A Dose-Effect Study of Beraprost Sodium in Intermittent Claudication

Lièvre, Michel; Azoulay, Salomon; Lion, L.; Morand, Sophie; Girre, J P; Boissel, Jean-Pièrre

doi:10.1097/00005344-199606000-00004

Cited by 50 publications

(12 citation statements)

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“…The absence of any effect of the treatment on the ABI before treadmill exercise and on the loss in this index during exercise could be anticipated from the results of the BERCI dose-effect study 9 and are in accordance with the results of most clinical trials in intermittent claudication. 11,19,20 In 1 study of cilostazol, however, the increase in walking distance was accompanied by a small but significant increase in the ABI compared with placebo.…”

Section: Discussionsupporting

confidence: 77%

“…7 We assessed the effects of BPS on walking distances in patients with intermittent claudication in the Beraprost et Claudication Intermittente (BERCI) dose-effect study. 9 In this 12-week study, BPS increased the pain-free walking distance, compared with placebo, at doses of 20 and 40 g TID but not at This trial was financed by an unrestricted grant from Laboratories Hoechst Houde (France). Drs Lievre and Boissel received an institutional grant from Laboratories Hoechst Houde for data management and analysis of the BERCI-2 study.…”

mentioning

confidence: 90%

“…7 We assessed the effects of BPS on walking distances in patients with intermittent claudication in the Beraprost et Claudication Intermittente (BERCI) dose-effect study. 9 In this 12-week study, BPS increased the pain-free walking distance, compared with placebo, at doses of 20 and 40 g TID but not at 60 g. Because 40 g TID appeared to offer the best combination of both the antiplatelet and the symptomatic effects of BPS, this dose regimen was chosen for the phase III trial that we report in this article. This trial (BERCI-2) was designed to demonstrate the 6-month efficacy of BPS on walking distances and cardiovascular events in patients with intermittent claudication.…”

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confidence: 99%

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Oral Beraprost Sodium, a Prostaglandin I ₂ Analogue, for Intermittent Claudication

et al. 2000

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Background-Beraprost sodium (BPS) is a new stable, orally active prostaglandin I 2 analogue with antiplatelet and vasodilating properties. We report the results of a phase III clinical trial of BPS in patients with intermittent claudication. Methods and Results-Patients (nϭ549) with a pain-free walking distance of between 50 and 300 m were entered into a 4-week single-blind placebo run-in phase. Patients whose pain-free walking distance had changed by Ͻ25% were then randomized to receive either BPS (40 g TID, nϭ209) or placebo (nϭ213) in a double-blind manner for 6 months. Pain-free and maximum walking distances were measured on the occasion of treadmill exercise tests performed at baseline and 1.5, 3, 4.5, and 6 months after randomization. Success was defined as an improvement of Ͼ50% in pain-free walking distance at month 6 and in Ն1 earlier treadmill exercise test in the absence of critical cardiovascular events. Success was observed more frequently in the BPS group (43.5%) than in the placebo group (33.3%, Pϭ0.036). Pain-free walking distances increased by 81.5% and 52.5%, respectively, in the BPS and placebo groups (Pϭ0.001) and maximum walking distances by 60.1% and 35.0%, respectively (Pϭ0.004). The incidence of critical cardiovascular events was 4.8% in the BPS group and 8.9% in the placebo group. Conclusions-These results show that BPS is an effective symptomatic treatment of patients with intermittent claudication.The beneficial effects of BPS on critical cardiovascular events should be confirmed in appropriate clinical trials. Key Words: claudication Ⅲ beraprost sodium Ⅲ prostaglandins I ntermittent claudication is a common presentation of lower-limb arterial disease, with a prevalence of 1% to 7% in men 50 to 75 years old. 1,2 Medical therapy for patients with intermittent claudication has 2 goals: improvement of symptoms and prevention of cardiovascular events. Many agents, including vasodilators, have been tried for the relief of symptoms, although their effectiveness is still subject to debate. The antiplatelet and vasodilating properties of epoprostenol (prostaglandin [PG] I 2 ) make it a theoretically interesting agent in the treatment of peripheral vascular disease. 3 Although promising results were reported for its use in the treatment of intermittent claudication, 4 its very short half-life and high chemical instability precluded its use as a therapeutic agent and led to the development of more stable synthetic analogues. Iloprost, to date the most extensively studied of these analogues, has been shown to provide pain relief and to accelerate ulcer healing in patients with stage III or IV critical leg ischemia 5 and has been licensed in some countries for the treatment of thromboangiitis obliterans. The need for an intravenous infusion of iloprost, although acceptable for the treatment of critical ischemia, makes it unacceptable for the long-term treatment of intermittent claudication.Beraprost sodium (BPS) is a new stable, orally active PGI 2 analogue with antiplatelet and vasodilating prope...

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Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 90%

“…7 We assessed the effects of BPS on walking distances in patients with intermittent claudication in the Beraprost et Claudication Intermittente (BERCI) dose-effect study. 9 In this 12-week study, BPS increased the pain-free walking distance, compared with placebo, at doses of 20 and 40 g TID but not at 60 g. Because 40 g TID appeared to offer the best combination of both the antiplatelet and the symptomatic effects of BPS, this dose regimen was chosen for the phase III trial that we report in this article. This trial (BERCI-2) was designed to demonstrate the 6-month efficacy of BPS on walking distances and cardiovascular events in patients with intermittent claudication.…”

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confidence: 99%

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Oral Beraprost Sodium, a Prostaglandin I ₂ Analogue, for Intermittent Claudication

et al. 2000

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“…11 The treadmill protocol used to assess the primary study endpoint was the G-test. The study protocol was approved by the institutional review boards of the centers involved; each patient signed a written consent to participate in the study.…”

Section: Methodsmentioning

confidence: 99%

Reliability of treadmill testing in peripheral arterial disease: a comparison of a constant load with a graded load treadmill protocol

Labs

Nehler

Roessner³

et al. 1999

Vasc Med

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This study aims to evaluate the reliability of repeated graded workload treadmill testing (G-test; 2 mph; 0% grade, increasing 2% every 2 min) and to compare the reliability of a constant workload treadmill protocol (C-test; 2 mph; 12% grade) versus the graded workload treadmill protocol in patients with intermittent claudication, studied longitudinally.A clinical trial investigating an orally stable prostacycline derivative that included 330 patients with intermittent claudication was performed. The trial employed three active treatment groups and one placebo group. Because there were no significant inter-group differences at baseline or after treatment, data from all groups were pooled for the evaluation of treadmill test reliability. Treadmill data were obtained from a 2-week run-in phase where three G-tests were performed, as well as from the beginning and the end of a 3-month double-blind phase where a G-test and a C-test were performed in random order. Treadmill test reliability was described through test process-related and between-subject variances and also using variance-derived parameters such as the reliability coefficient (RC) and the relative precision (RP). A higher value for the RC and a lower value for the RP indicate that the test variability is predominantly due to betweensubject variance and not to test process-related variance. Estimates of variance were described for both the maximal or absolute claudication distance (ACD) and the initial claudication distance (ICD) with each treadmill test. Reliability estimates are reported for the total study sample and for patients with baseline claudication distances р300 feet and Ͼ300 feet (approximately р100 m; Ͼ100 m), as measured with the C-test. The cut-off value was empirically chosen to separate severely diseased from mild to moderately diseased claudicants. Theoretical considerations suggest that reliability measures may differ in these subgroups. With repeated testing during the run-in phase for the measure of ACD, the G-test had an RC of 0.952 and an RP of 21.9%. With the comparison of both test protocols in the entire study population for the measurement of ACD, the G-test had an RC of 0.902 and an RP of 31.3%, while the C-test had an RC of 0.876 and an RP of 35.2%. The results for ICD on the G-test were an RC of 0.809 and an RP of 43.7%, while the C-test had an RC of 0.737 and an RP of 51.3%. The reliability of the ACD measurement for RC and RP was numerically superior to those for the ICD for both protocols. In patients with a baseline ACD р300 feet, the RC for ACD on the G-test was 0.827 and the RP was 41.4%. In contrast, on the C-test the RC decreased to 0.250 and the RP increased to 86.6%. These changes in RC and RP were due to a marked decrease in the between-subject variance, demonstrating the inability of the C-test to separate appropriately the different claudication distances in populations with highly limited baseline claudication distances.During a run-in phase, the G-test has excellent test characteristics. During the l...

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“…Placebo-induced improvements in walking distance of more than 40% over baseline have been observed in several trials. [23][24][25] In another study a steady progressive improvement in claudication distance was reported for placebo increasing by 28% over 12 months. 15 This remarkable placebo effect is generally attributed to an improved exercise capacity from repeated examinations -a training effect.…”

Section: Discussionmentioning

confidence: 93%

Sarpogrelate, a 5-HT2A receptor antagonist in intermittent claudication. A Phase II European study

Norgren

Jawień

Mátyás³

et al. 2006

Vasc Med

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This was a multinational, multicentre, double-blind Phase II study in Europe to evaluate the efficacy and safety of two dose regimens (200 mg bid and 200 mg tid) of sarpogrelate (MCI-9042, 5-HT2A receptor antagonist) compared to placebo in patients with stable, moderately severe intermittent claudication. Following a single-blind placebo run-in period of 6 weeks, 364 (309 male and 55 female) patients (59.2 ± 8.4 years, mean SD) were randomized to receive sarpogrelate 200 mg bid, 200 mg tid or placebo for 24 weeks with a follow-up of 8 weeks. The primary objective was the increase of absolute claudication distance (ACD) at the end of treatment (week 24) compared to placebo. Analysis of covariance (ANCOVA) was performed on the log-transformed percentage of baseline ACD: loge (ACD/baseline). A responder analysis (defined as a 50% improvement in ACD) was also performed. There was a marked training/placebo effect on the ACD which persisted up to 16 weeks. At 24 weeks the primary objective did not reach statistical significance (200 mg bid vs placebo, p = 0.225; 200 mg tid vs placebo, p = 0.580). In the responder analysis, 200 mg bid showed a statistically significant difference vs placebo ( p = 0.035). In the exploratory analysis with completers (patients completing all treadmill tests), there was a statistical difference in ACD/baseline change for 200 mg bid ( p = 0.035) and in the responder analysis for 200 mg tid ( p = 0.044) at 24 weeks compared to placebo. Both treatments showed a carry-over effect for ACD during the 8-week follow-up (weeks 28-32). The treatment was well tolerated and no clinically significant safety concerns were reported. In conclusion, the study results confirm that sarpogrelate is well tolerated and although the primary endpoint failed to reach statistical significance, the responder analysis showed an increased absolute walking distance, which makes a further trial warranted, including a larger population, and possibly also a longer treatment period.

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A Dose-Effect Study of Beraprost Sodium in Intermittent Claudication

Cited by 50 publications

References 5 publications

Oral Beraprost Sodium, a Prostaglandin I ₂ Analogue, for Intermittent Claudication

Oral Beraprost Sodium, a Prostaglandin I ₂ Analogue, for Intermittent Claudication

Reliability of treadmill testing in peripheral arterial disease: a comparison of a constant load with a graded load treadmill protocol

Sarpogrelate, a 5-HT2A receptor antagonist in intermittent claudication. A Phase II European study

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A Dose-Effect Study of Beraprost Sodium in Intermittent Claudication

Cited by 50 publications

References 5 publications

Oral Beraprost Sodium, a Prostaglandin I 2 Analogue, for Intermittent Claudication

Oral Beraprost Sodium, a Prostaglandin I 2 Analogue, for Intermittent Claudication

Reliability of treadmill testing in peripheral arterial disease: a comparison of a constant load with a graded load treadmill protocol

Sarpogrelate, a 5-HT2A receptor antagonist in intermittent claudication. A Phase II European study

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Product

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Oral Beraprost Sodium, a Prostaglandin I ₂ Analogue, for Intermittent Claudication

Oral Beraprost Sodium, a Prostaglandin I ₂ Analogue, for Intermittent Claudication