Ho Jun Chin1,2, Dong-Wan Chae1, Yong Chul Kim3, Won Suk An4, ChunGyoo Ihm5, Dong-Chan Jin6, Sung Gyun Kim7, Yong-Lim Kim8, Yong-Soo Kim9, Yoon-Goo Kim10, Ho Seok Koo11, Jung Eun Lee12, Kang Wook Lee13, Jieun Oh14, Jung Hwan Park15, Hongsi Jiang16, Hyuncheol Lee17, Sang Koo Lee18. 1. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea. 2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea. 3. Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. 4. Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea sklee2@amc.seoul.kr. 5. Department of Nephrology, Kyunghee University Medical Center, Seoul, South Korea. 6. Department of Internal Medicine, St Vincent Hospital, Suwon, South Korea. 7. Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, South Korea. 8. Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea. 9. Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea. 10. Department of Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea. 11. Department of Internal Medicine, Inje University Seoul Paik Hospital, Seoul, South Korea sklee2@amc.seoul.kr. 12. Department of Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea sklee2@amc.seoul.kr. 13. Department of Nephrology, Chungnam National University Hospital, Daejeon, South Korea sklee2@amc.seoul.kr. 14. Department of Internal Medicine, Kangdong Sacred Heart Hospital, Seoul, South Korea. 15. Department of Internal Medicine, Konkuk University Medical Center, Seoul, South Korea. 16. Medical Affairs Asia Oceania, Astellas Pharma Singapore Pte. Ltd., Singapore. 17. Clinical Research, Astellas Pharma Korea Inc., Seoul, South Korea sklee2@amc.seoul.kr. 18. Department of Internal Medicine, Asan Medical Center, University of Ulsan, Seoul, South Korea sklee2@amc.seoul.kr.
Abstract
BACKGROUND: Tacrolimus is used as a steroid-sparing immunosuppressant in adults with minimal change nephrotic syndrome. However, combined treatment with tacrolimus and low-dose steroid has not been compared with high-dose steroid for induction of clinical remission in a large-scale randomized study. METHODS: In this 24-week open-label noninferiority study, we randomized 144 adults with minimal change nephrotic syndrome to receive 0.05 mg/kg twice-daily tacrolimus plus once-daily 0.5 mg/kg prednisolone, or once-daily 1 mg/kg prednisolone alone, for up to 8 weeks or until achieving complete remission. Two weeks after complete remission, we tapered the steroid to a maintenance dose of 5-7.5 mg/d in both groups until 24 weeks after study drug initiation. The primary end point was complete remission within 8 weeks (urine protein: creatinine ratio <0.2 g/g). Secondary end points included time until remission and relapse rates (proteinuria and urine protein: creatinine ratio >3.0 g/g) after complete remission to within 24 weeks of study drug initiation. RESULTS: Complete remission within 8 weeks occurred in 53 of 67 patients (79.1%) receiving tacrolimus and low-dose steroid and 53 of 69 patients (76.8%) receiving high-dose steroid; this difference demonstrated noninferiority, with an upper confidence limit below the predefined threshold (20%) in both intent-to-treat (11.6%) and per-protocol (17.0%) analyses. Groups did not significantly differ in time until remission. Significantly fewer patients relapsed on maintenance tacrolimus (3-8 ng/ml) plus tapered steroid versus tapered steroid alone (5.7% versus 22.6%, respectively; P=0.01). There were no clinically relevant safety differences. CONCLUSIONS: Combined tacrolimus and low-dose steroid was noninferior to high-dose steroid for complete remission induction in adults with minimal change nephrotic syndrome. Relapse rates were significantly lower with maintenance tacrolimus and steroid compared with steroid alone. No clinically-relevant differences in safety findings were observed.
BACKGROUND: Tacrolimus is used as a steroid-sparing immunosuppressant in adults with minimal change nephrotic syndrome. However, combined treatment with tacrolimus and low-dose steroid has not been compared with high-dose steroid for induction of clinical remission in a large-scale randomized study. METHODS: In this 24-week open-label noninferiority study, we randomized 144 adults with minimal change nephrotic syndrome to receive 0.05 mg/kg twice-daily tacrolimus plus once-daily 0.5 mg/kg prednisolone, or once-daily 1 mg/kg prednisolone alone, for up to 8 weeks or until achieving complete remission. Two weeks after complete remission, we tapered the steroid to a maintenance dose of 5-7.5 mg/d in both groups until 24 weeks after study drug initiation. The primary end point was complete remission within 8 weeks (urine protein: creatinine ratio <0.2 g/g). Secondary end points included time until remission and relapse rates (proteinuria and urine protein: creatinine ratio >3.0 g/g) after complete remission to within 24 weeks of study drug initiation. RESULTS: Complete remission within 8 weeks occurred in 53 of 67 patients (79.1%) receiving tacrolimus and low-dose steroid and 53 of 69 patients (76.8%) receiving high-dose steroid; this difference demonstrated noninferiority, with an upper confidence limit below the predefined threshold (20%) in both intent-to-treat (11.6%) and per-protocol (17.0%) analyses. Groups did not significantly differ in time until remission. Significantly fewer patients relapsed on maintenance tacrolimus (3-8 ng/ml) plus tapered steroid versus tapered steroid alone (5.7% versus 22.6%, respectively; P=0.01). There were no clinically relevant safety differences. CONCLUSIONS: Combined tacrolimus and low-dose steroid was noninferior to high-dose steroid for complete remission induction in adults with minimal change nephrotic syndrome. Relapse rates were significantly lower with maintenance tacrolimus and steroid compared with steroid alone. No clinically-relevant differences in safety findings were observed.
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