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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    2005-001970-29
    Trial protocol
    CZ  
    Global end of trial date
    30 Jul 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jun 2016
    First version publication date
    27 Mar 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SP777
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00596752
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB BIOSCIENCES GmbH
    Sponsor organisation address
    Alfred-Nobel-Straße 10, Monheim, Germany, 40789
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 1515, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 1515, clinicaltrials@ucb.com
    Sponsor organisation name
    UCB BIOSCIENCES GmbH
    Sponsor organisation address
    Alfred-Nobel-Straße 10, Monheim, Germany, 40789
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective of this study is to show a superior effect of Prostavasin® compared to placebo on the rate of complete healing of ischemic necroses and ulcerations at 12 weeks after the end of treatment as well as on the frequency and height of major amputations in subjects suffering from PAOD Fontaine stage IV at 24 weeks after the end of treatment.
    Protection of trial subjects
    Subjects were hospitalized during the 4-week treatment phase. Standard analgesic treatment was provided to all subjects. Antibiotic treatment was provided if necessary.
    Background therapy
    All subjects received in-house standard analgesic treatment and daily wound treatment.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    26 Mar 2004
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Poland: 90
    Country: Number of subjects enrolled
    Russian Federation: 406
    Country: Number of subjects enrolled
    Ukraine: 335
    Worldwide total number of subjects
    840
    EEA total number of subjects
    94
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    323
    From 65 to 84 years
    505
    85 years and over
    12

    Subject disposition

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    Recruitment
    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
    Screening 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.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Alprostadil
    Arm 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.
    Arm type
    Experimental

    Investigational medicinal product name
    Alprostadil
    Investigational medicinal product code
    Other name
    Prostavasin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    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. •Active Substance: Prostaglandin E1 •Concentration: 40 μg b.d.

    Arm title
    Placebo
    Arm description
    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.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    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. •Active Substance: Lactose •Concentration: 40 μg b.d.

    Number of subjects in period 1
    Alprostadil Placebo
    Started
    415
    425
    Randomized and Treated
    415
    424
    Completed
    289
    282
    Not completed
    126
    143
         SAE, fatal + AE, non-serious non-fatal
    -
    1
         Other Reason
    44
    49
         Protocol deviation
    1
    -
         Unsatisfactory Compliance
    9
    6
         Lack of efficacy
    4
    7
         SAE, non-fatal
    16
    17
         Adverse event, serious fatal
    13
    11
         Consent withdrawn by subject
    12
    9
         AE, non-serious non-fatal
    3
    3
         SAE, fatal + SAE, non-fatal
    2
    2
         Lost to follow-up
    22
    38

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alprostadil
    Reporting 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.

    Reporting group title
    Placebo
    Reporting group description
    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.

    Reporting group values
    Alprostadil Placebo Total
    Number of subjects
    415 425 840
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    153 170 323
        From 65-84 years
    257 248 505
        85 years and over
    5 7 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.8 ± 8.5 66.4 ± 9.3 -
    Gender categorical
    Units: Subjects
        Female
    122 119 241
        Male
    293 306 599
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    75.4 ± 11.9 76.5 ± 12.6 -

    End points

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    End points reporting groups
    Reporting group title
    Alprostadil
    Reporting 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.

    Reporting group title
    Placebo
    Reporting group description
    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.

    Subject analysis set title
    Safety Set (Placebo treated subjects)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety Set includes all randomized subjects who received at least one dose of trial medication. Subjects were analyzed according to the actual treatment received. 4 PBO subjects were treated with Alprostadil, 3 Alprostadil subjects were treated with PBO.1 PBO subject withdrew prior to start of study treatment.

    Subject analysis set title
    Safety Set (Alprostadil treated subjects)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety Set includes all randomized subjects who received at least one dose of trial medication. Subjects were analyzed according to the actual treatment received. 4 PBO subjects were treated with Alprostadil, 3 Alprostadil subjects were treated with PBO.1 PBO subject withdrew prior to start of study treatment.

    Subject analysis set title
    Full Analysis Set (Placebo treated subjects)
    Subject analysis set type
    Full analysis
    Subject analysis set 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.

    Subject analysis set title
    Full Analysis Set (Alprostadil treated subjects)
    Subject analysis set type
    Full analysis
    Subject analysis set 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.

    Primary: Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment

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    End point title
    Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment
    End point 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.
    End point type
    Primary
    End point timeframe
    At 12 weeks after the end of study drug treatment
    End point values
    Full Analysis Set (Alprostadil treated subjects) Full Analysis Set (Placebo treated subjects)
    Number of subjects analysed
    414 [1]
    424 [2]
    Units: participants
        Stage 1 (n=253, n=251)
    49
    43
        Stage 2 (n=161, n=173)
    27
    30
    Notes
    [1] - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values.
    [2] - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values.
    Statistical analysis title
    Statistical analysis of stage 1
    Statistical analysis description
    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.
    Comparison groups
    Full Analysis Set (Placebo treated subjects) v Full Analysis Set (Alprostadil treated subjects)
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.2587 [4]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - 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.
    [4] - 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.
    Statistical analysis title
    Statistical analysis of stage 1 and 2 combined
    Statistical analysis description
    Primary goal was to test the following null hypothesis: H01: πhealingPGE1≤ πhealingPlacebo, with πhealing=proportion of subjects with complete ulcer healing.
    Comparison groups
    Full Analysis Set (Alprostadil treated subjects) v Full Analysis Set (Placebo treated subjects)
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.3463 [6]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - 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.
    [6] - 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.

    Primary: Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment

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    End point title
    Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment
    End point 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.
    End point type
    Primary
    End point timeframe
    At 24 weeks after the end of study drug treatment
    End point values
    Full Analysis Set (Alprostadil treated subjects) Full Analysis Set (Placebo treated subjects)
    Number of subjects analysed
    414 [7]
    424 [8]
    Units: participants
        Stage 1 (n=253, n=251)
    32
    49
        Stage 2 (n=161, n=173)
    20
    13
    Notes
    [7] - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values.
    [8] - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values.
    Statistical analysis title
    Statistical analysis of stage 1
    Statistical analysis description
    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.
    Comparison groups
    Full Analysis Set (Alprostadil treated subjects) v Full Analysis Set (Placebo treated subjects)
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.0173 [10]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [9] - 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.
    [10] - 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.
    Statistical analysis title
    Statistical analysis of stage 1 and 2 combined
    Statistical analysis description
    Primary goal was to test the following null hypothesis: H02: πampPGE1≥ πampPlacebo, with πamp=proportion of subjects with major amputations.
    Comparison groups
    Full Analysis Set (Alprostadil treated subjects) v Full Analysis Set (Placebo treated subjects)
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.1154 [12]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [11] - 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.
    [12] - 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.

    Secondary: Complete Healing of Ischemic Necroses and Ulcerations at 24 Weeks After the End of Study Drug Treatment

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    End point title
    Complete Healing of Ischemic Necroses and Ulcerations at 24 Weeks After the End of Study Drug Treatment
    End point 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.
    End point type
    Secondary
    End point timeframe
    At 24 weeks after the end of study drug treatment
    End point values
    Full Analysis Set (Alprostadil treated subjects) Full Analysis Set (Placebo treated subjects)
    Number of subjects analysed
    289 [13]
    279 [14]
    Units: participants
    108
    103
    Notes
    [13] - Of the 414 subjects in the Full Analysis Set, 289 are included in the analysis of this endpoint.
    [14] - Of the 424 subjects in the Full Analysis Set, 279 are included in the analysis of this endpoint.
    No statistical analyses for this end point

    Secondary: Intensity of Rest Pain Induced by Ischemic Lesions at 24 Weeks After the End of Study Drug Treatment

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    End point title
    Intensity of Rest Pain Induced by Ischemic Lesions at 24 Weeks After the End of Study Drug Treatment
    End point 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.
    End point type
    Secondary
    End point timeframe
    At 24 weeks after the end of study drug treatment
    End point values
    Full Analysis Set (Alprostadil treated subjects) Full Analysis Set (Placebo treated subjects)
    Number of subjects analysed
    414 [15]
    424 [16]
    Units: millimeter(s)
        arithmetic mean (standard deviation)
    17.57 ± 25.33
    16.38 ± 25.08
    Notes
    [15] - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values.
    [16] - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values.
    No statistical analyses for this end point

    Secondary: Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment

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    End point title
    Increase/Decrease in Ulcer Area of ≥ 50 % at 24 Weeks After the End of Study Drug Treatment
    End point 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 %.
    End point type
    Secondary
    End point timeframe
    At 24 weeks after the end of study drug treatment
    End point values
    Full Analysis Set (Alprostadil treated subjects) Full Analysis Set (Placebo treated subjects)
    Number of subjects analysed
    233 [17]
    232 [18]
    Units: participants
        Complete healing
    101
    98
        Decrease by >= 50 %
    57
    56
        Remains unchanged
    45
    48
        Increase by >= 50 %
    30
    30
    Notes
    [17] - Of the 414 subjects in the Full Analysis Set, 233 are included in the analysis of this endpoint.
    [18] - Of the 424 subjects in the Full Analysis Set, 232 are included in the analysis of this endpoint.
    No statistical analyses for this end point

    Secondary: Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days)

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    End point title
    Consumption and Type of Analgesic Medication During the Course of the Study (up to 196 Days)
    End point description
    The number of subjects who used analgesics are summarized for different time points/intervals during the course of the study.
    End point type
    Secondary
    End point timeframe
    During the course of the study (up to 196 days)
    End point values
    Full Analysis Set (Alprostadil treated subjects) Full Analysis Set (Placebo treated subjects)
    Number of subjects analysed
    414
    424
    Units: participants
        Prior to treatment (n=414, n=424)
    300
    318
        Concomitant, Study Day 1 (n=414, n=424)
    292
    314
        Concomitant, Study Day 2 (n=414, n=424)
    295
    313
        Concomitant, Study Day 3 (n=413, n=424)
    295
    317
        Concomitant, Study Day 4 (n=412, n=423)
    292
    316
        Concomitant, Study Day 5 (n=411, n=423)
    294
    311
        Concomitant, Study Day 6 (n=411, n=423)
    290
    312
        Concomitant, Study Day 7 (n=409, n=422)
    290
    306
        Concomitant, Week 2 (n=409, n=422)
    292
    308
        Concomitant, Week 3 (n=399, n=416)
    259
    284
        Concomitant, Week 4 (n=393, n=404)
    238
    257
        Post treatment, Study Days 29-42 (n=348, n=354)
    170
    191
        Post treatment, Study Days 43-56 (n=361, n=370)
    164
    173
        Post treatment, Study Days 57-70 (n=361, n=346)
    155
    155
        Post treatment, Study Days 71-84 (n=352, n=344)
    146
    148
        Post treatment, Study Days 85-98 (n=341, n=339)
    143
    140
        Post treatment, Study Days 99-112 (n=321, n=318)
    132
    127
        Post treatment, Study Days 113-140 (n=309, n=301)
    122
    117
        Post treatment, Study Days 141-168 (n=306, n=304)
    118
    109
        Post treatment, Study Days 169-196 (n=272, n=271)
    98
    90
    No statistical analyses for this end point

    Secondary: Systolic Pressure at Ankle Level at 24 Weeks After the End of Study Drug Treatment

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    End point title
    Systolic Pressure at Ankle Level at 24 Weeks After the End of Study Drug Treatment
    End point 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.
    End point type
    Secondary
    End point timeframe
    At 24 weeks after the end of study drug treatment
    End point values
    Full Analysis Set (Alprostadil treated subjects) Full Analysis Set (Placebo treated subjects)
    Number of subjects analysed
    383 [19]
    394 [20]
    Units: mmHg
    arithmetic mean (standard deviation)
        Worst change analysis
    42.83 ± 30.16
    39.47 ± 28.32
        Worst value analysis
    39.39 ± 29.92
    36.45 ± 27.19
    Notes
    [19] - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values.
    [20] - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF) in case of missing values.
    No statistical analyses for this end point

    Secondary: Minor Amputations at 24 Weeks After the End of Study Drug Treatment

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    End point title
    Minor Amputations at 24 Weeks After the End of Study Drug Treatment
    End point 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.
    End point type
    Secondary
    End point timeframe
    At 24 weeks after the end of study drug treatment
    End point values
    Full Analysis Set (Alprostadil treated subjects) Full Analysis Set (Placebo treated subjects)
    Number of subjects analysed
    316 [21]
    297 [22]
    Units: participants
    65
    40
    Notes
    [21] - Of the 414 subjects in the Full Analysis Set, 316 are included in the analysis of this endpoint.
    [22] - Of the 424 subjects in the Full Analysis Set, 297 are included in the analysis of this endpoint.
    No statistical analyses for this end point

    Secondary: Revascularization Procedures at 24 Weeks After the End of Study Drug Treatment

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    End point title
    Revascularization Procedures at 24 Weeks After the End of Study Drug Treatment
    End point description
    The number of subjects with revascularization prior to or at 24 weeks after the end of study drug treatment is presented below.
    End point type
    Secondary
    End point timeframe
    At 24 weeks after the end of study drug treatment
    End point values
    Full Analysis Set (Alprostadil treated subjects) Full Analysis Set (Placebo treated subjects)
    Number of subjects analysed
    294 [23]
    283 [24]
    Units: participants
    6
    7
    Notes
    [23] - Of the 414 subjects in the Full Analysis Set, 294 are included in the analysis of this endpoint.
    [24] - Of the 424 subjects in the Full Analysis Set, 283 are included in the analysis of this endpoint.
    No statistical analyses for this end point

    Secondary: All-cause Mortality During the Course of the Study (up to 196 Days)

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    End point title
    All-cause Mortality During the Course of the Study (up to 196 Days)
    End point description
    End point type
    Secondary
    End point timeframe
    During the course of the study (up to 196 days)
    End point values
    Safety Set (Alprostadil treated subjects) Safety Set (Placebo treated subjects)
    Number of subjects analysed
    416
    423
    Units: participants
    20
    15
    No statistical analyses for this end point

    Secondary: Cardiovascular Mortality During the Course of the Study (up to 196 Days)

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    End point title
    Cardiovascular Mortality During the Course of the Study (up to 196 Days)
    End point description
    End point type
    Secondary
    End point timeframe
    During the course of the study (up to 196 days)
    End point values
    Safety Set (Alprostadil treated subjects) Safety Set (Placebo treated subjects)
    Number of subjects analysed
    416
    423
    Units: participants
    11
    14
    No statistical analyses for this end point

    Secondary: Cardiovascular Morbidity During the Course of the Study (up to 196 Days)

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    End point title
    Cardiovascular Morbidity During the Course of the Study (up to 196 Days)
    End point description
    Cardiovascular morbidity is presented as number of subjects with myocardial infarction and/or stroke during the course of the study.
    End point type
    Secondary
    End point timeframe
    During the course of the study (up to 196 days)
    End point values
    Safety Set (Alprostadil treated subjects) Safety Set (Placebo treated subjects)
    Number of subjects analysed
    416
    423
    Units: participants
        Myocardial infarctions
    5
    6
        Strokes
    3
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected during the course of the study from Study Day 0 up to Study Day 196.
    Adverse event reporting additional 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.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Alprostadil
    Reporting 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. • Active Substance: Prostaglandin E1 • Pharmaceutical Form: solution for infusion • Concentration: 40 μg b.d. • Route of Administration: intravenous infusion

    Reporting group title
    Placebo
    Reporting group description
    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. • Active Substance: Lactose • Pharmaceutical Form: solution for infusion • Concentration: 40 μg b.d. • Route of Administration: intravenous infusion

    Serious adverse events
    Alprostadil Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 416 (20.91%)
    62 / 423 (14.66%)
         number of deaths (all causes)
    20
    15
         number of deaths resulting from adverse events
    1
    2
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    11 / 416 (2.64%)
    9 / 423 (2.13%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    10 / 416 (2.40%)
    9 / 423 (2.13%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrosis ischaemic
         subjects affected / exposed
    6 / 416 (1.44%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial thrombosis limb
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hypopharyngeal cancer stage III
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Ischaemic ulcer
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrosis
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Death
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 416 (0.24%)
    3 / 423 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound necrosis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb traumatic amputation
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 416 (0.72%)
    3 / 423 (0.71%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Cardiac failure
         subjects affected / exposed
    3 / 416 (0.72%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Angina pectoris
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 416 (0.48%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 416 (0.48%)
    4 / 423 (0.95%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Myocardial infarction
         subjects affected / exposed
    2 / 416 (0.48%)
    3 / 423 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Atrioventricular block complete
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 416 (0.00%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute right ventricular failure
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal arrhythmia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hydrothorax
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    2 / 416 (0.48%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Cerebrovascular accident
         subjects affected / exposed
    1 / 416 (0.24%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic coma
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Convulsion
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric artery embolism
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    4 / 416 (0.96%)
    5 / 423 (1.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 416 (0.48%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gangrene
         subjects affected / exposed
    14 / 416 (3.37%)
    11 / 423 (2.60%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 12
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    3 / 416 (0.72%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 416 (0.72%)
    3 / 423 (0.71%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    2 / 416 (0.48%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 416 (0.72%)
    2 / 423 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Purulent discharge
         subjects affected / exposed
    2 / 416 (0.48%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 416 (0.48%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 416 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 416 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Alprostadil Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 416 (14.66%)
    62 / 423 (14.66%)
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    40 / 416 (9.62%)
    41 / 423 (9.69%)
         occurrences all number
    41
    45
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    24 / 416 (5.77%)
    26 / 423 (6.15%)
         occurrences all number
    29
    28

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2004
    Protocol Amendment 1 introduced the following changes: - The angiography to be performed as a pre-requisite for inclusion was extended to the calf to meet more adequately the requirements for documentation of PAOD. Inclusion Criterion 5 was updated accordingly. - Monitor checks of the data in the electronic case report form (eCRF) were performed twice a week instead of daily for feasibility reasons.
    23 Apr 2004
    Protocol Amendment 2 introduced the following changes: - The volume of the isotonic sodium chloride solution used for alprostadil (Prostavasin®) 40 μg and Placebo infusion was increased from 50 mL to 150 mL to allow for better control when using drip infusions instead of infusion pumps. - Change in responsibility for the position of Drug Safety Officer. - Reports about immediately reportable adverse events (AEs) were to be transmitted electronically by completion of the appropriate pages in the eCRF instead by facsimile to allow for storage of all study information in a central database located at the CRO. The transmission of information already contained in the eCRF/database became unnecessary.
    03 Dec 2004
    Protocol Amendment 4 introduced the following changes: - The rate of subjects with an increase or decrease in the ulcer area of ≥ 50 % became an additional secondary efficacy criterion. This criterion was added to evaluate treatment effects below the level of complete healing as well as possible increases in ulcer area more exactly. - Picture(s) of the ulcer(s) together with a calibrated ruler were taken to allow assessments of the ulcer area. - Subjects in the position to be primarily revascularized but refusing surgery were allowed to be included in the study. - Subjects with a major amputation on the affected extremity were excluded from the study, as major amputations could have interfered with ulcer healing. - In order to standardize the evaluation of pictures from angiography and skin lesions, a committee of medical experts was appointed to decide in compliance with the Clinical Trial Protocol whether a subject was allowed to be included in the study.
    05 Jul 2006
    Protocol Amendment 5 introduced the following changes: - Concomitant use of vasoactive medication (eg, naftidrofuryl, pentoxifylline, buflomedil, cilostazol) or other prostaglandins became prohibited during the entire study participation of each subject, as these drugs could have interfered with the study medication. - Subjects had to be withdrawn from the study if treatment with vasoactive medication or other prostaglandins was deemed necessary by the investigator. - Subjects had to be withdrawn from the study if the ulcer(s) under investigation was/were removed by a major amputation. - Results of investigations performed within the last 7 days prior to the first day of the Run-In Phase were allowed to be used as Baseline values if deemed appropriate by the investigator. - Changes in responsibilities for the positions of Head of Medical Experts and Medical Director. - The study was extended to the Czech Republic to increase the recruitment rate. - A new section specifying the reference documents for the sponsor’s assessment of expectedness was inserted. This section was later revised as per Protocol Amendment 8.
    18 Aug 2006
    Protocol Amendment 6 provided the following definition for Adverse Events (AEs) representing deterioration of PAOD: - AEs representing a deterioration of PAOD such as the increase in lesion area (ulcer/necrosis), number of lesion (ulcer/necrosis) or rest pain induced by ischemic lesions were defined as AEs of disease origin. These AEs were not to be assessed as serious adverse events (SAEs) even if they led to amputation and therefore required inpatient hospitalization, led to prolongation of existing inpatient hospitalization or resulted in persistent or significant disability/incapacity. The investigator had to report the AEs of disease origin within 24 hours to the responsible drug safety unit. The responsible drug safety unit reviewed the events and, in case a specific event did not fulfill the above mentioned criteria for AE of disease origin, the event was reported to the sponsor. The sponsor decided whether the AEs had to be revised into SAEs.
    18 Jun 2009
    Protocol Amendment 8 introduced the following changes: - Change in responsibility for the position of the Clinical Lead. - The email-addresses of UCB/Schwarz Pharma Deutschland GmbH personnel changed from XXX@ucb-group.com to XXX@ucb.com. - It was defined that the sponsor’s assessment of expectedness of AEs was performed according to the information given in the Company Core Data Sheet for subjects in all countries instead of according to the information given in the international core data sheet/core summary of product characteristics for subjects in Russia, Ukraine, Poland and Czech Republic as well as according to the German “Fachinformation” for subjects in Germany. - According to the recommendation of the independent data monitoring committee (IDMC), the study was continued and the number of subjects to be included in the second stage was increased from 50 subjects per Treatment group to 170 subjects per treatment group. It was added that the IDMC did not raise any objections against the continuation of the study or the increase in the sample size.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Not applicable
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