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    Clinical Trial Results:
    A Pilot study of Response to Velcade combination chemotherapy in AL amyloidosis (REVEAL)

    Summary
    EudraCT number
    2009-014906-33
    Trial protocol
    GB  
    Global end of trial date
    18 Dec 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Apr 2017
    First version publication date
    09 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL/08/0254
    Additional study identifiers
    ISRCTN number
    ISRCTN33283585
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    REVEAL Trial Coordinator, CR UK & UCL Cancer Trials Centre , ctc.sponsor@ucl.ac.uk
    Scientific contact
    REVEAL Trial Coordinator, CR UK & 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
    21 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy, safety and tolerability of two bortezomib-based combination chemotherapy regimens: VD (bortezomib [Velcade], and dexamethasone) and CVD (cyclophosphamide, bortezomib [Velcade] and dexamethasone) in a randomized parallel phase II design in patients with AL amyloidosis who have Mayo stage II or III disease.
    Protection of trial subjects
    Due to the potential effect of the trial treatment on pregnancy and lactation, and effect of doxorubicin on exposed sperm, the trial subjects had consented to use a reliable and acceptable form of contraception during the trial and for at least 6 months after the last trial treatment. All women of childbearing potential at risk of becoming pregnant had to undergo pregnancy tests during baseline investigations and prior to start of each cycle. Since the trial population were patients with cardiac amyloidosis, a 24 hour Holter monitor was used to monitor heart rate and rhythm. Trial subjects who experienced related non-haematological toxicity had their next dose of the drug withheld or delayed start of next cycle, those who experienced grade 4 neutropenia or febrile neutropenia were considered for G-CSF. The trial treatment were to be discontinued if already withheld and the AE did not resolve as expected. For adverse events attributable to Bortezomib, other than peripheral neuropathy, re-start of the treatment was to be at a reduced dose after resolution. The trial also incorporated several dose adjustments for renal and hepatic insufficiency. Since fluid retention is a common side effect of Dexamethasone in patients with amyloidosis, optimisation and close monitoring of fluid balance or dose adjustment of the drug was advised. Trial subjects who experienced generalised oedema, greater than grade 3 local reactions or painful local reactions were allowed intravenous administration of bortezomib until resolution of the reaction. Trial subjects had regular clinic visits during and after treatment where they were assessed for toxicity and monitored for adverse events. If these occurred out of clinic hours, all trial subjects were given patient cards with contact details of the local haematology team that they could access at any time for advice. All trial subjects received prophylaxis during treatment and until a specified time after as applicable.
    Background therapy
    - Oral acyclovir 200 mg three times daily with dose modified according to renal function or appropriate alternative. - Oral Lansoprazole 15 mg once daily or Omeprazole 20mg once daily or appropriate alternative - Oral Fluconazole 50mg once daily (unless contraindicated due to abnormal liver function tests or allergy) - Oral Co-trimoxazole 480 mg twice daily given three times weekly (unless contraindicated).
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Jul 2007
    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: 7
    Worldwide total number of subjects
    7
    EEA total number of subjects
    7
    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)
    5
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The 7 trial subjects were recruited between 15/03/2012 - 26/07/2013 from 2 Trial Sites.

    Pre-assignment
    Screening details
    Patients aged at least 18 years presenting with systemic AL amyloidosis with measurable clonal disease and of Mayo stage II or III were screened for eligibility at the Trial site. The participating investigators kept screening logs of all patients screened for eligibility who were not registered in the trial due to ineligibility.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    PAD Regimen
    Arm description
    Bortezomib, Doxorubicin & Dexamethasone
    Arm type
    Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    L01XX32
    Other name
    Velcade
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Initially, bortezomib was given twice weekly in combination with Doxorubicin and Dexamethasone (PAD) at a dose of 1mg/m^2 intravenously on days 1, 4, 8 and 11 of each 21-day cycle for a minimum of 3 cycles to a maximum of 6 cycles. This was given with doxorubicin at 18mg/m^2 i.v. on days 1 & 8 and dexamethasone at 20mg PO on days 1, 4, 8 and 11. Following a protocol amendment, route of administration for bortezomib was changed to subcutaneous and day 8 of doxorubicin removed from the schedule.

    Arm title
    VD Regimen
    Arm description
    Bortezomib with Dexamethasone
    Arm type
    Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    L01XX32
    Other name
    Velcade
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    After a review of the safety data by the IDMC, the trial protocol was amended to remove doxorubicin from the combination regimen. Patients from this point onward were treated on bortezomib and dexamethasone. Dosage and administration of bortezomib was changed to from twice weekly to weekly in combination with Dexamethasone only (VD) at a dose of 1.3mg/m^2 s.c. on days 1, 8, 15 and 22 of each 35-day cycle for a minimum of 3 cycles to a maximum of 6 cycles. Dexamethasone was given 20mg PO on days 1, 8, 15 and 22

    Arm title
    CVD Regimen
    Arm description
    Cyclophosphamide, Bortezomib and Dexamethasone
    Arm type
    Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    L01XX32
    Other name
    Velcade
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Initially, bortezomib was given twice weekly with the combination of cyclophosphamide and dexamethasone (CVD) at a dose of 1mg/m^2 on days 1, 4, 8, 11 and 15 of each 21-day cycle for a minimum of 3 cycles to a maximum of 6 cycles. After a protocol amendment, dosage and administration was changed to weekly in at a dose of 1.3mg/m^2 on days 1, 8, 15 and 22 of each 35-day cycle for a minimum of 3 cycles to a maximum of 6 cycles. Cyclophosphamide was given 350mg/m^2 (max 500mg) PO on days 1 and 15 Dexamethasone 20mg PO on days 1 - 4

    Number of subjects in period 1
    PAD Regimen VD Regimen CVD Regimen
    Started
    3
    1
    3
    Completed
    2
    1
    1
    Not completed
    1
    0
    2
         Adverse event, serious fatal
    1
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PAD Regimen
    Reporting group description
    Bortezomib, Doxorubicin & Dexamethasone

    Reporting group title
    VD Regimen
    Reporting group description
    Bortezomib with Dexamethasone

    Reporting group title
    CVD Regimen
    Reporting group description
    Cyclophosphamide, Bortezomib and Dexamethasone

    Reporting group values
    PAD Regimen VD Regimen CVD Regimen Total
    Number of subjects
    3 1 3 7
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    2 0 3 5
        From 65-84 years
    1 1 0 2
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    57 (57 to 65) 68 (68 to 68) 48 (35 to 59) -
    Gender categorical
    Units: Subjects
        Female
    1 0 1 2
        Male
    2 1 2 5
    ECOG performance status
    Grade 0 - Fully Active - Able to carry out all normal activity without restriction Grade 1 - Work Able - Restricted in physically strenuous activity; ambulatory, can do light work Grade 2 - Not Work Able - Ambulatory and capable of all self-care but unable to carry out any work; up and about more than 50% of waking hours Grade 3 - Limited Self Care - Capable of only limited self-care; confined to bed or chair for more than 50% of waking hours Grade 4 - Disabled - Completely disabled; cannot carry out any self-care; totally confined to bed or chair
    Units: Subjects
        Fully Active
    1 0 0 1
        Work Able
    2 1 1 4
        Not Work Able
    0 0 1 1
        Limited Self Care
    0 0 1 1
        Disabled
    0 0 0 0
    NYHA Class
    NYHA Heart Failure Class I - Patients with no limitation of activities; they suffer no symptoms from ordinary activities. II - Patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion. III - Patients with marked limitation of activity; they are comfortable only at rest. IV - Patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest.
    Units: Subjects
        Class I
    2 0 0 2
        Class II
    1 1 2 4
        Class III
    0 0 1 1
        Class IV
    0 0 0 0
    Mayo Stage
    Stage I: Both NT-proBNP and cardiac troponin-T normal defined as NT-proBNP ≤36 pMol/L and cardiac troponin T ≤0.03 ng/ml (or cardiac high sensitivity troponin T ≤ 0.05 μg/L) Stage II: Either one of NT-proBNP or cardiac troponin T abnormal defined as: NT-proBNP>36 pMol/L or cardiac troponin T >0.03 ng/ml (or cardiac high sensitivity troponin T >0.05 μg/L) Stage III: Both NT-proBNP and cardiac troponin T abnormal defined as: NT-proBNP >36 pMol/L and cardiac troponin T >0.03 ng/ml (or cardiac high sensitivity troponin T >0.05 μg/L) As published by Dispenzieri et al 2004.
    Units: Subjects
        Stage I
    0 0 0 0
        Stage II
    2 1 0 3
        Stage III
    1 0 3 4
    Organ Involvement Site
    Amyloid-related organ site
    Units: Subjects
        Heart
    1 0 1 2
        Heart & Kidney
    1 0 2 3
        Heart & Other Organs
    1 0 0 1
        Kidney
    0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    PAD Regimen
    Reporting group description
    Bortezomib, Doxorubicin & Dexamethasone

    Reporting group title
    VD Regimen
    Reporting group description
    Bortezomib with Dexamethasone

    Reporting group title
    CVD Regimen
    Reporting group description
    Cyclophosphamide, Bortezomib and Dexamethasone

    Primary: Clonal response of the underlying plasma cell dyscrasia

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    End point title
    Clonal response of the underlying plasma cell dyscrasia [1]
    End point description
    No statistical analyses was done due to small number of Trial subjects
    End point type
    Primary
    End point timeframe
    Response was assessed at the end of 3 cycles of chemotherapy
    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 trial was prematurely terminated, thus a small number of trial subjects was recruited. No statistical analysis for the primary endpoint could be done due to the sample size.
    End point values
    PAD Regimen VD Regimen CVD Regimen
    Number of subjects analysed
    3
    1
    3
    Units: Trial Subjects
    1
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Trial subjects alive at 12 months

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    End point title
    Number of Trial subjects alive at 12 months
    End point description
    Note: No statistical analyses have been specified for the endpoint. Due to premature closure of trial, only a few trial subjects were recruited, therefore formal statistical analyses could not be carried out
    End point type
    Secondary
    End point timeframe
    From date of first randomisation to 12 months post first randomisation
    End point values
    PAD Regimen VD Regimen CVD Regimen
    Number of subjects analysed
    3
    1
    3
    Units: percentage
    1
    1
    1
    Attachments
    Overall Survival
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (including serious) that occurred between informed consent and 30 days post last trial treatment administration (or after this date if thought to be related to the trial treatment)
    Adverse event reporting additional description
    Trial subjects were assessed for adverse events prior the start of each treatment cycle. All adverse events were recorded in the patient notes and the trial CRFs. Those meeting the definition of a Serious Adverse Event 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
    4.03
    Reporting groups
    Reporting group title
    PAD Regimen
    Reporting group description
    Bortezomib, Doxorubicin & Dexamethasone

    Reporting group title
    VD Regimen
    Reporting group description
    Bortezomib with Dexamethasone

    Reporting group title
    CVD Regimen
    Reporting group description
    Cyclophosphamide, Bortezomib and Dexamethasone

    Serious adverse events
    PAD Regimen VD Regimen CVD Regimen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 1 (100.00%)
    3 / 3 (100.00%)
         number of deaths (all causes)
    2
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 1 (0.00%)
    2 / 3 (66.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delusion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    PAD Regimen VD Regimen CVD Regimen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 1 (100.00%)
    1 / 3 (33.33%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Lethargy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Localised oedema
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    1
    Haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Oral dysaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Other - Cramps in ankle and leg
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Other - leg Cramp
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Other - Night cramps
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Other - spasm in left hand
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    infection with normal ANC
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2011
    • The eligibility criteria was changed to include untreated Mayo Stage II and III patients with AL amyloidosis instead of pre-treated relapsed or refractory patients. • IV administration of bortezomib was replaced by subcutaneous administration as main route of administration. IV administration was allowed if a patient had conditions which in the investigator’s assessment would contraindicate use of bortezomib subcutaneously.
    01 Jun 2012
    An urgent safety measure was implemented on 01/06/2012, recruitment was suspended with immediate effect. A higher than expected rate of sudden cardiac deaths among the first few patients entered into the trial was seen had been reported thus requiring a necessary review of the safety data by the Independent Data Monitoring Committee before further patients could be recruited. Sites were informed that they were not to approach further patients about participating in the trial until further notice.
    29 Oct 2012
    A substantial amendment was submitted for approval for the re-start of the trial following the Urgent Safety Measure and also to implement changes made to the trial schedule and relevant trial documentation. • Removal of doxorubicin from the PAD regimen • Increase of cycle days from 21 to 35 •Bortezomib dosage changed from twice weekly to weekly dose.
    24 Jan 2013
    This substantial amendment was sent to the REC only. Change of Principal Investigator: - Dr Stephen Hawkins has replaced Dr Patrick Chu at Royal Liverpool University Hospitals NHS Trust Addition of Research Site: Central Manchester University Hospitals NHS FT, Manchester Royal Infirmary; Principal Investigator: Dr Simon Gibbs
    08 Apr 2013
    This substantial amendment was sent to the REC only. The Patient Information Sheet and GP Letter were updated to correct the information given regarding the number of visits to be made by the trial subjects to the National Amyloidosis Centre.
    29 Oct 2014
    This substantial amendment was sent to the REC only. The premature closure of 2 sites was requested, as they had notified us they would no longer be able to take part in the clinical trial.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Jun 2012
    An urgent safety measure was implemented on 01/06/2012, recruitment was suspended with immediate effect. A higher than expected rate of sudden cardiac deaths among the first few patients entered into the trial was seen had been reported thus requiring a necessary review of the safety data by the Independent Data Monitoring Committee before further patients could be recruited. Sites were informed that they were not to approach further patients about participating in the trial until further notice.
    15 Feb 2013

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    - Serious and non-serious AEs are listed under non-serious AEs - Non-serious AEs: 'occurrences all number' can't be provided as only highest grade experienced by patients are collected on CRFs; subjects affected number is entered instead.
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