Alprostadil in Peripheral Arterial Occlusive Disease (PAOD) Stage IV

Study Overview
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Brief Summary
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The study is to confirmatorily show a superior effect of Alprostadil compared to placebo on the rate of complete healing of ischemic necroses and ulcerations as well as on the frequency and height of major amputations in patients suffering from PAOD stage IV.

Official Title
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Multinational, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel Groups Study to Assess the Efficacy and Safety of Prostaglandin E1 in Subjects With Critical Limb Ischemia (Fontaine Stage IV)

Conditions
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Peripheral Arterial Occlusive Disease

Intervention / Treatment
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* Drug: Alprostadil
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is at least 45 years of age Subjects with macro-angiopathy, proven PAOD Stage IV with up to 2 ischaemic skin lesions for more than 2 weeks Subject has a complete angiography of pelvis, thigh and calf within one month of inclusion Systolic ankle pressure ≤ 70 mmHg in subjects without media sclerosis of the lower limb artery or systolic big toe pressure ≤ 50 mmHg in diabetics with media sclerosis of the lower limb artery Subject is not in the position to be primarily revascularized or refuses surgery Exclusion Criteria: Imminent or foreseeable amputation Major amputation on the affected extremity History of chronic alcohol or drug abuse More than two ischemic ulcerations One ulcer ≥ 6 cm^2, both ulcers ≤ 1 cm^2 or at least one ulcer affecting the bone or tendons Acute ischemia and peripheral vascular disorders of inflammatory or immunologic origin Neuropathic or venous ulcers Buerger's disease Septic gangrene Use of vasoactive medication or prostaglandins Treatment with prostanoids within 3 months prior to inclusion Surgical or interventional measures performed on the affected extremity within 3 months prior to study drug treatment

Ages Eligible for Study
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Minimum Age: 45 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alprostadil<br>Prostavasin® 40 μg will be infused intravenously twice daily over 2 hours in 50 to 150 ml isotonic sodium chloride solution during a Treatment Phase of 4 weeks. | Drug: Alprostadil<br>* Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion<br>* Other names: Prostavasin;|
| Placebo Comparator: Placebo<br>Placebo will be infused intravenously twice daily over 2 hours in 50 to 150 ml isotonic sodium chloride solution during a Treatment Phase of 4 weeks. | Other: Placebo<br>* Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment | The assessment of ulcer area was collected per lesion with up to 2 lesions per subject (both legs could be affected). In the analysis a subject is only considered completely healed at a time point, if all ischemic lesions are reported as completely healed at that time point. | At 12 weeks after the end of study drug treatment | 
| Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment | Assessment of amputations was collected per leg affected by a lesion with up to 2 lesions per subject. Amputations were regarded as major if they were performed at the ankle joint level or above. Amputations of toes or part of the foot leaving a stump thereon the subject can walk were regarded as minor. An affected leg is defined as a leg with at least 1 lesion on Study Day -6 to -2 and only amputations of affected legs are considered in the efficacy analysis of amputations. A subject is counted as major/minor amputated, if at least 1 affected leg was major/minor amputated. | At 24 weeks after the end of study drug treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Healing of Ischemic Necroses and Ulcerations at 24 Weeks After the End of Study Drug Treatment | The assessment of ulcer area was collected per lesion with up to 2 lesions per subject (both legs could be affected). In the analysis a subject is only considered completely healed at a time point, if all ischemic lesions are reported as completely healed at that time point. | At 24 weeks after the end of study drug treatment | 
| Intensity of Rest Pain Induced by Ischemic Lesions at 24 Weeks After the End of Study Drug Treatment | Visit values of intensity of rest pain from a visual analogue scale, ranging from 0 mm (no pain) to 100 mm (maximum conceivable pain), had to be reported in the case of presence of rest pain only. If the leading question in regard to the presence of rest pain is answered with No and no visit value is specified, the visit value will be set to 0 for the analysis. | At 24 weeks after the end of study drug treatment | 
| Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment | In case of two ulcers the worse ulcer status is analyzed. The categories of investigator assessment are: complete healing, decrease by ≥ 50 %, unchanged, increase by ≥ 50 %. | At 24 weeks after the end of study drug treatment | 
| Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | The number of subjects who used analgesics are summarized for different time points/intervals during the course of the study. | During the course of the study (up to 196 days) | 
| Systolic Pressure at Ankle Level at 24 Weeks After the End of Study Drug Treatment | Systolic pressure at ankle level was measured at the Arteria tibialis posterior and the Arteria dorsalis pedis. Two individual series of measurements of arterial pressures per subject across the assessed visits were selected for the analysis. For the first analysis (worst change analysis) the series of measurements in the one artery which has the worst change from Baseline at the final measurement was used. For the second analysis (worst value analysis) the series of measurements which has the worst final post-Baseline measurement was used. The series relevant for the analyses was selected from the series for the affected leg or legs only. The selection is 1 out of up to 4 series available per subject. Series without Baseline value and series with at least 1 measurement of more than 150 mmHg were excluded from the selection process due to the suspicion of media sclerosis of the lower limb artery. | At 24 weeks after the end of study drug treatment | 
| Minor Amputations at 24 Weeks After the End of Study Drug Treatment | Assessment of amputations was collected per leg affected by a lesion with up to 2 lesions per subject. Amputations were regarded as major if they were performed at the ankle joint level or above. Amputations of toes or part of the foot leaving a stump thereon the subject can walk were regarded as minor. An affected leg is defined as a leg with at least 1 lesion on Study Day -6 to -2 and only amputations of affected legs are considered in the efficacy analysis of amputations. A subject is counted as major/minor amputated, if at least 1 affected leg was major/minor amputated. The number of subjects with minor amputation prior to or at 24 weeks after the end of study drug treatment is presented below. | At 24 weeks after the end of study drug treatment | 
| Revascularization Procedures at 24 Weeks After the End of Study Drug Treatment | The number of subjects with revascularization prior to or at 24 weeks after the end of study drug treatment is presented below. | At 24 weeks after the end of study drug treatment | 
| All-cause Mortality During the Course of the Study (up to 196 Days) |  | During the course of the study (up to 196 days) | 
| Cardiovascular Mortality During the Course of the Study (up to 196 Days) |  | During the course of the study (up to 196 days) | 
| Cardiovascular Morbidity During the Course of the Study (up to 196 Days) | Cardiovascular morbidity is presented as number of subjects with myocardial infarction and/or stroke during the course of the study. | During the course of the study (up to 196 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alprostadil, Prostavasin, PAOD, Fontaine Stage IV