Prostaglandin E1 in Outpatients With Intermittent Claudication

Study Overview
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Brief Summary
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Investigate, under outpatient conditions, both the effect of 4 weeks of daily treatment with Prostaglandin E1 and that of 4 weeks of interval treatment (two infusions per week) on the pain-free walking distance in patients with Intermittent Claudication.

Official Title
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Intravenous Prostaglandin E1 Treatment in Outpatients With Intermittent Claudication

Conditions
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Stage II Peripheral Arterial Occlusive Disease, Intermittent Claudication Fontaine Stage II PAOD

Intervention / Treatment
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* Drug: Alprostadil (Prostaglandin E1)
* Drug: Pentoxifylline
* Drug: Placebo to Pentoxifylline oral
* Drug: Placebo to Alprostadil (Prostaglandin E1) intravenous


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with Peripheral Arterial Occlusive Disease (PAOD) of the lower extremity in Fontaine stage II Maximum walking distance on the treadmill (12 %, 3 km/h) between 30 and 150 m Stable Intermittent Claudication of at least 6 months standing with no acute shortening of walking distance over the past 3 months Stenoses or occlusions below the Femoral Bifurcation (above-knee or below-knee type) confirmed by duplex US or angiography Ankle/brachial index ≤ 0.90 with a decrease in systolic ankle pressure of ≥ 10 % after maximum loading (maximum walking distance on the treadmill at 3 km/h, 12 %) The patient is physically and mentally capable of participating in the trial Patient age > 40 years, male and female Patient is informed and given ample time and opportunity to think about her/his participation and has given her/his written informed consent Patient is willing and able to comply with all trial requirements Exclusion Criteria: Surgical or other interventional measures performed on the affected extremity and Prostaglandin treatment within the 6 months immediately prior to the trial Rest pain and Necroses Systolic ankle pressure less than 50 mmHg Change in maximum walking distance during the one-week Run-in Phase of more than ± 25 % of Baseline Successful physical walking training within the 6 months immediately prior to the trial Inflammatory vascular diseases Polyneuropathy in Diabetes Mellitus Diseases limiting walking distance (Arthrosis, inflammatory diseases of the joints, neurological disease, diseases of the Vertebral Column, cardiopulmonary diseases) History of Pulmonary Oedema Myocardial infarction within the past 6 months Pregnancy or nursing Known hypersensitivity to any components of the trial medication or comparative drug Renal insufficiency, compensated retention (creatinine > 2.0 mg/dL) Severe retinal Haemorrhage Massive Haemorrhage Known existing malignant diseases Vasoactive concomitant medication (e.g. Naftidrofuryl, Pentoxifylline, Buflomedil, Cilostazol), or other Prostaglandins Untreated or uncontrolled Hypertension (systolic blood pressure ≥ 180 mmHg, diastolic blood pressure ≥ 110 mmHg) Previous participation of the patient in the present trial Participation of the patient in a trial with the same objectives within the past 6 months, or is currently participating in another trial Illness of the patient due to alcohol or drug-abuse within the past 6 months Serious illness of the patient that the investigator considers to compromise his/her participation in the trial

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alprostadil<br>Alprostadil (Prostaglandin E1) intravenous and matching Placebo to Pentoxifylline oral | Drug: Alprostadil (Prostaglandin E1)<br>* 4-week Daily Treatment Period 1: 4 weeks of 1 x daily intravenous infusion of 3 ampoules (20 µg) of Prostaglandin E1 (total 60 µg) in 50 - 250 ml physiological saline solution over 2 hours. 4-week Interval Treatment Period 2: 4 weeks of 2 x weekly intravenous infusion of 3 ampoules (20 µg) of Prostaglandin E1 (total 60 µg) in 50 - 250 ml physiological saline solution over 2 hours.<br>* Other names: Prostavasin;Drug: Placebo to Pentoxifylline oral<br>* 4-week Daily Treatment Period 1: 4 weeks of 2 x daily (including weekends) matching Placebo to Pentoxifylline tablets. 4-week Interval Treatment Period 2: 4 weeks of 2 x daily (including weekends) matching Placebo to Pentoxifylline tablets.<br>|
| Active Comparator: Pentoxifylline<br>Pentoxifylline oral and matching Placebo to Alprostadil (Prostaglandin E1) intravenous | Drug: Pentoxifylline<br>* 4-week Daily Treatment Period 1: 4 weeks of 2 x daily (including weekends) 600 mg Pentoxifylline tablets. 4-week Interval Treatment Period 2: 4 weeks of 2 x daily (including weekends) 600 mg Pentoxifylline tablets.<br>* Other names: Trental®;Drug: Placebo to Alprostadil (Prostaglandin E1) intravenous<br>* 4-week Daily Treatment Period 1: 4 weeks of 1 x daily intravenous infusion of Placebo in 50 - 250 ml physiological saline solution over 2 hours. 4-week Interval Treatment Period 2: 4 weeks of 2 x weekly intravenous infusion of Placebo in 50 - 250 ml physiological saline solution over 2 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of Pain-free Walking Distance After Period 2 in Comparison With the Findings at Baseline | The ratio of pain-free walking distance was calculated by the pain-free walking distance after Period 2 divided by the pain-free walking distance at Baseline with determination of pain-free walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From Baseline to the end of 4 weeks of Interval Treatment (Period 2) | 
| Ratio of Pain-free Walking Distance After Period 3 in Comparison With the Findings at Baseline | The ratio of pain-free walking distance was calculated by the pain-free walking distance after Period 3 divided by the pain-free walking distance at Baseline with determination of pain-free walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From Baseline to the end of 6-months Follow-up (Period 3) | 
| Ratio of Pain-free Walking Distance After Period 1 in Comparison With the Findings at Baseline | The ratio of pain-free walking distance was calculated by the pain-free walking distance after Period 1 divided by the pain-free walking distance at Baseline with determination of pain-free walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From Baseline to the end of 4 weeks of Daily Treatment (Period 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of Pain-free Walking Distance After Period 2 in Comparison With the Findings After Period 1 | The ratio of pain-free walking distance was calculated by the pain-free walking distance after Period 2 divided by the pain-free walking distance after Period 1 with determination of pain-free walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From the end of 4 weeks of Daily Treatment (Period 1) to the end of 4 weeks of Interval Treatment (Period 2) | 
| Ratio of Pain-free Walking Distance After Period 3 in Comparison With the Findings After Period 1 | The ratio of pain-free walking distance was calculated by the pain-free walking distance after Period 3 divided by the pain-free walking distance after Period 1 with determination of pain-free walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From the end of 4 weeks of Daily Treatment (Period 1) to the end of 6-months Follow-up (Period 3) | 
| Ratio of Pain-free Walking Distance After Period 3 in Comparison With the Findings After Period 2 | The ratio of pain-free walking distance was calculated by the pain-free walking distance after Period 3 divided by the pain-free walking distance after Period 2 with determination of pain-free walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From the end of 4 weeks of Interval Treatment (Period 2) to the end of 6-months Follow-up (Period 3) | 
| Ratio of Maximum Walking Distance After Period 1 in Comparison With the Findings at Baseline | The ratio of maximum walking distance was calculated by the maximum walking distance after Period 1 divided by the maximum walking distance at Baseline with determination of maximum walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From Baseline to the end of 4 weeks of Daily Treatment (Period 1) | 
| Ratio of Maximum Walking Distance After Period 2 in Comparison With the Findings at Baseline | The ratio of maximum walking distance was calculated by the maximum walking distance after Period 2 divided by the maximum walking distance at Baseline with determination of maximum walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From Baseline to the end of 4 weeks of Interval Treatment (Period 2) | 
| Ratio of Maximum Walking Distance After Period 2 in Comparison With the Findings After Period 1 | The ratio of maximum walking distance was calculated by the maximum walking distance after Period 2 divided by the maximum walking distance after Period 1 with determination of maximum walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From the end of 4 weeks of Daily Treatment (Period 1) to the end of 4 weeks of Interval Treatment (Period 2) | 
| Ratio of Maximum Walking Distance After Period 3 in Comparison With the Findings at Baseline | The ratio of maximum walking distance was calculated by the maximum walking distance after Period 3 divided by the maximum walking distance at Baseline with determination of maximum walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From Baseline to the end of 6-months Follow-up (Period 3) | 
| Ratio of Maximum Walking Distance After Period 3 in Comparison With the Findings After Period 1 | The ratio of maximum walking distance was calculated by the maximum walking distance after Period 3 divided by the maximum walking distance after Period 1 with determination of maximum walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From the end of 4 weeks of Daily Treatment (Period 1) to the end of 6-months Follow-up (Period 3) | 
| Ratio of Maximum Walking Distance After Period 3 in Comparison With the Findings After Period 2 | The ratio of maximum walking distance was calculated by the maximum walking distance after Period 3 divided by the maximum walking distance after Period 2 with determination of maximum walking distances on the treadmill (12 % grade and 3 km/h). If a subject was not familiar with the treadmill, at least two test determinations were performed to accustom him/her to the treadmill. For all treadmill determinations the subject has been prevented from observing the treadmill display of the walking distance achieved. | From the end of 4 weeks of Interval Treatment (Period 2) to the end of 6-months Follow-up (Period 3) | 
| Changes in Quality of Life (as Measured With the PAVK 86 Questionnaire) From Baseline to the End of Period 1 | Scores for subscales were calculated by summing non-missing item scores ranging from 1 (not at all; best possible outcome) to 4 (extremely; worst possible outcome) divided by the number of non-missing items. Hence each subscale score ranges from 1 (best possible outcome) to 4 (worst possible outcome). For subscales 'Mood' and 'Treatment expectation' five items each had to be reversed in order. Additionally, subjects were asked to assess their general health and quality of life on an ordinal scale between 0 (very good) and 10 (very poor). Negative changes show a decrease from Baseline. | From Baseline to the end of 4 weeks of Daily Treatment (Period 1) | 
| Changes in Quality of Life (as Measured With the PAVK 86 Questionnaire) From Baseline to the End of Period 3 | Scores for subscales were calculated by summing non-missing item scores ranging from 1 (not at all; best possible outcome) to 4 (extremely; worst possible outcome) divided by the number of non-missing items. Hence each subscale score ranges from 1 (best possible outcome) to 4 (worst possible outcome). For subscales 'Mood' and 'Treatment expectation' five items each had to be reversed in order. Additionally, subjects were asked to assess their general health and quality of life on an ordinal scale between 0 (very good) and 10 (very poor). Negative changes show a decrease from Baseline. | From Baseline to the end of 6-months Follow-up (Period 3) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alprostadil, Prostaglandin E1, Prostavasin®, PAOD