A multinational phase IIb/III trial of beraprost sodium, an orally active prostacyclin analogue, in patients with primary glomerular disease or nephrosclerosis (CASSIOPEIR trial), rationale and study design

Nakamoto, Hidetomo; Fujita, Toshiro; Origasa, Hideki; Isono, Masanao; Kurumatani, Hajimu; Okada, Kiyonobu; Kanoh, Hideo; Kiriyama, T; Yamada, S.

doi:10.1186/1471-2369-15-153

Cited by 6 publications

(8 citation statements)

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“…Based on the findings of this trial, we have further been conducting a phase IIb/III trial, CASSIOPEIR ( C RF As ian S tudy w i th O ral P GI 2 derivative for E valuating I mprovement of R enal function) [ 42 ]. This new trial will enroll patients who have more severe disease than those enrolled in this trial in order to ensure that a sufficient number of clinical events can be observed within a designated time period, using renal composite endpoints to evaluate treatment outcome.…”

Section: Discussionmentioning

confidence: 99%

Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial

et al. 2015

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BackgroundEvidence increasingly points to the importance of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease (ESRD). Beraprost sodium (BPS) is an orally active prostacyclin (PGI2) analogue demonstrating prevention of the progression of chronic kidney disease (CKD) in various animal models by maintaining renal blood flow and attenuating renal ischemic condition.MethodsThis multicenter, randomized, double-blind, placebo-controlled, phase II trial was designed to determine the recommended dose of the sustained-release form of BPS (TRK-100STP 120 μg/day or 240 μg/day) in Japanese patients with CKD. TRK-100STP was administered to a total of 112 patients. The primary efficacy endpoint was the difference in the slope of the regression line of reciprocal of serum creatinine (1/SCr) over time, obtained by the least-squares method.ResultsRegarding the primary endpoint, statistical superiority of TRK-100STP 240 μg over placebo was not confirmed and so a recommended dose was not determined. Compared to placebo, however, the slope of regression line of 1/SCr, elevation of SCr and serum cystatin C during the treatment period revealed greater improvement at 120 μg, at both doses, and at 240 μg, respectively. In terms of safety, both TRK-100STP treatment groups were well tolerated.ConclusionsAlthough the study failed to meet the primary endpoint, results indicate that TRK-100STP may potentially prevent the decline in renal function of CKD patients independent of blood pressure or urinary protein levels.Trial registrationNCT02480751. June 21, 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0130-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial

et al. 2015

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“…The protocol of the CASSIOPEIR study was previously reported [ 18 ]. To summarize, this study was a multicenter, randomized, double‐blind, placebo‐controlled comparative study of TRK‐100STP (120 or 240 μg/day) in non‐diabetic CKD patients with primary glomerular disease or nephrosclerosis.…”

Section: Methodsmentioning

confidence: 99%

“…The definition of primary glomerular disease was the same as in our previous Ph‐II study [ 17 ], and was specified in the protocol. In addition, secondary glomerular diseases such as diabetic nephropathy, lupus nephritis, ANCA‐related nephritis, so on, are excluded in the exclusion criteria of the protocol [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…Plasma samples of all patients were collected for PPK analysis. Among the pharmacokinetics analysis set (PKAS) [ 18 ], data obtained during 8, 12, 36, 48, 72, and 84 weeks of treatment (i.e., non‐trough points having morning medication) were analyzed. The plasma level of BPS was measured at Toray Research Center (TRC, Tokyo, Japan) according to protocol.…”

Section: Methodsmentioning

confidence: 99%

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Prostacyclin analog beraprost sodium efficacy in primary glomerular disease or nephrosclerosis: Analysis of the Japanese subgroup in CASSIOPEIR study

et al. 2021

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We conducted a multicenter, randomized, double-blind, placebo-controlled, phase IIb/III study (CASSIOPEIR) using a renal composite endpoint (i.e., doubling of SCr or end-stage renal disease) in seven Asian countries/region. CASSIOPEIR compared TRK-100STP (120 μg and 240 μg) with placebo in patients with non-diabetic CKD patients with primary glomerular disease or nephrosclerosis (n = 892). However, the superiority of TRK-100STP over placebo was not observed. A prior phase II study on which the Phase IIb/III study design was based included only Japanese patients. We therefore evaluated TRK-100STP efficacy and safety in a subgroup of Japanese patients using the CASSIOPEIR dataset. As the timing of treatment initiation is important in CKD, we conducted additional subgroup analyses based on the baseline serum creatinine (SCr) and eGFR. ITT analysis was performed in a Japanese subgroup (n = 339) in which the primary endpoint was the first occurrence of renal composite endpoint. Significant differences were observed for TRK-100STP 240 μg vs. placebo (P = 0.0493; HR 0.69 [95% CI: 0.47, 1.00]), but no significant difference was observed between TRK-100 120 μg and placebo (P = 0.3523; HR 0.85). More prominent improvement was observed with TRK-100STP 240 μg vs. placebo for baseline SCr < 3.0 mg/dL (P = 0.0031; HR 0.43); SCr < 3.5 mg/dL (P = 0.0237, HR 0.59); and eGFR ≥ 10 mL/min/1.73 m 2 (P = 0.0339, HR0.67), respectively.No significant changes in urinary albumin/creatinine ratio and blood pressure were observed. TRK-100STP was generally well tolerated and most adverse drug reactions were mild or moderate in severity. In conclusion, in the Japanese subgroup of CASSIOPEIR, TRK-100STP 240 μg/day significantly improved the renal composite endpoint compared with placebo, with greater efficacy in subjects with SCr < 3.5 or eGFR ≥ 10 mL/min/1.73 m 2 .

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“…In the 80s and 90s, scientific literature put great emphasis on the prostacyclin system and on the use of prostacyclin analogs in kidney disease (14,35,36). The main application field was ischemic injury, but there are also some reported experiences in the field of transplantation.…”

Section: Discussionmentioning

confidence: 99%

Iloprost in Acute Post-kidney Transplant Atheroembolism: A Case Report of Two Successful Treatments

et al. 2020

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Cholesterol embolization (CE) is a rare and alarming post-transplant complication, responsible for primary non-function (PNF) or delayed graft function (DGF). Its incidence is expected to rise due to increasingly old donors and recipients and the extended criteria for donation. Therapy with statins and steroids has not been shown to be effective, while agonism of prostaglandin I 2 has been reported to be useful in systemic CE. We report two cases of acute post-transplant CE in which intravenous iloprost (0.05 mg/kg/day) was added to standard statin and steroid therapy. In the first instance, CE was due to embolization from the kidney artery resulting in embolization of the small vessels; after a long DGF and 15 days of iloprost therapy, renal function recovered. The second instance is a case of embolization from the iliac artery of the recipient, where CE manifested as a partial renal infarction. After 5 days of iloprost administration, creatinine levels improved. Iloprost acts on vasodilation and on different inflammatory pathways, improving the anti-inflammatory profile. Post-transplant CE is difficult to diagnose and, if not treated, can lead to loss of function. Iloprost added to standard therapy could be beneficial in accelerating renal function recovery immediately after transplant.

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A multinational phase IIb/III trial of beraprost sodium, an orally active prostacyclin analogue, in patients with primary glomerular disease or nephrosclerosis (CASSIOPEIR trial), rationale and study design

Cited by 6 publications

References 32 publications

Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial

Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial

Prostacyclin analog beraprost sodium efficacy in primary glomerular disease or nephrosclerosis: Analysis of the Japanese subgroup in CASSIOPEIR study

Iloprost in Acute Post-kidney Transplant Atheroembolism: A Case Report of Two Successful Treatments

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