ESPECIAL: Alprostadil in Peripheral Arterial Occlusive Disease (PAOD) Stage IV

• Sponsor: UCB BIOSCIENCES GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00596752
• Collaborator: Aptiv Solutions (Industry)
• Enrollment: 840
• Locations: 78
• Arms: 2
• Duration (Months): 112
• Patients Per Site: 10.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Peripheral Arterial Occlusive Disease	Drug: Alprostadil; Other: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 840 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: Mar 1, 2004
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alprostadil 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; Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion; Other Names: Prostavasin
Placebo Comparator: Placebo 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; Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion

Outcome Measures

Primary Outcome Measures

1. Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment [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.

2. Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment [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.

Secondary Outcome Measures

1. Complete Healing of Ischemic Necroses and Ulcerations at 24 Weeks After the End of Study Drug Treatment [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.

2. Intensity of Rest Pain Induced by Ischemic Lesions at 24 Weeks After the End of Study Drug Treatment [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.

3. Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment [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 %.

4. Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) [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.

5. Systolic Pressure at Ankle Level at 24 Weeks After the End of Study Drug Treatment [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.

6. Minor Amputations at 24 Weeks After the End of Study Drug Treatment [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.

7. Revascularization Procedures at 24 Weeks After the End of Study Drug Treatment [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.

8. All-cause Mortality During the Course of the Study (up to 196 Days) [During the course of the study (up to 196 days)]

9. Cardiovascular Mortality During the Course of the Study (up to 196 Days) [During the course of the study (up to 196 days)]

10. Cardiovascular Morbidity During the Course of the Study (up to 196 Days) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	404	Plzen		Czechia
2	414	Usti Nad Labem		Czechia
3	1	Karlsbad		Germany
4	502	Aguascalientes		Mexico
5	505	Merida		Mexico
6	501	Queretaro		Mexico
7	306	Bydgoszcz		Poland
8	321	Konskie		Poland
9	320	Krakow		Poland
10	314	Lublin		Poland
11	315	Lublin		Poland
12	316	Poznan		Poland
13	317	Poznan		Poland
14	301	Szczecin		Poland
15	304	Szczecin		Poland
16	319	Warsaw		Poland
17	307	Warszawa		Poland
18	308	Warszawa		Poland
19	309	Warszawa		Poland
20	318	Warszawa		Poland
21	312	Wroclaw		Poland
22	322	Zamosc		Poland
23	246	Barnaul		Russian Federation
24	205	Chelyabinsk		Russian Federation
25	244	Chelyabinsk		Russian Federation
26	223	Ekaterinburg		Russian Federation
27	247	Ekaterinburg		Russian Federation
28	228	Irkutsk		Russian Federation
29	242	Kazan		Russian Federation
30	227	Kemerovo		Russian Federation
31	201	Moscow		Russian Federation
32	202	Moscow		Russian Federation
33	203	Moscow		Russian Federation
34	209	Moscow		Russian Federation
35	219	Moscow		Russian Federation
36	220	Moscow		Russian Federation
37	230	Moscow		Russian Federation
38	248	Moscow		Russian Federation
39	231	Novosibirsk		Russian Federation
40	232	Novosibirsk		Russian Federation
41	222	Omsk		Russian Federation
42	217	Petrozavodsk		Russian Federation
43	206	Rostov-on-Don		Russian Federation
44	225	Rostov-on-Don		Russian Federation
45	236	Rostov-on-Don		Russian Federation
46	239	Rostov-on-Don		Russian Federation
47	224	Ryazan		Russian Federation
48	218	Samara		Russian Federation
49	237	Saratov		Russian Federation
50	210	St Petersburg		Russian Federation
51	212	St Petersburg		Russian Federation
52	213	St Petersburg		Russian Federation
53	214	St Petersburg		Russian Federation
54	215	St Petersburg		Russian Federation
55	216	St Petersburg		Russian Federation
56	243	Tula		Russian Federation
57	238	Tumen		Russian Federation
58	234	Tver		Russian Federation
59	241	Ufa		Russian Federation
60	240	Volgograd		Russian Federation
61	221	Yaroslavl		Russian Federation
62	112	Dnipropetrovsk		Ukraine
63	109	Donetsk		Ukraine
64	110	Donetsk		Ukraine
65	114	Ivano-Frankivsk		Ukraine
66	111	Kharkov		Ukraine
67	101	Kiev		Ukraine
68	102	Kiev		Ukraine
69	103	Kiev		Ukraine
70	104	Kiev		Ukraine
71	105	Kiev		Ukraine
72	106	Lviv		Ukraine
73	118	Odessa		Ukraine
74	119	Odessa		Ukraine
75	113	Uzhgorod		Ukraine
76	116	Vinnytsya		Ukraine
77	107	Zaporozhye		Ukraine
78	108	Zaporozhye		Ukraine

Sponsors and Collaborators

• UCB BIOSCIENCES GmbH
• Aptiv Solutions

Investigators

• Study Director: UCB Clinical Trial Call Center, [phone] (UCB)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• FDA Safety Alerts and Recalls

Publications

None provided.

• Responsible Party: UCB BIOSCIENCES GmbH
• ClinicalTrials.gov Identifier: NCT00596752
• Other Study ID Numbers: SP0777; 2005-001970-29
• First Posted: Jan 17, 2008
• Last Update Posted: Apr 4, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by UCB BIOSCIENCES GmbH: Alprostadil; Prostavasin; PAOD; Fontaine Stage IV
• Additional relevant MeSH terms: Arterial Occlusive Diseases; Peripheral Arterial Disease; Alprostadil

Study Results

Participant Flow

Recruitment Details	This study started to enroll subjects in March 2004 in order to end up with 840 enrolled subjects. The study was conducted using a two-stage group sequential adaptive design with possible sample size adjustment after the planned interim analysis, which was performed after stage 1. After the interim analysis subjects were included in stage 2.
Pre-assignment Detail	Participant Flow refers to the Randomized Set (RS). RS consists of all subjects randomized into the study who have completed the study or terminated prematurely.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Period Title: Overall Study
STARTED	415	425
Randomized and Treated	415	424
COMPLETED	289	282
NOT COMPLETED	126	143

Baseline Characteristics

Arm/Group Title	Alprostadil	Placebo	Total
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	Total of all reporting groups
Overall Participants	416	423	839
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	153 36.8%	170 40.2%	323 38.5%
>=65 years	263 63.2%	253 59.8%	516 61.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.8 (8.5)	66.4 (9.3)	66.6 (8.9)
Sex: Female, Male (Count of Participants)
Female	123 29.6%	117 27.7%	240 28.6%
Male	293 70.4%	306 72.3%	599 71.4%
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	75.4 (11.9)	76.6 (12.6)	76.0 (12.2)

Outcome Measures

1. Primary Outcome

Title	Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment
Description	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.
Time Frame	At 12 weeks after the end of study drug treatment

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values. FAS consists of all randomized subjects who received at least one dose of trial medication and who provide valid data to assess at least one of the primary efficacy endpoints.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	414	424
Stage 1 (n=253, n=251)	49 11.8%	43 10.2%
Stage 2 (n=161, n=173)	27 6.5%	30 7.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alprostadil, Placebo
	Comments	Primary goal was to test the following null hypothesis: H01: πhealingPGE1≤ πhealingPlacebo, with πhealing=proportion of subjects with complete ulcer healing. The planned information rate for stage 1 of the two-stage group sequential test design with an overall one-sided comparison-wise α=0.0125 for this co-primary endpoint is given by 0.83. This is the statistical analysis of stage 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2587
	Comments	For confirmatory hypothesis testing the p-values of the normal approximation test for comparing two rates was used as input for the weighted inverse normal method. The 1-sided boundary p-value for stage 1 is given by p1=0.00587.
	Method	Cochran-Mantel-Haenszel
	Comments	The 2 primary endpoints were tested at one-sided 0.0125 each so that the overall type I error rate of 0.025 was controlled in a strong sense.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alprostadil, Placebo
	Comments	Primary goal was to test the following null hypothesis: H01: πhealingPGE1≤ πhealingPlacebo, with πhealing=proportion of subjects with complete ulcer healing. This is the statistical analysis of stage 1 and stage 2 combined.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3463
	Comments	For confirmatory hypothesis testing the p-values of the normal approximation test for comparing two rates was used as input for the weighted inverse normal method. The 1-sided boundary p-value for stage 1 and 2 combined is given by p2=0.01085.
	Method	Cochran-Mantel-Haenszel
	Comments	The 2 primary endpoints were tested at one-sided 0.0125 each so that the overall type I error rate of 0.025 was controlled in a strong sense.

2. Primary Outcome

Title	Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment
Description	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.
Time Frame	At 24 weeks after the end of study drug treatment

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values. FAS consists of all randomized subjects who received at least one dose of trial medication and who provide valid data to assess at least one of the primary efficacy endpoints.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	414	424
Stage 1 (n=253, n=251)	32 7.7%	49 11.6%
Stage 2 (n=161, n=173)	20 4.8%	13 3.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alprostadil, Placebo
	Comments	Primary goal was to test the following null hypothesis: H02: πampPGE1≥ πampPlacebo, with πamp=proportion of subjects with major amputations. The planned information rate for stage 1 of the two-stage group sequential test design with an overall one-sided comparison-wise α=0.0125 for this co-primary endpoint is given by 0.83. This is the statistical analysis of stage 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0173
	Comments	For confirmatory hypothesis testing the p-values of the normal approximation test for comparing two rates was used as input for the weighted inverse normal method. The 1-sided boundary p-value for stage 1 is given by p1=0.00587.
	Method	Cochran-Mantel-Haenszel
	Comments	The 2 primary endpoints were tested at one-sided 0.0125 each so that the overall type I error rate of 0.025 was controlled in a strong sense.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alprostadil, Placebo
	Comments	Primary goal was to test the following null hypothesis: H02: πampPGE1≥ πampPlacebo, with πamp=proportion of subjects with major amputations. This is the statistical analysis of stage 1 and stage 2 combined.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1154
	Comments	For confirmatory hypothesis testing the p-values of the normal approximation test for comparing two rates was used as input for the weighted inverse normal method. The 1-sided boundary p-value for stage 1 and 2 combined is given by p2=0.01085.
	Method	Cochran-Mantel-Haenszel
	Comments	The 2 primary endpoints were tested at one-sided 0.0125 each so that the overall type I error rate of 0.025 was controlled in a strong sense.

3. Secondary Outcome

Title	Complete Healing of Ischemic Necroses and Ulcerations at 24 Weeks After the End of Study Drug Treatment
Description	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.
Time Frame	At 24 weeks after the end of study drug treatment

Outcome Measure Data

Analysis Population Description

Of the 838 subjects in the Full Analysis Set (FAS), 568 are included in the analysis of this outcome measure. FAS consists of all randomized subjects who received at least one dose of trial medication and who provide valid data to assess at least one of the primary efficacy endpoints.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	289	279
Number [participants]	108 26%	103 24.3%

4. Secondary Outcome

Title	Intensity of Rest Pain Induced by Ischemic Lesions at 24 Weeks After the End of Study Drug Treatment
Description	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.
Time Frame	At 24 weeks after the end of study drug treatment

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values. FAS consists of all randomized subjects who received at least one dose of trial medication and who provide valid data to assess at least one of the primary efficacy endpoints.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	414	424
Mean (Standard Deviation) [millimeters (mm)]	17.57 (25.33)	16.38 (25.08)

5. Secondary Outcome

Title	Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment
Description	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 %.
Time Frame	At 24 weeks after the end of study drug treatment

Outcome Measure Data

Analysis Population Description

Of the 838 subjects in the Full Analysis Set (FAS), 465 are included in the analysis of this outcome measure. FAS consists of all randomized subjects who received at least one dose of trial medication and who provide valid data to assess at least one of the primary efficacy endpoints.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	233	232
Complete healing	101 24.3%	98 23.2%
Decrease by >= 50 %	57 13.7%	56 13.2%
Remains unchanged	45 10.8%	48 11.3%
Increase by >= 50 %	30 7.2%	30 7.1%

6. Secondary Outcome

Title	Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days)
Description	The number of subjects who used analgesics are summarized for different time points/intervals during the course of the study.
Time Frame	During the course of the study (up to 196 days)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of all randomized subjects who received at least one dose of trial medication and who provide valid data to assess at least one of the primary efficacy endpoints.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	414	424
Prior to treatment (n=414, n=424)	300 72.1%	318 75.2%
Concomitant, Study Day 1 (n=414, n=424)	292 70.2%	314 74.2%
Concomitant, Study Day 2 (n=414, n=424)	295 70.9%	313 74%
Concomitant, Study Day 3 (n=413, n=424)	295 70.9%	317 74.9%
Concomitant, Study Day 4 (n=412, n=423)	292 70.2%	316 74.7%
Concomitant, Study Day 5 (n=411, n=423)	294 70.7%	311 73.5%
Concomitant, Study Day 6 (n=411, n=423)	290 69.7%	312 73.8%
Concomitant, Study Day 7 (n=409, n=422)	290 69.7%	306 72.3%
Concomitant, Week 2 (n=409, n=422)	292 70.2%	308 72.8%
Concomitant, Week 3 (n=399, n=416)	259 62.3%	284 67.1%
Concomitant, Week 4 (n=393, n=404)	238 57.2%	257 60.8%
Post treatment, Study Days 29-42 (n=348, n=354)	170 40.9%	191 45.2%
Post treatment, Study Days 43-56 (n=361, n=370)	164 39.4%	173 40.9%
Post treatment, Study Days 57-70 (n=361, n=346)	155 37.3%	155 36.6%
Post treatment, Study Days 71-84 (n=352, n=344)	146 35.1%	148 35%
Post treatment, Study Days 85-98 (n=341, n=339)	143 34.4%	140 33.1%
Post treatment, Study Days 99-112 (n=321, n=318)	132 31.7%	127 30%
Post treatment, Study Days 113-140 (n=309, n=301)	122 29.3%	117 27.7%
Post treatment, Study Days 141-168 (n=306, n=304)	118 28.4%	109 25.8%
Post treatment, Study Days 169-196 (n=272, n=271)	98 23.6%	90 21.3%

7. Secondary Outcome

Title	Systolic Pressure at Ankle Level at 24 Weeks After the End of Study Drug Treatment
Description	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.
Time Frame	At 24 weeks after the end of study drug treatment

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values. FAS consists of all randomized subjects who received at least one dose of trial medication and who provide valid data to assess at least one of the primary efficacy endpoints.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	383	394
Worst change analysis	42.83 (30.16)	39.47 (28.32)
Worst value analysis	39.39 (29.92)	36.45 (27.19)

8. Secondary Outcome

Title	Minor Amputations at 24 Weeks After the End of Study Drug Treatment
Description	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.
Time Frame	At 24 weeks after the end of study drug treatment

Outcome Measure Data

Analysis Population Description

Of the 838 subjects in the Full Analysis Set (FAS), 613 are included in the analysis of this outcome measure. FAS consists of all randomized subjects who received at least one dose of trial medication and who provide valid data to assess at least one of the primary efficacy endpoints.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	316	297
Number [participants]	65 15.6%	40 9.5%

9. Secondary Outcome

Title	Revascularization Procedures at 24 Weeks After the End of Study Drug Treatment
Description	The number of subjects with revascularization prior to or at 24 weeks after the end of study drug treatment is presented below.
Time Frame	At 24 weeks after the end of study drug treatment

Outcome Measure Data

Analysis Population Description

Of the 838 subjects in the Full Analysis Set (FAS), 577 are included in the analysis of this outcome measure. FAS consists of all randomized subjects who received at least one dose of trial medication and who provide valid data to assess at least one of the primary efficacy endpoints.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	294	283
Number [participants]	6 1.4%	7 1.7%

10. Secondary Outcome

Title	All-cause Mortality During the Course of the Study (up to 196 Days)
Time Frame	During the course of the study (up to 196 days)

Outcome Measure Data

Analysis Population Description

Safety Set consists of all randomized subjects who received at least one dose of trial medication.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	416	423
Number [participants]	20 4.8%	15 3.5%

11. Secondary Outcome

Title	Cardiovascular Mortality During the Course of the Study (up to 196 Days)
Time Frame	During the course of the study (up to 196 days)

Outcome Measure Data

Analysis Population Description

Safety Set consists of all randomized subjects who received at least one dose of trial medication.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	416	423
Number [participants]	11 2.6%	14 3.3%

12. Secondary Outcome

Title	Cardiovascular Morbidity During the Course of the Study (up to 196 Days)
Description	Cardiovascular morbidity is presented as number of subjects with myocardial infarction and/or stroke during the course of the study.
Time Frame	During the course of the study (up to 196 days)

Outcome Measure Data

Analysis Population Description

Safety Set consists of all randomized subjects who received at least one dose of trial medication.

Arm/Group Title	Alprostadil	Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion	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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
Measure Participants	416	423
Myocardial infarctions	5 1.2%	6 1.4%
Strokes	3 0.7%	3 0.7%

Adverse Events

Time Frame	Adverse Events were collected during the course of the study from Study Day 0 up to Study Day 196.
Adverse Event Reporting Description	Adverse Events refer to the Safety Set. Safety Set consists of all subjects who have completed the study or terminated prematurely and who have received at least 1 dose of study medication.
Arm/Group Title	Alprostadil		Placebo
Arm/Group Description	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. Alprostadil: - Active Substance: Prostaglandin E1 Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion		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. Placebo: - Active Substance: Lactose Pharmaceutical Form: solution for infusion Concentration: 40 μg b.d. Route of Administration: intravenous infusion
All Cause Mortality
	Alprostadil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Alprostadil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	87/416 (20.9%)		62/423 (14.7%)
Blood and lymphatic system disorders
ANAEMIA	1/416 (0.2%)	1	0/423 (0%)	0
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION	3/416 (0.7%)	3	3/423 (0.7%)	3
CARDIAC FAILURE	3/416 (0.7%)	3	1/423 (0.2%)	1
ANGINA PECTORIS	2/416 (0.5%)	2	0/423 (0%)	0
ATRIAL FIBRILLATION	2/416 (0.5%)	2	1/423 (0.2%)	1
CARDIAC FAILURE ACUTE	2/416 (0.5%)	2	4/423 (0.9%)	4
MYOCARDIAL INFARCTION	2/416 (0.5%)	2	3/423 (0.7%)	3
ATRIOVENTRICULAR BLOCK COMPLETE	1/416 (0.2%)	1	0/423 (0%)	0
CARDIOPULMONARY FAILURE	1/416 (0.2%)	1	1/423 (0.2%)	1
MYOCARDIAL ISCHAEMIA	1/416 (0.2%)	1	0/423 (0%)	0
VENTRICULAR FIBRILLATION	1/416 (0.2%)	1	1/423 (0.2%)	1
ACUTE CORONARY SYNDROME	0/416 (0%)	0	2/423 (0.5%)	2
ACUTE RIGHT VENTRICULAR FAILURE	0/416 (0%)	0	1/423 (0.2%)	2
CARDIAC FAILURE CHRONIC	0/416 (0%)	0	1/423 (0.2%)	1
NODAL ARRHYTHMIA	0/416 (0%)	0	1/423 (0.2%)	1
Gastrointestinal disorders
DUODENAL ULCER	1/416 (0.2%)	1	0/423 (0%)	0
GASTRIC ULCER HAEMORRHAGE	1/416 (0.2%)	1	0/423 (0%)	0
INTESTINAL HAEMORRHAGE	1/416 (0.2%)	1	0/423 (0%)	0
PANCREATITIS ACUTE	1/416 (0.2%)	1	0/423 (0%)	0
MESENTERIC ARTERY EMBOLISM	0/416 (0%)	0	1/423 (0.2%)	1
General disorders
ISCHAEMIC ULCER	2/416 (0.5%)	2	0/423 (0%)	0
NECROSIS	2/416 (0.5%)	2	0/423 (0%)	0
SUDDEN DEATH	2/416 (0.5%)	2	0/423 (0%)	0
DEATH	1/416 (0.2%)	1	0/423 (0%)	0
IMPAIRED HEALING	1/416 (0.2%)	1	0/423 (0%)	0
MULTI-ORGAN FAILURE	1/416 (0.2%)	1	0/423 (0%)	0
PAIN	1/416 (0.2%)	1	3/423 (0.7%)	3
PYREXIA	1/416 (0.2%)	1	0/423 (0%)	0
CHEST PAIN	0/416 (0%)	0	1/423 (0.2%)	1
WOUND NECROSIS	0/416 (0%)	0	1/423 (0.2%)	1
Hepatobiliary disorders
CHOLELITHIASIS	1/416 (0.2%)	1	0/423 (0%)	0
Infections and infestations
GANGRENE	14/416 (3.4%)	14	11/423 (2.6%)	12
BRONCHOPNEUMONIA	3/416 (0.7%)	3	0/423 (0%)	0
CELLULITIS	3/416 (0.7%)	3	3/423 (0.7%)	3
PNEUMONIA	3/416 (0.7%)	3	2/423 (0.5%)	2
INFECTED SKIN ULCER	2/416 (0.5%)	2	1/423 (0.2%)	1
PURULENT DISCHARGE	2/416 (0.5%)	2	0/423 (0%)	0
SEPSIS	2/416 (0.5%)	2	1/423 (0.2%)	1
OSTEOMYELITIS	1/416 (0.2%)	1	0/423 (0%)	0
POSTOPERATIVE WOUND INFECTION	1/416 (0.2%)	1	0/423 (0%)	0
WOUND INFECTION STAPHYLOCOCCAL	1/416 (0.2%)	1	0/423 (0%)	0
ABSCESS LIMB	0/416 (0%)	0	1/423 (0.2%)	1
ARTHRITIS BACTERIAL	0/416 (0%)	0	1/423 (0.2%)	1
LOBAR PNEUMONIA	0/416 (0%)	0	1/423 (0.2%)	1
LOCALISED INFECTION	0/416 (0%)	0	1/423 (0.2%)	1
Injury, poisoning and procedural complications
LIMB TRAUMATIC AMPUTATION	1/416 (0.2%)	1	0/423 (0%)	0
SHUNT THROMBOSIS	1/416 (0.2%)	1	0/423 (0%)	0
JAW FRACTURE	0/416 (0%)	0	1/423 (0.2%)	1
WOUND DEHISCENCE	0/416 (0%)	0	1/423 (0.2%)	1
Metabolism and nutrition disorders
DEHYDRATION	1/416 (0.2%)	1	0/423 (0%)	0
HYPERKALAEMIA	1/416 (0.2%)	1	0/423 (0%)	0
DIABETES MELLITUS	0/416 (0%)	0	1/423 (0.2%)	1
Musculoskeletal and connective tissue disorders
PAIN IN EXTREMITY	2/416 (0.5%)	2	1/423 (0.2%)	1
BURSITIS	1/416 (0.2%)	1	0/423 (0%)	0
TENOSYNOVITIS	1/416 (0.2%)	1	0/423 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
HYPOPHARYNGEAL CANCER STAGE III	1/416 (0.2%)	1	0/423 (0%)	0
LUNG NEOPLASM	1/416 (0.2%)	1	0/423 (0%)	0
Nervous system disorders
ISCHAEMIC STROKE	2/416 (0.5%)	2	2/423 (0.5%)	2
CEREBROVASCULAR ACCIDENT	1/416 (0.2%)	1	1/423 (0.2%)	1
DIABETIC COMA	1/416 (0.2%)	1	0/423 (0%)	0
SYNCOPE	1/416 (0.2%)	1	0/423 (0%)	0
CAROTID ARTERY STENOSIS	0/416 (0%)	0	1/423 (0.2%)	1
CEREBROVASCULAR INSUFFICIENCY	0/416 (0%)	0	1/423 (0.2%)	1
CONVULSION	0/416 (0%)	0	1/423 (0.2%)	1
PSYCHOMOTOR HYPERACTIVITY	0/416 (0%)	0	1/423 (0.2%)	1
TRANSIENT ISCHAEMIC ATTACK	0/416 (0%)	0	1/423 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
HYDROTHORAX	1/416 (0.2%)	1	0/423 (0%)	0
PULMONARY ARTERY THROMBOSIS	1/416 (0.2%)	1	0/423 (0%)	0
PULMONARY EMBOLISM	0/416 (0%)	0	1/423 (0.2%)	1
Skin and subcutaneous tissue disorders
SKIN ULCER	4/416 (1%)	4	5/423 (1.2%)	5
DRY GANGRENE	2/416 (0.5%)	2	0/423 (0%)	0
SKIN NECROSIS	1/416 (0.2%)	1	0/423 (0%)	0
Vascular disorders
PERIPHERAL ISCHAEMIA	11/416 (2.6%)	14	9/423 (2.1%)	9
EXTREMITY NECROSIS	10/416 (2.4%)	11	9/423 (2.1%)	9
NECROSIS ISCHAEMIC	6/416 (1.4%)	6	0/423 (0%)	0
CIRCULATORY COLLAPSE	2/416 (0.5%)	2	0/423 (0%)	0
ARTERIAL THROMBOSIS LIMB	1/416 (0.2%)	1	0/423 (0%)	0
HYPERTENSION	1/416 (0.2%)	1	0/423 (0%)	0
HYPERTENSIVE CRISIS	1/416 (0.2%)	1	0/423 (0%)	0
ISCHAEMIA	1/416 (0.2%)	1	1/423 (0.2%)	1
VENOUS THROMBOSIS LIMB	1/416 (0.2%)	1	0/423 (0%)	0
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	0/416 (0%)	0	1/423 (0.2%)	1
THROMBOPHLEBITIS	0/416 (0%)	0	1/423 (0.2%)	1
THROMBOSIS	0/416 (0%)	0	1/423 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Alprostadil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/416 (14.7%)		62/423 (14.7%)
Skin and subcutaneous tissue disorders
SKIN ULCER	24/416 (5.8%)	29	26/423 (6.1%)	28
Vascular disorders
PERIPHERAL ISCHAEMIA	40/416 (9.6%)	41	41/423 (9.7%)	45

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.