The Effect Of Fragmin In The Treatment Of Neuroischaemic Foot Ulcers In Diabetic Patients (A6301086)

A 6 Month, Prospective, Open-Label Multiple Center Extension Trial To Evaluate The Long Term Safety And Sustained Efficacy Of Fragmin In The Treatment Of Chronic Foot Ulcers In Diabetic Patients With Peripheral Arterial Occlusive Disease

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00765063

Enrollment

Registered

2008-10-02

Start date

2008-10-31

Completion date

2010-10-31

Last updated

2012-01-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetic Foot Ulcer

Keywords

Diabetic Foot Ulcers Neuroischaemic

Brief summary

The primary objective of this 6 month open-label extension trial is to evaluate long-term safety and tolerability of dalteparin in treatment of chronic neuroischaemic foot ulcers in diabetic patients with peripheral arterial occlusive disease (PAOD) and peripheral neuropathy.

Interventions

DRUGFragmin

Pre-filled syringes containing a single dose of 5000 IU Fragmin/ Dalteparin Sodium

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Subjects must have completed the 6 month study duration in the A6301083 study. * Subjects must have a positive ulcer treatment response, defined as a reduction in the study ulcer area size (ie, ulcer area reduction \>0%) at Visit 8 (EOT Visit) from baseline in the A6301083 study. * All ulcers must have an ulcer staging of 1C, 2C, 1D or 2D according to the University of Texas wound classification system

Exclusion criteria

* Subjects who have the following: * Intact skin healing (defined as 100% reduction in ulcer surface area with full epithelialisation at or prior to the EOT visit in the A6301083 study). * A study ulcer area at Visit 8 (EOT visit) which is greater or equal to the baseline ulcer area (ie, ulcer area increase ≥0%) in the A6301083 study. * Subjects with an ulcer grading of 0 or 3 or staging of A or B according to the University of Texas wound classification system. * Subjects with a known bleeding disorder or evidence of active bleeding. * Subjects who are on dialysis. * Subjects who where found to be major protocol violators in A6301083 study. * Subjects who did not complete the 6 month study period of the A6301083 study

Design outcomes

Primary

Measure	Time frame	Description
Number of All Hemorrhages	Baseline to Week 24 (end of treatment [EOT]) or early termination (ET)	Major hemorrhages: defined as fatal bleeding, clinically overt bleeding causing a fall in hemoglobin greater than or equal to 20 gram (g)/litre (L) (2 g/ decilitre \[dL\]), clinically overt bleeding leading to transfusion of greater 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 Major Hemorrhages	Baseline to Week 24 (EOT) or ET	Major hemorrhages: defined as fatal bleeding, clinically overt bleeding causing a fall in hemoglobin greater than or equal to 20 g/L (2 g/dL), clinically overt bleeding leading to transfusion of greater 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).
Number of Minor Hemorrhages	Baseline to Week 24 (EOT) or ET	Minor hemorrhages: defined as bleeding that did not meet the definition of major bleeding.
Number of Clinically Relevant Minor Hemorrhages	Baseline to Week 24 (EOT) or ET	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.
Number of Trivial Hemorrhages	Baseline to Week 24 (EOT) or ET	Trivial bleeding was defined as all minor bleeding that did not meet the definition of clinically relevant minor bleeding.

Secondary

Measure	Time frame	Description
Number of Participants With Major Cardiovascular Disease Events (MCVE)	Baseline through Week 24 (EOT) or ET	MCVE 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.
Number of Participants With Intact Skin Healing	Baseline through Week 24 (EOT) or ET	Intact skin healing was defined as 100 percent reduction in ulcer surface area with full epithelialisation. The ulcer area was measured in square millimetre (mm) by measuring the longest width and length of the ulcer after debridement. The area was calculated from an acetate tracing. Ulcers were also documented by standardized photographs. The largest ulcer was considered the study ulcer in participants with multiple ulcers.
36-Item Short-Form Health Survey (SF-36) Score	Baseline and Week 24 (EOT) or ET	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 ET	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.
Number of Participants With Improved Ulcer Healing	Baseline through Week 24 (EOT) or ET	Improved ulcer healing was defined as greater than or equal to 50 percent reduction in ulcer surface area from baseline of the A6301083 study excluding intact skin healing. The ulcer area was measured in square mm by measuring the longest width and length of the ulcer after debridement. Ulcers were also documented by standardized photographs.
Number of Participants Who Underwent Amputation	Baseline through Week 24 (EOT) or ET	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 to Intact Skin Healing	Baseline through Week 24 (EOT) or ET	Median time (in months) taken to achieve intact skin healing which was defined as 100 percent reduction in ulcer surface area with full epithelialisation.
Time to First Amputation	Baseline through Week 24 (EOT) or ET	—

Countries

Austria, Belgium, Canada, Czechia, Denmark, Germany, Greece, Italy, Norway, Poland, Russia, Sweden, Ukraine, United Kingdom

Participant flow

Recruitment details

This was a follow-up study of A6301083 (NCT00662831)

Participants by arm

Arm	Count
Dalteparin Dalteparin sodium 5000 International Units (IU) (0.2 mL) administered subcutaneously (s.c.) once daily (OD) for a maximum duration of 24 weeks.	62
Total	62

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	4
Overall Study	Lack of Efficacy	5
Overall Study	Other	16
Overall Study	Protocol Violation	6
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Dalteparin
Age Continuous	65.2 years STANDARD_DEVIATION 11
Sex: Female, Male Female	16 Participants
Sex: Female, Male Male	46 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	26 / 62
serious Total, serious adverse events	11 / 62

Outcome results

Primary

Number of All Hemorrhages

Major hemorrhages: defined as fatal bleeding, clinically overt bleeding causing a fall in hemoglobin greater than or equal to 20 gram (g)/litre (L) (2 g/ decilitre \[dL\]), clinically overt bleeding leading to transfusion of greater 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: Baseline to Week 24 (end of treatment [EOT]) or early termination (ET)

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	3 Hemorrhages

Primary

Number of Clinically Relevant Minor 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.

Time frame: Baseline to Week 24 (EOT) or ET

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 Clinically Relevant Minor Hemorrhages	2 Hemorrhages

Primary

Number of Major Hemorrhages

Major hemorrhages: defined as fatal bleeding, clinically overt bleeding causing a fall in hemoglobin greater than or equal to 20 g/L (2 g/dL), clinically overt bleeding leading to transfusion of greater 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).

Time frame: Baseline to Week 24 (EOT) or ET

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 Major Hemorrhages	0 Hemorrhages

Primary

Number of Minor Hemorrhages

Minor hemorrhages: defined as bleeding that did not meet the definition of major bleeding.

Time frame: Baseline to Week 24 (EOT) or ET

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 Minor Hemorrhages	3 Hemorrhages

Primary

Number of Trivial Hemorrhages

Trivial bleeding was defined as all minor bleeding that did not meet the definition of clinically relevant minor bleeding.

Time frame: Baseline to Week 24 (EOT) or ET

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 Trivial Hemorrhages	1 Hemorrhages

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 ET

Population: ITT population included all participants who were enrolled into the study.

Arm	Measure	Group	Value (MEAN)	Dispersion
Dalteparin	11-point Likert Pain Scale	Baseline	2.4 Units on a scale	Standard Deviation 2.1
Dalteparin	11-point Likert Pain Scale	EOT	2.2 Units on a scale	Standard Deviation 2.1

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 ET

Population: ITT population included all participants who were enrolled into the study. 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	Baseline: Physical Functioning (n= 43)	34.7 Units on a scale	Standard Deviation 11.7
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	Baseline: Role-Physical (n= 43)	36.5 Units on a scale	Standard Deviation 10.7
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	Baseline: Bodily Pain (n= 43)	45.1 Units on a scale	Standard Deviation 9.6
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	Baseline: General Health (n= 43)	44.1 Units on a scale	Standard Deviation 4.5
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	Baseline: Visibility (n= 43)	48.1 Units on a scale	Standard Deviation 5.7
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	Baseline: Social Functioning (n= 43)	34.3 Units on a scale	Standard Deviation 7.6
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	Baseline: Role-Emotional (n= 43)	36.6 Units on a scale	Standard Deviation 13.8
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	Baseline: Mental Health (n= 43)	42.1 Units on a scale	Standard Deviation 6.4
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	Baseline: Physical (PCS) (n= 43)	40.1 Units on a scale	Standard Deviation 7.7
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	Baseline: Mental (MCS) (n= 43)	41.4 Units on a scale	Standard Deviation 7.2
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: Physical Functioning (n= 57)	34.8 Units on a scale	Standard Deviation 11.2
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: Role-Physical (n= 57)	35.1 Units on a scale	Standard Deviation 11
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: Bodily Pain (n= 57)	45.5 Units on a scale	Standard Deviation 11.3
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: General Health (n= 57)	42.9 Units on a scale	Standard Deviation 4.6
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: Visibility (n= 57)	48.7 Units on a scale	Standard Deviation 6.3
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: Social Functioning (n= 57)	35.1 Units on a scale	Standard Deviation 4.5
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: Role-Emotional (n= 57)	36.3 Units on a scale	Standard Deviation 14.9
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: Mental Health (n= 57)	42.2 Units on a scale	Standard Deviation 7.1
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: Physical (PCS) (n= 57)	39.4 Units on a scale	Standard Deviation 9
Dalteparin	36-Item Short-Form Health Survey (SF-36) Score	EOT: Mental (MCS) (n= 57)	41.9 Units on a scale	Standard Deviation 7.9

Secondary

Number of Participants Who Underwent 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.