Peripheral Arterial Occlusive Disease
Conditions
Keywords
Alprostadil, Prostavasin, PAOD, Fontaine Stage IV
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.
Interventions
DRUGAlprostadil
* Active Substance: Prostaglandin E1 * Pharmaceutical Form: solution for infusion * Concentration: 40 μg b.d. * Route of Administration: intravenous infusion
OTHERPlacebo
* Active Substance: Lactose * Pharmaceutical Form: solution for infusion * Concentration: 40 μg b.d. * Route of Administration: intravenous infusion
Sponsors
Aptiv Solutions
UCB BIOSCIENCES GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 %. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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) | 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. |
| 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. |
| 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. |
Countries
Czechia, Germany, Mexico, Poland, Russia, Ukraine
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Alprostadil: - Active Substance: Prostaglandin E1
* Pharmaceutical Form: solution for infusion
* Concentration: 40 μg b.d.
* Route of Administration: intravenous infusion | 416 |
| 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.
Placebo: - Active Substance: Lactose
* Pharmaceutical Form: solution for infusion
* Concentration: 40 μg b.d.
* Route of Administration: intravenous infusion | 423 |
| Total | 839 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 34 | 34 |
| Overall Study | Lack of Efficacy | 4 | 7 |
| Overall Study | Lost to Follow-up | 22 | 38 |
| Overall Study | Other Reason | 44 | 49 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Unsatisfactory Compliance | 9 | 6 |
| Overall Study | Withdrawal by Subject | 12 | 9 |
Baseline characteristics
| Characteristic | Placebo | Alprostadil | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 253 Participants | 263 Participants | 516 Participants |
| Age, Categorical Between 18 and 65 years | 170 Participants | 153 Participants | 323 Participants |
| Age, Continuous | 66.4 years STANDARD_DEVIATION 9.3 | 66.8 years STANDARD_DEVIATION 8.5 | 66.6 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 117 Participants | 123 Participants | 240 Participants |
| Sex: Female, Male Male | 306 Participants | 293 Participants | 599 Participants |
| Weight | 76.6 kilogram (kg) STANDARD_DEVIATION 12.6 | 75.4 kilogram (kg) STANDARD_DEVIATION 11.9 | 76.0 kilogram (kg) STANDARD_DEVIATION 12.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 61 / 416 | 62 / 423 |
| serious Total, serious adverse events | 87 / 416 | 62 / 423 |
Outcome results
Primary
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.
Time frame: At 12 weeks after the end of study drug treatment
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alprostadil | Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment | Stage 1 (n=253, n=251) | 49 participants |
| Alprostadil | Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment | Stage 2 (n=161, n=173) | 27 participants |
| Placebo | Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment | Stage 1 (n=253, n=251) | 43 participants |
| Placebo | Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment | Stage 2 (n=161, n=173) | 30 participants |
Comparison: 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.p-value: 0.2587Cochran-Mantel-Haenszel
Comparison: 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.p-value: 0.3463Cochran-Mantel-Haenszel
Primary
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.
Time frame: At 24 weeks after the end of study drug treatment
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alprostadil | Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment | Stage 1 (n=253, n=251) | 32 participants |
| Alprostadil | Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment | Stage 2 (n=161, n=173) | 20 participants |
| Placebo | Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment | Stage 1 (n=253, n=251) | 49 participants |
| Placebo | Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment | Stage 2 (n=161, n=173) | 13 participants |
Comparison: 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.p-value: 0.0173Cochran-Mantel-Haenszel
Comparison: 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.p-value: 0.1154Cochran-Mantel-Haenszel
Secondary
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)
Population: Safety Set consists of all randomized subjects who received at least one dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alprostadil | All-cause Mortality During the Course of the Study (up to 196 Days) | 20 participants |
| Placebo | All-cause Mortality During the Course of the Study (up to 196 Days) | 15 participants |
Secondary
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.
Time frame: During the course of the study (up to 196 days)
Population: Safety Set consists of all randomized subjects who received at least one dose of trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alprostadil | Cardiovascular Morbidity During the Course of the Study (up to 196 Days) | Myocardial infarctions | 5 participants |
| Alprostadil | Cardiovascular Morbidity During the Course of the Study (up to 196 Days) | Strokes | 3 participants |
| Placebo | Cardiovascular Morbidity During the Course of the Study (up to 196 Days) | Myocardial infarctions | 6 participants |
| Placebo | Cardiovascular Morbidity During the Course of the Study (up to 196 Days) | Strokes | 3 participants |
Secondary
Cardiovascular Mortality During the Course of the Study (up to 196 Days)
Time frame: During the course of the study (up to 196 days)
Population: Safety Set consists of all randomized subjects who received at least one dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alprostadil | Cardiovascular Mortality During the Course of the Study (up to 196 Days) | 11 participants |
| Placebo | Cardiovascular Mortality During the Course of the Study (up to 196 Days) | 14 participants |
Secondary
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.
Time frame: At 24 weeks after the end of study drug treatment
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Alprostadil | Complete Healing of Ischemic Necroses and Ulcerations at 24 Weeks After the End of Study Drug Treatment | 108 participants |
| Placebo | Complete Healing of Ischemic Necroses and Ulcerations at 24 Weeks After the End of Study Drug Treatment | 103 participants |
Secondary
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.
Time frame: During the course of the study (up to 196 days)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Prior to treatment (n=414, n=424) | 300 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 1 (n=414, n=424) | 292 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 2 (n=414, n=424) | 295 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 3 (n=413, n=424) | 295 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 4 (n=412, n=423) | 292 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 5 (n=411, n=423) | 294 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 6 (n=411, n=423) | 290 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 7 (n=409, n=422) | 290 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Week 2 (n=409, n=422) | 292 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Week 3 (n=399, n=416) | 259 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Week 4 (n=393, n=404) | 238 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 29-42 (n=348, n=354) | 170 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 43-56 (n=361, n=370) | 164 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 57-70 (n=361, n=346) | 155 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 71-84 (n=352, n=344) | 146 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 85-98 (n=341, n=339) | 143 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 99-112 (n=321, n=318) | 132 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 113-140 (n=309, n=301) | 122 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 141-168 (n=306, n=304) | 118 participants |
| Alprostadil | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 169-196 (n=272, n=271) | 98 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 113-140 (n=309, n=301) | 117 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Prior to treatment (n=414, n=424) | 318 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Week 4 (n=393, n=404) | 257 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 1 (n=414, n=424) | 314 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 85-98 (n=341, n=339) | 140 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 2 (n=414, n=424) | 313 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 29-42 (n=348, n=354) | 191 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 3 (n=413, n=424) | 317 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 169-196 (n=272, n=271) | 90 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 4 (n=412, n=423) | 316 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 43-56 (n=361, n=370) | 173 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 5 (n=411, n=423) | 311 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 99-112 (n=321, n=318) | 127 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 6 (n=411, n=423) | 312 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 57-70 (n=361, n=346) | 155 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Study Day 7 (n=409, n=422) | 306 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 141-168 (n=306, n=304) | 109 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Week 2 (n=409, n=422) | 308 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Post treatment, Study Days 71-84 (n=352, n=344) | 148 participants |
| Placebo | Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days) | Concomitant, Week 3 (n=399, n=416) | 284 participants |
Secondary
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 %.
Time frame: At 24 weeks after the end of study drug treatment
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alprostadil | Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment | Complete healing | 101 participants |
| Alprostadil | Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment | Decrease by >= 50 % | 57 participants |
| Alprostadil | Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment | Remains unchanged | 45 participants |
| Alprostadil | Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment | Increase by >= 50 % | 30 participants |
| Placebo | Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment | Increase by >= 50 % | 30 participants |
| Placebo | Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment | Complete healing | 98 participants |
| Placebo | Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment | Remains unchanged | 48 participants |
| Placebo | Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment | Decrease by >= 50 % | 56 participants |
Secondary
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.
Time frame: At 24 weeks after the end of study drug treatment
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alprostadil | Intensity of Rest Pain Induced by Ischemic Lesions at 24 Weeks After the End of Study Drug Treatment | 17.57 millimeters (mm) | Standard Deviation 25.33 |
| Placebo | Intensity of Rest Pain Induced by Ischemic Lesions at 24 Weeks After the End of Study Drug Treatment | 16.38 millimeters (mm) | Standard Deviation 25.08 |
Secondary
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.
Time frame: At 24 weeks after the end of study drug treatment
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Alprostadil | Minor Amputations at 24 Weeks After the End of Study Drug Treatment | 65 participants |
| Placebo | Minor Amputations at 24 Weeks After the End of Study Drug Treatment | 40 participants |
Secondary
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.
Time frame: At 24 weeks after the end of study drug treatment
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Alprostadil | Revascularization Procedures at 24 Weeks After the End of Study Drug Treatment | 6 participants |
| Placebo | Revascularization Procedures at 24 Weeks After the End of Study Drug Treatment | 7 participants |
Secondary
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.
Time frame: At 24 weeks after the end of study drug treatment
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alprostadil | Systolic Pressure at Ankle Level at 24 Weeks After the End of Study Drug Treatment | Worst change analysis | 42.83 mmHg | Standard Deviation 30.16 |
| Alprostadil | Systolic Pressure at Ankle Level at 24 Weeks After the End of Study Drug Treatment | Worst value analysis | 39.39 mmHg | Standard Deviation 29.92 |
| Placebo | Systolic Pressure at Ankle Level at 24 Weeks After the End of Study Drug Treatment | Worst change analysis | 39.47 mmHg | Standard Deviation 28.32 |
| Placebo | Systolic Pressure at Ankle Level at 24 Weeks After the End of Study Drug Treatment | Worst value analysis | 36.45 mmHg | Standard Deviation 27.19 |