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    Clinical Trial Results:
    Prospective, phase II/III, randomized clinical study to compare BEGEDINA® versus "conventional treatment" for treating steroid resistant acute graft-versus host disease

    Summary
    EudraCT number
    		 2015-001360-19
    Trial protocol
    		 DE   ES   GB   FR   IT  
    Global end of trial date
    31 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2019
    First version publication date
    15 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ADN011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02411084
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 -: -
    Sponsors
    Sponsor organisation name
    ADIENNE S.A
    Sponsor organisation address
    Via Zurigo, 46, Lugano, Switzerland, 6900
    Public contact
    Clinical Project Manager, ADIENNE S.A, +41 7657305069, renata.palmieri@adienne.com
    Scientific contact
    Clinical Project Manager, ADIENNE S.A, +41 7657305069, renata.palmieri@adienne.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
    25 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the efficacy of BEGEDINA® versus conventional therapy in steroid-resistant acute graft-versus-host disease (GvHD) in terms of overall response at 28 days and transplant-related mortality (TRM) up to 180 days.
    Protection of trial subjects
    All subjects were free to withdraw from participation in the study at any time, for any reason, specified or unspecified and without prejudice to further treatment. In case of any intolerable AE or clinically significant laboratory value occurence, which could have compromised the subject's safety, the investigator decided that the subject's treatment should be discontinued for the health and welfare of the subject. In the situation where subjects needed supportive care, this was administered according to local regulations and standards of care and institutional and international guidelines. The care included, but was not limited to, the following: -Oral decontamination and oral hygiene; -Antibacterial, antiviral, antifungal prophylaxis; notably for: cytomegalovirus (CMV), gram positive (encapsulated) bacteria, Pneumocystis carinii and fungal infections per institutional practice; -Monitoring and treatment of CMV, Epstein-Barr virus (EBV), human herpesvirus 6 and adenovirus viremia (for "matched unrelated donor" follow specific Epstein-Barr virus monitoring); -Transfusions of erythrocite and platelet concentrates; all blood products were leukocyte depleted and irradiated; -Antiemetic prophylaxis and pain therapy.
    Background therapy
    		 During the study period, the subjects were allowed to the following medications and therapies: -Blood products; -Steroid therapy and calcineurin inhibitor were allowed as concomitant baseline therapy per protocol; -Subjects could continue any prior therapy used for prophylaxis at a stable dose from baseline if it has not been discontinued and restarted after initiating steroid treatment for acute GvHD; -Subjects with stable disease (SD) or progressive disease at Study Day 28 or subjects who cannot tolerate the randomized study treatment received third-line treatment for steroid-resistant acute GvHD; -Other routine supportive care as per standard practice.
    Evidence for comparator
    		 At the beginning of this clinical trial, there were no approved regimens for the treatment of steroid-refractory acute GvHD in adults. Therefore in the study, the choice of conventional treatment was at the discretion of the investigator (physician's best choice). The study design was unblinded, because the administration schedule could have varied between the different conventional treatments chosen and also between the conventional treatments and BEGEDINA.
    Actual start date of recruitment
    19 Feb 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    36
    EEA total number of subjects
    24
    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)
    35
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Out of the 29 sites selected (USA, France, Italy, Spain, Switzerland, UK, Germany) for participation in this study, 22 of them have activated screening and enrolment procedures, and 15 sites have effectively enrolled and randomized participants in the study. The first site approved was in Spain on 07 October 2015.

    Pre-assignment
    Screening details
    		 Out of 184 subjects planned, 37 subjects were screened and 36 subjects were randomized by IVRS in a 1:1 ratio. All subjects signed the informed consent and met all eligibility criteria except one case that had an incomplete screening procedure (some blood tests have not been performed for the screening visit as requested by the protocol).

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study team of the Sponsor and CRO (except the on-site monitors, pharmacovigilance and personnel as specified in the study-specific blinding plan), were blinded regarding the study treatment up to database lock and general unblinding. The same applied for the independent hematologist who evaluated the response. The DSMB members received unblinded outputs generated by a dedicated unblinded statistician and statistical programmer (both separated from the blinded study team members).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BEGEDINA
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BEGEDINA
    Investigational medicinal product code
    Other name
    Begelomab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Parenteral use
    Dosage and administration details
    Subjects have received BEGEDINA 2.7 mg/m2/day IV for 5 consecutive days (Study Days 1, 2, 3, 4, 5) and then on Study Days 10, 14, 17, 21, 24 and 28, for a total of 11 doses. A window (+/- 1 day) was permitted for doses from Day 10 to Day 28, however, all efforts have been made to plan these doses with at least 48 hours between doses. The total volume of BEGEDINA to be administered was diluted in 100 mL of sodium chloride 9 mg/mL (0.9%) solution for injection prior to administration. The infusion lasted for 60 minutes.

    Arm title
    		 Conventional Treatment
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Entanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dose: 25mg - administered in accordance with SPC

    Investigational medicinal product name
    Extracorporeal photopheresis
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Extracorporeal use
    Dosage and administration details
    The dose was established by the physician for each patient depending on the weight.

    Investigational medicinal product name
    Antithymocyte globulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 100mg once per day

    Investigational medicinal product name
    Mycophenolate Mofetil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 1000mg/8 hours or 1000mg/12 hours

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 0.5 mg twice per day

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 5mg twice per day, or 10 mg twice per day

    Investigational medicinal product name
    Methoxsalen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Dose: 200mcg according to SPC

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose 500mg

    Number of subjects in period 1
    		BEGEDINA Conventional Treatment
    Started
    18
    18
    Completed
    18
    18
    Period 2
    Period 2 title
    End of treatment (Day 28)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BEGEDINA
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BEGEDINA
    Investigational medicinal product code
    Other name
    Begelomab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Parenteral use
    Dosage and administration details
    Subjects have received BEGEDINA 2.7 mg/m2/day IV for 5 consecutive days (Study Days 1, 2, 3, 4, 5) and then on Study Days 10, 14, 17, 21, 24 and 28, for a total of 11 doses. A window (+/- 1 day) was permitted for doses from Day 10 to Day 28, however, all efforts have been made to plan these doses with at least 48 hours between doses. The total volume of BEGEDINA to be administered was diluted in 100 mL of sodium chloride 9 mg/mL (0.9%) solution for injection prior to administration. The infusion lasted for 60 minutes.

    Arm title
    		 Conventional Treatment
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Entanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dose: 25mg - administered in accordance with PCR

    Investigational medicinal product name
    Extracorporeal photopheresis
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Parenteral use
    Dosage and administration details
    The dose was established by the physician for each patient, depending on the weight.

    Investigational medicinal product name
    Antithymocyte globulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 100mg QOD

    Investigational medicinal product name
    Mycophenolate Mofetil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 1000mg/8 hours or 1000mg/12 hours

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 0.5 mg twice a day

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 5mg twice per day, or 10 mg twice per day

    Investigational medicinal product name
    Methoxsalen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Dose: 200mcg according to PCR

    Number of subjects in period 2
    		BEGEDINA Conventional Treatment
    Started
    18
    18
    Completed
    5
    5
    Not completed
    13
    13
         Adverse event, serious fatal
    5
    4
         Adverse event, non-fatal
    2
    1
         Other reasons
    -
    5
         Lack of efficacy
    6
    3
    Period 3
    Period 3 title
    End of Study (Day 180)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BEGEDINA
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BEGEDINA
    Investigational medicinal product code
    Other name
    Begelomab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Parenteral use
    Dosage and administration details
    Subjects have received BEGEDINA 2.7 mg/m2/day IV for 5 consecutive days (Study Days 1, 2, 3, 4, 5) and then on Study Days 10, 14, 17, 21, 24 and 28, for a total of 11 doses. A window (+/- 1 day) was permitted for doses from Day 10 to Day 28, however, all efforts have been made to plan these doses with at least 48 hours between doses. The total volume of BEGEDINA to be administered was diluted in 100 mL of sodium chloride 9 mg/mL (0.9%) solution for injection prior to administration. The infusion lasted for 60 minutes.

    Arm title
    		 Conventional Treatment
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Entanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dose: 25mg - administered in accordance with PCR

    Investigational medicinal product name
    Extracorporeal photopheresis
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Parenteral use
    Dosage and administration details
    The dose was established by the physician for each patient, depending on the weight.

    Investigational medicinal product name
    Antithymocyte globulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 100mg QOD

    Investigational medicinal product name
    Mycophenolate Mofetil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 1000mg/8 hours or 1000mg/12 hours

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 0.5 mg twice a day

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 5mg twice per day, or 10 mg twice per day

    Investigational medicinal product name
    Methoxsalen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Dose: 200mcg according to PCR

    Number of subjects in period 3
    		BEGEDINA Conventional Treatment
    Started
    5
    5
    Completed
    2
    4
    Not completed
    3
    1
         Adverse event, serious fatal
    2
    1
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BEGEDINA
    Reporting group description
    		 -

    Reporting group title
    Conventional Treatment
    Reporting group description
    		 -

    Reporting group values
    		 BEGEDINA Conventional Treatment Total
    Number of subjects
    		 18 18 36
    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)
    		 17 18 35
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 5 7 12
        Male
    		 13 11 24

    End points

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    End points reporting groups
    Reporting group title
    BEGEDINA
    Reporting group description
    		 -

    Reporting group title
    Conventional Treatment
    Reporting group description
    		 -
    Reporting group title
    BEGEDINA
    Reporting group description
    		 -

    Reporting group title
    Conventional Treatment
    Reporting group description
    		 -
    Reporting group title
    BEGEDINA
    Reporting group description
    		 -

    Reporting group title
    Conventional Treatment
    Reporting group description
    		 -

    Primary: Efficacy

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    End point title
    		 Efficacy [1]
    End point description
    Analysis of primary efficacy endpoints could not be perfomed because of the premature discontinuation of the study.
    End point type
    Primary
    End point timeframe
    Day 180
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis of primary efficacy endpoints could not be performed because of the premature discontinuation of the study.
    End point values
    		 BEGEDINA Conventional Treatment BEGEDINA Conventional Treatment BEGEDINA Conventional Treatment
    Number of subjects analysed
    18
    18
    5
    5
    2
    4
    Units: percentage
    18
    18
    5
    5
    2
    4
    No statistical analyses for this end point

    Secondary: Safety

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    End point title
    		 Safety
    End point description
    The secondary safety objectives were: -to compare the safety and tolerability of BEGEDINA and conventional therapy. -to gather additional information on the safety of BEGEDINA in subjects with Grades II-IV acute GvHD, who have failed to respond to steroid treatment. -to evaluate the immunogenicity of BEGEDINA - to evaluate the effect of BEGEDINA on glucose metabolism. -to compare the incidence of second malignancies at the end of the follow-up between BEGEDINA and convetional therapy
    End point type
    Secondary
    End point timeframe
    Day 0 until Day 180.
    End point values
    		 BEGEDINA Conventional Treatment BEGEDINA Conventional Treatment BEGEDINA Conventional Treatment
    Number of subjects analysed
    18
    18
    5
    5
    2
    4
    Units: percentage
    18
    18
    5
    5
    2
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    A total of 650 adverse events were recorded during the study, almost similar distributed in both groups: 326 cases in BEGEDINA® group (301 non–serious AEs and 25 serious AEs) vs 324 cases in Conventional treatment group (295 non-serious and 29 serious)
    Adverse event reporting additional description
    Information about all AEs, whether volunteered by the subjects, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, were collected and recorded on the eCRF AE section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    BEGEDINA group
    Reporting group description
    		 The most frequent adverse events recorded after administration of BEGEDINA® were platelet count decreased (19.4% cases), anemia (16.7% cases), leukocytes count decreased (11.1% cases). Cytomegalovirus infection was found in 16.7% cases and peripheral edema in 13.9% cases. There were recorded 25 serious adverse events. At the end of the study rate of serious adverse events which determined early discontinuation in BEGEDINA® group was 22.2 % ( 4 subjects). At the end of the study (approx. day 180), death occurred in 36.1 % (13 subjects) in BEGEDINA® group.

    Reporting group title
    Conventional treatment
    Reporting group description
    		 The most frequent adverse events recorded in the conventional treatment arm were peripheral edema(22.2% cases), pyrexia (19.4% cases). Cytomegalovirus infection was found in 13.9% cases. There were recorded 29 serious adverse events. At Day 28, death occurred in 11.1% cases in this treatment group. At the end of the study rate of serious adverse events which determined early discontinuation in conventional treatment arm was 5.6 % (one subject). Mortality (approx. day 180) was 22.2 % (8 subjects) in the conventional treatment group.

    Serious adverse events
    		 BEGEDINA group Conventional treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 18 (88.89%)
    13 / 18 (72.22%)
         number of deaths (all causes)
    13
    8
         number of deaths resulting from adverse events
    13
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Shock haemorrhagic
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Graft versus host disease in liver
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute graft versus host disease
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Acute graft versus host disease in skin
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Obliterative bronchiolitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         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
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         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
    Rash maculo-papular
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (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
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cytomegalovirus enteritis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Phlebitis infective
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Device related infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 BEGEDINA group Conventional treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 18 (100.00%)
    18 / 18 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    2 / 18 (11.11%)
    5 / 18 (27.78%)
         occurrences all number
    2
    5
    Hypotension
         subjects affected / exposed
    3 / 18 (16.67%)
    4 / 18 (22.22%)
         occurrences all number
    3
    4
    Shock
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Superior vena cava occlusion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Transurethral bladder resection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Chest pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Face oedema
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    3 / 18 (16.67%)
    3 / 18 (16.67%)
         occurrences all number
    4
    6
    Gait disturbance
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hypothermia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    5 / 18 (27.78%)
    8 / 18 (44.44%)
         occurrences all number
    7
    9
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Localised oedema
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 18 (16.67%)
    6 / 18 (33.33%)
         occurrences all number
    4
    7
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Graft versus host disease in liver
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Acute graft versus host disease
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oedema genital
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Pelvic pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Penile pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Acute respiratory failure
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Aspiration
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Hiccups
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Hypoxia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Pleural effusion
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Pneumonitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pulmonary oedema
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Adjustment disorder with depressed mood
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Anxiety
         subjects affected / exposed
    4 / 18 (22.22%)
    2 / 18 (11.11%)
         occurrences all number
    5
    3
    Apathy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Confusional state
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Delirium
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
         occurrences all number
    2
    2
    Disorientation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hallucination
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hallucination, auditory
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Mental status changes
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Bradyphrenia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
         occurrences all number
    7
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    Blood bilirubin increased
         subjects affected / exposed
    5 / 18 (27.78%)
    1 / 18 (5.56%)
         occurrences all number
    10
    1
    Blood creatine increased
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Blood magnesium decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Haptoglobin decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    7
    5
    Neutrophil count decreased
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
         occurrences all number
    5
    2
    Platelet count decreased
         subjects affected / exposed
    7 / 18 (38.89%)
    1 / 18 (5.56%)
         occurrences all number
    24
    6
    Weight decreased
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Weight increased
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    White blood cell count decreased
         subjects affected / exposed
    4 / 18 (22.22%)
    2 / 18 (11.11%)
         occurrences all number
    8
    2
    Transaminases increased
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Troponin increased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Staphylococcus test positive
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Klebsiella test positive
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Liver function test increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 18 (5.56%)
    4 / 18 (22.22%)
         occurrences all number
    1
    5
    Excoriation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Rib fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Cardiac disorder
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Mitral valve disease
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Dysgeusia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Encephalopathy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Hemiparesis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Intention tremor
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Memory impairment
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Spinal cord compression
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 18 (16.67%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 18 (33.33%)
    4 / 18 (22.22%)
         occurrences all number
    11
    6
    Leukopenia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
         occurrences all number
    3
    2
    Neutrophilia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Eustachian tube disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Visual impairment
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    3 / 18 (16.67%)
    4 / 18 (22.22%)
         occurrences all number
    5
    10
    Abdominal pain lower
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Diarrhoea
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
         occurrences all number
    3
    2
    Dry mouth
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Dyspepsia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Enterocolitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastric dilatation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Haematemesis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Ileus
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Pancreatitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    4
    Vomiting
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    3
    2
    Anal haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Bile duct stenosis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hepatobiliary disease
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Decubitus ulcer
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Dermatitis bullous
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Ecchymosis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nail dystrophy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Petechiae
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    3
    Skin atrophy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin ulcer
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Oliguria
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 18 (11.11%)
         occurrences all number
    2
    2
    Proteinuria
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Renal failure
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Urethral pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Bladder disorder
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Renal impairment
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 18 (16.67%)
         occurrences all number
    2
    4
    Acute kidney injury
         subjects affected / exposed
    4 / 18 (22.22%)
    1 / 18 (5.56%)
         occurrences all number
    4
    1
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bacterial disease carrier
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Cellulitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Epstein-Barr virus infection
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 18 (5.56%)
         occurrences all number
    3
    1
    Liver abscess
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 18 (22.22%)
    2 / 18 (11.11%)
         occurrences all number
    4
    2
    Wound infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Stenotrophomonas infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Parvovirus infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oesophageal infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Adenovirus infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Enterococcal infection
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Escherichia infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Candida infection
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Cytomegalovirus infection
         subjects affected / exposed
    6 / 18 (33.33%)
    4 / 18 (22.22%)
         occurrences all number
    8
    6
    Fungal infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Sepsis
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Bacterial sepsis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Device related infection
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 18 (16.67%)
         occurrences all number
    2
    3
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Diabetes mellitus
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Haemochromatosis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    7 / 18 (38.89%)
    3 / 18 (16.67%)
         occurrences all number
    11
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    6
    0
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 18 (16.67%)
    4 / 18 (22.22%)
         occurrences all number
    3
    5
    Hypocalcaemia
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    3
    3
    Hypomagnesaemia
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 18 (16.67%)
         occurrences all number
    2
    5
    Hyponatraemia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    Hypophosphataemia
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
         occurrences all number
    8
    1
    Hypovolaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Tetany
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Malnutrition
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Decreased appetite
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Arthralgia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 18 (16.67%)
         occurrences all number
    1
    6
    Bone pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Sarcopenia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    4 / 18 (22.22%)
    3 / 18 (16.67%)
         occurrences all number
    13
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2015
    Protocol version 1.0 was submitted in US only and have received comments from US authorities
    12 May 2015
    Protocol version 2.0 (12-May-2015) of the protocol was never submitted to the authorities and was only for internal use.
    25 Jun 2015
    Protocol version 3.0, was submitted to FDA, FR, DE, IT, ES, UK and Switzerland. In addition, modifications that have been requested by the health authorities in the United Kingdom and Spain (and issued in these countries, specific versions 3.1) regarding acceptable methods of birth control have been incorporated here. Protocol version 3.1 was approved in UK on 01-SEP-2015 ans in Spain on 22-OCT-2015.
    14 Oct 2016
    Protocol Version 4.0 has never been implemented.
    13 Mar 2017
    Protocol version 5.0 Protocol version 5.0 has been amended to reduce follow-up time in line with endpoints of the protocol, from 365 days to 180 days. Also, from Version 3.0 to 5.0, a number of changes have been made regarding the: study enrolment period, Inclusion and exclusion criteria, laboratory assessments, blinding methods, a list of secondary efficacy objectives was added, changes in protocol background and protocol references.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Mar 2017
    The study was prematurely terminated because of the lack of enrollment
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Lack of enrollment
    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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