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研究生:黃山耘
研究生(外文):Shan-YunHuang
論文名稱:以連續型反應為評估依據之三階段藥物監控設計
論文名稱(外文):Three-Stage Design for Drug Screening Trials Based on Continuous Endpoints
指導教授:馬瀰嘉馬瀰嘉引用關係
指導教授(外文):Mi-Chia Ma
學位類別:碩士
校院名稱:國立成功大學
系所名稱:統計學系碩博士班
學門:數學及統計學門
學類:統計學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:75
中文關鍵詞:三階段設計最小化期望樣本數標靶藥物
外文關鍵詞:three-stage designminimized expected sample sizetarget therapy
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在癌症臨床研究上,第二期臨床試驗主要在了解藥品的有效性與安全性,進而決定給藥的方式及劑量等,作為是否進入第三期臨床試驗的依據。基於道德立場考量和保障受試者健康的前提下,應避免受試者長期處於無療效或副作用過高的療程中,因此單臂無對照組的兩階段設計經常應用於第二期臨床試驗上。
基於標靶藥物研究日益興盛,不同於傳統化療藥物衡量腫瘤縮小程度,標靶藥物多半屬細胞穩定性藥物,可使腫瘤停止生長一段時間,因此若用傳統腫瘤反應率作為藥效評估將失去其意義。Tsou等人於2008年提出兩階段藥物監控設計,不同於Simon (1989)兩階段設計以腫瘤反應率作為終點評估,該研究以藥物反應值作為終點評估。
本論文延續 Tsou等人所提出的概念一方面將兩階段設計擴展成三階段設計做為比較;另一方面將原本的常態分配假設擴展成指數分配和珈瑪分配,針對不同分配之下進行數值模擬計算,在固定型I 、型II誤差之下, 藉由最小化期望樣本數,以得到最佳的樣本數。

Due to the development of target therapy, the evaluation in cancer clinical trials will change. Different with drugs of chemotherapy, the drug of target therapy belong to the cytostatic drugs and the main goal is to stopping the growth of tumor for a period of time. Hence the traditional methods of evaluating the tumor by tumor response rate are meaningless.
Tsou et al. (2008) proposed a two stage drug screening trials based on continuous endpoints to improve Simon’s two-stage design which used tumor response rate as primary endpoints. We extend the two-stage drug screening trials to a three-stage design based on the concept of Tsou et al. (2008) and change the normal distribution to exponential distribution and gamma distribution. To fix type I and type II error rate, the best solution can be obtained by minimized expected sample size and total sample size.

1. Introduction………………………………………………………………………1
2. Literature Review…………………………………………………………………7
2.1 Traditional single-stage design………………………………………………7
2.2 Simon’s two-stage design……………………………………………………8
2.3 Chen’s optimal three-stage design……………………………………………9
2.4 Two-stage screening design…………………………………………………11
3. The Proposed Design……………………………………………………13
3.1 Three-stage design for normal distribution…………………………………13
3.1.1 MinEN(u0)design…………………………………………………16
3.1.2 Min(n) design………………………………………………………17
3.1.3 Min((EN(u0)+EN(u1))/2 ) design…………………………………18
3.2 Three-stage design for exponential distribution……………………………20
3.3 Three-stage design for gamma distribution…………………………………25
4. Simulation and Result……………………………………………………………..29
4.1 The simulation………………………………………………………………29
4.2 The results…………………………………………………………………31
4.2.1 Normal distribution………………………………………………31
4.2.2 Exponential distribution…………………………………………32
4.2.3 Gamma distribution……………………………………………….33
5. Conclusion…………………………………………………………………………34
Reference……………………………………………………………………………35
Appendix……………………………………………………………………………37
(1)Normal distribution………………………………………………………………37
(2)Exponential distribution…………………………………………………………38
(3)Gamma distribution………………………………………………………………39
Tables…………………………………………………………………………………40

Buzaianu EM, Chen PY. (2009). A Hybrid Selection and Testing Procedure with Curtailment for Comparative Clinical Trials. Sequential Analysis Vol. 28: P.02-20.

Chen TT.(1997). Optimal three-stage designs for phase II clinical trials. Statistics in Medicine; Vol. 16, P. 01–11.

Chi YC, Chen CM. (2008). Curtailed two-stage designs in phase II clinical trials. Statistics in Medicine; Vol. 27, P. 6175-6189.

Dunnett CW.(1955). A Multiple Comparison Procedure for Comparing Several Treatments with a Control. Journal of the American Statistical Association; Vol. 50,
P.1096-1121.

Ensign LG, Gehen EA, Kamen DS, Thall PF. (1994). An optimal three-stage design for phase II clinical trials. Statistics in Medicine; Vol. 13, P.1727-1736.

Fleming TR.(1982). One-Sample Multiple Testing Procedure for Phase II Clinical Trials. International Biometric Society; Vol. 38, P.143-151.

Gehan EA. (1961).The determination of the number of patients required in a follow-up trial of a new chemotherapeutic agent. J Chron Dis; Vol. 13, P.346-353,

Ma MC, Hsu WT. (2010). The Study of Two-Stage Design with Curtailment for Comparative Clinical Trials. National Cheng Kung University, Master’s Dissertation. Electronic Theses and Dissertations.

Ma MC, Ye SB. (2011). Sample Size Determination for Two Stage Equivalence Test, Journal of Taiwan Intelligent Technologies and Applied Statistics, 9(1), P. 25-41.

Simon R. (1989). Optimal two-stage design for phase II clinical trials, Controlled Clinical Trials; Vol. 10, P.01-10.

Tsou HH, Hsiao CF, Chow SC, Liu JP. (2008). A two-stage designs for drug screening trials based on continuous endpoints. Drug Information Journal; Vol. 42, P. 253-262.

Wong KF, Tsai CL. (2006). Two-Stage Designs for Phase II Clinical Trials. National University of Kaohsiung Repository System.

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