Diabetic Foot Ulcer
Conditions
Keywords
Diabetic Foot Ulcers Neuroischaemic
Brief summary
The purpose of the study isto see the effect of Fragmin on the healing of diabetic foot ulcers by determining the number of subjects with ≥50% reduction in ulcer surface area including intact skin healing.
Interventions
DRUGFragmin/ Dalteparin Sodium
Pre-filled syringes containing a single dose of 5000 IU Fragmin/ Dalteparin Sodium.
DRUGPlacebo for Fragmin/ Dalteparin Sodium
Pre-filled syringes containing a single dose of placebo for 5000 IU Fragmin/ Dalteparin Sodium.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects 18 years of age with type 1 or type 2 diabetes. * Subjects with peripheral occlusive arterial disease (PAOD) and a neuropathy disability score (NDS) of \>3
Exclusion criteria
* Subjects who have undergone vascular reconstruction or angioplasty less than 1 month prior to randomization. Subjects with an ulcer grading of 0 or 3 and staging of A, B or D according to the University of Texas wound classification system. * Subjects with a known bleeding disorder or evidence of active bleeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing | Week 24 [end of treatment (EOT)] or early termination | University of Texas (UT) system assesses ulcer depth, wound infection and clinical signs of lower-extremity ischemia. UT Wound Classification (1C/2C) was based on grade (0= healed site to 3= penetrating wound to bone or joint) and stage (A= clean wounds to D= ischaemic infected wounds) of wounds. Participants were evaluated at 4 stratums: Stratum 1: Toe pressure\>30 mm of mercury (mmHg) and UT grade and stage 1C. Stratum 2: Toe pressure\<=30 mmHg and UT grade and stage 1C. Stratum 3: Toe pressure\>30 mmHg and UT grade and stage 2C. Stratum 4: Toe pressure\<=30 mmHg and UT grade and stage 2C. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died | Week 24 (EOT) or early termination | — |
| 36-Item Short-Form Health Survey (SF-36) Score | Baseline and Week 24 (EOT or early termination) | SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). |
| 11-point Likert Pain Scale | Baseline and Week 24 (EOT or early termination) | The 11 point Likert pain scale which used a 0 (no pain) to 10 (worst possible pain) point rating system was used to assess participant's pain score. No distinction was made between neuropathy and inflammatory (nociceptive) pain. |
| Transcutaneous Local Tissue Oxygenation (pO2) | Baseline and Week 24 (EOT or early termination) | Transcutaneous pO2 was assessed at the dorsum of the foot in the first intermetatarsal space using an appropriately calibrated instrument. The skin oxygen partial pressure was determined by measuring the oxygen reduction current by means of a measuring cell. |
| Number of Participants With Intact Skin Healing | Week 24 (EOT) or early termination | Intact skin healing was defined as 100 percent reduction in ulcer surface area with full epithelialisation. UT system assesses ulcer depth, wound infection and clinical signs of lower-extremity ischemia. Participants were evaluated at 4 stratums: Stratum 1: Toe pressure\>30 mm of mercury (mmHg) and UT grade and stage 1C. Stratum 2: Toe pressure\<=30 mmHg and UT grade and stage 1C. Stratum 3: Toe pressure\>30 mmHg and UT grade and stage 2C. Stratum 4: Toe pressure\<=30 mmHg and UT grade and stage 2C. |
| Number of Participants Who Underwent Any Amputation | Week 24 (EOT) or early termination | Any amputation included both major and minor amputations. A major amputation was defined as above the ankle and was reported as below-the-knee and above-the-knee amputations. A minor amputation was defined as below the ankle amputation. |
| Number of Participants Who Underwent Major and Minor Amputation | Week 24 (EOT) or early termination | A major amputation was defined as above the ankle and was reported as below-the-knee and above-the-knee amputations. A minor amputation was defined as below the ankle amputation. |
| Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS) | Baseline and Week 24 (EOT or early termination) | EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state. |
| Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing | Week 24 (EOT) or early termination | University of Texas (UT) system assesses ulcer depth, wound infection and clinical signs of lower-extremity ischemia. UT Wound Classification (1C/2C) was based on grade (0= healed site to 3= penetrating wound to bone or joint) and stage (A= clean wounds to D= ischaemic infected wounds) of wounds. Participants were evaluated at 4 stratums: Stratum 1: Toe pressure\>30 mm of mercury (mmHg) and UT grade and stage 1C. Stratum 2: Toe pressure\<=30 mmHg and UT grade and stage 1C. Stratum 3: Toe pressure\>30 mmHg and UT grade and stage 2C. Stratum 4: Toe pressure\<=30 mmHg and UT grade and stage 2C. |
| Number of Participants With Major Cardiovascular Disease Events (MCVE) | Week 24 (EOT) or early termination | Major cardiovascular events were defined as death due to vascular cause; non-fatal myocardial infarction (MI) excluding procedure related to MI; coronary revascularization procedures not related to MIs; hospitalization for unstable angina or non-fatal stroke. |
| Time to Intact Skin Healing | Week 24 (EOT) or early termination | Median time taken to achieve intact skin healing which was defined as 100 percent reduction in ulcer surface area with full epithelialisation. |
| Median Time to First Amputation | Week 24 (EOT) or early termination | — |
| Euro Quality of Life-5 Dimensions (EQ-5D)- Utility Score | Baseline and Week 24 (EOT or early termination) | EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. It assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (eg, confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain in profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Clinically Relevant Minor Hemorrhages and Trivial Hemorrhages | Week 24 (EOT) or early termination | Clinically relevant minor (non-major) bleeding was defined as any bleeding compromising hemodynamics, leading to hospitalization, subcutaneous haematoma more than 25 cm\^2, intramuscular haematoma, epistaxis lasting for more than 5 minutes, spontaneous gingival bleeding, macroscopic hematuria and gastrointestinal hemorrhage (including at least 1 episode of melaena or hematemesis), rectal blood loss, hemoptysis, and any other bleeding with clinical consequences. Trivial bleeding was defined as all minor bleeding that did not meet the definition of clinically relevant minor bleeding. |
| Number of Major and Minor Hemorrhages | Week 24 (EOT) or early termination | Major hemorrhages: defined as fatal bleeding, clinically overt bleeding causing a fall in hemoglobin more than or equal to 20 gram (g)/litre (L) (2 g/ decilitre \[dL\]), clinically overt bleeding leading to transfusion of more than or equal to 2 units of whole blood or red cells, or symptomatic bleeding in areas of special concern (intracranial, retroperitoneal, intraocular, intraspinal, pericardial, intramuscular with compartmental syndrome, or intraarticular). Minor hemorrhages: defined as bleeding that did not meet the definition of major bleeding. |
| Number of All Hemorrhages | Week 24 (EOT) or early termination | Major hemorrhages: defined as fatal bleeding, clinically overt bleeding causing a fall in hemoglobin more than or equal to 20 gram (g)/litre (L) (2 g/ decilitre \[dL\]), clinically overt bleeding leading to transfusion of more than or equal to 2 units of whole blood or red cells, or symptomatic bleeding in areas of special concern (intracranial, retroperitoneal, intraocular, intraspinal, pericardial, intramuscular with compartmental syndrome, or intraarticular). Minor hemorrhages: defined as bleeding that did not meet the definition of major bleeding. |
Countries
Austria, Belgium, Canada, Czechia, Denmark, Finland, Germany, Greece, Italy, Lithuania, Norway, Poland, Russia, Spain, Sweden, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dalteparin Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET). | 184 |
| Placebo Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET. | 92 |
| Total | 276 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 23 | 16 |
| Overall Study | Death | 4 | 1 |
| Overall Study | Lack of Efficacy | 6 | 6 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 62 | 31 |
| Overall Study | Protocol Violation | 8 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Dalteparin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.8 years STANDARD_DEVIATION 10.3 | 64.7 years STANDARD_DEVIATION 10.9 | 64.8 years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 63 Participants | 30 Participants | 93 Participants |
| Sex: Female, Male Male | 121 Participants | 62 Participants | 183 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 76 / 184 | 36 / 92 |
| serious Total, serious adverse events | 33 / 184 | 18 / 92 |
Outcome results
Primary
Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing
University of Texas (UT) system assesses ulcer depth, wound infection and clinical signs of lower-extremity ischemia. UT Wound Classification (1C/2C) was based on grade (0= healed site to 3= penetrating wound to bone or joint) and stage (A= clean wounds to D= ischaemic infected wounds) of wounds. Participants were evaluated at 4 stratums: Stratum 1: Toe pressure\>30 mm of mercury (mmHg) and UT grade and stage 1C. Stratum 2: Toe pressure\<=30 mmHg and UT grade and stage 1C. Stratum 3: Toe pressure\>30 mmHg and UT grade and stage 2C. Stratum 4: Toe pressure\<=30 mmHg and UT grade and stage 2C.
Time frame: Week 24 [end of treatment (EOT)] or early termination
Population: Intention to treat (ITT) population included all participants who were randomized. Last observation carried forward (LOCF) method was used. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dalteparin | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing | Stratum 3 (n= 29, 14) | 21 participants |
| Dalteparin | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing | Stratum 2 (n= 39, 19) | 23 participants |
| Dalteparin | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing | Stratum 4 (n= 19, 10) | 9 participants |
| Dalteparin | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing | Stratum 1 (n= 97, 49) | 68 participants |
| Placebo | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing | Stratum 4 (n= 19, 10) | 6 participants |
| Placebo | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing | Stratum 2 (n= 39, 19) | 14 participants |
| Placebo | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing | Stratum 3 (n= 29, 14) | 10 participants |
| Placebo | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Including Intact Skin Healing | Stratum 1 (n= 97, 49) | 31 participants |
Secondary
11-point Likert Pain Scale
The 11 point Likert pain scale which used a 0 (no pain) to 10 (worst possible pain) point rating system was used to assess participant's pain score. No distinction was made between neuropathy and inflammatory (nociceptive) pain.
Time frame: Baseline and Week 24 (EOT or early termination)
Population: ITT population included all participants who were randomized. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dalteparin | 11-point Likert Pain Scale | Baseline | 4.20 Units on a scale | Standard Deviation 2.76 |
| Dalteparin | 11-point Likert Pain Scale | EOT (n= 155, 75) | 2.10 Units on a scale | Standard Deviation 2.27 |
| Placebo | 11-point Likert Pain Scale | Baseline | 4.50 Units on a scale | Standard Deviation 2.83 |
| Placebo | 11-point Likert Pain Scale | EOT (n= 155, 75) | 2.50 Units on a scale | Standard Deviation 2.54 |
Secondary
36-Item Short-Form Health Survey (SF-36) Score
SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).
Time frame: Baseline and Week 24 (EOT or early termination)
Population: ITT population included all participants who were randomized. This was calculated only when more than half of the questions within dimension were answered. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Bodily Pain (n= 156, 76) | 47.50 Units on a scale | Standard Deviation 10.3 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Mental Health (n= 156, 76) | 41.90 Units on a scale | Standard Deviation 6.2 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Physical Functioning | 34.70 Units on a scale | Standard Deviation 12.06 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Role-Physical | 35.40 Units on a scale | Standard Deviation 11.22 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Bodily Pain | 42.30 Units on a scale | Standard Deviation 11.19 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: General Health | 42.30 Units on a scale | Standard Deviation 5.52 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Visibility | 48.30 Units on a scale | Standard Deviation 5.63 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Social Functioning | 33.00 Units on a scale | Standard Deviation 6.49 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Role-Emotional | 39.10 Units on a scale | Standard Deviation 13.48 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Mental Health | 41.90 Units on a scale | Standard Deviation 6.57 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Physical (PCS) | 38.10 Units on a scale | Standard Deviation 9.42 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Mental (MCS) | 42.40 Units on a scale | Standard Deviation 7.26 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Physical Functioning (n= 156, 76) | 37.10 Units on a scale | Standard Deviation 11.71 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Role-Physical (n= 155, 76) | 39.30 Units on a scale | Standard Deviation 11.25 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: General Health (n= 156, 76) | 42.50 Units on a scale | Standard Deviation 5.1 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Visibility (n= 156, 76) | 48.20 Units on a scale | Standard Deviation 5.58 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Social Functioning (n= 152, 73) | 33.30 Units on a scale | Standard Deviation 6.13 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Role-Emotional (n= 155, 76) | 41.20 Units on a scale | Standard Deviation 13.44 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Physical (PCS) (n= 151, 73) | 41.70 Units on a scale | Standard Deviation 9.04 |
| Dalteparin | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Mental (MCS) (n= 151, 73) | 42.10 Units on a scale | Standard Deviation 6.89 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Role-Emotional (n= 155, 76) | 38.80 Units on a scale | Standard Deviation 13.48 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Bodily Pain (n= 156, 76) | 45.00 Units on a scale | Standard Deviation 10.73 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Physical (PCS) | 36.70 Units on a scale | Standard Deviation 8.75 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Mental Health (n= 156, 76) | 42.00 Units on a scale | Standard Deviation 6.8 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Visibility (n= 156, 76) | 48.80 Units on a scale | Standard Deviation 5.15 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Physical Functioning | 32.50 Units on a scale | Standard Deviation 10.96 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Mental (MCS) | 42.80 Units on a scale | Standard Deviation 7.37 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Role-Physical | 35.20 Units on a scale | Standard Deviation 11.41 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Mental (MCS) (n= 151, 73) | 41.60 Units on a scale | Standard Deviation 6.46 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Bodily Pain | 40.30 Units on a scale | Standard Deviation 11.52 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Physical Functioning (n= 156, 76) | 35.50 Units on a scale | Standard Deviation 11.39 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: General Health | 42.60 Units on a scale | Standard Deviation 5.1 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Social Functioning (n= 152, 73) | 32.30 Units on a scale | Standard Deviation 5.83 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Visibility | 48.70 Units on a scale | Standard Deviation 5.02 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Role-Physical (n= 155, 76) | 37.50 Units on a scale | Standard Deviation 11.31 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Social Functioning | 33.10 Units on a scale | Standard Deviation 6.9 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: Physical (PCS) (n= 151, 73) | 40.10 Units on a scale | Standard Deviation 8.6 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Role-Emotional | 38.30 Units on a scale | Standard Deviation 13.49 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | EOT: General Health (n= 156, 76) | 42.80 Units on a scale | Standard Deviation 5.15 |
| Placebo | 36-Item Short-Form Health Survey (SF-36) Score | Baseline: Mental Health | 41.30 Units on a scale | Standard Deviation 6.72 |
Secondary
Euro Quality of Life-5 Dimensions (EQ-5D)- Utility Score
EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. It assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (eg, confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain in profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state.
Time frame: Baseline and Week 24 (EOT or early termination)
Population: ITT population included all participants who were randomized. Participants were only considered when all items contributing to the score had been answered. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dalteparin | Euro Quality of Life-5 Dimensions (EQ-5D)- Utility Score | Baseline | 0.60 Units on a scale | Standard Deviation 0.26 |
| Dalteparin | Euro Quality of Life-5 Dimensions (EQ-5D)- Utility Score | EOT (n= 154, 74) | 0.70 Units on a scale | Standard Deviation 0.22 |
| Placebo | Euro Quality of Life-5 Dimensions (EQ-5D)- Utility Score | Baseline | 0.60 Units on a scale | Standard Deviation 0.3 |
| Placebo | Euro Quality of Life-5 Dimensions (EQ-5D)- Utility Score | EOT (n= 154, 74) | 0.60 Units on a scale | Standard Deviation 0.33 |
Secondary
Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS)
EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state.
Time frame: Baseline and Week 24 (EOT or early termination)
Population: ITT population included all participants who were randomized. Participants were only considered when all items contributing to the score had been answered. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dalteparin | Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS) | Baseline | 60.20 mm | Standard Deviation 18.68 |
| Dalteparin | Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS) | EOT (n= 157, 76) | 63.30 mm | Standard Deviation 18.76 |
| Placebo | Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS) | Baseline | 55.30 mm | Standard Deviation 19.72 |
| Placebo | Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS) | EOT (n= 157, 76) | 60.70 mm | Standard Deviation 18.02 |
Secondary
Median Time to First Amputation
Time frame: Week 24 (EOT) or early termination
Population: The data was not analyzed as planned because the study enrollment was terminated before the planned number of randomized participants was obtained.
Secondary
Number of Participants Who Died
Time frame: Week 24 (EOT) or early termination
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalteparin | Number of Participants Who Died | 4 participants |
| Placebo | Number of Participants Who Died | 3 participants |
Secondary
Number of Participants Who Underwent Any Amputation
Any amputation included both major and minor amputations. A major amputation was defined as above the ankle and was reported as below-the-knee and above-the-knee amputations. A minor amputation was defined as below the ankle amputation.
Time frame: Week 24 (EOT) or early termination
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalteparin | Number of Participants Who Underwent Any Amputation | 8 participants |
| Placebo | Number of Participants Who Underwent Any Amputation | 2 participants |
Secondary
Number of Participants Who Underwent Major and Minor Amputation
A major amputation was defined as above the ankle and was reported as below-the-knee and above-the-knee amputations. A minor amputation was defined as below the ankle amputation.
Time frame: Week 24 (EOT) or early termination
Population: ITT population included all participants who were randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dalteparin | Number of Participants Who Underwent Major and Minor Amputation | Major amputation | 2 participants |
| Dalteparin | Number of Participants Who Underwent Major and Minor Amputation | Minor amputation | 7 participants |
| Placebo | Number of Participants Who Underwent Major and Minor Amputation | Major amputation | 1 participants |
| Placebo | Number of Participants Who Underwent Major and Minor Amputation | Minor amputation | 1 participants |
Secondary
Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing
University of Texas (UT) system assesses ulcer depth, wound infection and clinical signs of lower-extremity ischemia. UT Wound Classification (1C/2C) was based on grade (0= healed site to 3= penetrating wound to bone or joint) and stage (A= clean wounds to D= ischaemic infected wounds) of wounds. Participants were evaluated at 4 stratums: Stratum 1: Toe pressure\>30 mm of mercury (mmHg) and UT grade and stage 1C. Stratum 2: Toe pressure\<=30 mmHg and UT grade and stage 1C. Stratum 3: Toe pressure\>30 mmHg and UT grade and stage 2C. Stratum 4: Toe pressure\<=30 mmHg and UT grade and stage 2C.
Time frame: Week 24 (EOT) or early termination
Population: ITT population included all participants who were randomized. LOCF method was used. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dalteparin | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing | Stratum 1 (n= 97, 49) | 33 participants |
| Dalteparin | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing | Stratum 2 (n= 39, 19) | 8 participants |
| Dalteparin | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing | Stratum 3 (n= 29, 14) | 13 participants |
| Dalteparin | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing | Stratum 4 (n= 19, 10) | 8 participants |
| Placebo | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing | Stratum 4 (n= 19, 10) | 2 participants |
| Placebo | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing | Stratum 1 (n= 97, 49) | 15 participants |
| Placebo | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing | Stratum 3 (n= 29, 14) | 6 participants |
| Placebo | Number of Participants With Greater Than or Equal to 50 Percent Reduction in Ulcer Surface Area Excluding Intact Skin Healing | Stratum 2 (n= 39, 19) | 10 participants |
Secondary
Number of Participants With Intact Skin Healing
Intact skin healing was defined as 100 percent reduction in ulcer surface area with full epithelialisation. UT system assesses ulcer depth, wound infection and clinical signs of lower-extremity ischemia. Participants were evaluated at 4 stratums: Stratum 1: Toe pressure\>30 mm of mercury (mmHg) and UT grade and stage 1C. Stratum 2: Toe pressure\<=30 mmHg and UT grade and stage 1C. Stratum 3: Toe pressure\>30 mmHg and UT grade and stage 2C. Stratum 4: Toe pressure\<=30 mmHg and UT grade and stage 2C.
Time frame: Week 24 (EOT) or early termination
Population: ITT population included all participants who were randomized. LOCF method was used. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dalteparin | Number of Participants With Intact Skin Healing | Stratum 1 (n= 97, 49) | 35 participants |
| Dalteparin | Number of Participants With Intact Skin Healing | Stratum 2 (n= 39, 19) | 15 participants |
| Dalteparin | Number of Participants With Intact Skin Healing | Stratum 3 (n= 29, 14) | 8 participants |
| Dalteparin | Number of Participants With Intact Skin Healing | Stratum 4 (n= 19, 10) | 1 participants |
| Placebo | Number of Participants With Intact Skin Healing | Stratum 4 (n= 19, 10) | 4 participants |
| Placebo | Number of Participants With Intact Skin Healing | Stratum 1 (n= 97, 49) | 16 participants |
| Placebo | Number of Participants With Intact Skin Healing | Stratum 3 (n= 29, 14) | 4 participants |
| Placebo | Number of Participants With Intact Skin Healing | Stratum 2 (n= 39, 19) | 4 participants |
Secondary
Number of Participants With Major Cardiovascular Disease Events (MCVE)
Major cardiovascular events were defined as death due to vascular cause; non-fatal myocardial infarction (MI) excluding procedure related to MI; coronary revascularization procedures not related to MIs; hospitalization for unstable angina or non-fatal stroke.
Time frame: Week 24 (EOT) or early termination
Population: The data was not analyzed as planned because the study enrollment was terminated before the planned number of randomized participants was obtained.
Secondary
Time to Intact Skin Healing
Median time taken to achieve intact skin healing which was defined as 100 percent reduction in ulcer surface area with full epithelialisation.
Time frame: Week 24 (EOT) or early termination
Population: The data was not analyzed as planned because the study enrollment was terminated before the planned number of randomized participants was obtained.
Secondary
Transcutaneous Local Tissue Oxygenation (pO2)
Transcutaneous pO2 was assessed at the dorsum of the foot in the first intermetatarsal space using an appropriately calibrated instrument. The skin oxygen partial pressure was determined by measuring the oxygen reduction current by means of a measuring cell.
Time frame: Baseline and Week 24 (EOT or early termination)
Population: ITT population included all participants who were randomized. Participants were analyzed at selected sites only, based on availability. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dalteparin | Transcutaneous Local Tissue Oxygenation (pO2) | Baseline | 31.80 Units on a scale | Standard Deviation 21.29 |
| Dalteparin | Transcutaneous Local Tissue Oxygenation (pO2) | EOT (n= 32, 19) | 38.80 Units on a scale | Standard Deviation 19.58 |
| Placebo | Transcutaneous Local Tissue Oxygenation (pO2) | Baseline | 36.00 Units on a scale | Standard Deviation 17.11 |
| Placebo | Transcutaneous Local Tissue Oxygenation (pO2) | EOT (n= 32, 19) | 39.70 Units on a scale | Standard Deviation 16.18 |
Other Pre-specified
Number of All Hemorrhages
Major hemorrhages: defined as fatal bleeding, clinically overt bleeding causing a fall in hemoglobin more than or equal to 20 gram (g)/litre (L) (2 g/ decilitre \[dL\]), clinically overt bleeding leading to transfusion of more than or equal to 2 units of whole blood or red cells, or symptomatic bleeding in areas of special concern (intracranial, retroperitoneal, intraocular, intraspinal, pericardial, intramuscular with compartmental syndrome, or intraarticular). Minor hemorrhages: defined as bleeding that did not meet the definition of major bleeding.
Time frame: Week 24 (EOT) or early termination
Population: Safety analysis population included all participants who were known to have taken at least one dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalteparin | Number of All Hemorrhages | 10 hemorrhages |
| Placebo | Number of All Hemorrhages | 2 hemorrhages |
Other Pre-specified
Number of Clinically Relevant Minor Hemorrhages and Trivial Hemorrhages
Clinically relevant minor (non-major) bleeding was defined as any bleeding compromising hemodynamics, leading to hospitalization, subcutaneous haematoma more than 25 cm\^2, intramuscular haematoma, epistaxis lasting for more than 5 minutes, spontaneous gingival bleeding, macroscopic hematuria and gastrointestinal hemorrhage (including at least 1 episode of melaena or hematemesis), rectal blood loss, hemoptysis, and any other bleeding with clinical consequences. Trivial bleeding was defined as all minor bleeding that did not meet the definition of clinically relevant minor bleeding.
Time frame: Week 24 (EOT) or early termination
Population: Safety analysis population included all participants who were known to have taken at least one dose of the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dalteparin | Number of Clinically Relevant Minor Hemorrhages and Trivial Hemorrhages | Clinically relevant minor hemorrhages | 5 hemorrhages |
| Dalteparin | Number of Clinically Relevant Minor Hemorrhages and Trivial Hemorrhages | Trivial hemorrhages | 3 hemorrhages |
| Placebo | Number of Clinically Relevant Minor Hemorrhages and Trivial Hemorrhages | Clinically relevant minor hemorrhages | 1 hemorrhages |
| Placebo | Number of Clinically Relevant Minor Hemorrhages and Trivial Hemorrhages | Trivial hemorrhages | 1 hemorrhages |
Other Pre-specified
Number of Major and Minor Hemorrhages
Major hemorrhages: defined as fatal bleeding, clinically overt bleeding causing a fall in hemoglobin more than or equal to 20 gram (g)/litre (L) (2 g/ decilitre \[dL\]), clinically overt bleeding leading to transfusion of more than or equal to 2 units of whole blood or red cells, or symptomatic bleeding in areas of special concern (intracranial, retroperitoneal, intraocular, intraspinal, pericardial, intramuscular with compartmental syndrome, or intraarticular). Minor hemorrhages: defined as bleeding that did not meet the definition of major bleeding.
Time frame: Week 24 (EOT) or early termination
Population: Safety analysis population included all participants who were known to have taken at least one dose of the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dalteparin | Number of Major and Minor Hemorrhages | Major hemorrhages | 2 hemorrhages |
| Dalteparin | Number of Major and Minor Hemorrhages | Minor hemorrhages | 8 hemorrhages |
| Placebo | Number of Major and Minor Hemorrhages | Major hemorrhages | 0 hemorrhages |
| Placebo | Number of Major and Minor Hemorrhages | Minor hemorrhages | 2 hemorrhages |