Safety and Efficacy Study of Urokinase for the Treatment of Diabetic Foot Syndrome and Critical Limb Ischemia

Study Overview
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Brief Summary
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In this randomized clinical trial (RCT) the investigators are trying to find out whether a low-dose therapy with daily short infusions of urokinase using 10 to 21 doses over a maximum of 30 days is capable of prolonging the survival time without major amputation.

Detailed Description
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August-2 is a trial embedded in the August-1 registry study. All patients enrolled in August-2 are also part of August-1, but there will be patients who are documented in the register, but will not take part in August-2. The investigators want to find out to which extent the patients in the registry are representative to the overall population suffering from this condition and how the therapeutic success of other therapy regimes can be described.

Official Title
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Patients With Diabetic Foot Syndrome and Critical Limb Ischemia - a Randomized Clinical Trial With Urokinase

Conditions
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Diabetic Foot, Critical Limb Ischemia

Intervention / Treatment
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* Drug: urokinase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 years or older angiopathic or angioneuropathic critical limb ischemia (at least Wagner-Armstrong stadium II) participation in the August-1 Register revascularization not possible or residual ischemia after revascularization persisting ulcerations despite antibiosis, adjustment of blood glucose levels and debridement expected further hospitalization for at least 3 weeks (pressure relief and antibiosis) fibrinogen >= 4g/l signed informed consent Exclusion Criteria: life expectancy < 1 year prior major amputation planned major amputation prior therapy of the current episode of diabetic foot syndrome with urokinase (except in cases of revascularization when the duration between the intervention and randomization must not exceed 7 days) mechanical heart valve substitute cerebral event with CT-detectable changes in the last 3 months non-remediated proliferation retinopathy uncontrolled hypertension (systolic >180 mmg, diastolic >100 mmHg) hemorrhagic diathesis (spontaneous quick < 50%, spontaneous PTT > 40 s, thrombocytes < 100 Gpt/l) gastrointestinal bleeding or ulcers in the last 4 weeks prior reverse bypass operation contraindications against therapy with urokinase acc. to the SMPc concurrent participation in another clinical trial insufficient compliance pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: standard therapy<br>patients receiving standard therapy for diabetic foot syndrome with critical limb ischemia, i. e. structured therapy of lesions with antibiosis, pressure relief and therapy of risk factors according to the relevant guidelines. | |
| Active Comparator: urokinase<br>patients receiving urokinase short infusions in addition to standard therapy | Drug: urokinase<br>* daily short infusions, i. e. i. v. application of 1.000.000 I.E. urokinase over 30 min. for at least 10 and up to 21 days during the 30 days after randomization<br>* Other names: Urokinase HS medac;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of survival without major amputation in urokinase group compared to group with standard therapy |  | within the FU of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| total mortality |  | 12 months after randomization | 
| minor amputation |  | 12 months after randomization | 
| Number of necessary revisions in case of minor amputation |  | 12 months after randomization | 
| complete healing of targeted lesion |  | within the FU of 12 months | 
| new lesions on previously affected leg |  | within the FU of 12 months | 
| efficacy in dialysis patients |  | within the FU of 12 months | 
| duration of hospital stay |  | from baseline examination until first release (expected average of 2 weeks in general) | 
| re-hospitalization after dismissal following end of therapy with urokinase |  | within the FU of 12 months | 
| Necessity for parenteral therapy with vasoactive substances | During the follow-up it will be documented wether the administration of parenterally applied vasoactive substances or thrombocyte aggregation inhibitors was necessary. | from baseline to end of 12 months FU | 
| cardiovascular events | Any major cardiovascular events during the follow-up period. Duration, severity, outcome and causal relationship with urokinase therapy will be documented. | from baseline to end of 12 months FU | 
| incidence and type of bleeding events |  | from randomization until day 33 | 
| incidence and type of other adverse events |  | from baseline to end of 12 months FU | 
| new lesions on the contralateral leg |  | within the FU of 12 months |