Supplementary appendix This appendix is a supplement to: Graham R. Foster, Stephen Pianko, Curtis Cooper, et al. Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with HCV genotype 3 and treatment-experienced cirrhotic patients with HCV genotype 2. Gastroenterology 2015 1
Table of Contents Page BOSON Study Group.. 3 Hypothesis Testing.. 4 Justification of Non-inferiority Margin. 8 Table 1. Reasons for Screen Failure... 9 Figure 1. Patient Disposition. 10 Table 2. Proportion of Patients with HCV RNA <LLOQ While on Treatment by Visit 11 Table 3. SVR12 by Subgroup in Patients with Genotype 2 HCV... 12 Table 4. SVR12 by Subgroup in Patients with Genotype 3 HCV... 14 Table 5. SVR12 by Dose Modifications... 16 Table 6. Treatment-Emergent Serious Adverse Events... 17 Table 7. Treatment-Emergent Graded Laboratory Abnormalities... 18 Table 8. Safety Profile in Treatment-naïve Patients 20 Table 9. Safety Profile in Treatment-experienced Patients 21 Table 10. Proportion of patients with HCV RNA <LLOQ by Response (SVR12 vs relapse). 22 2
BOSON Study Group Australia Peter W. Angus, Jacob George, Barbara Leggett, Graeme MacDonald, Gerry MacQuillan, Stephen Pianko, Stuart Roberts, David R. Shaw, Simone Strasser, Katherine Stuart, Alexander Thompson, Amany Zekry Canada Brian Conway, Curtis Cooper, Magdy Elkhashab, Jordan Feld, Scott Fung, Kelly Kaita, Paul Marotta, Alnoor Ramji, Stephen Shafran, Mark Swain, Keith Tsoi, Marie-Louise Vachon, Bernard Willems, Eric Yoshida New Zealand Edward Gane, Michael Schultz, Nigel Stace, Catherine Stedman, Frank Weilert United Kingdom Kosh Agarwal, Aftab Ala, Mark Aldersley, Graeme Alexander, Richard Aspinall, Jonathan Ball, Stephen Barclay, Eleanor Barnes, Ashley Brown, Gary Burgess, Jane Collier, Graham Cooke, Mathew Cramp, John Dillon, Dan Forton, Graham Foster, Charles Gore, Neil Guha, Peter Hayes, Cham Herath, Chris Holmes, Anita Howe, William Irving, Neil Jenkins, Paul Kellam, Salim Khakoo, Paul Klenerman, Diana Koletzki, Clifford Leen, Natasha Martin, Tamyo Mbisa, Jane McKeating, John McLauchlan, Stuart McPherson, Peter Mills, Alec Miners, Sulleman Moreea, Andrea Murray, David Mutimer, Mark Nelson, Paul Richardson, Richard Riley, William Malcolm Charles Rosenberg, Stephen Ryder, Peter Shaw, Peter Simmonds, Chris Spencer, Paul Targett-Adams, Emma Thomson, Andrew Ustianowski, Peter Vickerman, Mark Wright, Nicole Zitzmann United States Nezam H.Afdhal, M. Tarek Al-Assi, Leslie Bank, Michael T. Bennett, James Bredfeldt, Cynthia Brinson, Natalie Bzowej, Mitchell Davis, Greg Everson, Todd Frederick, Stuart C.Gordon, Robert Herring, Ira M. Jacobson, Zeid Kayali, Marcelo Kugelmas, Jay Lalezari, Ronald G.Nahass, Michael Porayko, Michael Ryan, Eugene R. Schiff, Aasim Sheikh, Jihad Slim, Coleman Smith, Ziad Younes 3
Hypothesis Testing In the primary efficacy analysis, a gatekeeping approach was used to control the familywise error rate for the sequence of hypotheses to be tested (see Figure on page 7). The 3 treatment arms are noted as 24 WK SOF+RBV, 16 WK SOF+RBV, and 12 WK SOF+RBV+PEG, with the SVR12 rates of P24, P16, and P12, respectively. A non-inferiority margin of 12% was used. 4
5
6
Figure: Gatekeeping Procedure H1 STAGE I Assess if 16 wks is NI to 24 wks (H2; =0.025 one-sided) H2 H3 Assess if 24 wks is NI to 16 wks (H3; =0.025 one-sided) If 24 wks trt is non-inferior to 16 wks trt then test, using a Hochberg procedure test H31 & H32. STAGE II Assess if 16 wks is NI to 12 wks (H21; =0.025 one-sided) H21 Assess if 24 wks is Superior to 16 wks (H31; =0.0125 or =0.025 one-sided using Hochberg Procedure) H31 H32 Test if 12 wks trt is superior to 16 wks trt (H32; =0.0125 or =0.025 one sided using Hochberg Procedure) STAGE III STAGE IV Assess if 16 wks is superior to 12 wks (H211; =0.025 onesided) H211 Assess if 24 wks is NI to 12 wks (H311; =0.0125 on-sided) Assess if 24 wks is superior to 12 wks (H3111; =0.0125 one-sided) H311 H3111 H321 Test if 12 wks trt is superior to 24 wks trt (H321; =0.0125 one-sided) 7
Justification of Non-inferiority Margin 8
Table 1. Reasons for Screen Failure 9
Figure 1. Patient Disposition 10
Table 2. Proportion of Patients with HCV RNA <LLOQ While on Treatment by Visit 11
Table 3. SVR12 by Subgroup in Patients with Genotype 2 HCV 12
Table 3. SVR12 by Subgroup in Patients with Genotype 2 HCV (continued) 13
Table 4. SVR12 by Subgroup in Patients with Genotype 3 HCV 14
Table 4. SVR12 by Subgroup in Patients with Genotype 3 HCV (continued) 15
Table 5. SVR12 by Dose Modifications 16
Table 6. Treatment-Emergent Serious Adverse Events 17
Table 7. Treatment-Emergent Grade 3 and 4 Laboratory Abnormalities 18
Table 7. Treatment-Emergent Graded Laboratory Abnormalities (cont d) 19
Table 8. Safety Profile in Treatment-naïve Patients 20
Table 9. Safety Profile in Treatment-experienced Patients 21
Table 10. Proportion of patients with HCV RNA <LLOQ by Response (SVR12 vs relapse) 22