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    Clinical Trial Results:
    A phase II study investigating preoperative MPDL3280A in operable transitional cell carcinoma of the bladder

    Summary
    EudraCT number
    		 2015-001112-35
    Trial protocol
    		 GB   ES   DE   FR   NL  
    Global end of trial date
    11 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jun 2021
    First version publication date
    23 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    010463QM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02662309
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Clinicaltrials.gov: NCT02662309
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    Mile End Road, London, United Kingdom, E1 4NS
    Public contact
    ABACUS Trial Coordinator, Queen Mary University of London, +44 02078828497, bci-cecmmonitoring@qmul.ac.uk
    Scientific contact
    Prof Thomas Powles, Queen Mary University of London, +44 02078828497, bci-cecmmonitoring@qmul.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 May 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine MPDL3280A's (also known as atezolizumab) ability to reduce the size of bladder cancer before surgery (measured as pathological complete response rate), and assess the impact of the drug on the body's immune system.
    Protection of trial subjects
    The study design aimed to minimise potential risks. Eligibility criteria were selected to enhance the safety of patients in this trial and a number of exclusion criteria were specifically based on the known safety profile of the study drug. Treatment with atezolizumab in the "window of opportunity" between enrolment and surgery did not delay participants' planned cystectomy surgeries. Participants were fully informed about the study prior to participation, including planned study procedures and the potential risks. Many of the procedures/ assessments carried out in the study are offered as standard-of-care, and participant safety was monitored at regular study visits. Relevant data protection and privacy regulations were followed throughout.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Feb 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
    Netherlands: 7
    Country: Number of subjects enrolled
    Spain: 56
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    France: 9
    Worldwide total number of subjects
    96
    EEA total number of subjects
    72
    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)
    17
    From 65 to 84 years
    77
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 29-Feb-2016, 118 patients were screened for the ABACUS trial. 96 patients were subsequently enrolled. Patients were recruited from multiple centres in the UK, Spain, France, and Netherlands. 1 patient was withdrawn prior to treatment as eligibility criteria were not met. 95 patients continued to receive treatment and are included in analyses.

    Pre-assignment
    Screening details
    		 Inclusion criteria included patients with histologically confirmed muscle-invasive bladder cancer (T2-4aN0M0) with a majority of urothelial component and residual disease after transurethral resection of the bladder tumour. Patients were either ineligible for or refused cisplatin-based neoadjuvant chemotherapy.

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

    Arms
    Arm title
    		 Atezolizumab Treatment (Full analysis set)
    Arm description
    		 Patients receive 2x 3-weekly cycles of atezolizumab (one infusion on the first day of each cycle) prior to cystectomy surgery. This arm/population includes all patients who meet the eligibility criteria and have had at least 1 cycle of atezolizumab, regardless of whether they were later found to be ineligible or a protocol violator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 cycles of 1200 mg atezolizumab administered by IV infusion every 3 weeks.

    Number of subjects in period 1 [1]
    		Atezolizumab Treatment (Full analysis set)
    Started
    95
    Received Cycle 1 of atezolizumab
    95
    Received Cycle 2 of atezolizumab
    75
    Underwent cystectomy
    87
    Completed
    69
    Not completed
    26
         Consent withdrawn by subject
    2
         Death
    22
         Lost to follow-up
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number enrolled in the trial is 96 subjects. This includes 1 subject that was enrolled in error and not included in any analysis sets. The ‘Overall trial’ / baseline period is effectively the safety set and full analysis set (FAS) population of 95 subjects. It does not include the 1 subject that was excluded from the study following enrolment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Includes all patients who meet the eligibility criteria and received at least one administration of atezolizumab.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 95 95
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 17 17
        From 65-84 years
    		 76 76
        85 years and over
    		 2 2
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 73 (53 to 87) -
    Gender categorical
    Units: Subjects
        Female
    		 14 14
        Male
    		 81 81
    Race
    Units: Subjects
        Asian (Bangladeshi)
    		 1 1
        Black (African)
    		 1 1
        Other
    		 1 1
        White
    		 89 89
        Not specified
    		 3 3
    Tumour grade
    Units: Subjects
        Grade 1
    		 1 1
        Grade 2
    		 9 9
        Grade 3
    		 75 75
        Grade 4
    		 9 9
        N/A
    		 1 1
    Tumour stage (Pathological)
    Units: Subjects
        T2a (invades superficial muscle propria)
    		 39 39
        T2b (invades deep muscle propria)
    		 31 31
        T3a (invades perivesical tissue microscopically)
    		 9 9
        T3b (invades perivesical tissue macroscopically)
    		 8 8
        T4a (invades prostate, uterus, vagina)
    		 8 8
    Lymph node stage
    Units: Subjects
        N0 (No lymph node metastasis)
    		 95 95
    Metastatic stage
    Units: Subjects
        M0 (No distant metastasis)
    		 95 95
    Has the patient had previous NMIBC?
    NMIBC = Non-Muscle Invasive Bladder Cancer
    Units: Subjects
        Yes
    		 14 14
        No
    		 81 81
    Stage of previous NMIBC
    Units: Subjects
        Tis
    		 1 1
        Ta
    		 5 5
        T1
    		 8 8
        Not applicable
    		 81 81
    Previous NMIBC: CIS
    Units: Subjects
        Yes
    		 5 5
        No
    		 9 9
        Not applicable
    		 81 81
    PD-L1 status
    PD-L1 positive is defined as all patients with a value greater than or equal to 5 for PD-L1 at the pre-treatment visit. PD-L1 negative is defined as all patients with a value less than 5 for PD-L1 at the pre-treatment visit. PD-L1 status unknown is defined as all patients without PD-L1 data at the pre-treatment visit.
    Units: Subjects
        PD-L1 positive
    		 39 39
        PD-L1 negative
    		 51 51
        PD-L1 status unknown
    		 5 5
    CD8-GZMB status
    CD8-GZMB high (low) are defined as all patients with a value greater than (less than or equal to) the median for that measurement at the pre-treatment visit. CD8-GZMB status of unknown is defined as all patients without data at the pre-treatment visit for that measurement.
    Units: Subjects
        CD8-GZMB high
    		 36 36
        CD8-GZMB low
    		 35 35
        CD8-GZMB status unknown
    		 24 24
    TMB status
    TMB high (low) are defined as all patients with a value greater than (less than or equal to) the median for that measurement at the pre-treatment visit. TMB status of unknown is defined as all patients without data at the pre-treatment visit for that measurement.
    Units: Subjects
        TMB high
    		 39 39
        TMB low
    		 42 42
        TMB status unknown
    		 14 14
    Radiological measurable disease
    Measurable disease at baseline is a tumour diameter of >10mm.
    Units: Subjects
        Yes
    		 69 69
        No
    		 20 20
        Unknown
    		 6 6
    Received BCG vaccination
    Units: Subjects
        Yes
    		 11 11
        No
    		 84 84
    Smoking status
    Units: Subjects
        Never at any time been a regular smoker
    		 21 21
        Ex-smoker (smoked regularly in the past)
    		 53 53
        Current smoker (either regular or occasional)
    		 21 21
    ECOG Performance Status
    ECOG = Eastern Cooperative Oncology Group
    Units: Subjects
        ECOG Grade 0
    		 71 71
        ECOG Grade 1
    		 24 24
    Pathological tumour size
    Units: millimeter(s)
        median (inter-quartile range (Q1-Q3))
    		 25 (0 to 80) -
    Intertumoral CD8 count
    N=89 for this baseline characteristic, due to the remainder of patients having missing CD8 count data at baseline.
    Units: CD8
        median (inter-quartile range (Q1-Q3))
    		 186.3 (69.8 to 396.2) -

    End points

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    End points reporting groups
    Reporting group title
    Atezolizumab Treatment (Full analysis set)
    Reporting group description
    		 Patients receive 2x 3-weekly cycles of atezolizumab (one infusion on the first day of each cycle) prior to cystectomy surgery. This arm/population includes all patients who meet the eligibility criteria and have had at least 1 cycle of atezolizumab, regardless of whether they were later found to be ineligible or a protocol violator.

    Primary: Efficacy of atezolizumab pre-cystectomy with respect to pathological complete response rate (pCRR)

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    End point title
    		 Efficacy of atezolizumab pre-cystectomy with respect to pathological complete response rate (pCRR) [1]
    End point description
    Pathological complete response (pCR) is defined as no microscopic evidence of residual disease in the bladder based on histological evaluation of the resected bladder specimen collected during cystectomy (pT0/Tis/Cis). Pathological complete response rate (pCRR) is defined as the number of patients with a pCR divided by the number of patients analysed.
    End point type
    Primary
    End point timeframe
    2-3 months (timeframe dependent on delay to surgery)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: ABACUS was a single arm study with no comparison groups, therefore statistical analysis section not relevant.
    End point values
    		 Atezolizumab Treatment (Full analysis set)
    Number of subjects analysed
    88 [2]
    Units: Patients
        Patients with pathological complete response (pCR)
    27
        Patients with major pathological response (MPR)
    7
    Notes
    [2] - 88 patients were eligible for pCR/MPR analysis.
    No statistical analyses for this end point

    Primary: Effect of atezolizumab pre-cystectomy with respect to dynamic changes in T-cell levels

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    End point title
    		 Effect of atezolizumab pre-cystectomy with respect to dynamic changes in T-cell levels [3]
    End point description
    T cell sub-populations in tumour samples collected from patients receiving at least 1 cycle of treatment. Pre-treatment is tumour samples taken before the start of Atezolizumab (biopsy) and post-treatment is samples taken at the end of Atezolizumab (excision/biopsy).
    End point type
    Primary
    End point timeframe
    2-3 months (timeframe dependent on delay to surgery)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: ABACUS was a single arm study with no comparison groups, therefore statistical analysis section not relevant.
    End point values
    		 Atezolizumab Treatment (Full analysis set)
    Number of subjects analysed
    54 [4]
    Units: CD8
    median (inter-quartile range (Q1-Q3))
        Pre-treatment CD8
    111.9 (48.9 to 291.4)
        Post-treatment CD8
    198.8 (69.4 to 558.1)
    Notes
    [4] - Patients with pre and post-treatment CD8 result.
    No statistical analyses for this end point

    Secondary: Efficacy of atezolizumab pre-cystectomy with respect to anti-tumour effects as measured by radiological response (RR)

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    End point title
    		 Efficacy of atezolizumab pre-cystectomy with respect to anti-tumour effects as measured by radiological response (RR)
    End point description
    CT or MRI scan taken at screening and pre-cystectomy visits. RR is defined as a ≥30% decrease in tumour diameter from the baseline scan.
    End point type
    Secondary
    End point timeframe
    Approx 34 weeks (timeframe dependent on delay to pre-cystectomy visit)
    End point values
    		 Atezolizumab Treatment (Full analysis set)
    Number of subjects analysed
    58 [5]
    Units: Patients with radiological response (RR)
    13
    Notes
    [5] - Patients eligible for radiological response rate analysis
    No statistical analyses for this end point

    Secondary: Efficacy of atezolizumab pre-cystectomy with respect to anti-tumour effects based on disease free survival (DFS)

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    End point title
    		 Efficacy of atezolizumab pre-cystectomy with respect to anti-tumour effects based on disease free survival (DFS)
    End point description
    Disease and survival data is reviewed at post-surgery visits and at 1 and 2 years post-cystectomy. Disease recurrence is defined as the first evidence of relapse (based on local investigator assessments) or death from any cause.
    End point type
    Secondary
    End point timeframe
    Up to 2 years post-cystectomy
    End point values
    		 Atezolizumab Treatment (Full analysis set)
    Number of subjects analysed
    95 [6]
    Units: Percentage
        DFS rate at 12 months
    73
        DFS rate at 24 months
    68
    Notes
    [6] - Median DFS was Not Reached.
    No statistical analyses for this end point

    Secondary: Efficacy of atezolizumab pre-cystectomy with respect to anti-tumour effects based on overall survival (OS)

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    End point title
    		 Efficacy of atezolizumab pre-cystectomy with respect to anti-tumour effects based on overall survival (OS)
    End point description
    Disease and survival data is reviewed at post-surgery visits and at 1 and 2 years post-cystectomy.
    End point type
    Secondary
    End point timeframe
    Up to 2 years post-cystectomy
    End point values
    		 Atezolizumab Treatment (Full analysis set)
    Number of subjects analysed
    95 [7]
    Units: Percentage
        OS rate at 12 months
    84
        OS rate at 24 months
    77
    Notes
    [7] - Median OS was Not Reached.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from informed consent up to 4 weeks post-cystectomy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Safety Set population
    Reporting group description
    		 Safety Set population is defined as all patients enrolled into the trial who received at least one administration of study treatment.

    Serious adverse events
    		 Safety Set population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 95 (33.68%)
         number of deaths (all causes)
    22
         number of deaths resulting from adverse events
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Wound dehiscence
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 95 (4.21%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    12 / 95 (12.63%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Abdominal infection
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac infection
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Set population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    87 / 95 (91.58%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    8 / 95 (8.42%)
         occurrences all number
    8
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 95 (5.26%)
         occurrences all number
    6
    Hypotension
         subjects affected / exposed
    4 / 95 (4.21%)
         occurrences all number
    4
    Hot flush
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Lymphorrhoea
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    39 / 95 (41.05%)
         occurrences all number
    50
    Pyrexia
         subjects affected / exposed
    10 / 95 (10.53%)
         occurrences all number
    10
    Pain
         subjects affected / exposed
    6 / 95 (6.32%)
         occurrences all number
    8
    Oedema
         subjects affected / exposed
    5 / 95 (5.26%)
         occurrences all number
    6
    Influenza like illness
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Chills
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    3
    Mucosal inflammation
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Pelvic haematoma
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 95 (8.42%)
         occurrences all number
    8
    Dyspnoea
         subjects affected / exposed
    5 / 95 (5.26%)
         occurrences all number
    7
    Respiratory failure
         subjects affected / exposed
    4 / 95 (4.21%)
         occurrences all number
    4
    Pleural effusion
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Bronchial obstruction
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Catarrh
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Sneezing
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Confusional state
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Agitation
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    9 / 95 (9.47%)
         occurrences all number
    12
    Transaminases increased
         subjects affected / exposed
    7 / 95 (7.37%)
         occurrences all number
    18
    Weight decreased
         subjects affected / exposed
    5 / 95 (5.26%)
         occurrences all number
    7
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Lymphocyte count increased
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Nutritional condition abnormal
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Platelet count increased
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Wound dehiscence
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Urostomy complication
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Gastroparesis postoperative
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Infusion related reaction
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Atrial flutter
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Coronary artery disease
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Myocardial infarction
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Palpitations
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Taste disorder
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Cognitive disorder
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Neuromyopathy
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Frontotemporal dementia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    19 / 95 (20.00%)
         occurrences all number
    40
    Leukocytosis
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    2
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    16 / 95 (16.84%)
         occurrences all number
    21
    Diarrhoea
         subjects affected / exposed
    11 / 95 (11.58%)
         occurrences all number
    13
    Ileus
         subjects affected / exposed
    9 / 95 (9.47%)
         occurrences all number
    9
    Abdominal pain
         subjects affected / exposed
    6 / 95 (6.32%)
         occurrences all number
    7
    Vomiting
         subjects affected / exposed
    4 / 95 (4.21%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    4 / 95 (4.21%)
         occurrences all number
    4
    Dry mouth
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Abdominal distension
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Dyspepsia
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Fistula of small intestine
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Hernial eventration
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Glossodynia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Ascites
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Buccal mucosal roughening
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    11 / 95 (11.58%)
         occurrences all number
    12
    Rash
         subjects affected / exposed
    9 / 95 (9.47%)
         occurrences all number
    9
    Cold sweat
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Dry skin
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Decubitus ulcer
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    9 / 95 (9.47%)
         occurrences all number
    10
    Dysuria
         subjects affected / exposed
    6 / 95 (6.32%)
         occurrences all number
    6
    Acute kidney injury
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Nocturia
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Urinary incontinence
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Chronic kidney disease
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Proteinuria
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    3
    Urinary tract obstruction
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Glycosuria
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Oliguria
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Leukocyturia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Pollakiuria
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Renal impairment
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Hyperparathyroidism
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 95 (4.21%)
         occurrences all number
    5
    Musculoskeletal pain
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    5
    Ligament sprain
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    20 / 95 (21.05%)
         occurrences all number
    24
    Respiratory tract infection
         subjects affected / exposed
    9 / 95 (9.47%)
         occurrences all number
    11
    Abdominal infection
         subjects affected / exposed
    4 / 95 (4.21%)
         occurrences all number
    4
    Wound infection
         subjects affected / exposed
    4 / 95 (4.21%)
         occurrences all number
    4
    Fungal infection
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Infection
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Bacterial infection
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    3
    Sepsis
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Viral skin infection
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 95 (16.84%)
         occurrences all number
    22
    Hypophosphataemia
         subjects affected / exposed
    5 / 95 (5.26%)
         occurrences all number
    7
    Hyperkalaemia
         subjects affected / exposed
    3 / 95 (3.16%)
         occurrences all number
    3
    Hypokalaemia
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Hyperglycaemia
         subjects affected / exposed
    2 / 95 (2.11%)
         occurrences all number
    2
    Hyperamylasaemia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Hypermagnesaemia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Hyperproteinaemia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 95 (1.05%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Sep 2018
    Change of sponsor representative and statistician. Clarification of trial endpoints. Safety update and updated Investigator's Brochure.
    01 Oct 2018
    Further clarification of primary trial endpoints.

    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/31686036
    http://www.ncbi.nlm.nih.gov/pubmed/33612455
    For support, Contact us.
    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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