(Circulation. 1997;95:2298-2302.)
© 1997 American Heart Association, Inc.
Articles |
Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of AS-013, a Prostaglandin E1 Prodrug, in Patients With Intermittent Claudication
Ninewells Hospital and Medical School, Dundee (J.J.F.B., R.D.M.); Leicester Royal Infirmary (P.R.F.B.); Advisory Services (Clinical and General) Ltd, London (D.C.); St George's Hospital, London (J.A.D.); and St James' University Hospital, Leeds (R.C.K.), UK; St Marianna University, Sugao, Kawasaki, Japan (Y.M.); and Edinburgh Royal Infirmary (C.V.R.); Middlesex Hospital, London (J.H.S.); and St Mary's Hospital, London (J.H.N.W.), UK.
Correspondence to Professor J.J.F. Belch, Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background Intermittent claudication due to peripheral arterial occlusive disease (PAOD) is a common cause of pain and disability in the middle-aged. Clinical trials of the potent vasodilator prostaglandin E1 have been disappointing. This is the first report of a controlled clinical trial of AS-013, a novel prodrug of prostaglandin E1 incorporated into lipid microspheres that has been developed to improve delivery of the active compound to blood vessel walls.
Methods and Results Eighty patients with stenosis or occlusion, symptoms of intermittent claudication, and maximum walking distance of 
30 and 
300 m on a standard treadmill test were randomized to placebo or one of three dosage regimens of AS-013. Drug was administered by intravenous injection 5 d/wk for 4 weeks. Treadmill tests and other assessments were completed at weeks 0, 4, and 8. A statistically significant increase in maximum walking distance was observed at 4 weeks (for placebo: median, 4.5 m; interquartile range [IQR], 20; for active treatment: median, 28.0 m; IQR, 81; P<.01, Mann-Whitney test). A similar response was seen at 8 weeks (for placebo: median, -11.2 m; IQR, 35; for active treatment: median, 35 m; IQR, 68; P<.01, Mann-Whitney test). Dose-related improvements in pain-free walking distance and quality of life were observed. No serious safety issues were noted.
Conclusions These promising clinical data indicate that AS-013, a new prodrug of prostaglandin E1, could provide an effective and acceptable treatment for patients with intermittent claudication. Studies to investigate the optimal dosing regimen, duration of clinical benefit, and effects in more severe forms of peripheral arterial disease are warranted.
Key Words: prostaglandins • peripheral vascular disease • claudication
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Peripheral arterial occlusive disease, presenting as intermittent claudication, is one of the most common causes of pain and disability in the middle-aged.1 In a population sample of men and women between 55 and 74 years old, the prevalence of intermittent claudication was
5%, with signs of major asymptomatic disease occurring in another 8%.2 Pharmacological therapy for intermittent claudication has been difficult to study clinically because of the variable natural history of the disease and the absence of simple, reliable means to assess it.3 4 In the past, the scientific literature has reported many small intermittent claudication studies with poor controls and suspect end points. More recently, and particularly with the publication of the European Guidelines for pharmacological studies in intermittent claudication,5 it has been possible to devise studies containing sufficient patient numbers and standardized end points. Using these guidelines, we have evaluated the effect of a prodrug of PGE1, AS-013, as a treatment for intermittent claudication. PGE1 is a potent vasodilator as well as an inhibitor of platelet aggregation.6 With the growing evidence that both platelets and white blood cells are involved in the pathogenesis of PAOD,7 8 clinical investigators have begun to focus attention on the use of prostaglandins as treatments for intermittent claudication. PGE1 has been evaluated in a number of studies,9 and a small but statistically significant increase in walking distance was seen in some of these.10 11 However, because PGE1 is rapidly inactivated in the lungs, it has to be given either intra-arterially into the obstructed artery or in large doses intravenously. Intra-arterial administration is not an appropriate delivery system for the treatment of intermittent claudication, and the larger intravenous doses given over 6 to 8 h/d for 2 to 3 weeks produce significant side effects, such as diarrhea, hypotension, and intense local injection site irritation, with each infusion.9 In an effort to overcome these problems, a drug delivery system that targets the drug to its preferred site of action has been developed.12 Liposomes have long been considered as possible drug carriers. There is evidence that both response to a drug and safety of the compound increase when it is incorporated into liposomes.13 14 However, practical use of this procedure has been impeded because of difficulty with mass production, sterilization, and suitability of the liposomes. Lipid microspheres have also been evaluated and appear to be a better drug carrier.15 16 Furthermore, large amounts of lipid microspheres have been given to patients under the trade name of Intralipid (Pharmacia) for nearly 50 years.17 Lipo-PGE1 preparations have suffered two main disadvantages,12 namely, chemical instability of the PGE1 and rapid leakage from the lipid microspheres into the bloodstream, which is mainly a result of its interaction with serum albumin.18
AS-013 is an acylated, esterified PGE1 derivative enclosed in lipid microspheres. The modified PGE1 in AS-013 has a higher solubility and reduced leakage from the lipid microsphere compared with previous preparations, allowing delivery to the target site at the blood vessel wall, where it is hydrolyzed to PGE1.19 20
The aim of this study was to evaluate the effect of three different dosing regimens of AS-013 on the PFWD and the MWD of patients with intermittent claudication, PAOD Fontaine class II. The study was multicenter, randomized, double-blind, and placebo controlled, consisting of four parallel groups of patients.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients
Eighty patients, 64 men and 16 women >40 years old, were enrolled into the study after informed written consent had been obtained. Ethical approval for this study was obtained before the start of the study at all participating centers (n=7). All subjects had symptoms of intermittent claudication, with ABPIs
0.8 measured on two separate occasions. In patients with diabetes and an ABPI of >0.8, evidence of arterial disease was verified by an arteriogram, color duplex mapping, or a toe blood pressure of <60 mm Hg. All patients had an MWD of 30 and 300 m on a treadmill slope of 10% and at a speed of 2 km/h. All subjects who tolerated aspirin continued on this therapy during the study. Treatment with other vasoactive drugs for PAOD was not allowed during the study and was discontinued for at least 4 weeks before study entry.
Study Design
The study was a phase II, seven-center, randomized, double-blind, placebo-controlled parallel trial comparing 10 µg (given either as a daily injection of 2 µg for 5 days or as 5 µg/d given on 2 days with placebo given on 3 days) and 25 µg AS-013/wk (5 µg/d for 5 days) versus placebo (Table 1
). Treatment was assigned in a randomized code generated from random-number lists. Patients were informed that they might receive active treatment or placebo. The study was conducted on an outpatient basis, and patients attended the hospital for intravenous injections. The bolus injection was given into an arm vein over a period of 10 minutes on weekdays (Monday through Friday) for a period of 4 weeks. Follow-up was completed 4 weeks after the final injection.
|
Assessment of Response
At the screening visit, patients were asked to undergo a treadmill walking test positioned with a slope of 10% and a speed of 2 km/h to determine both the PFWD and the MWD. Each patient was required to complete two consecutive tests resulting in MWDs that varied by no more than 30% to qualify for entry into the study. A maximum of four treadmill tests were allowed before entry, and all were separated by a minimum period of 3 days. The treadmill tests were repeated before administration of the first injection at study entry, after administration of the last injection at week 4, and at follow-up at week 8. Also at these visits, the ABPIs were measured before the treadmill tests, again after patients had reached their MWDs, and at 30 and 60 minutes after exercise.
Factor VIII von Willebrand factor antigen, a marker of endothelial damage,21 was measured in a plasma sample prepared from blood taken immediately before and after the first and last injections of the study period.
A quality-of-life questionnaire was completed by the patients at baseline, week 4, and week 8 (Table 2).
|
Safety Evaluation
After each injection, patients were monitored for adverse events, with heart rate and blood pressure recorded at 20-minute intervals for 1 hour or until any adverse event had resolved. Any clinically significant change in heart rate and blood pressure was recorded as an adverse event. Routine physical examination was carried out before, during, and after the treatment schedule. Blood and urine testing was carried out before the start of the study and at weeks 2, 4, and 8 for routine hematology, biochemistry, and urinalysis. Patients were withdrawn from the study if their clinical condition deteriorated, if necessary after an adverse event, or if requested by the patient.
Statistical Analysis
The statistical analysis was carried out by an independent company (Adiem). Primary efficacy end points were the relative change in the PFWD and the MWD from the beginning to the end of the 4-week active treatment period. A 30% difference in PFWD was regarded as clinically relevant if the change in the MWD and quality-of-life assessment correlated with this finding.22
The secondary end points were the frequency of patients experiencing a relative change of 60% and 100% in the PFWD and MWD and the global assessment of treatment effect as detected by the quality-of-life assessment.
Data in relation to the primary end point were examined by ANOVA. If there was an overall significant difference between treatment groups, individual dose-to-placebo comparisons were examined, and an ANCOVA was undertaken to examine the dose-response relationship. Secondary efficacy variables were analyzed by the same techniques, but the results of hypothesis tests were regarded as only exploratory. All hypothesis tests were two-tailed, with a level of 
=.05. Safety and other data were dealt with descriptively. All analyses were conducted on the principle of intention to treat, and no patient was excluded from the study analysis for any reason other than nonavailability of data.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The total number of patients enrolled in the study was 80: 21 in group 1, 19 in group 2, 18 in group 3, and 22 in group 4. Seventy-six patients completed the study. Four patients (2 from group 1 and 1 each from groups 2 and 4) discontinued the study prematurely, 2 of them because of adverse events described later. The demographic details of all patients are summarized in Table 3
. There were no statistically significant differences between treatment groups. The same set of demographic variables was examined by center; again, no statistically significant differences were detected. In addition, no differences were detected in the treadmill tests for PFWD and MWD between treatment groups at screening or study entry (Table 4).The use of vasoactive or platelet-active drugs (including aspirin) showed no statistically significant differences between groups at baseline and remained unchanged throughout the study. None of the patients received antithrombotic treatment during the study. There were no significant differences between groups in cholesterol or triglyceride levels at baseline or changes in cholesterol or triglyceride levels during study treatment.
|
|
Fig 1 shows the medians and IQRs for the increase in PFWD compared with baseline for all four treatment groups at the start of the study, at 4 weeks, and at 8 weeks. On visual examination, there does appear to be a clear dose response, although there were no statistically significant differences in PFWD between placebo and any active treatment group or between placebo and all active treatments combined. After 4 weeks, median increases in PFWD reached 19.5 m (IQR, 33.0 m) for group 4 compared with 9.0 m (IQR, 17.8 m) for placebo, and at 8 weeks, median increases of 20.9 m (IQR, 42.6 m) were observed in group 4 compared with 0 m (IQR, 28.8 m) for placebo. It should be noted that the total dose administered to patients in groups 2 and 3 was the same but the dose schedule was different.
|
A similar dose-response curve for MWD (Fig 2) was observed. In particular, there was an overall treatment effect indicating a change from baseline demonstrable at week 4 (Kruskal-Wallis P=.04) that persisted at week 8 (Kruskal-Wallis P=.01), when all active treatment groups were compared versus placebo (group 1). Individual treatment group comparisons against placebo by the Mann-Whitney test showed statistically significant increases in MWD at week 4 for group 2 (95% CI, -0.4 to 47.1) and group 4 (95% CI, 8.02 to 78.31). Statistical significance for changes in MWD were observed for each treatment group versus placebo at week 8. Ninety-five percent CIs were 9.3 to 59.1 for group 2, 1.98 to 46.02 for group 3, and 8.02 to 78.31 for group 4.
|
The clinical significance of an increase in PFWD is considered to be achieved by an increase of 30% over baseline when supported by similar changes in MWD.22 The proportion of patients exhibiting an increase in PFWD and MWD of 30% showed a clear dose-response relationship. In group 4, 50% (PFWD) and 55% (MWD) of patients showed a 30% response compared with only 33% (PFWD) and 9.5% (MWD) of placebo patients.
The secondary end points included the frequency of patients experiencing a relative change of 60% and 100% in the treadmill tests. Overall, the frequency of patients experiencing such a change in the PFWD and MWD in response to active treatment was higher in all active groups than on placebo. Statistical significance was reached when active treatment was compared with placebo for MWD for 60% response levels (Fisher's exact test P=.01) (Table 5).
|
Analysis of the quality-of-life questionnaire revealed a linear dose-response relationship, with deterioration on placebo and progressive improvement on active treatments at weeks 4 and 8. The cumulative data in the quality-of-life questionnaire (baseline to week 8) are summarized in Table 6. Patients' responses to each question were classified as better (higher score) or worse (lower score) compared with baseline; the overall response of patients in each treatment group was calculated from the total number of patients scoring "worse" minus the total number of patients scoring "better" in that treatment group.
|
There were no statistically significant differences between any of the active treatment groups and placebo in the change from baseline in the ABPI at study entry, before exercise, immediately after exercise, and 30 and 60 minutes after exercise. Examination of plasma factor VIII von Willebrand levels did not show any statistical difference between weeks 1 and 4 either before or after injection of AS-013.
Two severe, possibly treatment-related adverse events were reported. One patient in group 3 developed atrial fibrillation, and 1 patient in group 4 developed hypotension that lasted 2 hours after the AS-013 injection. Both patients recovered, but the first was withdrawn from the study. A second withdrawal from the study occurred when 1 patient in the placebo group developed a flulike illness at week 4. Dyspepsia occurred in 3 patients in group 2 and not in any other treatment groups, and the flulike illness, reported as severe in the 1 patient defined above, affected a further 6 patients, giving a total of 7 patients with these symptoms. Two patients were in the placebo group, 3 in group 2, none in group 3, and 2 in group 4. A mild reaction at the injection site affected 4 patients in the highest-dose group and 1 each in groups 2 and 3. There were no injection site reactions in the placebo group. Mean pulse rates for all groups at all time points were not significantly altered by the treatment or placebo. Mean systolic or diastolic blood pressures did not change throughout the study either by visit or by treatment group. Furthermore, there were no statistically significant changes in hematology, biochemistry, or urinalysis results across time for any treatment group.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Following the European Guidelines for the study of drug treatments for intermittent claudication, we have evaluated three dose regimens of AS-013, a chemically modified PGE1 enclosed in lipid microspheres, versus placebo. Bolus injection could be used, which was much more acceptable than the previously studied 6- to 8-hour PGE1 infusions. A clear dose response was observed for both PFWD and MWD at the end of a course of 20 injections (4 weeks), and this was maintained at 8 weeks. The improvement in MWD reached statistical significance in the highest-dose group compared with placebo at both 4 and 8 weeks and was also statistically significant when all active treatments together were compared versus placebo. The quality-of-life questionnaire showed a subjective benefit for patients on active treatment as opposed to placebo, particularly again in the highest-dose group.
Although 2 patients were withdrawn from the study after adverse events (atrial fibrillation, flulike illness), the compound was generally well tolerated. Adverse events were not significantly more common or severe on active treatment than with placebo.
In conclusion, this study has shown a significant improvement in the MWD in patients with intermittent claudication given 25 µg/wk AS-013 (5 µg for 5 days) given over 4 weeks. The changes appear to be dose related and are sustained for a period of 4 weeks beyond the end of the active treatment (ie, at 8 weeks).
AS-013 has theoretical and practical advantages over PGE1 infusion, and we suggest that further studies are warranted: first, to determine the duration of treatment effect beyond 8 weeks, and second, to consider whether such a compound may be a useful treatment in patients with more severe arterial disease, for example, those with Fontaine stage III or IV disease.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
The authors would like to thank The Green Cross Corp, Seikagaku Corp, Asahi Glass Company Ltd, and Taisho Pharmaceutical Co Ltd, of Japan, for providing financial support and the drug supplies for the study. Monitoring services were provided by Advisory Services (Clinical and General) Ltd, London, UK.
Received September 23, 1996; revision received November 27, 1996; accepted December 2, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Leng GC, Fowkes FGR. The epidemiology of peripheral arterial disease. Vasc Med Rev. 1993;4:5-18.
2.
Fowkes FGR, Housley E, Cawood EHH, Macintyre CCA, Ruckley CV, Prescott RJ. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol. 1991;20:384-391.
3. Cameron HA, Waller PC, Ramsay LE. Drug treatment of intermittent claudication: a critical analysis of the methods and findings of published clinical trials, 1965-1985. Br J Clin Pharmacol. 1988;26:569-576.[Medline] [Order article via Infotrieve]
4.
Duprez D, Clement DL. Medical treatment of peripheral vascular disease: good or bad? Eur Heart J. 1992;13:149-151.
5. CPMP Efficacy Working Party. Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Chronic Peripheral Arterial Occlusive Disease. London, UK: The European Agency for the Evaluation of Medicinal Products; December 1994 (revised November 1995).
6. Vane JR. The release and fate of vasoactive hormones in the circulation. Br J Pharmacol. 1968;35:209-214.[Medline] [Order article via Infotrieve]
7. Belch JJF, McKay A, McArdle B, Lowe GDO, Pollock JG, Leiberman P, Forbes CD, Prentice CRM. A double blind study of the effect of prostacyclin infusion in severe peripheral vascular disease. Lancet. 1983;8320:315-317.
8. Belch JJF. The role of the white blood cell in arterial disease. Blood Coagul Fibrinolysis. 1990;1:183-192.[Medline] [Order article via Infotrieve]
9. Sinzinger H. Prostaglandins in ischaemic peripheral vascular disease. In: Therapeutic Applications of Prostaglandins. Vane J, O'Grady J, eds. London, UK: Edward Arnold; 1993:209-218.
10. Rudofsky G. Intravenöse PGE1-Infusionsbehandlung bei Patienten mit arterieller Verschlusskrankheit im Stadium IIb. In: Heidrich H, Bohme H, Rogatti W, eds. Prostaglandin EI: Wirkungen und therapeutische Wirksamkeit. Berlin, Germany: Springer Verlag; 1988:103-111.
11. Hepp W, von Bary S, Corovic D, Diehm C, Muhe E, Rudofsky G, Scheffler P, Trubestein G, Vogelpohl M. Therapeutic efficacy of intravenous prostaglandin E1 versus pentoxifylline in patients with intermittent claudication. In: Diehm C, Sinzinger H, Rogatti E, eds. Prostaglandin EI: New Aspects of Pharmacology, Metabolism and Clinical Efficacy. Heidelberg, Germany: Springer Verlag; 1991:101-108.
12. Mizushima Y. Lipo-prostaglandin preparations. Prostaglandins Leukot Essent Fatty Acids. 1991;42:1-6.[Medline] [Order article via Infotrieve]
13. Fendler JH, Romero A. Liposomes as drug carriers. Life Sci. 1977;20:1109-1120.[Medline] [Order article via Infotrieve]
14. Bundgarrd H, Hansen AB, Kofod H, eds. Optimization of Drug Delivery. Copenhagen, Denmark: Munksgaard; 1982.
15. Mizushima Y, Yanagawa A, Hoski K. Prostaglandin E1 is more effective, when incorporated in lipid microspheres, for treatment of peripheral vascular diseases in man. J Pharm Pharmacol. 1983;35:666-667.[Medline] [Order article via Infotrieve]
16. Mizushima Y. Application of lipid microspheres for targeting therapy. J Bioact Compat Polymer. 1988;3:148-156.
17. Davis S, Hadgraft J, Palin KJ. Pharmaceutical emulsions. In: Becher P, ed. Encyclopedia of Emulsion Technology. New York, NY: Marcel Dekker; 1985;3:159.
18.
Fitzpatric FA, Liggett WP, Wynalda MA. Albumin-eicosanoid interactions: a model system to determine their attributes and inhibition. J Biol Chem. 1984;259:2722-2727.
19. Igarashi R, Mizushima Y, Takenaga M, Matsumoto K, Morizawa Y, Yasuda A. A stable PGE1 prodrug for targeting therapy. J Controlled Release. 1992;20:37-46.
20. Cho MJ. Reduced hydrolytic liability of epoprostenol in the presence of cationic micelles. J Pharmacol Sci. 1982;71:453-454.[Medline] [Order article via Infotrieve]
21. Belch JJF, Zoma A, Richards I, Forbes CD, Sturrock RD. Vascular damage and factor VIII related antigen in the rheumatic diseases. Rheumatol Int. 1987;7:107-111.[Medline] [Order article via Infotrieve]
22. Heidrich H, Cachovan M, Creutzig A, Rieger H, Trampisch HJ. Guidelines for therapeutic studies in Fontaine's stages II-IV peripheral arterial occlusive disease. Vasa. 1995;24:114-119.
This article has been cited by other articles:
 |
|
 |
|
  M. Sobel and R. Verhaeghe Antithrombotic Therapy for Peripheral Artery Occlusive Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 815S - 843S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A Creager, R. L Pande, and W. R Hiatt A randomized trial of iloprost in patients with intermittent claudication Vascular Medicine, February 1, 2008; 13(1): 5 - 13. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Amendt PGE1 and Other Prostaglandins in the Treatment of Intermittent Claudication: A Meta-analysis Angiology, July 1, 2005; 56(4): 409 - 415. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Casey, B. H. Tonnessen, W. C. Sternbergh III, and S. R. Money Medical Management of Intermittent Claudication Vascular and Endovascular Surgery, September 1, 2004; 38(5): 391 - 399. [Abstract] [PDF]
|
|
|
|
|
|
G. P. Clagett, M. Sobel, M. R. Jackson, G. Y. H. Lip, M. Tangelder, and R. Verhaeghe Antithrombotic Therapy in Peripheral Arterial Occlusive Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 609S - 626S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. T. Cooper Beraprost for the treatment of intermittent claudication J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1687 - 1689. [Full Text] [PDF]
|
|
|
|
|
|
S. M Dean Pharmacologic treatment for intermittent claudication Vascular Medicine, November 1, 2002; 7(4): 301 - 309. [Abstract] [PDF]
|
|
|
|
 |
|
 W. R. Hiatt Medical Treatment of Peripheral Arterial Disease and Claudication N. Engl. J. Med., May 24, 2001; 344(21): 1608 - 1621. [Full Text] [PDF]
|
|
|
|
|
|
M. R. Jackson and G. P. Clagett Antithrombotic Therapy in Peripheral Arterial Occlusive Disease Chest, January 1, 2001; 119(1_suppl): 283S - 299S. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lievre, S. Morand, B. Besse, J.-N. Fiessinger, and J.-P. Boissel Oral Beraprost Sodium, a Prostaglandin I2 Analogue, for Intermittent Claudication : A Double-Blind, Randomized, Multicenter Controlled Trial Circulation, July 25, 2000; 102(4): 426 - 431. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||