14.2 有効性の結果
14.2.2 副次評価項目
14.2.2.1 SVR 24
Note: Baseline is the last available value on/prior to the first dose date of study regimen.
a HCV RNA analyzed using Roche Taqman V 2.0 assay for use with High Pure system with limit of quantitation 25 IU/mL.
Programming Details: .../version1/prog/t-demog.sas v9.2 28JAN2013:15:29 Source: CSR Table 8-5
区間（59.1%～71.4%）］と同程度であった。SVR24 率における層別因子を調整した両群間の差
（95%信頼区間）は 1.1%（95%信頼区間：−6.7% ～ 9.0%）であった。両群間におけるSVR24率 はSVR12率と類似しており（SOF+RBV群 67.2%；Peg-IFN+RBV 群66.7%）、これら2測定時点 における SVR率は高い相関関係にあり、SVR12の達成はSVR24の達成と相関しているという公 表文献の報告と一致していた。投与終了後 24 週時までに、有効性に関して他に特筆すべき変化 はみられなかった。
表2.7.6.14 -6 P7977-1231（FISSION）試験：SVR24（最大の解析対象集団）
SOF+RBV vs.
Peg-IFN+RBV SOF+RBV
(N=253) Peg-IFN+RBV (N=243)
Proportion Difference Adjusted for Stratum
(95% CI)a Number of Subjects Who Were
< LLOQ at Their Last Observed On−Treatment HCV RNA Value
249 217
SVR24 169/253 (66.8%) 159/243 (65.4%) 1.1% (−6.7% to 9.0%)
95% CIb 60.6% to 72.6% 59.1% to 71.4%
NOTE: HCV RNA analyzed using Roche TaqMan V 2.0 assay for use with High Pure system with limit of quantitation 25 IU/mL
NOTE: SVRx is sustained virologic response (HCV RNA < LLOQ) x weeks after stopping treatment.
NOTE: A missing SVR value was imputed as a success if it was bracketed by values that were termed successes (ie, '<LLOQ TND' or '<LLOQ detected'); otherwise, the missing SVR value was imputed as a failure. TND = target not detected.
a Difference in proportions between treatment groups and associated 95% CI were calculated based on stratum−adjusted Mantel−Haenszel proportions.
b The exact 95% CI for the proportion within treatment group was based on the Clopper−Pearson method.
Source: Appendix 5, Table 12 Source: CSR Synopsis
14.2.2.2 ウイルス学的治療不成功
最大の解析対象集団におけるウイルス学的転帰（SVR、ウイルス学的治療不成功、その他）を
表 2.7.6.14 -7について示す。SOF+RBV群の75例（29.6%）でウイルス学的治療不成功がみられ
ており大多数（75例中74例）が再燃によるものであり、再燃は主に投与終了後のWeek 4来院時 までに起きていた。SOF+RBV群の1例では、治験薬投与期間中のWeek 8時点でウイルス学的治 療不成功がみられた。当該被験者の薬物動態測定結果で、Week 8 時点又はその前後及び投与終 了（治験薬投与期間中の Week 12）時点での薬物レベルが検出不能であったことから、被験者に SOF の投与不遵守があったことが示唆された。Peg-IFN+RBV 群の 64 例（26.3%）にウイルス学 的治療不成功がみられた。Peg-IFN+RBV 群のウイルス学的治療不成功例の大多数（64 例中 46 例）は再燃によるものであり、主に治験薬投与終了後のWeek 4又はWeek 8の来院時に起きてい た。治験薬投与期間中に起きたウイルス学的治療不成功は Peg-IFN+RBV 群（18 例；7.4%）で
SOF+RBV群（上述の1例；0.4%）に比してより高い割合でみられていた。
2.7.6.14 - 11
表2.7.6.14 -7 P7977-1231（FISSION）試験：ウイルス学的転帰（最大の解析対象集団）
SOF+RBV vs.
Peg-IFN+RBV SOF+RBV
(N=253) Peg-IFN+RBV
(N=243) Prop Diff (95% CI)b,c
SVR12 170/253 ( 67.2%) 162/243 ( 66.7%) 0.3% (−7.5% to 8.0%)
Overall Virologic Failure 75/253 ( 29.6%) 64/243 ( 26.3%) 3.3% (−4.6% to 11.2%)
Relapsea 74/249 ( 29.7%) 46/217 ( 21.2%)
Study Drug Completer 71/242 ( 29.3%) 37/188 ( 19.7%) Study Drug Non−Completer 3/7 ( 42.9%) 9/29 ( 31.0%) On−Treatment Virologic Failurec 1/253 ( 0.4%) 18/243 ( 7.4%)
Otherd 8/253 ( 3.2%) 17/243 ( 7.0%)
Note: HCV RNA analyzed using Roche Taqman V 2.0 assay for use with High Pure system with limit of quantitation 25 IU/mL.
a The denominator for ‘relapse’ is the number of subjects with HCV RNA < LLOQ at their last on−treatment assessment.
b For SVR12, difference in proportions and associated 95% CI are calculated based on stratum−adjusted MH proportions.
c For virologic failure, the 95% CI on the difference is based on the exact method (standardized statistic and inverting two 1−sided tests).
d Other = Subject who did not achieve SVR12 and did not meet virologic failure criteria.
Source: Section 15.1, Table 10
Source: m5.3.5.1.1, P7977 1231 CSR, Section 9.2 Table 9−2
14.2.2.3 有効性のサブグループ解析
あらかじめ設定したサブグループ別に SVR12 を達成した被験者の割合での投与群間差の点推 定及び95%信頼区間を図2.7.6.14 -2及び表2.7.6.14 -8にて示す。ジェノタイプ2のHCV感染患者
における SVR12率では、SOF+RBV群において Peg-IFN+RBV群に比較してより高率に認められ
た（それぞれ 97.1% 対 77.6%）。層別因子を調整した差は 19.1%（95%信頼区間：7.4% ～
30.7%）であった。その他の全サブグループでの群間差の95%信頼区間は0を跨いでいた。
Differences in Proportions (95% CI)
-40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100
Source: .../version1/prog/t-svr-subgroup.sas v9.2 Output file: g-forest-svr12-subgroup.out 28JAN2013:15:35 Data Extracted: 25Jan2013
Note: If cirrhosis status was missing, then CIRRHOSIS=NO for purposes of analysis unless cirrhosis was documented post-baseline.
Note: Relative to the vertical line at 0, differences on the right favor SOF+RBV and differences on the left favor PEG+RBV.
Note: For subgroups, the 95% CI on the difference is based on the exact method (standardized statistic and inverting two 1-sided tests).
Note: For the overall result, difference in proportions and associated 95% CI are calculated based on stratum-adjusted Mantel-Haenszel proportions.
Overall Age (Years) < 50 >= 50 MaleSex Female BlackRace Non-Black Ethnicity Hispanic or Latino Not Hispanic or Latino Cirrhosis No Yes HCV Genotype GT-2 GT-3 Baseline HCV RNA < 6 log10 IU/mL >= 6 log10 IU/mL Baseline BMI < 30 kg/m2 >= 30 kg/m2 Region Non-US US Baseline ALT <= 1.5 x ULN > 1.5 x ULN IL28B CC Non-CC Study Drug Completer Yes No
Source: Section 15.1, Figure 3.2
Source: m5.3.5.1.1, P7977 1231 CSR, Section 9.2 Figure 9−1
図2.7.6.14 -2 P7977-1231（FISSION）試験：サブグループ別SVR12のフォレストプロット（最大の解析対象集団）
2.7.6.14 - 13
表2.7.6.14 -8 P7977-1231（FISSION）試験：サブグループ別SVR12（最大の解析対象集団）
SOF+RBV vs.
Peg-IFN+RBV SOF+RBV
(N=253) Peg-IFN+RBV
(N=243) Prop Diff (95% CI) Overallb 170/253 ( 67.2%) 162/243 ( 66.7%) 0.3% (−7.5% to 8.0%) Age (Years)
< 50 80/126 ( 63.5%) 86/118 ( 72.9%) −9.4% (−21.1% to 2.4%)
95% CI 54.4% to 71.9% 63.9% to 80.7%
>= 50 90/127 ( 70.9%) 76/125 ( 60.8%) 10.1% (−1.7% to 21.8%)
95% CI 62.1% to 78.6% 51.7% to 69.4%
Sex
Male 103/168 ( 61.3%) 96/156 ( 61.5%) −0.2% (−10.9% to 10.4%)
95% CI 53.5% to 68.7% 53.4% to 69.2%
Female 67/85 ( 78.8%) 66/87 ( 75.9%) 3.0% (−9.8% to 15.7%)
95% CI 68.6% to 86.9% 65.5% to 84.4%
Race
Black 9/12 ( 75.0%) 2/5 ( 40%) 35.0% (−17.8% to 76.6%)
95% CI 42.8% to 94.5% 5.3% to 85.3%
Non−Black 161/241 ( 66.8%) 160/238 ( 67.2%) −0.4% (−9.0% to 8.0%)
95% CI 60.5% to 72.7% 60.9% to 73.2%
Ethnicity
Hispanic or Latino 29/40 ( 72.5%) 20/31 ( 64.5%) 8.0% (−14.2% to 30.5%)
95% CI 56.1% to 85.4% 45.4% to 80.8%
Not Hispanic or Latino 141/213 ( 66.2%) 142/212 ( 67.0%) −0.8% (−10% to 8.3%)
95% CI 59.4% to 72.5% 60.2% to 73.3%
Cirrhosisa
No 147/204 ( 72.1%) 143/193 ( 74.1%) −2.0% (−10.8% to 6.8%)
95% CI 65.4% to 78.1% 67.3% to 80.1%
Yes 23/49 ( 46.9%) 19/50 ( 38.0%) 8.9% (−11.0% to 28.3%)
95% CI 32.5% to 61.7% 24.7% to 52.8%
HCV Genotypeb
GT−2 68/70 ( 97.1%) 52/67 ( 77.6%) 19.1% (7.4% to 30.7%)
95% CI 90.1% to 99.7% 65.8% to 86.9%
GT−3 102/183 ( 55.7%) 110/176 ( 62.5%) −6.9% (−16.6% to 2.9%)
95% CI 48.2% to 63.1% 54.9% to 69.7%
Baseline HCV RNA
< 6 log10 IU/mL 80/107 ( 74.8%) 71/106 ( 67.0%) 7.8% (−4.6% to 20%)
95% CI 65.4% to 82.7% 57.2% to 75.8%
>= 6 log10 IU/mL 90/146 ( 61.6%) 91/137 ( 66.4%) −4.8% (−16.1% to 6.5%)
95% CI 53.2% to 69.6% 57.9% to 74.3%
SOF+RBV vs.
Peg-IFN+RBV SOF+RBV
(N=253) Peg-IFN+RBV
(N=243) Prop Diff (95% CI) Baseline BMI
< 30 kg/m2 120/176 ( 68.2%) 117/172 ( 68.0%) 0.2% (−9.7% to 10.1%)
95% CI 60.8% to 75.0% 60.5% to 74.9%
>= 30 kg/m2 50/77 ( 64.9%) 45/71 ( 63.4%) 1.6% (−14.3% to 17.1%)
95% CI 53.2% to 75.5% 51.1% to 74.5%
Region
Non−US 48/91 ( 52.7%) 58/92 ( 63.0%) −10.3% (−24.5% to 4.3%)
95% CI 42.0% to 63.3% 52.3% to 72.9%
US 122/162 ( 75.3%) 104/151 ( 68.9%) 6.4% (−3.6% to 16.4%)
95% CI 67.9% to 81.7% 60.8% to 76.2%
Baseline ALT
<= 1.5 x ULN 82/116 ( 70.7%) 70/97 ( 72.2%) −1.5% (−13.7% to 11.0%)
95% CI 61.5% to 78.8% 62.1% to 80.8%
> 1.5 x ULN 88/137 ( 64.2%) 92/146 ( 63.0%) 1.2% (−10.1% to 12.7%)
95% CI 55.6% to 72.2% 54.6% to 70.8%
IL28B
CC 74/106 ( 69.8%) 82/106 ( 77.4%) −7.5% (−19.5% to 4.4%)
95% CI 60.1% to 78.3% 68.2% to 84.9%
Non−CC 96/145 ( 66.2%) 79/136 ( 58.1%) 8.1% (−3.5% to 19.5%)
95% CI 57.9% to 73.8% 49.3% to 66.5%
Study Drug Completer
Yes 169/242 ( 69.8%) 147/189 ( 77.8%) −7.9% (−16.2% to 0.5%)
95% CI 63.6% to 75.5% 71.2% to 83.5%
No 1/11 ( 9.1%) 15/54 ( 27.8%) −18.7% (−36.2% to
15.4%)
95% CI 0.2% to 41.3% 16.5% to 41.6%
Note: HCV RNA analyzed using Roche Taqman V 2.0 assay for use with High Pure system with limit of quantitation 25 IU/mL.
Note: A missing SVR4 value is imputed as a success if it is bracketed by values that are termed successes (ie, '<LLOQ TND' or '<LLOQ detected'), otherwise, the missing SVR4 value is imputed as a failure. TND = Target not detected.
Note: The exact 95% CI for proportion within treatment group and subgroup is based on the Clopper−Pearson method.
Note: For subgroups other than HCV genotype, the 95% CI on the difference is based on the exact method (standardized statistic and inverting two 1−sided tests).
a If cirrhosis status was missing, then CIRRHOSIS=NO for purposes of analysis unless cirrhosis was documented post−baseline.
b For the overall result and for results by HCV genotype, differences in proportions and associated 95% CI are calculated based on strata adjusted Mantel−Haenszel proportions.
Source: Section 15.1, Table 8.4 and Table 8.5 Source: CSR, Table 9−4.
2.7.6.14 - 15
14.2.2.4 HCV RNAレベルが定量下限未満となった被験者の来院別の割合
HCV RNA レベルが定量下限未満となった被験者の割合を表 2.7.6.14 -9に来院別及び投与群別
に示す。Peg-IFN+RBV 群と比較して SOF+RBV 群でより急激に HCV RNA の抑制がみられた。
Week 2 来院時までに SOF+RBV 群の 92.0%において、また Peg-IFN+RBV 群の 31.5%において
HCV RNA が定量下限未満となった。投与群間差は時間と共に減少したが、全投与期間を通して、
SOF+RBV群で HCV RNA定量下限未満を達成した被験者の割合は、Peg-IFN+RBV群と比較して
数値的に高かった。同様に、HCV RNA の定量下限未満が初めてみられるまでに要した時間の中
央値は、SOF+RBV群で 2.0週であり、Peg-IFN+RBV 群では 3.0週であった。ALTが正常化した
被験者の割合においても、治験薬投与期間中の各測定時点で SOF+RBV 群が Peg-IFN+RBV 群と 比較してより高かった（図2.7.6.14 -3）。
表2.7.6.14 -9 P7977-1231（FISSION）試験：治験薬投与期間中にHCV RNAが 定量下限未満となった被験者の来院別の割合（最大の解析対象集団）
SOF+RBV vs. Peg-IFN+RBV SOF+RBV
(N=253) Peg-IFN+RBV
(N=243) Prop Diff (95% CI)a Baseline
< LLOQ 0/253 0/243
Week 1
< LLOQ 110/252 ( 43.7%) 16/243 ( 6.6%) 37.3% (30.8% to 43.7%)
< LLOQ detected 86/252 ( 34.1%) 9/243 ( 3.7%)
< LLOQ TND 24/252 ( 9.5%) 7/243 ( 2.9%) Week 2
< LLOQ 231/251 ( 92.0%) 76/241 ( 31.5%) 60.6% (53.8% to 67.3%)
< LLOQ detected 115/251 ( 45.8%) 44/241 ( 18.3%)
< LLOQ TND 116/251 ( 46.2%) 32/241 ( 13.3%) Week 3
< LLOQ 247/250 ( 98.8%) 123/239 ( 51.5%) 47.0% (40.6% to 53.4%)
< LLOQ detected 66/250 ( 26.4%) 49/239 ( 20.5%)
< LLOQ TND 181/250 ( 72.4%) 74/239 ( 31.0%) Week 4
< LLOQ 249/250 ( 99.6%) 158/236 ( 66.9%) 32.3% (26.4% to 38.3%)
< LLOQ detected 41/250 ( 16.4%) 42/236 ( 17.8%)
< LLOQ TND 208/250 ( 83.2%) 116/236 ( 49.2%) Week 8
< LLOQ 247/248 ( 99.6%) 198/231 ( 85.7%) 13.7% (8.9% to 18.6%)
< LLOQ detected 2/248 ( 0.8%) 25/231 ( 10.8%)
< LLOQ TND 245/248 ( 98.8%) 173/231 ( 74.9%) Week 12
< LLOQ 242/244 ( 99.2%) 207/224 ( 92.4%) 6.6% (2.5% to 10.7%)
< LLOQ detected 3/244 ( 1.2%) 11/224 ( 4.9%)
< LLOQ TND 239/244 ( 98.0%) 196/224 ( 87.5%) Week 16
< LLOQ N/A 201/203 ( 99.0%)
< LLOQ detected 5/203 ( 2.5%)
< LLOQ TND 196/203 ( 96.6%)
Week 20
< LLOQ N/A 198/199 ( 99.5%)
< LLOQ detected 3/199 ( 1.5%)
< LLOQ TND 195/199 ( 98.0%)
Week 24
< LLOQ N/A 188/190 ( 98.9%)
< LLOQ detected 4/190 ( 2.1%)
2.7.6.14 - 17
SOF+RBV vs. Peg-IFN+RBV SOF+RBV
(N=253) Peg-IFN+RBV
(N=243) Prop Diff (95% CI)a
< LLOQ TND 184/190 ( 96.8%)
Note: HCV RNA analyzed using Roche Taqman V 2.0 assay for use with High Pure system with limit of quantitation 25 IU/mL.
Note: Missing values for on−treatment visits are imputed up to the time of last dose (if the study day associated with the last dose date is greater than the lower bound of a visit window, the missing value at the visit will be imputed, otherwise, the value will be excluded from analysis).
Note: Missing values bracketed by values of '< LLOQ TND' will be set to '< LLOQ TND'; bracketed by '< LLOQ detected', or '< LLOQ TND' and '< LLOQ detected' will be set to '< LLOQ detected'; otherwise, the missing values will be set to '>= LLOQ'. TND = Target Not Detected.
a Difference in proportions between treatment groups and associated 95% CI are calculated based on stratum−adjusted Mantel−Haenszel proportions.
Source: Section 15.1, Table 11.1 Source: CSR, Table 9−5.
Proportion of Subjects with HCV RNA < LLOQ
0 10 20 30 40 50 60 70 80 90 100
Weeks on Study
BL 1 2 3 4 8 12 16 20 24
0 10 20 30 40 50 60 70 80 90 100
PEG+RBV (n=): 243 243 241 239 236 231 224 203 199 190
SOF+RBV (n=): 253 252 251 250 250 248 244
Source: .../version1/emf/i-intext-rna-ontrt.sas v9.2 Output file: g-rna-ontrt.out 28JAN2013:15:31 Data Extracted: 25Jan2013
Note: Offsets have been applied to the SOF+RBV and PEG+RBV treatment groups.
Note: The vertical line represents exact 95% CI for the proportion within treatment group based on the Clopper-Pearson method.
Note: Baseline value is the last available value on or prior to the first dose date of study regimen.
= SOF+RBV
= PEG+RBV
Source: Section 15.1, Figure 5
Source: m5.3.5.1.1, P7977 1231 CSR, Section 9.2 Figure 9−2.
図2.7.6.14 -3 P7977-1231（FISSION）試験：治験薬投与期間中にHCV RNAが 定量下限未満となった被験者の来院別の割合（最大の解析対象集団）