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    Clinical Trial Results:
    Multicentre, randomised, controlled and double-blind clinical trial to evaluate the effectiveness and safety of bemiparin sodium as a treatment for diabetic foot ulcers (ROV-BEM-2006-01)

    Summary
    EudraCT number
    		 2006-005201-60
    Trial protocol
    		 ES  
    Global end of trial date
    23 Dec 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Aug 2016
    First version publication date
    05 Aug 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ROV-BEM-2006-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Laboratorios Farmacéuticos ROVI, S.A.
    Sponsor organisation address
    C/ Julián Camarillo, 35, Madrid, Spain, 28037
    Public contact
    Medical Department Laboratorios Farmacéuticos Rovi, SA, Laboratorios Farmacéuticos ROVI, S.A. C/ Julián Camarillo, 35 28037 Madrid, +34 912444434,
    Scientific contact
    Medical Department Laboratorios Farmacéuticos Rovi, SA, Laboratorios Farmacéuticos ROVI, S.A. C/ Julián Camarillo, 35 28037 Madrid, +34 912444434, departamento.medico@rovi.es
    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
    29 May 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study the efficacy and safety of bemiparin sodium as a treatment for diabetic foot ulcers
    Protection of trial subjects
    In the case of the appearance of an adverse event, the necessary support measures were taken for the recovery and maintenance of the vital signs of the subject within normality. The principal investigator were responsible for assuring the availability of the resources and staff necessary with sufficient experience to face the emergency situations that may occur in the study. Data protection: All data were handled confidentially according to the applicable law on personal data protection. The subjects were only identified by a number (inclusion and/or randomisation code). It was kept the confidentiality, only the principal investigator and co-workers had access to the personal data of the patients. Authorised agents from the sponsor and/or regulatory authorities and/or Clinical Research Ethics Committees had access to the site records that were relevant for the study, including clinical histories, laboratory reports with results, admission reports or summaries of discharge and other tests directly related to the study for verifying the data and information related to this protocol. In case the access to these medical records required express authorization or different from the informed consent, the investigator obtained directly and in writing this authorization from the patient before entry in the study.
    Background therapy
    		 Diabetic foot ulcer is characterised by a poor outcome, and a third of the cases can experience amputation after 3 years. Appropriate skin microcirculation and an adequate blood supply to the ulcer are critically important for healing the diabetic foot lesion. It has been also seen that in chronic wounds, the concentrations of growth factors such as platelet-derived growth factor and tumour growth factor are reduced. Both are essential for ulcer healing and there are studies describing that heparin can increase their production. Non-enzyme glycation of proteins of the endothelial basal membrane occurring in patients with diabetes mellitus affects the synthesis of heparin sulphate, a major endogenous activator of antithrombin III, that appears to play an essential role in the maintenance of homeostasis and endothelial function. It must be noted, for its significance in this protocol, that heparin stimulates the synthesiof heparin sulphate in endothelial culture cells and also in studies on the effect of heparin on diabetic angiopathy in animal models, identifying positive changes in the endothelial basal membrane. In humans treated with heparin, an improvement of diabetic retinopathy has been seen, with a reduction in the number of exudates and a reduction of proteinuria. In the context of diabetic foot ulcer, encouraging results have been also found in patients treated with heparin. Low-molecular weight heparins are known antithrombotics and antiinflammatories that can enhance microcirculation. A clinical trial has already shown that a LMWH (dalteparin) improves the outcome of diabetic foot ulcer in patients with peripheral occlusive arterial disease. A double-blind, placebo-controlled clinical trial has been also performed to evaluate the efficacy of bemiparin (another LMWH) in patients with diabetic foot ulcers. Preliminary results of this study appear to show that bemiparin sodium could have a beneficial effect on the healing of this type of wounds.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Mar 2007
    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
    Romania: 126
    Country: Number of subjects enrolled
    Serbia: 19
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    Croatia: 78
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Spain: 47
    Worldwide total number of subjects
    329
    EEA total number of subjects
    262
    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)
    329
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The recruitment of the study was from 21 March 2007 until 1 July 2009. The study was conducted in the following countries: Spain, Croatia, Russia, Romania, Serbia and Polonia.

    Pre-assignment
    Screening details
    		 In this period 416 patients, of which 329 were randomized finally being excluded a total of 87 (20.9%) patients (56 patients did not meet the selection criteria, 23 ulcers Neuropathic were not included, and 8 patients withdrew informed consent after inclusion).

    Pre-assignment period milestones
    Number of subjects started
    		 416 [1]
    Number of subjects completed
    		 329

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Inframalleolar ulcers / no neuropatic ulcers: 23
    Reason: Number of subjects
    		 Consent withdrawn by subject: 8
    Reason: Number of subjects
    		 Patients did not meet selection criteria: 56
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In this period 416 patients, of which 329 were randomized finally being excluded a total of 87 (20.9%) patients (56 patients did not meet the selection criteria, 23 ulcers Neuropathic were not included, and 8 patients withdrew informed consent after inclusion).
    Period 1
    Period 1 title
    Visit 1 (day-6 to -4) Selection Visit
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    If patients met inclusion criteria and none of the exclusion, they were registered for randomization. With this registry a stratified randomization process was performed for each patient, classificating them into strata based on characteristic criteria. After this process a randomization code is generated which identifies the patient with the corresponding treatment by randomization. Both MCI and placebo were physically the same including dosage in order to maintain double blind of study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sodic Bemiparine
    Arm description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Placebo

    Number of subjects in period 1
    		Sodic Bemiparine Placebo
    Started
    164
    165
    Completed
    164
    165
    Period 2
    Period 2 title
    Visit 2 (Day 0) Treatment Initiation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sodic Bemiparine
    Arm description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Placebo

    Number of subjects in period 2
    		Sodic Bemiparine Placebo
    Started
    164
    165
    Completed
    164
    165
    Period 3
    Period 3 title
    Visit 3 (4 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sodic Bemiparine
    Arm description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Placebo

    Number of subjects in period 3
    		Sodic Bemiparine Placebo
    Started
    164
    165
    Completed
    159
    158
    Not completed
    5
    7
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    2
    7
         Protocol deviation
    2
    -
    Period 4
    Period 4 title
    Visit 4 (8 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sodic Bemiparine
    Arm description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Placebo

    Number of subjects in period 4
    		Sodic Bemiparine Placebo
    Started
    159
    158
    Completed
    151
    148
    Not completed
    8
    10
         Consent withdrawn by subject
    -
    2
         Physician decision
    -
    4
         Lost to follow-up
    7
    2
         Protocol deviation
    1
    2
    Period 5
    Period 5 title
    Visit 5 (12 weeks) End of treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sodic Bemiparine
    Arm description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Placebo

    Number of subjects in period 5
    		Sodic Bemiparine Placebo
    Started
    151
    148
    Completed
    141
    143
    Not completed
    10
    5
         Consent withdrawn by subject
    6
    5
         Lost to follow-up
    4
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Sodic Bemiparine
    Reporting group description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 Sodic Bemiparine Placebo Total
    Number of subjects
    		 164 165 329
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 164 165 329
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.5 ( 10.9 ) 61 ( 11.1 ) -
    Gender categorical
    The percentage of men and women (71.3% - 28.7% respectively and 77.8% bemiparina - 22.2% placebo), mean age of the patients (61.5 years, 95% CI (59.5, 63.5) bemiparina, 61.0 years (95% CI 59.0, 63.0) placebo) and BMI of patients (27.7 kg / m2 95% CI (26.9, 28.6) bemiparina, 28.5 kg / m2 95% (27.7, 29.4) placebo) show no significant differences between treatment groups in study.
    Units: Subjects
        Female
    		 52 46 98
        Male
    		 112 119 231
    Ulcer
    Units: Subjects
        Grade I
    		 51 53 104
        Grade II
    		 113 112 225
    Antiplatelet treatment
    Units: Subjects
        Yes
    		 41 38 79
        No
    		 123 127 250
    Previous ulcers
    Units: Subjects
        Yes
    		 62 60 122
        No
    		 102 105 207
    Previous foot ulcers location
    Units: Subjects
        Righ foot
    		 28 31 59
        Left foot
    		 34 29 63
        None
    		 102 105 207
    Previous ulcers amputations
    Units: Subjects
        Yes
    		 39 42 81
        No
    		 23 18 41
        None
    		 102 105 207
    Type previous ulcers amputations
    Units: Subjects
        Majors
    		 7 6 13
        Minors
    		 32 36 68
        None
    		 125 123 248
    Type of diabetes mellitus
    Units: Subjects
        DM1
    		 22 20 42
        DM2
    		 142 145 287
    Treatment of diabetes mellitus
    Units: Subjects
        Yes
    		 156 152 308
        No
    		 8 13 21
    Retinopathy
    Units: Subjects
        Yes
    		 66 53 119
        No
    		 98 112 210
    Nephropathy
    Units: Subjects
        Yes
    		 37 30 67
        No
    		 127 135 262
    Neurophathy
    Units: Subjects
        Yes
    		 111 116 227
        No
    		 53 49 102
    Peripheral vascular disease
    Units: Subjects
        Yes
    		 67 65 132
        No
    		 97 100 197
    Cerebrovascular disease
    Units: Subjects
        Yes
    		 11 20 31
        No
    		 153 145 298
    Cardiovascular disease
    Units: Subjects
        Yes
    		 81 84 165
        No
    		 83 81 164
    Previous bleeding events
    Units: Subjects
        Yes
    		 4 2 6
        No
    		 160 163 323
    Dyslipidemia
    Units: Subjects
        Yes
    		 58 57 115
        No
    		 106 108 214
    Obesity
    Units: Subjects
        Yes
    		 43 44 87
        No
    		 121 121 242
    Hypertriglyceridemia
    Units: Subjects
        Yes
    		 43 50 93
        No
    		 121 115 236
    Hypercholesterolemia
    Units: Subjects
        Yes
    		 58 59 117
        No
    		 106 106 212
    Hypertension
    Units: Subjects
        Yes
    		 110 120 230
        No
    		 54 45 99
    Actual ulcer location
    Units: Subjects
        Righ foot
    		 83 75 158
        Left foot
    		 81 90 171
    Previous hospitalizations for ulcer in study
    Units: Subjects
        Yes
    		 20 24 44
        No
    		 144 141 285
    Clinical signs of infection in the ulcer in study
    Units: Subjects
        Yes
    		 8 12 20
        No
    		 156 153 309
    T/B Index
    T/B Index
    Units: Subjects
        0,9≥T/B≥0,7
    		 65 66 131
        T/B>0,9
    		 99 99 198
    Ulcer Area - Current location: Plantar
    Units: Subjects
        Yes
    		 61 59 120
        No
    		 103 106 209
    Ulcer Area - Current location: Dorsal
    Units: Subjects
        Yes
    		 17 17 34
        No
    		 147 148 295
    Ulcer Area - Current location: Digital
    Units: Subjects
        Yes
    		 58 74 132
        No
    		 106 91 197
    Ulcer Area - Current location: Interdigital
    Units: Subjects
        Yes
    		 7 6 13
        No
    		 157 159 316
    Ulcer Area - Current location: Heel
    Units: Subjects
        Yes
    		 30 15 45
        No
    		 134 150 284
    IMC (Kg/m2)
    IMC (Kg/m2)
    Units: subjects
        arithmetic mean (standard deviation)
    		 28.2 ( 4.8 ) 28.5 ( 4.6 ) -
    Years of evolution of diabetes mellitus (mead)
    Units: Years
        arithmetic mean (standard deviation)
    		 12.6 ( 9.5 ) 12.4 ( 9.7 ) -
    Weeks of evolution of the current ulcer
    Units: weeks
        arithmetic mean (standard deviation)
    		 28.1 ( ) 22.9 ( ) -
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Included all randomized patients who had a neuropathic ulcer (with inframalleolar location and index T / B ≥ 0.7) whose area of the ulcer in V2 is equal to or greater than 50 mm2 (using the measurement system VISITRAK wounds) which also had at least one post-randomization assessment of key variables (meet or not inclusion/exclusion) and they had received at least one dose of study medication. In the modified ITT population were not included 49 of the 164 patients included in the group bemiparina (36 patients for ulcer size <0.5 cm2, 8 of them with no features ulcers Neuropathic and supramalleolar or not and five location without at least one post-randomization evaluation of primary endpoint) and 48 of the 165 patients in the placebo group (37 ulcer size <0.5 cm2 5 with no neuropathic and supramalleolar or ulcers and 6 without at least an assessment postrandomization efficacy. Therefore the modified ITT population make up a total of 232 (115 in bemiparine group and 117 in placebo)

    Subject analysis set title
    Protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Included all patients who meet all requirements for ITT, the inclusion criteria and no exclusion criteria, which have had a compliance with study medication at least 80%, any prohibited medication had been administered and have not left the study for loss in follow-up during study medication treatment. In the protocol population were not included 36 of the 115 patients included in the group bemiparina (17 patients for poor adherence, 6 being treated with prohibited medication, 4 for failing to meet eligibility criteria and 9 patients older protocol deviations putting on compromise the integrity of the data) and 30 of the 117 patients in the placebo group (20 poor compliance, prohibited medication 3 1 did not meet selection criteria for engaging and 6 in major protocol deviations). Therefore the protocol population composes a total of 166 patients (79 patients in bemiparin group and 87 in placebo group).

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Included those randomized patients who received at least one dose of study medication. From 416 patients recruited were not included 87 patients (56 for failing to meet eligibility criteria, 23 inframaleolares / non-neuropathic ulcers and 8 informed consent withdrawal). So, 329 patients were randomized in which 164 were treated with bemiparin and 165 with placebo. These patients constituted the safety population, because they have received at least one dose of study medication.

    Subject analysis sets values
    		 ITT population Protocol population Safety population
    Number of subjects
    232
    166
    329
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    232
    166
    329
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.2 ( 11 )
    61.3 ( )
    61.8 ( )
    Gender categorical
    The percentage of men and women (71.3% - 28.7% respectively and 77.8% bemiparina - 22.2% placebo), mean age of the patients (61.5 years, 95% CI (59.5, 63.5) bemiparina, 61.0 years (95% CI 59.0, 63.0) placebo) and BMI of patients (27.7 kg / m2 95% CI (26.9, 28.6) bemiparina, 28.5 kg / m2 95% (27.7, 29.4) placebo) show no significant differences between treatment groups in study.
    Units: Subjects
        Female
    59
    36
    98
        Male
    173
    130
    231
    Ulcer
    Units: Subjects
        Grade I
    69
    54
    104
        Grade II
    163
    112
    225
    Antiplatelet treatment
    Units: Subjects
        Yes
    61
    42
    79
        No
    171
    124
    250
    Previous ulcers
    Units: Subjects
        Yes
    87
    61
    122
        No
    145
    105
    207
    Previous foot ulcers location
    Units: Subjects
        Righ foot
    42
    27
    59
        Left foot
    45
    34
    63
        None
    185
    105
    207
    Previous ulcers amputations
    Units: Subjects
        Yes
    63
    47
    81
        No
    24
    14
    41
        None
    145
    105
    207
    Type previous ulcers amputations
    Units: Subjects
        Majors
    8
    4
    13
        Minors
    55
    43
    68
        None
    169
    119
    248
    Type of diabetes mellitus
    Units: Subjects
        DM1
    32
    17
    42
        DM2
    200
    149
    287
    Treatment of diabetes mellitus
    Units: Subjects
        Yes
    216
    155
    308
        No
    16
    11
    21
    Retinopathy
    Units: Subjects
        Yes
    87
    59
    119
        No
    145
    107
    210
    Nephropathy
    Units: Subjects
        Yes
    44
    32
    67
        No
    188
    134
    262
    Neurophathy
    Units: Subjects
        Yes
    158
    119
    227
        No
    74
    47
    102
    Peripheral vascular disease
    Units: Subjects
        Yes
    87
    54
    132
        No
    145
    112
    197
    Cerebrovascular disease
    Units: Subjects
        Yes
    16
    11
    31
        No
    216
    155
    298
    Cardiovascular disease
    Units: Subjects
        Yes
    108
    82
    165
        No
    124
    84
    164
    Previous bleeding events
    Units: Subjects
        Yes
    4
    3
    6
        No
    228
    163
    323
    Dyslipidemia
    Units: Subjects
        Yes
    87
    55
    115
        No
    145
    111
    214
    Obesity
    Units: Subjects
        Yes
    52
    35
    87
        No
    180
    131
    242
    Hypertriglyceridemia
    Units: Subjects
        Yes
    62
    47
    93
        No
    170
    119
    236
    Hypercholesterolemia
    Units: Subjects
        Yes
    80
    54
    117
        No
    152
    112
    212
    Hypertension
    Units: Subjects
        Yes
    158
    111
    230
        No
    74
    55
    99
    Actual ulcer location
    Units: Subjects
        Righ foot
    116
    83
    158
        Left foot
    116
    83
    171
    Previous hospitalizations for ulcer in study
    Units: Subjects
        Yes
    34
    27
    44
        No
    198
    139
    285
    Clinical signs of infection in the ulcer in study
    Units: Subjects
        Yes
    16
    7
    20
        No
    216
    159
    309
    T/B Index
    T/B Index
    Units: Subjects
        0,9≥T/B≥0,7
    52
    60
    131
        T/B>0,9
    150
    106
    198
    Ulcer Area - Current location: Plantar
    Units: Subjects
        Yes
    101
    80
    120
        No
    131
    86
    209
    Ulcer Area - Current location: Dorsal
    Units: Subjects
        Yes
    21
    13
    34
        No
    211
    153
    295
    Ulcer Area - Current location: Digital
    Units: Subjects
        Yes
    81
    54
    132
        No
    151
    112
    197
    Ulcer Area - Current location: Interdigital
    Units: Subjects
        Yes
    9
    6
    13
        No
    223
    160
    316
    Ulcer Area - Current location: Heel
    Units: Subjects
        Yes
    29
    19
    45
        No
    203
    147
    284
    IMC (Kg/m2)
    IMC (Kg/m2)
    Units: subjects
        arithmetic mean (standard deviation)
    28.1 ( 4.6 )
    28.1 ( )
    28.3 ( )
    Years of evolution of diabetes mellitus (mead)
    Units: Years
        arithmetic mean (standard deviation)
    12.2 ( 9.5 )
    12.1 ( )
    12.5 ( )
    Weeks of evolution of the current ulcer
    Units: weeks
        arithmetic mean (standard deviation)
    25.5 ( 25.6 )
    25.3 ( )
    23.6 ( )

    End points

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    End points reporting groups
    Reporting group title
    Sodic Bemiparine
    Reporting group description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo
    Reporting group title
    Sodic Bemiparine
    Reporting group description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo
    Reporting group title
    Sodic Bemiparine
    Reporting group description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo
    Reporting group title
    Sodic Bemiparine
    Reporting group description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo
    Reporting group title
    Sodic Bemiparine
    Reporting group description
    		 Sodic Bemiparine 3.500 IU/day, prefilled syringes with 0,2 ml injectable solution

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Included all randomized patients who had a neuropathic ulcer (with inframalleolar location and index T / B ≥ 0.7) whose area of the ulcer in V2 is equal to or greater than 50 mm2 (using the measurement system VISITRAK wounds) which also had at least one post-randomization assessment of key variables (meet or not inclusion/exclusion) and they had received at least one dose of study medication. In the modified ITT population were not included 49 of the 164 patients included in the group bemiparina (36 patients for ulcer size <0.5 cm2, 8 of them with no features ulcers Neuropathic and supramalleolar or not and five location without at least one post-randomization evaluation of primary endpoint) and 48 of the 165 patients in the placebo group (37 ulcer size <0.5 cm2 5 with no neuropathic and supramalleolar or ulcers and 6 without at least an assessment postrandomization efficacy. Therefore the modified ITT population make up a total of 232 (115 in bemiparine group and 117 in placebo)

    Subject analysis set title
    Protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Included all patients who meet all requirements for ITT, the inclusion criteria and no exclusion criteria, which have had a compliance with study medication at least 80%, any prohibited medication had been administered and have not left the study for loss in follow-up during study medication treatment. In the protocol population were not included 36 of the 115 patients included in the group bemiparina (17 patients for poor adherence, 6 being treated with prohibited medication, 4 for failing to meet eligibility criteria and 9 patients older protocol deviations putting on compromise the integrity of the data) and 30 of the 117 patients in the placebo group (20 poor compliance, prohibited medication 3 1 did not meet selection criteria for engaging and 6 in major protocol deviations). Therefore the protocol population composes a total of 166 patients (79 patients in bemiparin group and 87 in placebo group).

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Included those randomized patients who received at least one dose of study medication. From 416 patients recruited were not included 87 patients (56 for failing to meet eligibility criteria, 23 inframaleolares / non-neuropathic ulcers and 8 informed consent withdrawal). So, 329 patients were randomized in which 164 were treated with bemiparin and 165 with placebo. These patients constituted the safety population, because they have received at least one dose of study medication.

    Primary: Significant improvement or complete healing of the ulcer

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    End point title
    		 Significant improvement or complete healing of the ulcer
    End point description
    Significant improvement defined as >=50% ulcer size reduction or 1 grade reduction on Wagner Scale
    End point type
    Primary
    End point timeframe
    3 months
    End point values
    		 Sodic Bemiparine Placebo ITT population
    Number of subjects analysed
    164 [1]
    165 [2]
    232
    Units: Percentage
        number (not applicable)
    66.1
    65.8
    65.9
    Notes
    [1] - ITT Sodic Bemiparine Results
    [2] - ITT Placebo Results
    Statistical analysis title
    		 ITT - Sodic Beniparine vs Placebo - Chi-Squared
    Comparison groups
    Sodic Bemiparine v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.965
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 PP - Sodic Beniparine vs Placebo - Chi-Squared
    Comparison groups
    Sodic Bemiparine v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.58
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Complete healing of the ulcer at the end of the study

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    End point title
    		 Complete healing of the ulcer at the end of the study
    End point description
    Complete healing of the ulcer at the end of the study
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Sodic Bemiparine Placebo
    Number of subjects analysed
    164 [3]
    165 [4]
    Units: Percentage
        number (not applicable)
    25.2
    25.6
    Notes
    [3] - ITT Sodic Beniparine Results
    [4] - ITT Placebo Results
    Statistical analysis title
    		 ITT - Sodic Beniparine vs Placebo - Chi-Squared
    Comparison groups
    Sodic Bemiparine v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.941
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 PP - Sodic Beniparine vs Placebo - Chi-Squared
    Comparison groups
    Sodic Bemiparine v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.884
    Method
    		 Chi-squared
    Confidence interval

    Other pre-specified: Complete healing of the ulcer by Wagner Scale Grade

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    End point title
    		 Complete healing of the ulcer by Wagner Scale Grade
    End point description
    Complete healing of the ulcer by Wagner Scale Grade
    End point type
    Other pre-specified
    End point timeframe
    3 months
    End point values
    		 Sodic Bemiparine Placebo
    Number of subjects analysed
    164 [5]
    165 [6]
    Units: Percentage
    number (not applicable)
        Grade I
    40
    60
        Grade II
    55.9
    44.1
    Notes
    [5] - ITT Sodic Beniparine Results
    [6] - ITT Placebo Results
    Statistical analysis title
    		 Grade I (Sodic Beniparine vs Placebo)-Chi-Squared
    Statistical analysis description
    Grade I (Sodic Beniparine vs Placebo)
    Comparison groups
    Sodic Bemiparine v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.423
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Grade II (Sodic Beniparine vs Placebo)-Chi-Squared
    Statistical analysis description
    Grade I (Sodic Beniparine vs Placebo) -Chi-Squared
    Comparison groups
    Sodic Bemiparine v Placebo
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.921
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety information was collected from the 329 randomized patients which received bemiparine or placebo treatment. SAEs were collected during the period of treatment, occurring after administration of treatment to 2 calendar days after completion.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Bemiparine Group
    Reporting group description
    		 -

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Serious adverse events
    		 Bemiparine Group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 164 (17.07%)
    21 / 165 (12.73%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Extremity necrosis
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrosis ischaemic
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular calcification
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Amputation
         subjects affected / exposed
    4 / 164 (2.44%)
    3 / 165 (1.82%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot amputation
         subjects affected / exposed
    3 / 164 (1.83%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodialysis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leg amputation
         subjects affected / exposed
    2 / 164 (1.22%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toe amputation
         subjects affected / exposed
    9 / 164 (5.49%)
    9 / 165 (5.45%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         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
    Disease progression
         subjects affected / exposed
    1 / 164 (0.61%)
    3 / 165 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Personality change due to a general medical condition
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose abnormal
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac hypertrophy
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    sudden death
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrogenic anaemia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Melaena
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    3 / 164 (1.83%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (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
    Abscess limb
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 164 (1.83%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    4 / 164 (2.44%)
    3 / 165 (1.82%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    6 / 164 (3.66%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    3 / 164 (1.83%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    4 / 164 (2.44%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    4 / 164 (2.44%)
    5 / 165 (3.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (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: 1%
    Non-serious adverse events
    		 Bemiparine Group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 164 (26.83%)
    33 / 165 (20.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Concomitant disease aggravated
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 165 (0.61%)
         occurrences all number
    1
    1
    Injection site haematoma
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Injection site haemorrhage
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Injection site pruritus
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 164 (0.61%)
    2 / 165 (1.21%)
         occurrences all number
    1
    2
    Blood pressure increased
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Poisoning
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Road traffic accident
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Skin injury
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Traumatic haematoma
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dementia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 165 (0.61%)
         occurrences all number
    1
    1
    Eosinophilia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Lymphocytosis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Monocytosis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Oesophagitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Excoriation
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Neuropathic ulcer
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Diabetic nephropathy
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Hypercreatininaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Diabetic retinopathy
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Cellulitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Fungal infection
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 165 (0.00%)
         occurrences all number
    2
    0
    Infected skin ulcer
         subjects affected / exposed
    11 / 164 (6.71%)
    8 / 165 (4.85%)
         occurrences all number
    11
    8
    Influenza
         subjects affected / exposed
    2 / 164 (1.22%)
    2 / 165 (1.21%)
         occurrences all number
    2
    2
    Lymphangitis
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 165 (1.21%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Osteomyelitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Purulent discharge
         subjects affected / exposed
    3 / 164 (1.83%)
    0 / 165 (0.00%)
         occurrences all number
    3
    0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 165 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Deficiency anaemia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Diabetic foot
         subjects affected / exposed
    2 / 164 (1.22%)
    3 / 165 (1.82%)
         occurrences all number
    2
    3
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    3 / 165 (1.82%)
         occurrences all number
    1
    3
    Hyperglycaemia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Hyperosmolar state
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 165 (0.61%)
         occurrences all number
    2
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 165 (0.61%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2007
    Version 2.0 dated 26/01/2007 was the second substantial amendment to protocol. It was authorized on 22/03/2007
    02 Jul 2007
    Version 3.0 dated 02/07/2007 was the third substantial amendment to protocol. It was authorized on 07/08/2007
    01 Jul 2008
    Version 4.0 dated 01/08/2008 was the 4th substantial amendment to protocol. It was authorized on 19/08/2008
    16 Jul 2008
    Version 5.0 dated 16/07/2008 was the 5th substantial amendment to protocol. It was authorized on 04/11/2008
    10 Mar 2009
    Version 6.0 dated 10/03/2009 was the 6th substantial amendment to protocolo. It was authorized on 19/05/2009
    02 Jul 2009
    Last version (ongoing) is 7.0 dated 02/07/2009 substantial amendment to protocol. It was authorized on 12/09/2009

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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