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    Clinical Trial Results:
    A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride versus placebo when administered to metastatic HER2 negative hormone receptor positive breast cancer subjects with bone metastases treated with hormonal treatment background therapy.

    Summary
    EudraCT number
    		 2014-002113-39
    Trial protocol
    		 GB   ES   AT   NO   CZ   DK   NL   SE   PL   FI   IE   FR   DE  
    Global end of trial date
    13 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jul 2020
    First version publication date
    03 Jul 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY88-8223/16298
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02258464
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    13 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of radium-223 dichloride in subjects with HER2 negative, hormone receptor positive breast cancer with bone metastases treated with hormonal treatment background therapy.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Israel: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United States: 10
    Worldwide total number of subjects
    99
    EEA total number of subjects
    47
    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)
    68
    From 65 to 84 years
    30
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 151 subjects were screened at 69 active centers in 20 countries, the first subject first visit was on 02 Mar 2015 and last subject last visit was on 13 Aug 2019

    Pre-assignment
    Screening details
    		 Of the 151 screened subjects, 99 subjects (65.6%) completed screening and were assigned to treatment: 49 in the radium 223 dichloride and 50 in the placebo arm

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Radium 223 dichloride
    Arm description
    		 Subjects treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride for a maximum of 6 cycles at intervals of 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium-223 dichloride
    Investigational medicinal product code
    BAY88-8223
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 kBq/kg (55 kBq/kg after implementation of NIST update) body weight every 4 weeks for 6 cycles, injected intravenously as a slow bolus

    Arm title
    		 Placebo
    Arm description
    		 Subjects treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Matching placebo (isotonic saline), injected intravenously as a slow bolus

    Number of subjects in period 1
    		Radium 223 dichloride Placebo
    Started
    49
    50
    Completed
    32
    25
    Not completed
    17
    25
         Consent withdrawn by subject
    5
    4
         Study drug never administered
    1
    1
         AE related to clinical disease progression
    1
    -
         AE not related to clinical disease progression
    1
    3
         Progressive disease
    9
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Radium 223 dichloride
    Reporting group description
    		 Subjects treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride for a maximum of 6 cycles at intervals of 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks

    Reporting group values
    		 Radium 223 dichloride Placebo Total
    Number of subjects
    		 49 50 99
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.08 ( 11.51 ) 58.74 ( 11.97 ) -
    Gender categorical
    Units: Subjects
        Female
    		 49 50 99
    Race
    Units: Subjects
        White
    		 35 40 75
        Black or African American
    		 1 0 1
        Asian
    		 9 9 18
        Not reported
    		 4 1 5
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 47 47 94
        Not reported
    		 2 3 5

    End points

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    End points reporting groups
    Reporting group title
    Radium 223 dichloride
    Reporting group description
    		 Subjects treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride for a maximum of 6 cycles at intervals of 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks

    Subject analysis set title
    Intent to treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    all randomized participants, the primary population for all efficacy analyses was the ITT analysis set

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all randomized subjects who received at least one dose of study medication (radium 223 dichloride or placebo)

    Primary: Symptomatic skeletal event free survival (SSE-FS)

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    End point title
    		 Symptomatic skeletal event free survival (SSE-FS)
    End point description
    Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of EBRT to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause
    End point type
    Primary
    End point timeframe
    Up to 51 months
    End point values
    		 Radium 223 dichloride Placebo
    Number of subjects analysed
    49
    50
    Units: months
        median (confidence interval 80%)
    30.1 (21.8 to 43.0)
    18.4 (9.1 to 28.2)
    Statistical analysis title
    		 Analysis based on Kaplan-Meier Curves
    Statistical analysis description
    The null hypothesis that both treatment groups have the same SSE-FS distribution will be tested against the alternative hypothesis that the distribution of SSE-FS time in radium-223 dichloride is different from the placebo group
    Comparison groups
    Radium 223 dichloride v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3339 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard Ratio (Radium 223/Placebo)
    Point estimate
    0.745
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.504
         upper limit
    		 1.102
    Notes
    [1] - The SSE-FS was compared using a stratified log-rank test with a 2-sided alpha of 0.2

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Time from randomization to death from any cause
    End point type
    Secondary
    End point timeframe
    Up to 51 months
    End point values
    		 Radium 223 dichloride Placebo
    Number of subjects analysed
    49 [2]
    50 [3]
    Units: months
        median (confidence interval 80%)
    43 (22.9 to 99999)
    32.4 (23.7 to 99999)
    Notes
    [2] - 99999: not estimable due to censored data
    [3] - 99999: not estimable due to censored data
    No statistical analyses for this end point

    Secondary: Time to opiate use for cancer pain

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    End point title
    		 Time to opiate use for cancer pain
    End point description
    Interval from the date of randomization to the date of opiate use
    End point type
    Secondary
    End point timeframe
    Up to 51 months
    End point values
    		 Radium 223 dichloride Placebo
    Number of subjects analysed
    48 [4]
    49 [5]
    Units: months
        median (confidence interval 80%)
    21.3 (8.3 to 99999)
    20.2 (8.8 to 99999)
    Notes
    [4] - 99999: not estimable due to censored data
    [5] - 99999: not estimable due to censored data
    No statistical analyses for this end point

    Secondary: Time to cytotoxic chemotherapy

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    End point title
    		 Time to cytotoxic chemotherapy
    End point description
    Time from the date of randomization to the date of the first cytotoxic chemotherapy
    End point type
    Secondary
    End point timeframe
    Up to 51 months
    End point values
    		 Radium 223 dichloride Placebo
    Number of subjects analysed
    49
    50
    Units: months
        median (confidence interval 80%)
    16.0 (14.1 to 22.4)
    17.3 (10.9 to 27.6)
    No statistical analyses for this end point

    Secondary: Radiological progression-free survival (rPFS)

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    End point title
    		 Radiological progression-free survival (rPFS)
    End point description
    Time from the date of randomization to the date of first radiological progression or death (if death occurs before progression)
    End point type
    Secondary
    End point timeframe
    Up to 51 months
    End point values
    		 Radium 223 dichloride Placebo
    Number of subjects analysed
    49
    50
    Units: months
        median (confidence interval 80%)
    8.1 (5.7 to 10.6)
    5.8 (5.1 to 7.9)
    No statistical analyses for this end point

    Secondary: Pain Improvement Rate

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    End point title
    		 Pain Improvement Rate
    End point description
    The percentage of participants (baseline WPS>=2) with confirmed pain improvement at any time point. Confirmed pain improvement is defined as a 2 point decrease in worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart
    End point type
    Secondary
    End point timeframe
    Up to 51 months
    End point values
    		 Radium 223 dichloride Placebo
    Number of subjects analysed
    32
    35
    Units: percent
    number (confidence interval 80%)
        Overall (confirmed)
    37.5 (25.9 to 50.4)
    25.7 (16.2 to 37.5)
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent adverse events

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    End point title
    		 Number of subjects with treatment-emergent adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    From the start of study drug administration until 30 days after the last study medication intake, assessed up to approximately 7 months
    End point values
    		 Radium 223 dichloride Placebo
    Number of subjects analysed
    48
    49
    Units: subjects
        Any TEAE
    46
    46
        Radium 223/Placebo related TEAEs
    21
    16
    No statistical analyses for this end point

    Secondary: Number of subjects with post-treatment adverse events including additional malignancies and chemotherapy related adverse events

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    End point title
    		 Number of subjects with post-treatment adverse events including additional malignancies and chemotherapy related adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    From 30 days after the last dose of study treatment until the end of study, assessed up to 44 months
    End point values
    		 Radium 223 dichloride Placebo
    Number of subjects analysed
    48
    49
    Units: subjects
        Anaemia
    1
    0
        Febrile neutropenia
    1
    0
        Chest pain
    1
    0
        Fibula fracture
    1
    0
        Rib fracture
    1
    0
        Tibia fracture
    1
    0
        Traumatic fracture
    1
    0
        Weight decreased
    0
    1
        Arthralgia
    1
    0
        Back pain
    4
    0
        Bone pain
    2
    3
        Muscle spasms
    1
    0
        Musculoskeletal chest pain
    1
    0
        Osteonecrosis of jaw
    1
    0
        Pain in extremity
    1
    1
        Pathological fracture
    5
    4
        Spinal pain
    0
    3
        Cauda equina syndrome
    0
    1
        Paraesthesia
    0
    1
        Spinal cord compression
    1
    1
        Acute kidney injury
    0
    1
        Any post-treatment AE
    15
    16
    No statistical analyses for this end point

    Secondary: Time to pain progression

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    End point title
    		 Time to pain progression
    End point description
    Time from randomization to the first date a subject (only in subjects with baseline WPS ≤8) experiences pain progression based on worst pain score (WPS) and analgesic use. Pain progression is defined as an increase of 2 or more points in the “Worst pain in 24 hours” score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurs first
    End point type
    Secondary
    End point timeframe
    Up to 51 months
    End point values
    		 Radium 223 dichloride Placebo
    Number of subjects analysed
    48
    49
    Units: months
        median (confidence interval 80%)
    14.8 (5.9 to 21.3)
    8.8 (3.7 to 14.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study drug administration until 30 days after the last study medication intake, assessed up to approximately 7 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Radium 223 dichloride
    Reporting group description
    		 Subjects treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride for a maximum of 6 cycles at intervals of 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks

    Serious adverse events
    		 Radium 223 dichloride Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 48 (8.33%)
    14 / 49 (28.57%)
         number of deaths (all causes)
    18
    18
         number of deaths resulting from adverse events
    0
    1
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         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 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nerve compression
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (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
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         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
    Chest pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 49 (6.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Radium 223 dichloride Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 48 (89.58%)
    42 / 49 (85.71%)
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 49 (4.08%)
         occurrences all number
    5
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 49 (6.12%)
         occurrences all number
    5
    5
    Hot flush
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 49 (6.12%)
         occurrences all number
    3
    3
    Headache
         subjects affected / exposed
    13 / 48 (27.08%)
    4 / 49 (8.16%)
         occurrences all number
    19
    4
    Paraesthesia
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 49 (8.16%)
         occurrences all number
    1
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 49 (6.12%)
         occurrences all number
    4
    7
    Leukopenia
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 49 (0.00%)
         occurrences all number
    6
    0
    Neutropenia
         subjects affected / exposed
    5 / 48 (10.42%)
    0 / 49 (0.00%)
         occurrences all number
    12
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 48 (25.00%)
    9 / 49 (18.37%)
         occurrences all number
    15
    10
    Influenza like illness
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 49 (2.04%)
         occurrences all number
    4
    1
    Oedema peripheral
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 49 (2.04%)
         occurrences all number
    3
    1
    Pain
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 48 (10.42%)
    2 / 49 (4.08%)
         occurrences all number
    6
    3
    Diarrhoea
         subjects affected / exposed
    10 / 48 (20.83%)
    7 / 49 (14.29%)
         occurrences all number
    15
    10
    Constipation
         subjects affected / exposed
    4 / 48 (8.33%)
    4 / 49 (8.16%)
         occurrences all number
    5
    4
    Nausea
         subjects affected / exposed
    12 / 48 (25.00%)
    9 / 49 (18.37%)
         occurrences all number
    18
    13
    Vomiting
         subjects affected / exposed
    7 / 48 (14.58%)
    7 / 49 (14.29%)
         occurrences all number
    7
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 49 (8.16%)
         occurrences all number
    1
    4
    Dyspnoea
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 49 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 48 (20.83%)
    11 / 49 (22.45%)
         occurrences all number
    13
    17
    Back pain
         subjects affected / exposed
    10 / 48 (20.83%)
    7 / 49 (14.29%)
         occurrences all number
    14
    10
    Bone pain
         subjects affected / exposed
    10 / 48 (20.83%)
    7 / 49 (14.29%)
         occurrences all number
    10
    13
    Musculoskeletal pain
         subjects affected / exposed
    6 / 48 (12.50%)
    4 / 49 (8.16%)
         occurrences all number
    10
    4
    Myalgia
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 49 (4.08%)
         occurrences all number
    5
    2
    Neck pain
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 49 (2.04%)
         occurrences all number
    5
    1
    Pain in extremity
         subjects affected / exposed
    5 / 48 (10.42%)
    6 / 49 (12.24%)
         occurrences all number
    7
    8
    Pathological fracture
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 49 (6.12%)
         occurrences all number
    3
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 49 (4.08%)
         occurrences all number
    4
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 49 (6.12%)
         occurrences all number
    3
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 48 (4.17%)
    4 / 49 (8.16%)
         occurrences all number
    2
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 48 (6.25%)
    5 / 49 (10.20%)
         occurrences all number
    3
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2014
    Amendment 1 (global amendment) forming integrated protocol Version 2.0
    29 Apr 2015
    Amendment 2 (global amendment) forming integrated protocol Version 3.0
    29 Jul 2015
    Amendment 4 (global amendment) forming integrated protocol Version 4.0
    11 Mar 2016
    Amendment 5 (global amendment) forming integrated protocol Version 5.0
    11 Jul 2016
    Amendment 6 (global amendment) forming integrated protocol Version 6.0
    23 May 2017
    Amendment 7 (global amendment) forming integrated protocol Version 7.0
    03 Apr 2018
    Amendment 8 (global amendment) forming current integrated protocol Version 8.0

    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.
    Due to the premature enrollment discontinuation, reduced sample size, and potentially curtailed active follow up, the planned number of SSE FS events was not achieved, limiting the assessment of the primary efficacy endpoint.
    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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