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A Randomized Double-Blind, Double-Dummy pISSN 1598-2998, eISSN 2005-9256 Cancer Res Treat. 2014;46(1):19-26 http://dx.doi.org/10.4143/crt.2014.46.1.19 Original Article Open Access A Randomized Double-Blind, Double-Dummy, Multicenter Trial of Azasetron versus Ondansetron to Evaluate Efficacy and Safety in the Prevention of Delayed Nausea and Vomiting Induced by Chemotherapy Hee Yeon Lee, MD 1 Purpose Hoon-Kyo Kim, MD 1 This study was conducted to evaluate the efficacy and safety of azasetron compared Kyung Hee Lee, MD 2 to ondansetron in the prevention of delayed chemotherapy-induced nausea and Bong-Seog Kim, MD 3 vomiting. MD 4 Hong Suk Song, Materials and Methods MD 5 Sung Hyun Yang, This study was a multi-center, prospective, randomized, double-dummy, double-blind MD 6 Joon Hee Kim, and parallel-group trial involving 12 institutions in Korea between May 2005 and MD 7 Yeul Hong Kim, December 2005. A total of 265 patients with moderately and highly emetogenic MD 8 Jong Gwang Kim, chemotherapy were included and randomly assigned to either the azasetron or MD 9 Sang-We Kim, ondansetron group. All patients received azasetron (10 mg intravenously) and MD 10 Dong-Wan Kim, dexamethasone (20 mg intravenously) on day 1 and dexamethasone (4 mg orally every MD 11 Si-Young Kim, 12 hours) on days 2-4. The azasetron group received azasetron (10 mg orally) with MD 12 Hee Sook Park, placebo of ondansetron (orally every 12 hours), and the ondansetron group received Department of Internal Medicine, ondansetron (8 mg orally every 12 hours) with placebo of azasetron (orally) on days 1St. Vincent's Hospital, 2-6. The Catholic University of Korea College of Medicine, Suwon, Results 2Yeungnam University Medical Center, Over days 2-6, the effective ratio of complete response in the azasetron and Yeungnam University College of Medicine, Daegu, 3Seoul Veterans Hospital, Seoul, ondansetron groups was 45% and 54.5%, respectively (95% confidence interval, 4Keimyung University Dongsan Medical Center, ‒21.4 to 2.5%). Thus, the non-inferiority of azasetron compared with ondansetron in Keimyung University School of Medicine, Daegu, delayed chemotherapy-induced nausea and vomiting was not proven in the present 5Korea Cancer Center Hospital, Korea Institute of Radiological and study. All treatments were well tolerated and no unexpected drug-related adverse Medical Sciences, Seoul, events were reported. The most common adverse events related to the treatment 6Inje University Seoul Paik Hospital, were constipation and hiccups, and there were no differences in the overall incidence Inje University College of Medicine, Seoul, 7Korea University Anam Hospital, of adverse events. Korea University School of Medicine, Seoul, 8Kyungpook National University Hospital, Conclusion Kyungpook National University In the present study, azasetron showed inferiority in the control of delayed chemother - School of Medicine, Daegu, 9Asan Medical Center, apy-induced nausea and vomiting compared with ondansetron whereas safety profiles University of Ulsan College of Medicine, Seoul, 10 Seoul National University Hospital, were similar between the two groups. Seoul National University College of Medicine, Seoul, 11 Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Key words 12 Soonchunhyang University Hospital, Vomiting, Vomiting/chemically induced, Soonchunhyang University Vomiting/prevention and control, College of Medicine, Seoul, Korea Antineoplastic agents, Serotonin antagonists, + + + + + + + + + + + + + + + + + + + + Azasetron, Ondansetron + C +o r+r e s+p o+n d+e n+c e+: H +o +on +-K +yo + K i+m ,+ M +D + + + + + D +e p+a r+tm +e n +t o+f I+n t e+r n +a l +M +ed +ic i n+e ,+ + + + + + + + + + + + + + + + + + + + + + + + + + + S +t. V+ i n+c e+n t +’s H+ o +sp +it a +l, T+h e+ C +a t h+o l+ic +U n+i v +e r s+i t y+ + o +f K +o r+e a + C +ol l +eg e+ o +f M +e d+i c +in e+, 9+3 J+u n+g b+u -+d a +e r +o, + + + + + + + + + + + + + + + + + + + + + P +a l d+a l+-g +u , +Su +w o+n +44 2+- 7 +2 3 +, K +o r +ea + + + + + + + T +e l :+ 8 2+- 3 +1- 2+4 9 +-7 1+2 7 + + + + + + + + + + + + + F +a x +: 8 +2- 3+1 - 2+5 3+- 8 +8 9 +8 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + E +- m +a i+l: m+ i o+n g+s o+k @+c a+t h +o l i+c . a+c . k+r + + + + + + + R +e c +e i v+e d+ M+ a +y 1+0 , +2 0 +1 3 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + A +c c+e p +te d+ J+u n+e 1+2 ,+ 2 0+1 3 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + │ http://www.cancerresearchandtreatment.org │ Copyright ⓒ 2014 by the Korean Cancer Association 19 │ http://www.e-crt.org │ This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/3.0/)which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Cancer Res Treat. 2014;46(1):19-26 Introduction 3-5) on day 1, and who were naïve to chemotherapy or had previous chemotherapy ≥3 weeks prior to screening [9]. Patients were required to have an Eastern Cooperative Chemotherapy-induced nausea and vomiting (CINV) is a Oncology Group (ECOG) performance status 1-2, a life significant concern for cancer patients undergoing expectancy ≥3 months, and adequate hepatic and renal chemotherapy and can result in various metabolic and function (aspartate aminotransferase and alanine amino - nutritional problems and sometimes even discontinuation of transferase ≤2.5 ×upper normal limit [UNL], bilirubin ≤ chemotherapy [1]. CINV is classified as anticipatory, acute 1.5 ×UNL, and creatinine ≤1.5 ×UNL). (within 24 hours after the initiation of chemotherapy), and Exclusion criteria were as follows: severe uncontrolled delayed emesis (2-5 days later). The 5-hydroxytryptamine-3 concurrent illness other than malignancy; other causes of (5-HT 3) receptor antagonists have exhibited efficacy and nausea and vomiting (hypercalcemia, intestinal obstruction); safety in the prevention of CINV, as well as postoperative current medications for active peptic ulcer; metastatic or and radiotherapy-induced nausea and vomiting [2-4]. primary tumor in the central nervous system (CNS); any Azasetron, a selective potent 5-HT 3 receptor antagonist, is a nausea or vomiting within 24 hours before chemotherapy; derivative of benzamide with a different chemical structure grade 3 or higher nausea or vomiting according to Common from other 5-HT 3 receptor antagonists, such as ondansetron, Terminology Criteria of Adverse Event, ver. 3.0 (CTCAE V.3) granisetron, ramosetron, and tropisetron, and has a longer in previous chemotherapies within 6 months; a known duration of action and a higher affinity for the 5-HT 3 hypersensitivity to 5-HT 3 receptor antagonists or dexametha - receptor [5,6]. Azasetron has shown efficacy and safety in the sone; medications that may affect the gastrointestinal (GI) prevention of CINV and postoperative nausea and vomiting, tract or CNS in the previous 48 hours; radiotherapy within 3 while that in delayed CINV has not been confirmed in weeks or unstable state after surgery; and participation in a prospective randomized controlled trial [3,7,8]. Therefore, another drug study. the present study was conducted to evaluate the efficacy and All patients were randomly assigned to one of the two safety of azasetron compared with ondansetron for the treatment groups before chemotherapy and instructed to prevention of delayed CINV. take a daily dose of antiemetics according to the regimens listed in Table 1. Patients who developed nausea or vomiting requiring rescue therapy discontinued the study and were managed appropriately in each institution. Materials and Methods The study was approved by the ethics committee of each institution and all patients gave written informed consent. 1. Patients and treatment 2. Assessment Patients were recruited for this trial from 12 institutions in Korea between May 2005 and December 2005. Eligibility Patients recorded episodes of nausea and vomiting, and criteria were men and women aged between 19 and 75 with visual analogue scale (VAS) in self diaries for 6 days (days confirmed malignancy, who planned to receive moderately 1-6). Patients visited the hospital on day 7 (+2) and week 4 or highly emetogenic chemotherapeutic drug (Hesketh level (±1 week), and laboratory examinations (complete blood Table 1. Treatment regimens Dose Regimen Study medication Day 1 Days 2-6 Azasetron Azasetron 10 mg iv 30 min-2 hr prior to chemotherapy 10 mg po Ondansetron Placebo po bid Dexamethasone 20 mg iv 30 min prior to chemotherapy 4 mg po bid on days 2-4 Ondansetron Azasetron 10 mg iv 30 min-2 hr prior to chemotherapy Placebo po Ondansetron 8 mg po bid Dexamethasone 20 mg iv 30 min prior to chemotherapy 4 mg po bid on days 2-4 iv, intravenously; po , orally; bid , every 12 hours. 20 CANCER RESEARCH AND TREATMENT Hee Yeon Lee, Azasetron in Delayed Chemotherapy-Induced Emesis 283 patients enrolled 136 patients assigned 147 patientis assigned to azasetron to ondansetron 13 patients did not receive treatment 5 patients did not receive treatment 7 met exclusion criteria 3 met exclusion criteria 4 met study discontinuation criteria 2 met study discontinuation criteria 2 withdrew consent 131 patients included 134 patients included in ITT set in ITT set 2 patients excluded from safety set 1 patient excluded from safety set 1 met stydy discontinuation criteria 1 withdrew consent 1 withdrew consent 129 patients included 133 patients included in safety set in sefety set Fig. 1. Trial profile. ITT, intention-to-treat. cell count [CBC], blood chemistry [BC], and urinalysis [UA]), 2-6) using the estimated lower boundary of the 95% electrocardiogram (ECG), and physical examinations includ - confidence interval (CI) in comparison with the predefined ing vital signs were checked.
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