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    Clinical Trial Results:
    Phase II study of Bortezomib, Adriamycin and Dexamethasone (PAD) therapy for previously untreated patients with multiple myeloma: Impact of minimal residual disease (MRD) in patients with deferred ASCT (PADIMAC)

    Summary
    EudraCT number
    2010-021598-35
    Trial protocol
    GB  
    Global end of trial date
    13 Nov 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    03 May 2021
    First version publication date
    03 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL/08/0255
    Additional study identifiers
    ISRCTN number
    ISRCTN03381785
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Funder reference: LRF/10018, REC reference : 10/H0502/58
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    PADIMAC Trial Coordinator, Cancer Research UK & UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    Scientific contact
    PADIMAC Trial Coordinator, Cancer Research 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
    26 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    PADIMAC is a phase II study designed as a single arm study to evaluate the safety of a no treatment option for patients achieving CR/VGPR post induction therapy on the PAD regimen and not proceeding to ACST. The main objective of the study is to provide a reliable estimate of the 2-year progression-free survival (PFS) for patients who, having achieved CR/VGPR following PAD therapy (measured following peripheral blood stem cell harvest, PBSCH), do not receive any further treatment until clinical indication of relapse. This is addressed separately for patients who are minimal residual disease positive (MRD+), and those who are MRD negative (MRD-), at end of induction therapy.
    Protection of trial subjects
    Pregnancy testing prior to each treatment cycle was mandated for all women of child bearing potential, due to the unknown risk from bortezomib exposure to human embryo /foetus, crossing of dexamethasone through the placenta causing possible foetal development abnormalities and possible teratogenicity of doxorubicin. All patients had to consent to trial acceptable methods of contraception during the study and for six months post trial treatment. Due to the possible effect of doxorubicin on male fertility, for safety reasons, men wanting babies were advised on sperm cryopreservation prior to trial treatment. Patients who did not achieve at least a PR following trial treatment, immediately went on to receive salvage treatment. Patients who were assigned to no further treatment, following trial treatment and a negative MRD result, were offered off-trial ASCT on relapse. Cardiac function assessment was done at the end of trial treatment, due to possible cardiotoxicity from doxorubicin. Local supportive care protocols including antiemetic schedules, mesna, thromboprophylaxis (to prevent tumour lysis), transfusion support, mouthcare and prophylactic antimicrobial therapy were followed as required. Prior to each trial treatment dose, patients were evaluated for possible toxicities that might have occurred from the previous dose. For each of the trial drugs, dose modifications were put in place for specific haematological and non-haematological toxicities. Treatment delays were also allowed for toxicities that were not related to any of the trial drugs.
    Background therapy
    Patients who achieved at least a partial response (PR) following the trial treatment received PBSC Mobilisation before peripheral blood stem cell harvest (PBSCH): Cyclophosphamide, iv infusion in 500 ml NaCl 0.9%, 1.5-3 g/m^2 G-CSF, subcutaneous, 5-10 mcg/kg/day or 150 mcg/m^2/day Patients who achieved a partial response (PR) with adequate PBSCH, received high dose melphalan with autologous stem cell rescue (ASCT): NaCl 0.9% + 20 mmol KCl, 1 litre/hour Furosemide, 20 to 40 mg, IV stat Dexamethasone, 8 mg, IV stat Granisetron, 3 mg, IV stat Melphalan, 200 mg/m^2, short infusion (as per local protocol) in 100 ml NaCl 0.9% NaCl 0.9%, 1 litre over 2 hours + KCl 20 mmol to maintain urine output of at least 500 ml/hr NaCl 0.9% + KCl 1 litre four hourly x 1 NaCl 0.9% + KCl 1 litre six hourly x 3
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Apr 2011
    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: 153
    Worldwide total number of subjects
    153
    EEA total number of subjects
    0
    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)
    129
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    14 UK sites were opened to participate in the trial over a period of 2 years (09/03/2011 to 13/03/2013). Of these, only 13 recruited patients into the trial. A total of 153 patients were recruited over 2 years and 9 months (01/04/2011 - 14/01/2014), a planned increase from the initial 120 target.

    Pre-assignment
    Screening details
    Patients aged ≥18 years with previously untreated symptomatic myeloma were screened. They had to have measurable disease, suitable for high dose therapy and ASCT, adequate full blood count, renal, cardiac, pulmonary and hepatobiliary functions. Patients with ≥Gr2 peripheral neuropathy/neuropathic pain were excluded. Screening logs were maintained.

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

    Arms
    Arm title
    PAD Regimen
    Arm description
    Bortezomib (Velcade), Doxorubicin and Dexamethasone
    Arm type
    Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    L01XX32
    Other name
    Velcade
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    At the start of the trial, bortezomib was given twice weekly in combination with Doxorubicin and Dexamethasone (PAD) at a dose of 1.3mg/m^2 as a bolus IV injection on days 1, 4, 8 and 11 of each 21-day cycle for a minimum of 4 cycles to a maximum of 6 cycles. It was given with doxorubicin on days 1 & 4 and with dexamethasone on days 1 & 4 for every cycle and days 8 & 11 for the first cycle only. Dose was calculated on D1 of each cycle and same dose was administered through out the days of that cycle. If a notable change in weight occurred within a cycle, as determined by an unscheduled weight assessment, dose was to be recalculated at that time. Following protocol amendments, bortezomib administration was changed to subcutaneous (2011) and then to either subcutaneous or intravenous routes (2014) using the same schedule. The preferred route of administration was subcutaneous, but IV injection was allowed only if a patient experienced ≥Gr2 SC injection site reactions.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    9mg/m^2 /day as continuous IV infusion or by IV bolus injection, on days 1 - 4 of each 21 day cycle (minimum 4, maximum 6). Doxorubicin was given with bortezomib on days 1 & 4, and with dexamethasone on days 1 - 4. Dose was calculated on D1 of each cycle and same dose was administered through out the days of that cycle.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    A01AC02, C05AA09
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/day on days 1 - 4 of each 21 day cycle (minimum of 4 and a maximum of 6). For the first cycle only, it was also administered on days 8 - 11 and days 15 - 18. It was given, in every cycle, with doxorubicin on days 1 - 4 and with bortezomib on days 1 & 4 (and days 8 & 11 for the first cycle only).

    Number of subjects in period 1
    PAD Regimen
    Started
    153
    Completed
    139
    Not completed
    14
         Physician decision
    5
         Lack of efficacy
    4
         Adverse event, non-fatal
    4
         Patient decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main trial (overall period)
    Reporting group description
    -

    Reporting group values
    Main trial (overall period) Total
    Number of subjects
    153 153
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    129 129
        From 65-84 years
    24 24
        85 years and over
    0 0
    Age continuous
    Dates of birth were collected on the case report forms, and age calculated from date registered and birth dates.
    Units: years
        median (full range (min-max))
    55 (28 to 71) -
    Gender categorical
    Units: Subjects
        Female
    55 55
        Male
    98 98
    ECOG Performance Status
    0 - Fully active, able to carry on all pre-disease performance without restriction 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work 2 - Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4 - Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5 - Dead
    Units: Subjects
        Grade 0
    55 55
        Grade 1
    73 73
        Grade 2
    15 15
        Grade 3
    9 9
        Missing
    1 1
    International Staging System (ISS) for Multiple Myeloma
    I - Serum β2-microglogulin <3.5mg/L; serum albumin >3.5g/dL II - Serum β2-microglogulin <3.5mg/L but serum albumin < 3.5g/dL OR Serum β2-microglogulin 3.5 to < 5.5mg/L irrespective of serum albumin level III - Serum ß2-microglobulin 5.5 mg/L
    Units: Subjects
        Stage 1
    51 51
        Stage 2
    67 67
        Stage 3
    34 34
        Missing
    1 1
    Paraprotein Isotype
    Units: Subjects
        IgG
    111 111
        IgA
    26 26
        LC (Light Chain)
    16 16
    Cytogenetic Risk by FISH
    Units: Subjects
        Standard risk
    113 113
        Adverse risk
    20 20
        Missing
    20 20

    End points

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    End points reporting groups
    Reporting group title
    PAD Regimen
    Reporting group description
    Bortezomib (Velcade), Doxorubicin and Dexamethasone

    Primary: 2-year PFS by MRD status within the VGPR-W&W group

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    End point title
    2-year PFS by MRD status within the VGPR-W&W group [1]
    End point description
    2-year progression free survival (PFS) for patients post PBSCH, who receive no further treatment after achieving a major response to induction therapy with PAD.
    End point type
    Primary
    End point timeframe
    Time from date of PBSCH to date of the first progression/relapse or date of death from all causes whichever occurs first estimated at 2 years post-PBSCH.
    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: Primary analyses are descriptive, with simple estimates and 95% confidence intervals. Exploratory comparison by MRD status at day 100: Cox regression HR=0.74 (95% CI: 0.40-1.37, p=0.33)
    End point values
    PAD Regimen
    Number of subjects analysed
    50 [2]
    Units: percent
    number (confidence interval 95%)
        MRD -ve
    55.6 (30.5 to 74.8)
        MRD +ve
    31.3 (16.4 to 47.3)
    Notes
    [2] - Number here is the 2-year rate
    No statistical analyses for this end point

    Secondary: Overall Response (OR) to PAD induction therapy

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    End point title
    Overall Response (OR) to PAD induction therapy
    End point description
    Disease response was measured by serum and urinary paraprotein, with Complete Response (CR), Very Good partial Response (VGPR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) defined as per the International response criteria (Durie et al, 2006). Patients achieving CR and VGPR were categorised as the ≥VGPR group.
    End point type
    Secondary
    End point timeframe
    Time from start of PAD therapy until post PBSCH
    End point values
    PAD Regimen
    Number of subjects analysed
    153 [3]
    Units: Subjects
        <PR post PAD
    27
        ≥VGPR post PBSCH
    63
        PR post PBSCH
    44
        PD post PBSCH
    2
        ≥post-PAD no harvest
    17
    Notes
    [3] - 36/44 PR post-PBSCH had ASCT OR rate post induction = 82.4%(126/153) with 63(41.2%) achieving ≥VGPR
    No statistical analyses for this end point

    Secondary: MRD status post PBSCH

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    End point title
    MRD status post PBSCH
    End point description
    MRD was assessed by Multiparameter Flow Cytometry (MPF) of bone marrow samples from patients after PBSCH
    End point type
    Secondary
    End point timeframe
    MRD status was assessed post stem cell harvesting (PBSCH)
    End point values
    PAD Regimen
    Number of subjects analysed
    153 [4]
    Units: Subjects
        MRD +ve
    65
        MRD -ve
    22
        Missing
    66
    Notes
    [4] - MRD -ve (25.3%) MRD +ve (74.7%)
    No statistical analyses for this end point

    Secondary: MRD status at D100 post-ASCT for PR-ASCT group

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    End point title
    MRD status at D100 post-ASCT for PR-ASCT group
    End point description
    MRD was assessed by MPF of bone marrow samples from patients after stem cell harvesting, at 100 days post ASCT for PR patients
    End point type
    Secondary
    End point timeframe
    MRD assessed at 100 days post ASCT
    End point values
    PAD Regimen
    Number of subjects analysed
    36 [5]
    Units: Subjects
        MRD +ve
    20
        MRD -ve
    7
        Missing
    9
    Notes
    [5] - 20 (74.1%) and 7 (25.9%)
    No statistical analyses for this end point

    Secondary: MRD status at D100 post-PBSCH for VGPR-W&W group

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    End point title
    MRD status at D100 post-PBSCH for VGPR-W&W group
    End point description
    MRD was assessed by MPF of bone marrow samples from patients at 100 days post-PBSCH for ≥VGPR patients. These are the patients that received no further treatment until relapse (VGPR-W&W)
    End point type
    Secondary
    End point timeframe
    MRD assessment at 100 days post-PBSCH
    End point values
    PAD Regimen
    Number of subjects analysed
    63 [6]
    Units: Subjects
        MRD +ve
    32
        MRD -ve
    18
        Missing
    13
    Notes
    [6] - 32 (64.0%) and 18 (36.0%)
    No statistical analyses for this end point

    Secondary: PFS post-PBSCH for PR-ASCT group

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    End point title
    PFS post-PBSCH for PR-ASCT group
    End point description
    Progression free survival (PFS) of patients proceeding to ASCT (PR-ASCT), following PBSCH
    End point type
    Secondary
    End point timeframe
    Time from date of Peripheral Blood Stem Cell Harvest (PBSCH), following PAD therapy, to date of the first progression/relapse or date of death from all causes whichever occurs first
    End point values
    PAD Regimen
    Number of subjects analysed
    36
    Units: Months
    median (confidence interval 95%)
        PR-ASCT
    19.6 (17.0 to 22.8)
        2-year PFS
    33.3 (18.8 to 48.6)
    No statistical analyses for this end point

    Secondary: 2-year PFS2 rate post-PBSCH

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    End point title
    2-year PFS2 rate post-PBSCH
    End point description
    Patients were followed up from PBSCH until second disease relapse or death.
    End point type
    Secondary
    End point timeframe
    2 years from date of PBSCH to the second relapse or death
    End point values
    PAD Regimen
    Number of subjects analysed
    99 [7]
    Units: Percentage
    number (confidence interval 95%)
        VGPR-W&W
    77.3 (64.7 to 85.9)
        PR-ASCT
    97.2 (81.9 to 99.6)
    Notes
    [7] - This includes the PR-ASCT and VGPR-W&W groups. Number refers to the 2-year rate
    No statistical analyses for this end point

    Secondary: 2-year OS rate

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    End point title
    2-year OS rate
    End point description
    Overall survival (OS) rate was measured from date of PBSCH to death. The VGPR-W&W and PR-ASCT groups were combined and OS was calculated by MRD status at D100 post PBSCH
    End point type
    Secondary
    End point timeframe
    2 years from date of PBSCH to death event
    End point values
    PAD Regimen
    Number of subjects analysed
    99 [8]
    Units: percent
    number (confidence interval 95%)
        VGPR-W&W
    91.9 (81.6 to 96.5)
        PR-ASCT
    100 (90.3 to 100)
    Notes
    [8] - Number refers to the 2-year rate
    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 occur between first administration of trial treatment (PAD) and 30 days post last trial treatment (PAD) 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 (AEs) prior the start of each PAD cycle. All AEs were recorded in the patient notes and the trial CRFs. Those meeting the definition of Serious, excluding exempted events, were to be reported using the trial specific SAE Reporting template within 24 hours of observing or learning of the event.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI - CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    PAD therapy
    Reporting group description
    Bortezomib, doxorubicin and dexamethasone

    Serious adverse events
    PAD therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 153 (17.65%)
         number of deaths (all causes)
    43
         number of deaths resulting from adverse events
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Heart Failure
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hiccups
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Autonomic neuropathy
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Localised oedema
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 153 (0.65%)
         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 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Avascular necrosis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung Infection
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
    Additional description: Reported as pyrexia from chest infection
         subjects affected / exposed
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    PAD therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    153 / 153 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    9 / 153 (5.88%)
         occurrences all number
    9
    Thrombosis
    Additional description: Reported as Thromboembolic event
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    8
    General disorders and administration site conditions
    Localised oedema
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    10
    Pain
         subjects affected / exposed
    15 / 153 (9.80%)
         occurrences all number
    15
    Oedema
    Additional description: Reported as 'Oedema - limbs'
         subjects affected / exposed
    43 / 153 (28.10%)
         occurrences all number
    43
    Fatigue
         subjects affected / exposed
    112 / 153 (73.20%)
         occurrences all number
    112
    Pyrexia
    Additional description: Reported as 'Fever'
         subjects affected / exposed
    22 / 153 (14.38%)
         occurrences all number
    22
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    8
    Insomnia
         subjects affected / exposed
    44 / 153 (28.76%)
         occurrences all number
    44
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    53 / 153 (34.64%)
         occurrences all number
    53
    Platelet count decreased
         subjects affected / exposed
    35 / 153 (22.88%)
         occurrences all number
    35
    Alkaline phosphatase increased
         subjects affected / exposed
    12 / 153 (7.84%)
         occurrences all number
    12
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 153 (7.19%)
         occurrences all number
    11
    Lymphocyte count decreased
         subjects affected / exposed
    12 / 153 (7.84%)
         occurrences all number
    12
    White blood cell count decreased
         subjects affected / exposed
    12 / 153 (7.84%)
         occurrences all number
    12
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 153 (13.73%)
         occurrences all number
    21
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    56 / 153 (36.60%)
         occurrences all number
    56
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    12 / 153 (7.84%)
         occurrences all number
    12
    Cough
         subjects affected / exposed
    19 / 153 (12.42%)
         occurrences all number
    19
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    105 / 153 (68.63%)
         occurrences all number
    105
    Dysgeusia
         subjects affected / exposed
    14 / 153 (9.15%)
         occurrences all number
    14
    Headache
         subjects affected / exposed
    15 / 153 (9.80%)
         occurrences all number
    15
    Paresthesia
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    8
    Dizziness
         subjects affected / exposed
    36 / 153 (23.53%)
         occurrences all number
    36
    Peripheral motor neuropathy
    Additional description: Reported as 'Neuropathy ( motor)'
         subjects affected / exposed
    20 / 153 (13.07%)
         occurrences all number
    20
    Eye disorders
    blurred vision
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    8
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    40 / 153 (26.14%)
         occurrences all number
    40
    Abdominal pain
         subjects affected / exposed
    19 / 153 (12.42%)
         occurrences all number
    19
    Constipation
         subjects affected / exposed
    83 / 153 (54.25%)
         occurrences all number
    83
    Diarrhoea
         subjects affected / exposed
    51 / 153 (33.33%)
         occurrences all number
    51
    Nausea
         subjects affected / exposed
    67 / 153 (43.79%)
         occurrences all number
    67
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    8
    Alopecia
         subjects affected / exposed
    27 / 153 (17.65%)
         occurrences all number
    27
    Rash
         subjects affected / exposed
    40 / 153 (26.14%)
         occurrences all number
    40
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    53 / 153 (34.64%)
         occurrences all number
    53
    Bone pain
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    8
    Pain in extremity
    Additional description: Reported as pain in lower limbs
         subjects affected / exposed
    12 / 153 (7.84%)
         occurrences all number
    12
    Pain - hip
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    8
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    8
    Hyperglycaemia
         subjects affected / exposed
    8 / 153 (5.23%)
         occurrences all number
    8
    Hyponatraemia
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    10
    Anorexia and bulimia syndrome
    Additional description: Reported as 'Anorexia'
         subjects affected / exposed
    20 / 153 (13.07%)
         occurrences all number
    20
    Infections and infestations
    Infection
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    10
    infection and infestation - other
         subjects affected / exposed
    10 / 153 (6.54%)
         occurrences all number
    10
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 153 (18.30%)
         occurrences all number
    28

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2011
    Protocol was amended to allow the following: - IV administration of bortezomib was replaced with subcutaneous administration - IV bolus injection administration of doxorubicin, administration of doxorubicin over 4 days (total dose 36/mg/m2) - inclusion criterion for Creatinine Clearance was changed from ≥ 30mL/min to ≥ 20mL/min - Serum free light chain essay was made mandatory post PBSCH and 100 days post PBSCH/ASCT Patient Information Sheet (PIS) was updated to include: - information on changed routes of administration for bortezomib and doxorubicin - additional details on effective contraception
    29 Nov 2011
    Urgent Safety Measure - There was an precautionary recall of the supplied bortezomib, Velcade, following a 'Dear Investigator' letter from the supplier. Due to GMP compliance issues identified at Ben Venue Laboratories, BVL, Ohio, USA, one of the manufacturing facilities for Velcade, there was a recall of batches manufactured at this site. Some of the clinical trial subcutaneous (SC) Velcade stock for the trial were affected and immediate action had to be taken as it was detrimental for patients not to receive treatment. The urgent measure taken was to allow patients to be treated subcutaneously using IV labelled trial supply, once it was confirmed by the manufacturer (Janssen) that the IV and SC formulations were the same. A site, where IV labelled supply was not available, was given the go ahead following confirmation from Janssen to administer the SC labelled supply from the affected batch to their patients. All sites were to revert to using new batches of unaffected sc labelled trial supply once received. Increased monitoring of adverse events at sites was advised. The plan of actions to be taken were discussed with the REC and MHRA before implementation.
    30 Nov 2012
    Protocol amendment: changes were made to protocol v2 - IV administration of bortezomib was allowed as an alternative route - Inclusion criteria states inclusion of patients with ECOG PS of 0-3. Patients with an ECOG performance score of >3 when this score is due to disease processes such as spinal cord compression, and who would otherwise have a score of ≤3, were included in the trial - exclusion of patients with active HIV, hepatitis B or C infection Detailed information on toxicity assessment, sample collection and other relevant information, were also included. The PIS was updated to include detailed explanation on side effects of bortezomib for both SC and IV routes, and other relevant updates made to the protocol.
    29 Aug 2014
    Target accrual number was increased from 120 to 153 Protocol was amended as follows: - Additional assessments and samples at relapse - RSI for subcutaneous bortezomib was changed from the Investigator's Brochure to the SPC
    04 Dec 2014
    Protocol was amended as follows: - Update to the trial endpoints and outcome measures: PFS2 (time from start of salvage treatment to 2nd relapse) and OS (overall survival) were added as secondary endpoints - Update to the outcome measures and assessment of the measures for the trial - Update to the long term follow-up schedule for the trial due to the addition of OS as a secondary endpoint - Update to the End of Trial definition

    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' can't be provided as only highest grade experienced by patients are collected on CRFs; number of subjects affected has been entered.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/33715154
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