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    Clinical Trial Results:
    A Randomised, Double-blind, Placebo-controlled, Phase I/II Trial of RNActive®-derived Cancer Vaccine (CV9104) in Asymptomatic or Minimally Symptomatic Patients with Metastatic Castrate-refractory Prostate Cancer

    Summary
    EudraCT number
    		 2011-006314-14
    Trial protocol
    		 DE   GB   ES   SE   CZ  
    Global end of trial date
    20 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2018
    First version publication date
    01 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CV-9104-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01817738
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CureVac AG
    Sponsor organisation address
    Paul-Ehrlich-Strasse 15, Tübingen, Germany, 72076
    Public contact
    Clinical Trials Information, CureVac AG, +49 7071-9883-0, clinicaltrials@curevac.com
    Scientific contact
    Clinical Trials Information, CureVac AG, +49 7071-9883-0, clinicaltrials@curevac.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
    20 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase I (safety lead-in): The primary objective of the safety lead-in portion of the study was to assess the safety and tolerability of CV9104 and to determine the dose for the randomised portion. Phase II (randomised portion): The primary objective of the randomised portion of the study was the comparison of overall survival (OS) in the CV9104 and placebo groups.
    Protection of trial subjects
    Additional measures for monitoring and minimizing potential risks were undertaken by involving an Independent Data Monitoring Committee (IDMC) to closely monitor all safety-related procedures and review safety data during the study conduct. The IDMC reviewed safety data during the safety lead-in and randomised portions of the study and also assessed interim data related to the primary efficacy endpoint of the randomised part of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Aug 2012
    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
    Poland: 40
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    Czech Republic: 20
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 79
    Country: Number of subjects enrolled
    Switzerland: 11
    Worldwide total number of subjects
    204
    EEA total number of subjects
    193
    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)
    58
    From 65 to 84 years
    142
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 204 patients were enrolled in the study. A total of 7 patients were included in the safety lead-in period (Phase I). A total of 197 patients were randomised in the Phase II period at 48 sites in 8 countries (Czech Republic, France, Germany, Poland, Spain, Sweden, Switzerland, and United Kingdom); 5 of which were not treated.

    Pre-assignment
    Screening details
    		 For Phase I, patients with asymptomatic or minimally symptomatic disease progressing after surgical castration or GNRH analogue therapy and after at least one second-line antihormonal manipulation. For Phase II, also previous chemotherapies and other malignancies were prohibited.

    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
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Phase I was open label to determine safety and tolerability of CV9104 and to determine dosage for Phase II. Phase II: After a patient had given informed consent, the interactive web response system (IWRS) assigned a subject identification number. Before the first vaccination, eligible patients were randomly assigned to either active vaccine or placebo by the IWRS based on a permuted block randomisation list. Vials containing active vaccine (CV9104) or placebo were identical in appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CV9104
    Arm description
    		 Phase I: At Weeks 1, 2, and 3, each patient received open-label vaccinations of CV9104 at a starting total dose of 1920 μg (320 μg of each of the 6 components administered in 12 intradermal (ID) injections) using a standard 3 + 3 design. Patients were offered to continue treatment, and were included in the safety analysis for the phase II part of the trial. Phase II: Patients received CV9104 at 1920 μg at weeks 1, 2, 3, 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months (Week 54) after the first vaccination and then every 3 months thereafter until one of the criteria for study treatment discontinuation were met. After discontinuation of study treatment, patients were to be followed-up for survival every 3 months until death or loss to follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CV9104
    Investigational medicinal product code
    CV9104
    Other name
    messenger ribonucleic acid (mRNA)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    CV9104 consists of 6 drug product components (320 µg each, 1920 μg total dose), each component stored as a sterile lyophilizate, for reconstitution with ringer lactate solution. At each vaccination timepoint, each of the 6 drug components was to be administered individually as 2 ID injections for a total of 12 injections distributed over 4 limbs. CV9104 was to be applied stricly intradermally into the thigh and upper arm of either side (4 sites total).

    Arm title
    		 Placebo
    Arm description
    		 Patients received placebo on Day 1 of weeks 1, 2, 3, 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months following the first vaccination and then every 3 months until one of the criteria for study treatment discontinuation were met. After discontinuation of study treatment, patients were to be followed-up for survival every 3 months until death or loss to follow-up.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    At each vaccination timepoint, the placebo was to be administered individually as 2 intradermal injections for a total of 12 injections distributed over 4 limbs.

    Number of subjects in period 1 [1]
    		CV9104 Placebo
    Started
    137
    63
    Completed
    132
    60
    Not completed
    5
    3
         Consent withdrawn by subject
    4
    2
         Lost to follow-up
    1
    1
    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: Of the 204 patients enrolled, 5 did not receive any IMP and were therefore excluded from any further analysis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CV9104
    Reporting group description
    		 Phase I: At Weeks 1, 2, and 3, each patient received open-label vaccinations of CV9104 at a starting total dose of 1920 μg (320 μg of each of the 6 components administered in 12 intradermal (ID) injections) using a standard 3 + 3 design. Patients were offered to continue treatment, and were included in the safety analysis for the phase II part of the trial. Phase II: Patients received CV9104 at 1920 μg at weeks 1, 2, 3, 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months (Week 54) after the first vaccination and then every 3 months thereafter until one of the criteria for study treatment discontinuation were met. After discontinuation of study treatment, patients were to be followed-up for survival every 3 months until death or loss to follow-up.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received placebo on Day 1 of weeks 1, 2, 3, 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months following the first vaccination and then every 3 months until one of the criteria for study treatment discontinuation were met. After discontinuation of study treatment, patients were to be followed-up for survival every 3 months until death or loss to follow-up.

    Reporting group values
    		 CV9104 Placebo Total
    Number of subjects
    		 137 63 200
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 38 19 57
        From 65-84 years
    		 96 43 139
        85 years and over
    		 3 1 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.1 ± 8.28 68.8 ± 8.34 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 137 63 200
    ECOG score
    ECOG (Eastern Cooperative Oncology Group) score
    Units: Subjects
        ECOG 0
    		 107 45 152
        ECOG 1
    		 30 18 48
        ECOG 2
    		 0 0 0
        ECOG 3
    		 0 0 0
        ECOG 4
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    CV9104
    Reporting group description
    		 Phase I: At Weeks 1, 2, and 3, each patient received open-label vaccinations of CV9104 at a starting total dose of 1920 μg (320 μg of each of the 6 components administered in 12 intradermal (ID) injections) using a standard 3 + 3 design. Patients were offered to continue treatment, and were included in the safety analysis for the phase II part of the trial. Phase II: Patients received CV9104 at 1920 μg at weeks 1, 2, 3, 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months (Week 54) after the first vaccination and then every 3 months thereafter until one of the criteria for study treatment discontinuation were met. After discontinuation of study treatment, patients were to be followed-up for survival every 3 months until death or loss to follow-up.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received placebo on Day 1 of weeks 1, 2, 3, 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months following the first vaccination and then every 3 months until one of the criteria for study treatment discontinuation were met. After discontinuation of study treatment, patients were to be followed-up for survival every 3 months until death or loss to follow-up.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The term ‘intention-to-treat (ITT) analysis set’ refers to all randomised patients. Patients were assigned to the randomised treatment groups, also in case a different treatment was actually given.

    Subject analysis set title
    Safety Analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The term ‘safety analysis set’ refers to patients who received at least 1 administration of study drug, including patients from safety lead-in phase. Patients without any post-baseline safety data were excluded from this analysis set.

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    patients were censored at last date known alive
    End point type
    Primary
    End point timeframe
    from randomization to death or end of study
    End point values
    		 CV9104 Placebo ITT
    Number of subjects analysed
    134
    63
    197
    Units: months
        median (confidence interval 95%)
    36.21 (28.39 to 43.01)
    33.94 (28.65 to 40.25)
    34.96 (30.72 to 39.49)
    Statistical analysis title
    		 Adjusted Cox PH model
    Statistical analysis description
    Cox proportional-hazards regression model
    Comparison groups
    CV9104 v Placebo
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0985 [2]
    Method
    		 Wald test
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.942
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.623
         upper limit
    		 1.427
    Variability estimate
    Standard deviation
    Notes
    [1] - The alternative hypothesis states that the treatment with CV9104 results in longer survival compared to treatment with placebo. The primary efficacy endpoint was analysed by a Cox proportional-hazards regression model with treatment and further explanatory variables.
    [2] - The 1 sided significance level for the primary analysis was 0.0985 according to the specified group sequential design (one interim and one primary analysis). This ensured an overall type-I error of 0.1.

    Secondary: Number of patients with TEAEs leading to discontinuation of study treatment

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    End point title
    		 Number of patients with TEAEs leading to discontinuation of study treatment
    End point description
    Number of patients with treatment-emergent adverse events (TEAEs) leading to discontinuation of study treatment
    End point type
    Secondary
    End point timeframe
    from informed consent up to 30 days after last IMP administration
    End point values
    		 CV9104 Placebo
    Number of subjects analysed
    137
    62
    Units: patients
    16
    6
    No statistical analyses for this end point

    Secondary: Number of patients with TEAE of NCI-CTCAE Grade => 3

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    End point title
    		 Number of patients with TEAE of NCI-CTCAE Grade => 3
    End point description
    End point type
    Secondary
    End point timeframe
    from informed consent up to 30 days after last IMP administration
    End point values
    		 CV9104 Placebo
    Number of subjects analysed
    137
    62
    Units: patients
    72
    37
    No statistical analyses for this end point

    Secondary: Number of patients with serious related TEAEs

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    End point title
    		 Number of patients with serious related TEAEs
    End point description
    End point type
    Secondary
    End point timeframe
    from informed consent up to 30 days after last IMP administration
    End point values
    		 CV9104 Placebo
    Number of subjects analysed
    137
    62
    Units: patients
    2
    3
    No statistical analyses for this end point

    Secondary: Number of patients with adverse events of special interest (AESI)

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    End point title
    		 Number of patients with adverse events of special interest (AESI)
    End point description
    End point type
    Secondary
    End point timeframe
    from informed consent up to 30 days after last IMP administration
    End point values
    		 CV9104 Placebo
    Number of subjects analysed
    137
    62
    Units: patients
        Vaccine-Associated Flu-like Symptoms
    93
    25
        Injection Site Reactions
    114
    30
        Urinary Retention
    15
    5
        Urinary Infections
    16
    6
        Cardiac Events
    16
    9
        Bone-related Events
    33
    21
        Anaphylaxis/hypersensitivity incl. local reactions
    20
    9
    No statistical analyses for this end point

    Secondary: Number of patients with TEAEs leading to death

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    End point title
    		 Number of patients with TEAEs leading to death
    End point description
    End point type
    Secondary
    End point timeframe
    from informed consent up to 30 days after last IMP administration
    End point values
    		 CV9104 Placebo
    Number of subjects analysed
    137
    62
    Units: patients
    10
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from informed consent up to 30 days after last IMP administration
    Adverse event reporting additional description
    Frequency tables show treatment emergent adverse events (TEAE), i.e. events that emerge during treatment, having been absent pre-treatment, or worsen relative to the pre-treatment state occurring within the specified timeframe. Patients with more than one TEAE within the same PT are only counted once.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered on Day 1 of weeks 1, 2, 3, 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months following the first vaccination and then every 3 months until one of the criteria for study treatment discontinuation is met.

    Reporting group title
    CV9104
    Reporting group description
    		 CV9104 at 1920 μg (recommended dose determined by the IDMC based on safety lead-in) at weeks 1, 2, 3, 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months (Week 54) after the first vaccination and then every 3 months thereafter until one of the criteria for study treatment discontinuation are met

    Serious adverse events
    		 Placebo CV9104
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 62 (43.55%)
    64 / 137 (46.72%)
         number of deaths (all causes)
    41
    75
         number of deaths resulting from adverse events
    5
    10
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mantle cell lymphoma
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pain
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Reproductive system and breast disorders
    Prostatic pain
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (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
    Arthropod sting
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone fissure
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Congenital, familial and genetic disorders
    Congenital spinal fusion
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tachyarrhythmia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Embolic stroke
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 137 (2.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Agranulocytosis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic diathesis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile neutropenia
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis haemorrhagic
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         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
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 62 (1.61%)
    5 / 137 (3.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 62 (0.00%)
    6 / 137 (4.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (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
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival abscess
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 137 (2.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         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
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 137 (0.73%)
         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
    		 Placebo CV9104
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 62 (96.77%)
    137 / 137 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 62 (14.52%)
    21 / 137 (15.33%)
         occurrences all number
    9
    21
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 62 (6.45%)
    17 / 137 (12.41%)
         occurrences all number
    4
    17
    Fatigue
         subjects affected / exposed
    18 / 62 (29.03%)
    34 / 137 (24.82%)
         occurrences all number
    18
    34
    Chills
         subjects affected / exposed
    1 / 62 (1.61%)
    25 / 137 (18.25%)
         occurrences all number
    1
    25
    Influenza like illness
         subjects affected / exposed
    8 / 62 (12.90%)
    34 / 137 (24.82%)
         occurrences all number
    8
    34
    Injection site erythema
         subjects affected / exposed
    25 / 62 (40.32%)
    108 / 137 (78.83%)
         occurrences all number
    25
    108
    Injection site pruritus
         subjects affected / exposed
    1 / 62 (1.61%)
    24 / 137 (17.52%)
         occurrences all number
    1
    24
    Injection site rash
         subjects affected / exposed
    3 / 62 (4.84%)
    9 / 137 (6.57%)
         occurrences all number
    3
    9
    Pyrexia
         subjects affected / exposed
    6 / 62 (9.68%)
    52 / 137 (37.96%)
         occurrences all number
    6
    52
    Injection site pain
         subjects affected / exposed
    3 / 62 (4.84%)
    10 / 137 (7.30%)
         occurrences all number
    3
    10
    Oedema peripheral
         subjects affected / exposed
    11 / 62 (17.74%)
    19 / 137 (13.87%)
         occurrences all number
    11
    19
    Spinal pain
         subjects affected / exposed
    1 / 62 (1.61%)
    12 / 137 (8.76%)
         occurrences all number
    1
    12
    General physical health deterioration
         subjects affected / exposed
    1 / 62 (1.61%)
    9 / 137 (6.57%)
         occurrences all number
    1
    9
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 62 (1.61%)
    10 / 137 (7.30%)
         occurrences all number
    1
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 62 (6.45%)
    13 / 137 (9.49%)
         occurrences all number
    4
    13
    Dyspnoea
         subjects affected / exposed
    4 / 62 (6.45%)
    6 / 137 (4.38%)
         occurrences all number
    4
    6
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 62 (6.45%)
    5 / 137 (3.65%)
         occurrences all number
    4
    5
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 62 (3.23%)
    7 / 137 (5.11%)
         occurrences all number
    2
    7
    C-reactive protein increased
         subjects affected / exposed
    1 / 62 (1.61%)
    7 / 137 (5.11%)
         occurrences all number
    1
    7
    Weight decreased
         subjects affected / exposed
    5 / 62 (8.06%)
    11 / 137 (8.03%)
         occurrences all number
    5
    11
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 62 (1.61%)
    7 / 137 (5.11%)
         occurrences all number
    1
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 62 (4.84%)
    11 / 137 (8.03%)
         occurrences all number
    3
    11
    Headache
         subjects affected / exposed
    3 / 62 (4.84%)
    7 / 137 (5.11%)
         occurrences all number
    3
    7
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    4 / 62 (6.45%)
    6 / 137 (4.38%)
         occurrences all number
    4
    6
    Anaemia
         subjects affected / exposed
    7 / 62 (11.29%)
    11 / 137 (8.03%)
         occurrences all number
    7
    11
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 62 (12.90%)
    15 / 137 (10.95%)
         occurrences all number
    8
    15
    Nausea
         subjects affected / exposed
    9 / 62 (14.52%)
    21 / 137 (15.33%)
         occurrences all number
    9
    21
    Vomiting
         subjects affected / exposed
    5 / 62 (8.06%)
    8 / 137 (5.84%)
         occurrences all number
    5
    8
    Constipation
         subjects affected / exposed
    6 / 62 (9.68%)
    9 / 137 (6.57%)
         occurrences all number
    6
    9
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 62 (3.23%)
    9 / 137 (6.57%)
         occurrences all number
    2
    9
    Nocturia
         subjects affected / exposed
    2 / 62 (3.23%)
    7 / 137 (5.11%)
         occurrences all number
    2
    7
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    21 / 62 (33.87%)
    27 / 137 (19.71%)
         occurrences all number
    21
    27
    Back pain
         subjects affected / exposed
    11 / 62 (17.74%)
    33 / 137 (24.09%)
         occurrences all number
    11
    33
    Arthralgia
         subjects affected / exposed
    12 / 62 (19.35%)
    28 / 137 (20.44%)
         occurrences all number
    12
    28
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 62 (8.06%)
    12 / 137 (8.76%)
         occurrences all number
    5
    12
    Pain in extremity
         subjects affected / exposed
    9 / 62 (14.52%)
    20 / 137 (14.60%)
         occurrences all number
    9
    20
    Groin pain
         subjects affected / exposed
    5 / 62 (8.06%)
    3 / 137 (2.19%)
         occurrences all number
    5
    3
    Musculoskeletal pain
         subjects affected / exposed
    8 / 62 (12.90%)
    10 / 137 (7.30%)
         occurrences all number
    8
    10
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    6 / 62 (9.68%)
    15 / 137 (10.95%)
         occurrences all number
    6
    15
    Nasopharyngitis
         subjects affected / exposed
    4 / 62 (6.45%)
    13 / 137 (9.49%)
         occurrences all number
    4
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 62 (4.84%)
    10 / 137 (7.30%)
         occurrences all number
    3
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2012
    • Exclusion criterion No. 11 was modified to include the allergies to any study drug component. • Exclusion criterion No. 17 was modified to include severe hypertension according to the WHO criteria. • Exclusion criterion No. 13 was revised to include “clinically relevant urinary retention/hydronephrosis requiring treatment by ultrasound or other appropriate imaging method”. • Week 12 blood sample collection timepoint was deleted from the immunological assessments and biomarker and circulating tumour cell assessments and Week 12 assessment was removed from definition and analysis sections of tertiary efficacy endpoints. • New text was added in study design to explain the similarity that the vaccination schedule in both Phase I and II for patients treated in the safety lead-in (Phase I) portion is identical to the schedule to be applied in the randomised portion (Phase II). • The Schedule of Assessments was revised. • A figure for vaccination schedules for Phase II was added. • Added to Safety Lead-in-portion (Phase I): o Treatment with study drug will initially be administered in Weeks 1, 2 and 3. In case no DLTs will be observed, the patients can continue vaccinations in Weeks 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months after the first vaccination and then every 3 months thereafter until one of the criteria for study treatment discontinuation is met. o During the Safety Lead-in portion, patients will initially receive 3 vaccinations in Weeks 1, 2 and 3. Patients will be monitored for adverse events and DLT evaluation will take place in Week 4. o Following the DLT observation period (Week 4), safety lead-in patients may continue to receive CV9104 in Weeks 5, 7, 9, 12, 15, 18 and 24, then every 6 weeks for up to 12 months after the first vaccination and then every 3 months thereafter until one of the criteria for study treatment discontinuation is met.
    09 Apr 2013
    • Inclusion criterion No. 2 modified: rephrased to clarify that patients who have received combined androgen blockade followed by anti-androgen withdrawal as second-line anti hormonal manipulation may be included in the trial / confirmation of progression by elevations of PSA was further specified to clarify that an anti-androgen withdrawal response must have been excluded after discontinuation of anti-androgen therapy only in patients having received initial combined androgen blockade or have shown a decline in PSA for ≥3 months after administration of an anti-androgen. • Per request from the Swedish competent authority (MPA): Inclusion criterion No. 7 was amended to follow the ICH (M3) guidelines concerning contraception aimed at prevention with high efficiency (risk according to Pearl Index <1) / Exclusion criterion No. 3 was modified / Exclusion criterion No. 12 (allergies to penicillins or other β-lactam antibiotics) was added due to the fact that ampicillin is used during the production process of RNActive / Exclusion criterion No. 15 was modified to include hydronephrosis / EOT criterion was added to exclude patients with active HIV or hepatitis B or C infection / observation period after administration in the randomised portion was extended to 2 hours following the first 3 vaccinations / statement clarifying the adequate treatment of urinary retention was added. • Per request from a Swiss EC, the process of publication of individual study data was amended. • Exclusion criterion No. 13 was modified to specify the applicable timepoint. • Exclusion criterion No. 5 was expanded to the exclusion of any immunomodulating agents including herbal remedies. • The blinding and unblinding process was modified to clarify the process of unblinding and avoid misunderstanding. • Definitions of secondary endpoints were further clarified.
    09 Jun 2015
    • Secondary objectives were updated to include comparison of combined progression free survival (S-PFS) between CV9104 and placebo groups and to exclude comparison of circulating tumour cells frequencies. • Secondary endpoints were updated: / included AEs of special interest / “NCI-CTCAE toxicity Grades ≥3” added for laboratory summaries / efficacy endpoint “Overall progression-free survival, radiographic progression-free survival and PSA progression-free survival from randomisation to second progression (S-PFS)” was added / endpoints to assess the effect of CV9104 treatment on circulating tumour cells frequencies were removed / humoral immune response rates was adapted to include response rates against all RNActive encoded antigens / Overall immune response rates against the 6 RNActive-encoded antigens added / time to symptom progression added / EQ-5D questionnaire: calculation of area under the curve (AUC) was added / Removal of absolute change from baseline of FACT-P total score and subscores. • EOT section was amended in order to specify how patients were to be treated in the case of unblinding the study. • Definition of the end of the study was updated. • Clarification for analysis of the primary and key secondary clinical endpoints based on PP and mITT sets in efficacy analysis section. • Covariates and the model building of the multivariate Cox regression approach were changed for analysis of primary endpoint. • Subgroup analyses: clarified that subgroup analysis was to be performed on the ITT set only for OS, PFS1, PFS2 and S-PFS. • Safety assessments section was updated to include analyses of TEAEs and additional safety variables (e.g., AESIs).
    11 Apr 2016
    • Changed the text regarding the storage of non-reconstituted CV9104 to reflect the storage conditions for all the study drug kits used in the study. • Editorial changes

    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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