT) - Appendix 14 provided sites with a guide to skin scoring patients using SWAT 2. The updated guidelines for the management of patients who experienced hyperlipidamia prior and during Bexarotene therapy was added to section 6.3 3. The Safety Reporting section of the protocol was amended to provide sites with comprehensive information regarding the current regulatory requirements that were in place and how adverse events should have been assessed and reported. Two additional appendices were also added which detailed the expected adverse events that arose from treatment with Gemcitabine and Bexarotene. This information was compiled from the Summary of Product Characteristics available for both drugs. Information on Pregnancy was also added.
    03 Dec 2008
    Patient diary cards were introduced allowing clinicians give written instructions to the patient about the dose of bexarotene that they should take each day, and also to allow patients to record whether the full dose was taken each day.
    21 Jul 2009
    Following the start of the trial, Bexarotene had become more widely used in standard clinical practise, including prolonged maintenance, therefore it was decided to bring the trial in line with standard clinical practice in terms of the duration of maintenance, and also in allowing patients previously treated with single agent Bexarotene to be entered into the trial. Various other practical issues arising from the first year of recruitment into the trial were also addressed. o Bexarotene maintenance no longer stopped at week 20, but continued until the patient either had disease progression, or could no longer tolerate bexarotene o Bone marrow aspirates /trephines and baseline chest x-ray were no longer required for the purposes of the trial o CT scan was only required at end of chemo and maintenance if patient had an abnormal CT scan at baseline o Photography requirements significantly reduced to baseline, end of combination chemo, week 24 and disease progression o Rules governing concomitant use of steroids changed so patients on a stable, low dose of steroids were allowed to enter the trial
    23 Jun 2010
    An audit of the patient information sheet (PIS) showed that contraception guidelines given to patients in the PIS was not accurate thus leading to an Urgent Safety Measure being taken. The Patient information sheet was updated advising patients to use adequate contraception during the duration of the study and for at least 6 months after stopping trial treatment (as suggested in the SmPC for Gemcitabine, which is one of the trial drugs for the study). A paragraph justifying the need of using contraception and listing examples of reliable forms of contraception was also added. The PIS was further modified to emphasise that the study doctor should be notified also in cases where a male trial patient’s partner became pregnant.
    02 Feb 2011
    The Bexarotene labels were amended to comply with Annexe 13 and labelling exemption for Gemcitabine was proposed as it was provided from hospital stock. The sponsor believed it fell under the remit of Regulation 46(2) of the Medicines for Human Use (Clinical Trials) Regulations

    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.
    Non serious AEs: 'occurrences all number' cannot be given as only highest grade experienced by patients were collected on CRFs; Subjects affected number is entered instead. Serious and non-serious AEs are listed under non-serious adverse events

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24136145
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