Toshinori Takada1, Ayako Mikami2, Nobutaka Kitamura3, Kuniaki Seyama4, Yoshikazu Inoue5, Katsura Nagai6, Masaru Suzuki6, Hiroshi Moriyama7, Keiichi Akasaka1,8, Ryushi Tazawa8, Toyohiro Hirai9, Michiaki Mishima9, Mie Hayashida10, Masaki Hirose5, Chikatoshi Sugimoto5, Toru Arai5, Noboru Hattori11, Kentaro Watanabe12, Tsutomu Tamada13, Hirohisa Yoshizawa8, Kohei Akazawa14, Takahiro Tanaka3, Keita Yagi15, Lisa R Young16, Francis X McCormack17, Koh Nakata8. 1. 1 Uonuma Institute of Community Medicine. 2. 2 Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan. 3. 3 Protocol Data Center. 4. 4 Division of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan. 5. 5 Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan. 6. 6 First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan. 7. 7 Division of Respiratory Medicine. 8. 8 Bioscience Medical Research Center, and. 9. 9 Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 10. 10 First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan. 11. 11 Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. 12. 12 Department of Respiratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan. 13. 13 Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. 14. 14 Department of Medical Informatics, Niigata University Medical and Dental Hospital, Niigata, Japan. 15. 15 Department of Clinical Pharmacology, Tokai University, Isehara, Japan. 16. 16 Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and. 17. 17 Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio.
Abstract
RATIONALE: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. OBJECTIVES: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. METHODS: We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. MEASUREMENTS AND MAIN RESULTS:Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax. CONCLUSIONS: Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.
RCT Entities:
RATIONALE: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. OBJECTIVES: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. METHODS: We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. MEASUREMENTS AND MAIN RESULTS: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimuspneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax. CONCLUSIONS: Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.
Authors: Timothy M Uyeki; Henry H Bernstein; John S Bradley; Janet A Englund; Thomas M File; Alicia M Fry; Stefan Gravenstein; Frederick G Hayden; Scott A Harper; Jon Mark Hirshon; Michael G Ison; B Lynn Johnston; Shandra L Knight; Allison McGeer; Laura E Riley; Cameron R Wolfe; Paul E Alexander; Andrew T Pavia Journal: Clin Infect Dis Date: 2019-03-05 Impact factor: 9.079
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