Trial Outcomes & Findings for Study Of The Effect Of Fragmin In The Treatment Of Neuroischaemic Foot Ulcers In Diabetic Patients (NCT NCT00662831)

Last Updated: 2018-12-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

276 participants

Primary outcome timeframe

Week 24 [end of treatment (EOT)] or early termination

Results posted on

2018-12-19

Participant Flow

Participant milestones

Participant milestones
Measure	Dalteparin Dalteparin 5000 International Units (IU) (0.2 milliliter \[mL\]) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Overall Study STARTED	184	92
Overall Study COMPLETED	78	33
Overall Study NOT COMPLETED	106	59

Reasons for withdrawal

Reasons for withdrawal
Measure	Dalteparin Dalteparin 5000 International Units (IU) (0.2 milliliter \[mL\]) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Overall Study Death	4	1
Overall Study Lack of Efficacy	6	6
Overall Study Lost to Follow-up	1	0
Overall Study Withdrawal by Subject	2	1
Overall Study Other	62	31
Overall Study Protocol Violation	8	4
Overall Study Adverse Event	23	16

Baseline Characteristics

Study Of The Effect Of Fragmin In The Treatment Of Neuroischaemic Foot Ulcers In Diabetic Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dalteparin n=184 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.	Total n=276 Participants Total of all reporting groups
Age, Continuous	64.8 years STANDARD_DEVIATION 10.3 • n=5 Participants	64.7 years STANDARD_DEVIATION 10.9 • n=7 Participants	64.8 years STANDARD_DEVIATION 10.5 • n=5 Participants
Sex: Female, Male Female	63 Participants n=5 Participants	30 Participants n=7 Participants	93 Participants n=5 Participants
Sex: Female, Male Male	121 Participants n=5 Participants	62 Participants n=7 Participants	183 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Dalteparin n=184 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
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	31 participants
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	14 participants
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	10 participants
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	6 participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Dalteparin n=184 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Number of Participants With Intact Skin Healing Stratum 1 (n= 97, 49)	35 participants	16 participants
Number of Participants With Intact Skin Healing Stratum 2 (n= 39, 19)	15 participants	4 participants
Number of Participants With Intact Skin Healing Stratum 3 (n= 29, 14)	8 participants	4 participants
Number of Participants With Intact Skin Healing Stratum 4 (n= 19, 10)	1 participants	4 participants

SECONDARY outcome

Timeframe: Week 24 (EOT) or early termination

Population: ITT population included all participants who were randomized.

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.

Outcome measures

Outcome measures
Measure	Dalteparin n=180 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=90 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Number of Participants Who Underwent Any Amputation	8 participants	2 participants

SECONDARY outcome

Timeframe: Week 24 (EOT) or early termination

Population: ITT population included all participants who were randomized.

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.

Outcome measures

Outcome measures
Measure	Dalteparin n=180 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=90 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Number of Participants Who Underwent Major and Minor Amputation Major amputation	2 participants	1 participants
Number of Participants Who Underwent Major and Minor Amputation Minor amputation	7 participants	1 participants

SECONDARY outcome

Timeframe: Week 24 (EOT) or early termination

Outcome measures

Outcome measures
Measure	Dalteparin n=184 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
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	15 participants
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	10 participants
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	6 participants
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	2 participants

SECONDARY outcome

Timeframe: Week 24 (EOT) or early termination

Population: ITT population included all participants who were randomized.

Outcome measures

Outcome measures
Measure	Dalteparin n=184 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Number of Participants Who Died	4 participants	3 participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Median time taken to achieve intact skin healing which was defined as 100 percent reduction in ulcer surface area with full epithelialisation.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Dalteparin n=182 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=88 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Euro Quality of Life-5 Dimensions (EQ-5D)- Utility Score Baseline	0.60 Units on a scale Standard Deviation 0.26	0.60 Units on a scale Standard Deviation 0.30
Euro Quality of Life-5 Dimensions (EQ-5D)- Utility Score EOT (n= 154, 74)	0.70 Units on a scale Standard Deviation 0.22	0.60 Units on a scale Standard Deviation 0.33

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Dalteparin n=182 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=91 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS) Baseline	60.20 mm Standard Deviation 18.68	55.30 mm Standard Deviation 19.72
Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS) EOT (n= 157, 76)	63.30 mm Standard Deviation 18.76	60.70 mm Standard Deviation 18.02

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Dalteparin n=184 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=90 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
36-Item Short-Form Health Survey (SF-36) Score Baseline: Mental Health	41.90 Units on a scale Standard Deviation 6.57	41.30 Units on a scale Standard Deviation 6.72
36-Item Short-Form Health Survey (SF-36) Score Baseline: Mental (MCS)	42.40 Units on a scale Standard Deviation 7.26	42.80 Units on a scale Standard Deviation 7.37
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	35.50 Units on a scale Standard Deviation 11.39
36-Item Short-Form Health Survey (SF-36) Score Baseline: Physical Functioning	34.70 Units on a scale Standard Deviation 12.06	32.50 Units on a scale Standard Deviation 10.96
36-Item Short-Form Health Survey (SF-36) Score Baseline: Role-Physical	35.40 Units on a scale Standard Deviation 11.22	35.20 Units on a scale Standard Deviation 11.41
36-Item Short-Form Health Survey (SF-36) Score Baseline: Bodily Pain	42.30 Units on a scale Standard Deviation 11.19	40.30 Units on a scale Standard Deviation 11.52
36-Item Short-Form Health Survey (SF-36) Score Baseline: General Health	42.30 Units on a scale Standard Deviation 5.52	42.60 Units on a scale Standard Deviation 5.10
36-Item Short-Form Health Survey (SF-36) Score Baseline: Visibility	48.30 Units on a scale Standard Deviation 5.63	48.70 Units on a scale Standard Deviation 5.02
36-Item Short-Form Health Survey (SF-36) Score Baseline: Social Functioning	33.00 Units on a scale Standard Deviation 6.49	33.10 Units on a scale Standard Deviation 6.90
36-Item Short-Form Health Survey (SF-36) Score Baseline: Role-Emotional	39.10 Units on a scale Standard Deviation 13.48	38.30 Units on a scale Standard Deviation 13.49
36-Item Short-Form Health Survey (SF-36) Score Baseline: Physical (PCS)	38.10 Units on a scale Standard Deviation 9.42	36.70 Units on a scale Standard Deviation 8.75
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	37.50 Units on a scale Standard Deviation 11.31
36-Item Short-Form Health Survey (SF-36) Score EOT: Bodily Pain (n= 156, 76)	47.50 Units on a scale Standard Deviation 10.30	45.00 Units on a scale Standard Deviation 10.73
36-Item Short-Form Health Survey (SF-36) Score EOT: General Health (n= 156, 76)	42.50 Units on a scale Standard Deviation 5.10	42.80 Units on a scale Standard Deviation 5.15
36-Item Short-Form Health Survey (SF-36) Score EOT: Visibility (n= 156, 76)	48.20 Units on a scale Standard Deviation 5.58	48.80 Units on a scale Standard Deviation 5.15
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	32.30 Units on a scale Standard Deviation 5.83
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	38.80 Units on a scale Standard Deviation 13.48
36-Item Short-Form Health Survey (SF-36) Score EOT: Mental Health (n= 156, 76)	41.90 Units on a scale Standard Deviation 6.20	42.00 Units on a scale Standard Deviation 6.80
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	40.10 Units on a scale Standard Deviation 8.60
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	41.60 Units on a scale Standard Deviation 6.46

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Dalteparin n=183 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=89 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
11-point Likert Pain Scale EOT (n= 155, 75)	2.10 Units on a scale Standard Deviation 2.27	2.50 Units on a scale Standard Deviation 2.54
11-point Likert Pain Scale Baseline	4.20 Units on a scale Standard Deviation 2.76	4.50 Units on a scale Standard Deviation 2.83

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Dalteparin n=47 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=26 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Transcutaneous Local Tissue Oxygenation (pO2) Baseline	31.80 Units on a scale Standard Deviation 21.29	36.00 Units on a scale Standard Deviation 17.11
Transcutaneous Local Tissue Oxygenation (pO2) EOT (n= 32, 19)	38.80 Units on a scale Standard Deviation 19.58	39.70 Units on a scale Standard Deviation 16.18

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Dalteparin n=184 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Number of All Hemorrhages	10 hemorrhages	2 hemorrhages

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Dalteparin n=184 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Number of Major and Minor Hemorrhages Major hemorrhages	2 hemorrhages	0 hemorrhages
Number of Major and Minor Hemorrhages Minor hemorrhages	8 hemorrhages	2 hemorrhages

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Dalteparin n=184 Participants Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 Participants Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Number of Clinically Relevant Minor Hemorrhages and Trivial Hemorrhages Clinically relevant minor hemorrhages	5 hemorrhages	1 hemorrhages
Number of Clinically Relevant Minor Hemorrhages and Trivial Hemorrhages Trivial hemorrhages	3 hemorrhages	1 hemorrhages

Adverse Events

Dalteparin

Serious events: 33 serious events

Other events: 76 other events

Deaths: 0 deaths

Placebo

Serious events: 18 serious events

Other events: 36 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Dalteparin n=184 participants at risk Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 participants at risk Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Cardiac disorders Acute myocardial infarction	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiac failure	1.1% 2/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 2/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiac failure congestive	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Myocardial infarction	1.1% 2/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Myocardial ischaemia	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Trifascicular block	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Retinal haemorrhage	1.6% 3/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Ascites	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Colonic stenosis	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Condition aggravated	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Oedema peripheral	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Ulcer	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Hepatobiliary disorders Cholelithiasis	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Arteriosclerotic gangrene	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Cellulitis	2.7% 5/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Erysipelas	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.3% 3/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Gangrene	2.2% 4/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Infected skin ulcer	1.6% 3/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Infection	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Influenza	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Localised infection	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 2/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Osteomyelitis	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Pneumonia	1.1% 2/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Urinary tract infection	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 2/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Diabetes mellitus	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Diabetic foot	1.1% 2/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Diabetic ketoacidosis	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyperuricaemia	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Back pain	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Cerebrovascular accident	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Renal failure acute	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Strangury	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Diabetic ulcer	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Skin necrosis	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Vascular disorders Venous thrombosis	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Other adverse events
Measure	Dalteparin n=184 participants at risk Dalteparin 5000 International Units (IU) (0.2 mL) subcutaneously (s.c.) once daily for 24 weeks or early termination (ET).	Placebo n=92 participants at risk Placebo (0.2 mL normal saline) administered s.c. once daily for 24 weeks or ET.
Blood and lymphatic system disorders Anaemia	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Anaemia of chronic disease	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Monocytopenia	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Normochromic normocytic anaemia	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Pancytopenia	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Angina pectoris	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Atrial fibrillation	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Bundle branch block left	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Sinus tachycardia	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Eye haemorrhage	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Retinal haemorrhage	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal distension	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal rigidity	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dyspepsia	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Erosive duodenitis	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastritis	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Reflux oesophagitis	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Retching	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Adverse drug reaction	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Asthenia	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Disease progression	0.00% 0/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Inflammation	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Influenza like illness	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Injection site haematoma	3.8% 7/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Injection site pain	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Oedema	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Oedema peripheral	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.3% 3/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Pain	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 1/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Ulcer	1.6% 3/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.3% 4/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Hepatobiliary disorders Liver disorder	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Immune system disorders Hypersensitivity	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Bronchitis	1.1% 2/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Cellulitis	1.1% 2/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Diabetic foot infection	2.2% 4/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 2/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Erysipelas	2.2% 4/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Gastroenteritis	0.54% 1/184 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/92 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.