臨床試験

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あまめしどり
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3 Biomedical Research 1964 The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic, and prophylactic procedures and the understanding of the aetiology and pathogenesis of disease. (Declaration of Helsinki. Intro)

4 A. (rational)

5 100 in situ cancers cancer trial

6 D.

7 Uncontrolled Trials: Nonrandomized Controlled Trials: Randomized Controlled Trials:

8 I : (tolerated dose) II : III : IV :

9 I II II III I/II, II/III X+Y+Z X phase I, Y phase II Z phase III phase I 2 AIDS

10 phase Phase I: 8 Phase II: performance status 0, 1, 2, or Phase III: 455 BCG Phase III: stage I BCG Stage I BCG

11 Phase III studies; Randomization AIDS AZT AZT ddi ddt CD4 AZT AZT 6 AZT AZT ddc AZT ddi AZT

13 Factorial design A B ST

14 Placebo or nothing A B A B

15 Y Y X + Y X Y X Z X + Z

16 Y Y Y Y Y Y

17 RST Y Y 12 XY Z Z Z 2

21 concept sheet

22 Schema Primary objectives Primary endpoint definition (only) Statistical consideration (up to sample size section) Patient selection criteria Design section Parameters table (sometimes an appendix) Background and rationale section consent form (6)

23 ACTG155 ZDV ZDV + ddc protocol chair

25 ACTG 155 A randomized, double blind comparative study of dideoxycytidine (ddc) alone or ddc/zdv combination versus zidovudine (ZDV) alone in patients with HIV infection who have received prior ZDV therapy. Sponsored by: The National Institute of Allergy and Infectious Diseases Protocol Co-Chairs: XXXX MD XXXX MD NIAID medical officer: XXXX MD Protocol specialist: XXXX RN Pharmaceutical Support Provided by: XXXX, Inc. XXXX company Version 5.0 FINAL March 20, 1992

26 1

27 SCHEMA ACTG155 Version 5.0 FINAL 03/20/92 Title: A Randomized, Double Blind, Comparative Study Of Dideoxycytidine (ddc) Alone OR ddc/zdv Combination Versus Zidovudine (ZDV) Alone In Patients With HIV Infection Who Have Received Prior ZDV Therapy. Design: Multicenter, randomized, double-blind, phase III study Population: 750 patients with prior ZDV therapy for >= 24 weeks who are either asymptomatic with a CD4 count cells / mm 3 or symptomatic with a CD4 count cells / mm 3. Stratification: Patients will be stratified by HIV disease status (asymptomatic or symptomatic), length of time receiving ZDV (> 1 year of ZDV and =< 1 year of ZDV), and systemic or local PCP prophylaxis. 750-Patients Randomized (214 patient) (214 patients) (322 patients) ZDV two 100 mg capsules ddc two mg tablets ddc two mg And two ddc placebo tablets and two ZDV placebo tablets and ZDV two Every 8 hours capsules every 8 hours 100 mg capsules every 8 hours Patients will be followed for up to two years after the last patient is enrolled unless the study is terminated earlier due to interim study results; mean follow-up is expected to be 28 months with a range of months. Patients who have reached a clinical AIDS-defining endpoint (after verification by the study chair) will be offered open-label combination ddc and ZDV. Endpoints: The development of an AIDS-defining opportunistic infection, AIDS-defining malignancy, AIDS-defining wasting syndrome, AID-dementia complex, or death. Study Co-Chairs: XXXX, M.D., University of XXXX XXXX, M.D., University of XXXX

28 1.0 Background and Rationale 1.1 Background 1.2 Preclinical 1.3 Clinical 1.4 Rationale

29 2.0 phase I preclinical

30 24 ZDV(zidovudine) CD4 300 cells/mm3 CD4 200 cells/mm3 ZDV ddc ZDV ddc ZDV ddc ZDV ddc 2.21 AIDS AIDS AIDS AIDS CD4 cell 2.24 p24* (* RNA )

31 ZDV(zidovudine) AIDS CD4 300 cells/mm3 CD4 200 cells/mm3 ZDV ddc ZDV ddc III 2 AIDS (open label) ddc ZDV

32 Inclusion criteria CD HIV ELISA HIV HIV ELISA CD , AIDS-related complex wasting syndrome (Appendix VIII) protocol chair

33 4.123 AIDS-related complex protocol chair

34 4.124 ELISA HIV mg zidovudine ZDV Kanjorsky s status Hb 9.2 g/dl (men), Hb 8.8 g/dl (women) / mm ,000 / mm GOT/GPT Cr HCG

35 Inclusion criteria

36 grade ZDV mg/day grade 3 ZDV grade ddc 4.25 ddi grade protocol chair

37 5.0 Number/Source/Management of patients ACTU ZDV 1 PCP 5.33 protocol chair ddc ZDV open label

38 ddc Hoffmann-LaRoche ZDV Burrought Wellcome 6.12 Ro Dideoxycytidine (ddc) mg (beige) scored tables Retrovir (zidovudine) 100 mg capsule Arm I: ZDV (100 mg) mg ddc 8

39 6.22 Arm II: 6.23 Arm III: 6.24 section 9.0, HIV ST (pyrimethamine 75 mg/day, sulfadiazine < 4 gm/day) 6.34 EPO, G-CSF, M-CSF

40 baseline evaluation: Karnofsky performance status CBC Na, K, Cl, HCO3, BUN, Cr, Cal, P, UA, BS, HCG (women) GOT, GPT, LDH, bil, ALP ,15

41 CD4, CD CD4, CD HIV

42 grade I 8.2 grade grade 2 (Appendix III) grade 2 ZDV ddc mg grade grade 3 (Hg mg/dl) ZDV/ddC

43 AIDS ddc ZDV open label

44 primary efficacy parameter wasting syndrome, Secondary efficacy parameter CD

45 ZDV(zidovudine) AIDS ZDV ddc ZDV ddc phase III, randomized, double-blind study ddc ddc ZDV ZDV ZDV AIDS 12 stratification ZDV ddc ZDV ddc 2:2:3

46 AIDS Primary endpoint Secondary endpoint / 116, 117 ZDV 6 6 ARC/AIDS (progression free) ACTG114 AIDS ARC 3 ZDV ddc ZDV randomized trial ACTG114 ddc ZDV ACTG155 (ddc ZDV 2 ACTG155

47 11.2 Sample size/ ACTU progression free rate 60 2-sided p=0.05, power 80% 50 2 Hazard ratio Sample size

48 11.3 log rank test Cox Intent-to-treat analysis data safety monitoring board (DSMB) O Brien- Fleming stopping rule

49 11.4 HIV ZDV 1 1 PCP 11.5 Revised statistical Considerations (ACTG 155. Version 5.0) sided p = hazard ratio

50 ACTG114 (a randomized trial comparing ddc versus ZDV for patients with AIDS or advanced ARC with less than three months prior ZDV therapy) Intent-to-treat analysis of time to death (2 ) cox regression Cox regression ddc ZDV AIDS 78% 88 ARC CD CD

51 ACTG114

52 ddc ZDV AIDS 50% 65 ARC CD CD ZDV ATCG155

53 Data Collection Case Report Form (CRF) Patient Identification Number (PID) Study Identification Number (SID) Frontier Science

54 12.21 Study Monitoring ACTG Pharmaceutical Product Development Inc (PPD) PPD FDA DAIDS AER XXXX-XXXX 24

55 5

56 FDA 13.2 IRB 13.3 FDA PPD NIAID

57 ddc DdC 14.2 ZDV 14.3 ddc p24 T 14.4 ZDV AIDS ARC

58 15.0 ACTG 16.0 HIV CDC

59 ( ) CD

60 (ddc) II CD4 (ddc) (ddc) CD4 CD (ddc) (ddc) &

61 CD4 200 /mm3 ZDV 24 CD4 300 /mm3 ZDV 24 (ddc) + (ddc) CD4 (ddc) (ddc) + ZDV ZDV (ddc) ZDV

62 / (ddc) 8 200mg (ddc) 0.75mg (ddc) cc

63 (ddc) (ddc) (ddc)

65 FDA XXX (XXXXXXXX)

67 Division of AIDS (DAIS) Adverse Experience Report (AER) DAIDS FDA HIV

68 DAIDS DAIDS 3 30

69 phase II/phase III grade 4 5 grade 5 24 XXXXX XXXXX 3 grade 3 or 4 5 grade 5 24 XXXXX XXXXX 3 XXXXXXXXXXXXXXXXXXXXXXXXXXXX

70 A B /

71 imbalance 5

73 Imbalance 2 A, B 4 1 [A, A, B, B][A, B, A, B][A, B, B, A][B, A, A, B][B, A, B, A][B, B, A, A] 6 4 block design AA 2 B 2 B

74 Stratification adjustment ,1,2 3 6

76 Dynamic treatment allocation rules 20 1,000 AIDS (PI) AZT AZT HIV-RNA 10, (#5) HIV-RNA 10,000 AZT #5 B A AZT, RNA > 10,000 B A B 4, 5, 8 RNA>10,000 1 #5 #5 A A A A A dynamic allocation strata strata (adaptation)

77 Dynamic treatment allocation rules

78 ACGT076 HIV AZT 900 (interim analysis ) 25 AZT 8 HIV

79 stopping rule

80 data safety monitoring board (DSMB) 2 1

81 2 2

82 2 3

83 1 DSMB DSMB Type I error type I error 5 1

84 I I

85 Pocock O Brien-Fleming type I error P 1 cut off z Peto O Brien-Fleming

86 O Brien-Fleming Peto Pocock

87 3 (p<0.05)

89 P 95 CI 95 CI 95 CI Z 95 CI

91 variability ANOVA

92 1

こんにちは由美子です

こんにちは由美子です Sample size power calculation Sample Size Estimation AZTPIAIDS AIDSAZT AIDSPI AIDSRNA AZTPr (S A ) = π A, PIPr (S B ) = π B AIDS (sampling)(inference) π A, π B π A - π B = 0.20 PI 20 20AZT, PI 10 6 8 HIV-RNA