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    Clinical Trial Results:
    A Phase III, Randomised, Double-blind, Multicentre Study to Compare the Efficacy, Safety, Pharmacokinetics and Immunogenicity between SB8 (proposed bevacizumab biosimilar) and Avastin® in Subjects with Metastatic or Recurrent Non-squamous Non-small Cell Lung Cancer

    Summary
    EudraCT number
    2015-004026-34
    Trial protocol
    DE   HU   PL   ES  
    Global end of trial date
    09 Aug 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Jan 2020
    First version publication date
    22 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SB8-G31-NSCLC
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Samsung Bioepis Co., Ltd.
    Sponsor organisation address
    107, Cheomdan-daero, Incheon, Korea, Republic of,
    Public contact
    Hye Jung Na, Samsung Bioepis Co., Ltd., +82 3180614224, nahjpost@samsung.com
    Scientific contact
    Hye Jung Na, Samsung Bioepis Co., Ltd., +82 3180614224, nahjpost@samsung.com
    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
    09 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the equivalence of SB8 to Avastin®, in terms of the best overall response rate (ORR) by 24 weeks of chemotherapy in subjects with metastatic or recurrent non squamous NSCLC.
    Protection of trial subjects
    The study and clinical study protocols were reviewed and approved by Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for each study centre. This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the latest International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP) and applicable local regulatory requirements and laws. The nature and purpose of the study was fully explained to each subject and written informed consent was obtained from each subject before the subject was entered into the study. The consent documents for the study were reviewed and approved by the appropriate IEC or IRB prior to use.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Jul 2016
    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
    Korea, Republic of: 29
    Country: Number of subjects enrolled
    Ukraine: 155
    Country: Number of subjects enrolled
    Russian Federation: 254
    Country: Number of subjects enrolled
    Belarus: 47
    Country: Number of subjects enrolled
    Georgia: 57
    Country: Number of subjects enrolled
    Serbia: 29
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    Thailand: 26
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Romania: 44
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Hungary: 51
    Worldwide total number of subjects
    763
    EEA total number of subjects
    155
    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)
    524
    From 65 to 84 years
    239
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants who meet the eligibility criteria were randomly assigned to one of the two treatments of this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SB8 (proposed bevacizumab biosimilar)
    Arm description
    Administered SB8 every 3 weeks until disease progression, unacceptable toxicity occurred, death, or EOS at a dose of 15 mg/kg body weight concurrently with chemotherapy (paclitaxel 200 mg/m^2 and carboplatin AUC 6 by IV infusion on Day 1 of every 3-week cycle) for at least 4 cycles and up to 6 cycles then received SB8 maintenance (mono-) therapy
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose regimen: 15 mg/kg every 3 weeks Mode of administration: Intravenous infusion

    Arm title
    EU Avastin
    Arm description
    Administered Avastin every 3 weeks until disease progression, unacceptable toxicity occurred, death, or EOS at a dose of 15 mg/kg body weight concurrently with chemotherapy (paclitaxel 200 mg/m^2 and carboplatin AUC 6 by IV infusion on Day 1 of every 3-week cycle) for at least 4 cycles and up to 6 cycles then received Avastin maintenance (mono-) therapy
    Arm type
    Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose regimen: 15 mg/kg every 3 weeks Mode of administration: Intravenous infusion

    Number of subjects in period 1
    SB8 (proposed bevacizumab biosimilar) EU Avastin
    Started
    379
    384
    Discontinued during induction treatment
    121
    107
    Completed induction treatment
    258
    277
    Discontinued during maintenance treatmen
    223
    239
    Was ongoing at the time of end of study
    35
    38
    Completed
    35
    38
    Not completed
    344
    346
         Progressive disease
    221
    225
         Death
    28
    35
         Other
    21
    18
         Non-compliance with study treatment
    5
    9
         Adverse event
    51
    35
         Consent withdrawn by subject
    18
    19
         Lost to follow-up
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SB8 (proposed bevacizumab biosimilar)
    Reporting group description
    Administered SB8 every 3 weeks until disease progression, unacceptable toxicity occurred, death, or EOS at a dose of 15 mg/kg body weight concurrently with chemotherapy (paclitaxel 200 mg/m^2 and carboplatin AUC 6 by IV infusion on Day 1 of every 3-week cycle) for at least 4 cycles and up to 6 cycles then received SB8 maintenance (mono-) therapy

    Reporting group title
    EU Avastin
    Reporting group description
    Administered Avastin every 3 weeks until disease progression, unacceptable toxicity occurred, death, or EOS at a dose of 15 mg/kg body weight concurrently with chemotherapy (paclitaxel 200 mg/m^2 and carboplatin AUC 6 by IV infusion on Day 1 of every 3-week cycle) for at least 4 cycles and up to 6 cycles then received Avastin maintenance (mono-) therapy

    Reporting group values
    SB8 (proposed bevacizumab biosimilar) EU Avastin Total
    Number of subjects
    379 384 763
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    255 269 524
        From 65-84 years
    124 115 239
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.2 ± 8.95 60.0 ± 9.18 -
    Gender categorical
    Units: Subjects
        Female
    127 128 255
        Male
    252 256 508

    End points

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    End points reporting groups
    Reporting group title
    SB8 (proposed bevacizumab biosimilar)
    Reporting group description
    Administered SB8 every 3 weeks until disease progression, unacceptable toxicity occurred, death, or EOS at a dose of 15 mg/kg body weight concurrently with chemotherapy (paclitaxel 200 mg/m^2 and carboplatin AUC 6 by IV infusion on Day 1 of every 3-week cycle) for at least 4 cycles and up to 6 cycles then received SB8 maintenance (mono-) therapy

    Reporting group title
    EU Avastin
    Reporting group description
    Administered Avastin every 3 weeks until disease progression, unacceptable toxicity occurred, death, or EOS at a dose of 15 mg/kg body weight concurrently with chemotherapy (paclitaxel 200 mg/m^2 and carboplatin AUC 6 by IV infusion on Day 1 of every 3-week cycle) for at least 4 cycles and up to 6 cycles then received Avastin maintenance (mono-) therapy

    Subject analysis set title
    Per-protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per-Protocol Set consisted of all FAS subjects who completed at least first 2 cycles of combination chemotherapy with a tumour assessment and did not have any major protocol deviations that impacted the primary efficacy assessment. Major protocol deviations that led to the exclusion from the PPS were pre-specified, and the PPS was determined prior to unblinding treatment codes.

    Primary: best ORR

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    End point title
    best ORR
    End point description
    The best ORR was defined as the proportion of subjects whose best overall response was either CR or PR according to RECIST v1.1 during the induction treatment period by 24 weeks. If a subject had either CR or PR at least once during induction treatment period by 24 weeks, the subject was considered as responder.
    End point type
    Primary
    End point timeframe
    The primary efficacy endpoint was the best ORR during induction treatment period by 24 weeks of chemotherapy.
    End point values
    SB8 (proposed bevacizumab biosimilar) EU Avastin Per-protocol Set
    Number of subjects analysed
    337
    328
    665
    Units: number
    169
    147
    316
    Statistical analysis title
    Equivalance test
    Comparison groups
    EU Avastin v SB8 (proposed bevacizumab biosimilar)
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    5.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    12.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reported from the time the ICF was signed until the EOT visit. After the EOT visit, only SAEs were reported. AEs which were accidently entered in the Electronic Data Capture (EDC) after the EOT visit, were not excluded in the analysis.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    SB8 (proposed bevacizumab biosimilar)
    Reporting group description
    Administered SB8 every 3 weeks until disease progression, unacceptable toxicity occurred, death, or EOS at a dose of 15 mg/kg body weight concurrently with chemotherapy (paclitaxel 200 mg/m^2 and carboplatin AUC 6 by IV infusion on Day 1 of every 3-week cycle) for at least 4 cycles and up to 6 cycles then received SB8 maintenance (mono-) therapy

    Reporting group title
    EU Avastin
    Reporting group description
    Administered Avastin every 3 weeks until disease progression, unacceptable toxicity occurred, death, or EOS at a dose of 15 mg/kg body weight concurrently with chemotherapy (paclitaxel 200 mg/m^2 and carboplatin AUC 6 by IV infusion on Day 1 of every 3-week cycle) for at least 4 cycles and up to 6 cycles then received Avastin maintenance (mono-) therapy

    Serious adverse events
    SB8 (proposed bevacizumab biosimilar) EU Avastin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    75 / 378 (19.84%)
    81 / 380 (21.32%)
         number of deaths (all causes)
    166
    171
         number of deaths resulting from adverse events
    22
    27
    Vascular disorders
    Shock haemorrhagic
         subjects affected / exposed
    3 / 378 (0.79%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 378 (0.53%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 378 (0.53%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Internal haemorrhage
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Drug hypersensitivity
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    4 / 378 (1.06%)
    6 / 380 (1.58%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 4
    0 / 6
    Infusion site extravasation
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 378 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural pneumothorax
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suture rupture
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 378 (1.06%)
    9 / 380 (2.37%)
         occurrences causally related to treatment / all
    1 / 4
    5 / 9
         deaths causally related to treatment / all
    0 / 2
    1 / 4
    Pneumothorax
         subjects affected / exposed
    3 / 378 (0.79%)
    3 / 380 (0.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    3 / 378 (0.79%)
    5 / 380 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    2 / 5
    Dyspnoea
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 378 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 378 (1.59%)
    4 / 380 (1.05%)
         occurrences causally related to treatment / all
    2 / 9
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 378 (0.53%)
    6 / 380 (1.58%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 378 (0.53%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 378 (0.53%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 378 (0.00%)
    3 / 380 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery occlusion
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 378 (0.26%)
    3 / 380 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Intercostal neuralgia
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachial plexopathy
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic atropy
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 378 (0.53%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric hypomotility
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 378 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis glandularis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    7 / 378 (1.85%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (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
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SB8 (proposed bevacizumab biosimilar) EU Avastin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    331 / 378 (87.57%)
    325 / 380 (85.53%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    49 / 378 (12.96%)
    39 / 380 (10.26%)
         occurrences all number
    65
    50
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    39 / 378 (10.32%)
    43 / 380 (11.32%)
         occurrences all number
    54
    59
    Weight decreased
         subjects affected / exposed
    37 / 378 (9.79%)
    28 / 380 (7.37%)
         occurrences all number
    37
    30
    Aspartate aminotransferase increased
         subjects affected / exposed
    32 / 378 (8.47%)
    27 / 380 (7.11%)
         occurrences all number
    51
    43
    Alanine aminotransferase increased
         subjects affected / exposed
    30 / 378 (7.94%)
    34 / 380 (8.95%)
         occurrences all number
    50
    48
    Blood urea increased
         subjects affected / exposed
    28 / 378 (7.41%)
    19 / 380 (5.00%)
         occurrences all number
    51
    40
    Platelet count decreased
         subjects affected / exposed
    18 / 378 (4.76%)
    19 / 380 (5.00%)
         occurrences all number
    22
    30
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    25 / 378 (6.61%)
    30 / 380 (7.89%)
         occurrences all number
    25
    32
    Cough
         subjects affected / exposed
    25 / 378 (6.61%)
    21 / 380 (5.53%)
         occurrences all number
    27
    23
    Dysphonia
         subjects affected / exposed
    24 / 378 (6.35%)
    16 / 380 (4.21%)
         occurrences all number
    26
    16
    Epistaxis
         subjects affected / exposed
    20 / 378 (5.29%)
    14 / 380 (3.68%)
         occurrences all number
    28
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    94 / 378 (24.87%)
    95 / 380 (25.00%)
         occurrences all number
    113
    121
    Neutropenia
         subjects affected / exposed
    75 / 378 (19.84%)
    69 / 380 (18.16%)
         occurrences all number
    124
    119
    Thrombocytopenia
         subjects affected / exposed
    59 / 378 (15.61%)
    46 / 380 (12.11%)
         occurrences all number
    99
    69
    Leukopenia
         subjects affected / exposed
    39 / 378 (10.32%)
    23 / 380 (6.05%)
         occurrences all number
    59
    44
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    38 / 378 (10.05%)
    54 / 380 (14.21%)
         occurrences all number
    39
    59
    Paraesthesia
         subjects affected / exposed
    32 / 378 (8.47%)
    32 / 380 (8.42%)
         occurrences all number
    33
    34
    Headache
         subjects affected / exposed
    26 / 378 (6.88%)
    29 / 380 (7.63%)
         occurrences all number
    29
    51
    Peripheral sensory neuropathy
         subjects affected / exposed
    24 / 378 (6.35%)
    35 / 380 (9.21%)
         occurrences all number
    25
    36
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    52 / 378 (13.76%)
    45 / 380 (11.84%)
         occurrences all number
    61
    57
    Fatigue
         subjects affected / exposed
    46 / 378 (12.17%)
    47 / 380 (12.37%)
         occurrences all number
    58
    59
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    76 / 378 (20.11%)
    79 / 380 (20.79%)
         occurrences all number
    179
    224
    Diarrhoea
         subjects affected / exposed
    32 / 378 (8.47%)
    25 / 380 (6.58%)
         occurrences all number
    41
    27
    Vomiting
         subjects affected / exposed
    25 / 378 (6.61%)
    20 / 380 (5.26%)
         occurrences all number
    33
    23
    Constipation
         subjects affected / exposed
    20 / 378 (5.29%)
    20 / 380 (5.26%)
         occurrences all number
    25
    26
    Renal and urinary disorders
    Renal cyst
         subjects affected / exposed
    20 / 378 (5.29%)
    13 / 380 (3.42%)
         occurrences all number
    20
    13
    Proteinuria
         subjects affected / exposed
    18 / 378 (4.76%)
    24 / 380 (6.32%)
         occurrences all number
    27
    40
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    184 / 378 (48.68%)
    185 / 380 (48.68%)
         occurrences all number
    185
    186
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    47 / 378 (12.43%)
    47 / 380 (12.37%)
         occurrences all number
    118
    93
    Myalgia
         subjects affected / exposed
    24 / 378 (6.35%)
    35 / 380 (9.21%)
         occurrences all number
    37
    57
    Musculoskeletal pain
         subjects affected / exposed
    19 / 378 (5.03%)
    16 / 380 (4.21%)
         occurrences all number
    55
    31
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    38 / 378 (10.05%)
    35 / 380 (9.21%)
         occurrences all number
    41
    48

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2015
    This amendment considered US FDA feedback and clarifications on: • Study design and eligibility criteria. • Statistical methods and sample size calculation. • Text was clarified, and editorial/administrative changes were implemented where appropriate.
    18 Aug 2016
    This amendment considered clarifications on: • Eligibility criteria. • Text was clarified, and editorial/administrative changes were implemented where appropriate.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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