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

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)

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.

Study Overview

• Status: Completed
• Conditions: Peripheral Arterial Occlusive Disease
• Intervention / Treatment: Drug: Alprostadil; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 840
• Phase: Phase 4

Contacts and Locations

Study Locations

• Czechia
  • Plzen, Czechia
    • 404
  • Usti Nad Labem, Czechia
    • 414
• Germany
  • Karlsbad, Germany
    • 1
• Mexico
  • Aguascalientes, Mexico
    • 502
  • Merida, Mexico
    • 505
  • Queretaro, Mexico
    • 501
• Poland
  • Bydgoszcz, Poland
    • 306
  • Konskie, Poland
    • 321
  • Krakow, Poland
    • 320
  • Lublin, Poland
    • 314
  • Lublin, Poland
    • 315
  • Poznan, Poland
    • 316
  • Poznan, Poland
    • 317
  • Szczecin, Poland
    • 301
  • Szczecin, Poland
    • 304
  • Warsaw, Poland
    • 319
  • Warszawa, Poland
    • 307
  • Warszawa, Poland
    • 308
  • Warszawa, Poland
    • 309
  • Warszawa, Poland
    • 318
  • Wroclaw, Poland
    • 312
  • Zamosc, Poland
    • 322
• Russian Federation
  • Barnaul, Russian Federation
    • 246
  • Chelyabinsk, Russian Federation
    • 205
  • Chelyabinsk, Russian Federation
    • 244
  • Ekaterinburg, Russian Federation
    • 223
  • Ekaterinburg, Russian Federation
    • 247
  • Irkutsk, Russian Federation
    • 228
  • Kazan, Russian Federation
    • 242
  • Kemerovo, Russian Federation
    • 227
  • Moscow, Russian Federation
    • 201
  • Moscow, Russian Federation
    • 202
  • Moscow, Russian Federation
    • 203
  • Moscow, Russian Federation
    • 209
  • Moscow, Russian Federation
    • 219
  • Moscow, Russian Federation
    • 220
  • Moscow, Russian Federation
    • 230
  • Moscow, Russian Federation
    • 248
  • Novosibirsk, Russian Federation
    • 231
  • Novosibirsk, Russian Federation
    • 232
  • Omsk, Russian Federation
    • 222
  • Petrozavodsk, Russian Federation
    • 217
  • Rostov-on-Don, Russian Federation
    • 206
  • Rostov-on-Don, Russian Federation
    • 225
  • Rostov-on-Don, Russian Federation
    • 236
  • Rostov-on-Don, Russian Federation
    • 239
  • Ryazan, Russian Federation
    • 224
  • Samara, Russian Federation
    • 218
  • Saratov, Russian Federation
    • 237
  • St Petersburg, Russian Federation
    • 210
  • St Petersburg, Russian Federation
    • 212
  • St Petersburg, Russian Federation
    • 213
  • St Petersburg, Russian Federation
    • 214
  • St Petersburg, Russian Federation
    • 215
  • St Petersburg, Russian Federation
    • 216
  • Tula, Russian Federation
    • 243
  • Tumen, Russian Federation
    • 238
  • Tver, Russian Federation
    • 234
  • Ufa, Russian Federation
    • 241
  • Volgograd, Russian Federation
    • 240
  • Yaroslavl, Russian Federation
    • 221
• Ukraine
  • Dnipropetrovsk, Ukraine
    • 112
  • Donetsk, Ukraine
    • 109
  • Donetsk, Ukraine
    • 110
  • Ivano-Frankivsk, Ukraine
    • 114
  • Kharkov, Ukraine
    • 111
  • Kiev, Ukraine
    • 101
  • Kiev, Ukraine
    • 102
  • Kiev, Ukraine
    • 103
  • Kiev, Ukraine
    • 104
  • Kiev, Ukraine
    • 105
  • Lviv, Ukraine
    • 106
  • Odessa, Ukraine
    • 118
  • Odessa, Ukraine
    • 119
  • Uzhgorod, Ukraine
    • 113
  • Vinnytsya, Ukraine
    • 116
  • Zaporozhye, Ukraine
    • 107
  • Zaporozhye, Ukraine
    • 108

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: UCB BIOSCIENCES GmbH
• Collaborators: Aptiv Solutions

Publications and helpful links

General Publications

• Lawall H, Pokrovsky A, Checinski P, Ratushnyuk A, Hamm G, Randerath O, Grieger F, Bentz JWG. Efficacy and Safety of Alprostadil in Patients with Peripheral Arterial Occlusive Disease Fontaine Stage IV: Results of a Placebo Controlled Randomised Multicentre Trial (ESPECIAL). Eur J Vasc Endovasc Surg. 2017 Apr;53(4):559-566. doi: 10.1016/j.ejvs.2016.12.035. Epub 2017 Feb 8.

Helpful Links

• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: December 21, 2007
• First Submitted That Met QC Criteria: January 16, 2008
• First Posted (Estimate): January 17, 2008

Study Record Updates

• Last Update Posted (Actual): April 4, 2018
• Last Update Submitted That Met QC Criteria: March 8, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Alprostadil; Prostavasin; PAOD; Fontaine Stage IV
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Atherosclerosis; Peripheral Vascular Diseases; Peripheral Arterial Disease; Arterial Occlusive Diseases; Vasodilator Agents; Urological Agents; Platelet Aggregation Inhibitors; Alprostadil
• Other Study ID Numbers: SP0777; 2005-001970-29 (EudraCT Number)