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    Clinical Trial Results:
    A Randomised Trial Evaluating the VEGF Inhibitor, Bevacizumab (Avastin), as Adjuvant Therapy following Resection of AJCC Stage IIB (T3bN0M0 & T4aN0M0), IIC (T4bN0M0) and III (TxN1-3M0) Cutaneous Melanoma

    Summary
    EudraCT number
    2006-005505-64
    Trial protocol
    GB  
    Global end of trial date
    31 Mar 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Apr 2023
    First version publication date
    08 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AVAST-M
    Additional study identifiers
    ISRCTN number
    ISRCTN81261306
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust
    Sponsor organisation address
    Hills Road, Cambridge, United Kingdom, CB2 0QQ
    Public contact
    Mrs Carrie Bayliss, Cambridge University Hospitals NHS Foundation Trust, Cambridge Clinical Trials Unit , +44 01223 348158, cuh.cctu@nhs.net
    Scientific contact
    Dr Pippa Corrie, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital , +44 01223 216083, philippa.corrie@nhs.net
    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
    15 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: To determine the overall survival of patients treated with bevacizumab, compared with standard observation after resection of high risk melanoma. Secondary Objectives: To compare the two arms of the study in terms of the following parameters: - Disease free interval - Distant metastasis-free interval - Safety and toxicity - Quality of life (QoL)
    Protection of trial subjects
    The study was approved by a Research Ethics Committee and received authorisation from the Medicine and Healthcare Product Regulatory Authority. Patients received verbal and written information prior to consenting to the trial, and had time to consider their participation and had an opportunity to ask questions. Consenting patients had a series of screening tests to ensure they were suitable for the study and it was safe to proceed. Only the participant's direct care team had access to their recruited participants personal/identifiable information during the trial. On registration to the trial the participants were allocated a unique trial identification number which was used on all data forms and samples sent to the Sponsor, alongside their date of birth and initials. Any participant related information shared by the Sponsor (e.g. for the purposes of analysing translational endpoints) was anonymised, with only reference to the participant's trial identification number being included. This allowed their personal data to remain anonymous.
    Background therapy
    N/A
    Evidence for comparator
    N/A
    Actual start date of recruitment
    04 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: 1343
    Worldwide total number of subjects
    1343
    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)
    1014
    From 65 to 84 years
    324
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    The AVAST-M trial planned to recruit 1320 patients (660 patients in each arm), with minimum 5 years follow up. Long term follow-up data for survival and disease recurrence would be collected up to 10 years where possible, or until death. Recruitment commenced on 04/07/2017 and closed on 31/03/2012. In total 1343 patients were randomised.

    Pre-assignment
    Screening details
    A total of 3394 patients were assessed for eligibility, 694 patients did not give informed consent. 1343 patients were sucessfully screened for eligibility and randomised. Target recruitment of 1320 patients was reached on 23/02/2012. Recruitment remained open to enable those who had already signed consent to enter the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment
    Arm description
    The treatment period continued for up to a total of 17 bevacizumab treatments or 1 calendar year, which ever occured sooner, or until recurrence of disease, or patient/clinician withdrawal for any other reason. After completion of the treatment period patients were followed-up every 3 months until 2 years, then 6 monthly until 5 years and then annually until up to 10 years from randomisation (where possible). If patients were withdrawn early from bevacizumab treatment (for reasons other than first distant recurrence) they, where possible, continued to have the scheduled study visits and investigations until first distant recurrence. In the event of first distant recurrence, follow up as per above schedule ceased and patients were monitored and managed as indicated locally. Annual follow up (survival and disease recurrence) continued until 10 years from randomisation (where possible), death, loss to follow up or withdrawal of consent.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    L01FG01
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab (Avastin) was administered by intravenous (i.v.) infusion in accordance with the instructions in the Summary of Product Characteristics, at a dose of 7.5mg/kg on day 1 of the study treatment period. Bevacizumab treatment did not commence within 28 days of major surgery and until all the surgical wounds had fully healed. Bevacizumab infusions were administered every 3 weeks (+/- 7 calendar days of the scheduled treatment day). Treatment was given for 1 calendar year (max 17 infusions over 1 year) or until disease recurred. Dose was based on actual weight at baseline visit, unless more than 10% body wieght change from baseline occurred. In this case dosage was recalculated. It was also acceptable to recalculate the bevacizumab dose every cycle using patients’ actual weight. Rounding of the dose was optional and if the investigator decided to round the dose it could only be rounded to the nearest ml. The recommended infusion duration was 30 (+/- 10) minutes.

    Arm title
    Observation
    Arm description
    Patients received no interventions on this arm. Patients were followed-up at 6 weeks, 3 months, then every 3 months until 2 years, then 6 monthly until 5 years and then annually until up to 10 years from randomisation (where possible). In the event of first distant recurrence or withdrawal from study, follow up as per above schedule ceased and patients were monitored and managed as indicated locally. Annual follow up (survival and disease recurrence) continued until 10 years from randomisation (where possible), death, loss to follow up or withdrawal of consent.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Treatment Observation
    Started
    671
    672
    Completed
    588
    600
    Not completed
    83
    72
         Consent withdrawn by subject
    12
    7
         Lost to follow-up
    71
    65

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    The treatment period continued for up to a total of 17 bevacizumab treatments or 1 calendar year, which ever occured sooner, or until recurrence of disease, or patient/clinician withdrawal for any other reason. After completion of the treatment period patients were followed-up every 3 months until 2 years, then 6 monthly until 5 years and then annually until up to 10 years from randomisation (where possible). If patients were withdrawn early from bevacizumab treatment (for reasons other than first distant recurrence) they, where possible, continued to have the scheduled study visits and investigations until first distant recurrence. In the event of first distant recurrence, follow up as per above schedule ceased and patients were monitored and managed as indicated locally. Annual follow up (survival and disease recurrence) continued until 10 years from randomisation (where possible), death, loss to follow up or withdrawal of consent.

    Reporting group title
    Observation
    Reporting group description
    Patients received no interventions on this arm. Patients were followed-up at 6 weeks, 3 months, then every 3 months until 2 years, then 6 monthly until 5 years and then annually until up to 10 years from randomisation (where possible). In the event of first distant recurrence or withdrawal from study, follow up as per above schedule ceased and patients were monitored and managed as indicated locally. Annual follow up (survival and disease recurrence) continued until 10 years from randomisation (where possible), death, loss to follow up or withdrawal of consent.

    Reporting group values
    Treatment Observation Total
    Number of subjects
    671 672 1343
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    513 501 1014
        From 65-84 years
    157 167 324
        85 years and over
    1 4 5
    Age continuous
    Units: years
        median (full range (min-max))
    56 (18 to 87) 55 (19 to 88) -
    Gender categorical
    Units: Subjects
        Female
    294 296 590
        Male
    377 376 753
    Breslow thickness of primary tumour
    Units: Subjects
        ≤2.0mm
    198 201 399
        >2.0mm - 4.0mm
    203 202 405
        >4.0mm
    221 217 438
        Unknown
    49 52 101
    Ulceration of primary tumour
    Units: Subjects
        Present
    262 256 518
        Absent
    310 323 633
        Unknown
    99 93 192
    N classification
    Units: Subjects
        N0
    169 160 329
        N1a
    100 96 196
        N1b
    119 119 238
        N2a
    41 39 80
        N2b
    65 67 132
        N2c
    61 68 129
        N3
    98 106 204
        NA
    18 17 35
    ECOG performance status
    Units: Subjects
        ECOG 0
    602 593 1195
        ECOG 1
    67 79 146
        Missing
    2 0 2
    Stage of melanoma
    Units: Subjects
        IIB
    103 106 209
        IIC
    84 71 155
        IIIA
    103 92 195
        IIIB
    240 255 495
        IIIC
    141 148 289
    Site of primary tumour
    Units: Subjects
        Head and Neck
    74 83 157
        Upper Limb
    112 97 209
        Lower Limb
    219 230 449
        Trunk
    233 228 461
        Unknown
    28 32 60
        Other
    5 2 7
    Regional lymph node involvement at any time
    Units: Subjects
        Yes - Detected by SLNB
    171 164 335
        Yes - Detected clinically
    249 264 513
        Yes - Unknown detection method
    0 1 1
        No
    222 214 436
        Not Assessed
    28 27 55
        Missing
    1 2 3
    Previous adjuvant treatment for melanoma
    Units: Subjects
        Yes- Radiotherapy
    9 14 23
        Yes - Chemotherapy
    0 1 1
        Yes - Hormonal therapy
    0 0 0
        Yes - Interferon
    3 2 5
        Yes - Vaccine
    1 3 4
        Yes - Other immunotherapy
    2 1 3
        No
    639 636 1275
        Missing
    17 13 30
        Yes - Radiotherapy and Chemotherapy
    0 1 1
        Yes - Radiotherapy and Other immunotherapy
    0 1 1
    BMI
    BMI at baseline was available for 662 subjects on the Treatment Arm and 641 subjects on the Observation Arm; Total n = 1303
    Units: kilogram(s)/square metre
        median (inter-quartile range (Q1-Q3))
    27.7 (24.6 to 31.2) 27.5 (24.7 to 30.6) -

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    The treatment period continued for up to a total of 17 bevacizumab treatments or 1 calendar year, which ever occured sooner, or until recurrence of disease, or patient/clinician withdrawal for any other reason. After completion of the treatment period patients were followed-up every 3 months until 2 years, then 6 monthly until 5 years and then annually until up to 10 years from randomisation (where possible). If patients were withdrawn early from bevacizumab treatment (for reasons other than first distant recurrence) they, where possible, continued to have the scheduled study visits and investigations until first distant recurrence. In the event of first distant recurrence, follow up as per above schedule ceased and patients were monitored and managed as indicated locally. Annual follow up (survival and disease recurrence) continued until 10 years from randomisation (where possible), death, loss to follow up or withdrawal of consent.

    Reporting group title
    Observation
    Reporting group description
    Patients received no interventions on this arm. Patients were followed-up at 6 weeks, 3 months, then every 3 months until 2 years, then 6 monthly until 5 years and then annually until up to 10 years from randomisation (where possible). In the event of first distant recurrence or withdrawal from study, follow up as per above schedule ceased and patients were monitored and managed as indicated locally. Annual follow up (survival and disease recurrence) continued until 10 years from randomisation (where possible), death, loss to follow up or withdrawal of consent.

    Primary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall survival time is the time between the date of randomisation and death, whatever the cause. Patients discontinuing the study, or lost to follow-up, and still alive were censored at the last known date alive.
    End point type
    Primary
    End point timeframe
    On study
    End point values
    Treatment Observation
    Number of subjects analysed
    671
    672
    Units: number of deaths
    280
    294
    Statistical analysis title
    Overall Survival
    Statistical analysis description
    A Cox proportional hazard model was used to compare overall survival across trial arms and obtain hazard ratios and associated 95% CIs.
    Comparison groups
    Treatment v Observation
    Number of subjects included in analysis
    1343
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.55
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.12

    Secondary: Disease free interval

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    End point title
    Disease free interval
    End point description
    Disease-free interval (DFI) is defined as the time between the date of randomisation and the date of tumour progression which occurs at any site of the body (inclusive of both distant and locoregional recurrence), or date of death due to melanoma, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    On study, until disease progression or death due to melanoma
    End point values
    Treatment Observation
    Number of subjects analysed
    671
    672
    Units: Events
    346
    386
    Statistical analysis title
    Disease free interval
    Statistical analysis description
    A Cox proportional hazard model was used to compare disease free interval across trial arms and obtain hazard ratios and associated 95% CIs.
    Comparison groups
    Observation v Treatment
    Number of subjects included in analysis
    1343
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    0.97

    Secondary: Distant metastasis-free interval

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    End point title
    Distant metastasis-free interval
    End point description
    Distant metastasis-free interval (DMFI) is defined as the time between the date of randomisation and the date of recurrent disease occurring at distant sites (excluding locoregional disease amenable to surgical resection), or date of death due to melanoma, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    On study until distant progression, or death due to melanoma
    End point values
    Treatment Observation
    Number of subjects analysed
    671
    672
    Units: Events
    301
    327
    Statistical analysis title
    Distant metastatic free interval
    Statistical analysis description
    A Cox proportional hazard model was used to compare distant metastatic free interval across trial arms and obtain hazard ratios and associated 95% CIs.
    Comparison groups
    Treatment v Observation
    Number of subjects included in analysis
    1343
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.04

    Secondary: Quality of life (QoL)

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    End point title
    Quality of life (QoL)
    End point description
    Global health scale assessed through the EORTC QLQC30 patient-completed questionnaire at time points: 3 monthly until 2 years, then at 2.5 years, 3 years, 4 years and 5 years
    End point type
    Secondary
    End point timeframe
    On Study until 5 years from randomisation
    End point values
    Treatment Observation
    Number of subjects analysed
    600
    626
    Units: Standardised area under a curve
        median (inter-quartile range (Q1-Q3))
    81.7 (69.8 to 90.7)
    81.9 (68.6 to 91.7)
    Statistical analysis title
    Global health scale
    Statistical analysis description
    The global heath scale of the EORTC-QLQ-C30 QoL questionnaire data were analysed by standardised area under the curve (AUC) and compared across trial arms using Wilcoxon rank sum tests
    Comparison groups
    Treatment v Observation
    Number of subjects included in analysis
    1226
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.52
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment arm: All adverse events which occurred from randomisation until 28 days after the final dose of study drug Observation arm: All adverse events which occurred from randomisation until year 1 or distant recurrence, whichever occurred first
    Adverse event reporting additional description
    The national cancer institute common terminology criteria for adverse events (CTCAE) version 3.0 were used in this study. All toxic events were graded according to NCI CTCAE V3.0.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Treatment
    Reporting group description
    -

    Reporting group title
    Observation
    Reporting group description
    -

    Serious adverse events
    Treatment Observation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    140 / 671 (20.86%)
    49 / 672 (7.29%)
         number of deaths (all causes)
    280
    294
         number of deaths resulting from adverse events
    8
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Secondary Malignancy
         subjects affected / exposed
    2 / 671 (0.30%)
    6 / 672 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    40 / 671 (5.96%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    44 / 49
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematoma
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal flow
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis/thrombus/embolism
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy of partner
         subjects affected / exposed
    2 / 671 (0.30%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    3 / 671 (0.45%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 671 (0.60%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fever
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (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
    7 / 671 (1.04%)
    3 / 672 (0.45%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rigors/chills
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 671 (0.15%)
    3 / 672 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sweating
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erectile dysfunction
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage vaginal
         subjects affected / exposed
    2 / 671 (0.30%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irregular menses
         subjects affected / exposed
    3 / 671 (0.45%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    3 / 671 (0.45%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest tightness
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Voice changes
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depression
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hemoglobin
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intraop Injury - Other (Specify)
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac General - Other (Specify)
         subjects affected / exposed
    4 / 671 (0.60%)
    2 / 672 (0.30%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac ischemia/infarction
         subjects affected / exposed
    4 / 671 (0.60%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac pain
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asystole
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular systolic dysfunction
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasovagal episode
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CNS hemorrhage
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CNS ischemia
         subjects affected / exposed
    3 / 671 (0.45%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    7 / 671 (1.04%)
    2 / 672 (0.30%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory neuropathy
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 671 (0.30%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Syncope (fainting)
         subjects affected / exposed
    2 / 671 (0.30%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ear and labyrinth disorders
    External ear pain
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoacusis
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blurred vision
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 671 (0.75%)
    2 / 672 (0.30%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    1 / 671 (0.15%)
    3 / 672 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal - Other (Specify, __)
         subjects affected / exposed
    1 / 671 (0.15%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage rectum
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal hemorrhage
         subjects affected / exposed
    2 / 671 (0.30%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis
         subjects affected / exposed
    2 / 671 (0.30%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 671 (0.30%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ruptured appendix
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 671 (0.30%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder pain
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage of liver
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Cirrhosis
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatology/Skin - Other (Specify, __)
         subjects affected / exposed
    1 / 671 (0.15%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 671 (0.30%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulceration
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 671 (0.30%)
    3 / 672 (0.45%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chest wall pain
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint pain
         subjects affected / exposed
    4 / 671 (0.60%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal/Soft Tissue - Other (Specify, __)
    Additional description: Granulomatous Erosion
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pain in extremity
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    8 / 671 (1.19%)
    7 / 672 (1.04%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection - Other
         subjects affected / exposed
    6 / 671 (0.89%)
    2 / 672 (0.30%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic infection
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    3 / 671 (0.45%)
    5 / 672 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    ALT
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AST
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GGT
         subjects affected / exposed
    3 / 671 (0.45%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypercalcemia
         subjects affected / exposed
    0 / 671 (0.00%)
    1 / 672 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphatemia
         subjects affected / exposed
    1 / 671 (0.15%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders Other (Specify, __)
    Additional description: Increased LDH
         subjects affected / exposed
    2 / 671 (0.30%)
    0 / 672 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment Observation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    624 / 671 (93.00%)
    414 / 672 (61.61%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    232 / 671 (34.58%)
    52 / 672 (7.74%)
         occurrences all number
    346
    57
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    39 / 671 (5.81%)
    15 / 672 (2.23%)
         occurrences all number
    45
    15
    Headache
         subjects affected / exposed
    162 / 671 (24.14%)
    30 / 672 (4.46%)
         occurrences all number
    262
    34
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    242 / 671 (36.07%)
    60 / 672 (8.93%)
         occurrences all number
    352
    61
    Pain
         subjects affected / exposed
    146 / 671 (21.76%)
    67 / 672 (9.97%)
         occurrences all number
    208
    77
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    43 / 671 (6.41%)
    18 / 672 (2.68%)
         occurrences all number
    45
    19
    Diarrhea
         subjects affected / exposed
    90 / 671 (13.41%)
    27 / 672 (4.02%)
         occurrences all number
    129
    30
    Nausea
         subjects affected / exposed
    100 / 671 (14.90%)
    22 / 672 (3.27%)
         occurrences all number
    141
    25
    Vomiting
         subjects affected / exposed
    47 / 671 (7.00%)
    7 / 672 (1.04%)
         occurrences all number
    59
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    54 / 671 (8.05%)
    28 / 672 (4.17%)
         occurrences all number
    60
    28
    Epistaxis
         subjects affected / exposed
    116 / 671 (17.29%)
    1 / 672 (0.15%)
         occurrences all number
    147
    1
    Voice changes
         subjects affected / exposed
    34 / 671 (5.07%)
    0 / 672 (0.00%)
         occurrences all number
    39
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    63 / 671 (9.39%)
    14 / 672 (2.08%)
         occurrences all number
    81
    14
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    56 / 671 (8.35%)
    28 / 672 (4.17%)
         occurrences all number
    60
    29
    Joint pain
         subjects affected / exposed
    50 / 671 (7.45%)
    16 / 672 (2.38%)
         occurrences all number
    64
    19
    Pain in extremity
         subjects affected / exposed
    41 / 671 (6.11%)
    36 / 672 (5.36%)
         occurrences all number
    46
    41

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2007
    -To include an appendix in the protocol for the treatment of hypertension -To make changes to the conduct of the trial, including inclusion and exclusion criteria -To add additional research bloods -To include a patient card -To update the protocol, patient information sheet and GP letter to reflect recently published information regarding use of bevacizumab in the treatment of melanoma and other cancers. -To update the protocol, patient information sheet and GP letter to reflect recently published information regarding use of interferon as adjuvant treatment of melanoma.
    10 Jul 2008
    - To include new patient groups (AJCC stage IIB (T3bNoMo)) - Lengthen time baseline CT/MRI scans and Chest X-ray need to be done prior to randomisation. - To clarify a number of points in the protocol especially regarding what happens to patients if they have recurrence. - To change the CI, to change the PI at some sites and to add new sites.
    13 Jul 2009
    Inclusion criteria: – Addition of 12 week timelimit from SLNB to CLND if these are the lastest surgeries for melanoma. – Addition that BP must be ≤ 150 systolic AND ≤ 100 diastolic mmHg. – Addition of the clause 'unless pre-existing abnormality' to the adequate liver function criterion. Exclusion criteria: – Deletion of 'even if previously treated' from evidence of CNS metastases criterion. – Deletion of the uncontrolled hypertension criterion, as BP values added to inclusion criteria. – Deletion of 'or participation in another clinical trial' from treatment with any other investigational agent criterion. – Changing treatment period from 51 weeks to 1 calendar year to make it easier to keep track of when the treatment period ends. – Inclusion of guidance on seromas. – Removal of dose capping for Avastin – Inclusion of a section on pregnancy reporting. – Adding into the study assessments, flowchart & schedule that contact needs to be made with patients for survival info annually from 5.5 yrs. – Other wording clarifications
    11 Mar 2011
    New sections have been added to reflect new safety information and study results. A number of points have been clarified to help with the conduct of the trial and several eligibility criteria have been amended. The PIS and ICF have been combined to make a single document. A number of grammatical changes & re-ordering of content have been made. Information has been added to reflect new study results and safety information. Addition of a sentence to say guidelines on the management of hypertension are available from the coordination team if required.
    03 Nov 2016
    Request to close the study to the MHRA for regulatory purposes in March 2017 to correspond with 5 year follow-up analysis. This amendment was declined by MHRA
    22 May 2017
    Update to reference safety information, addition of new undesirable effects
    28 Aug 2017
    As the 5 year final analysis has now been performed, patient clinic visits and trial interventions will cease following 5 years post randomisation. Survival and recurrence data only will continue to be collected until 10 years post randomisation up to 2022. Patients on the AVAST-M trial have consented to be followed up for up to 10 years after randomisation. This includes collecting survival and recurrence information. Once established, survival and recurrence data will be collected centrally until 2022 on an annual basis by remote data collection from the appropriate Government Department of Health national registry (i.e. Public Health England (National Cancer Registration and Analysis Service or Office for National Statistics). Long term follow-up data for survival and disease recurrence may be collected using NHS Spine by the local research team. Reference Safety Information identified for Investigational Medicinal Product in protocol as requested by the MHRA.
    28 Feb 2018
    Patients in Scotland and Wales (n=75) will not participate in remote data collection due to the financial aspects of applying to each different Government registry. All patients in the AVAST-M trial have already completed 5 years of follow-up after randomisation. The 5 year follow-up data has provided us with sufficient information to enable the main trial objectives for this stage in the trial to be answered. The 5 year analysis has now been performed and patient clinic visits and trial investigations have ceased (as per amendment 41). Survival and recurrence data only is being collected until up to 10 years post randomisation up to 2022 for patients in England only. Patients on the AVAST-M trial have consented to be followed up for up to 10 years after randomisation, therefore we will not be re-consenting patients to the trial as a result of this amendment A new Trial Participant letter for patients in Scotland and Wales which has been included as part of this substantial amendment outlining changes to follow-up arrangements for the AVAST-M trial for patients in Scotland and Wales.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24745696
    http://www.ncbi.nlm.nih.gov/pubmed/30010756
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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