Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Ira M. Jacobson, Eric Lawitz, Edward J. Gane, et al. Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials 1

2 Table of contents POLARIS-2 Study Investigators... 3 POLARIS-3 Study Investigators... 4 Patient Inclusion and Exclusion Criteria, POLARIS 2 and Table S1. Reasons for Screen Failure: POLARIS Figure S1. Patient disposition: POLARIS Table S2. Reasons for Screen Failure: POLARIS Figure S2. Patient disposition: POLARIS Table S3. Characteristics of patients who relapsed in POLARIS Table S4. Characteristics of patients who relapsed in POLARIS Table S5. SVR12 rates in POLARIS-2 and POLARIS-3 by baseline resistance Table S6. Serious adverse events in POLARIS Table S7. Serious adverse events in POLARIS Table S8. Grade 3 and 4 adverse events in POLARIS Table S9. Grade 3 and 4 adverse events in POLARIS Table S10. Grade 3 and 4 laboratory abnormalities in POLARIS Table S11. Grade 3 and 4 laboratory abnormalities in POLARIS

3 POLARIS-2 Study Investigators Australia Stuart Roberts, Gregory Dore, Wendy Cheng, Barbara Leggett, Alexander Thompson Canada Stephen Shafran, Brian Conway, Bernard Willems, Curtis Cooper, Alnoor Ramji, Jordan Feld, Sergio Borgia, Stephen Congly France Marc Bourliere, Stanislas Pol, Didier Samuel, Victor de Ledinghen, Danielle Botta-Fridlund, Ghassan Riachi, Christophe Hezode, Fabien Zoulim, Jean-Pierre Bronowicki, François Habersetzer, Philippe Mathurin, Dominique Guyader, Jean-Didier Grange, Véronique Loustaud Ratti, Vlad Ratziu, Lawrence Serfaty, Albert Tran, Xavier Causse, Dominique Larrey, Laurent Alric, Dominique Roulot, Tarik Asselah, Armando Abergel, Vincent Leroy, Sophie Metivier Germany Peter Buggisch, Stefan Zeuzem, Thomas Berg, Tobias Goeser, Ulrich Spengler, HeinerWedemeyer New Zealand Edward Gane, Catherine Stedman Puerto Rico Grissel Ortiz-Lasanta United Kingdom Stephen Ryder, Graham Foster, Ashley Brown, Kosh Agarwal, Andrew Ustianowski, Richard Aspinall, Jane Collier, Daniel Forton United States of America Adrian DiBisceglie, Mitchell Shiffman, Myron Tong, Peter Ruane, Eugene Schiff, Michael Bennett, Robert Brown Jr., Gregory Everson, Stuart Gordon, Ilan Weisberg, Kris Kowdley, Anna Lok, David Bernstein, Sergio Rojter, Michael Charlton, Lisa Nyberg, Raymond Chung, John Vierling, Marco Lacerda, Mandana Khalili, Steven Flamm, Raymond Rubin, William Smith, Mark Sulkowski, Tram Tran, Michael Curry, James Levin, Norman Gitlin, Rajender Reddy, Kimberly Workowski, Natarajan Ravendhran, Ronald Nahass, Michael Ryan, Eric Lawitz, Ziad Younes, Arun Sanyal, Federico Hinestrosa, Mindie Nguyen, Giuseppe Morelli, Bradley Freilich, Marcelo Kugelmas, Bal Raj Bhandari, Aasim Sheikh, Thomas Sepe, Mitchell Davis, David Pound, Constance Benson, Norbert Brau, Robert Herring, Timothy Morgan, John Poulos, Charles Landis, Zeid Kayali, Mordechai Rabinovitz, Shyamasundaran Kottilil, James Cooper, Brian Pearlman, Obaid Shaikh, William Harlan III, Elizabeth Verna, Ritu Agarwal, Hays Arnold, Ira Jacobson, Paul Kwo, David Wyles 3

4 POLARIS-3 Study Investigators Australia Simone Strasser, Stuart Roberts, Gregory Dore, Stephen Pianko, Barbara Leggett, Alexander Thompson Canada Stephen Shafran, Brian Conway, Alnoor Ramji, Jordan Feld, Sergio Borgia, Stephen Congly France Marc Bourliere, Stanislas Pol, Victor de Ledinghen, Danielle Botta-Fridlund, Christophe Hezode, Fabien Zoulim, Jean-Pierre Bronowicki, François Habersetzer, Dominique Guyader, Véronique Loustaud Ratti, Lawrence Serfaty, Albert Tran, Dominique Larrey, Dominique Roulot, Tarik Asselah, Armando Abergel, Pascal Potier Germany Peter Buggisch, Stefan Zeuzem, Thomas Berg, Tobias Goeser, Ulrich Spengler, HeinerWedemeyer New Zealand Edward Gane, Catherine Stedman Puerto Rico Grisell Ortiz-Lasanta United Kingdom Stephen Ryder, Kosh Agarwal, Andrew Ustianowski, Richard Aspinall, Jane Collier, Daniel Forton United States of America Mitchell Shiffman, Peter Ruane, Eugene Schiff, Michael Bennett, Stuart Gordon, Ilan Weisberg, Kris Kowdley, Anna Lok, Sergio Rojter, Michael Charlton, Lisa Nyberg, Raymond Chung, Mandana Khalili, Raymond Rubin, Gregory Everson, Mark Sulkowski, Tram Tran, Norman Gitlin, Kimberly Workowski, Natarajan Ravendhran, Ronald Nahass, Michael Ryan, Eric Lawitz, Arun Sanyal, Mindie Nguyen, Bal Raj Bhandari, Thomas Sepe, Mitchell Davis, David Pound, Norbert Brau, Robert Herring, Timothy Morgan, John Poulos, Charles Landis, Zeid Kayali, Mordechai Rabinovitz, Shyamasundaran Kottilil, Meena Bansal, Brian Pearlman, William Harlan III 4

5 Patient Inclusion and Exclusion Criteria, POLARIS 2 and 3 Eligibility criteria for POLARIS-2 and POLARIS-3 were identical, except in the areas highlighted in red or blue. SUBJECT POPULATIONS Number of Subjects and Subject Selection POLARIS-2: Approximately 780 DAA-naïve subjects with chronic HCV infection with or without cirrhosis will be enrolled. POLARIS-3: Approximately 200 DAA-naïve subjects with chronic genotype 3 HCV infection and cirrhosis will be enrolled. In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole discretion, may suspend screening and/or enrollment at any site or study-wide at any time. Inclusion Criteria Subjects must meet all of the following inclusion criteria to be eligible for participation in this study: 1) Willing and able to provide written informed consent 2) Male or female, age 18 years 3) Body mass index (BMI) 18 kg/m2 4) HCV RNA 104 IU/mL at Screening POLARIS-2: 5) Chronic HCV infection ( 6 months) documented by prior medical history or liver biopsy POLARIS-3: 5) HCV genotype 3 at Screening, as determined by the central laboratory. Chronic HCV infection ( 6 months) documented by prior medical history of liver biopsy 6) HCV treatment status of one of the following: a) Treatment-naïve with no prior exposure to any IFN, RBV, or approved or experimental HCV-specific DAA b) Treatment experienced with an IFN-based regimen and no prior exposure to an approved or experimental HCV-specific DAA i) The most recent treatment must have been completed at least 8 weeks prior to Screening ii) Subjects must not have discontinued the most recent regimen due to either an adverse event or virologic failure due to noncompliance The subject s medical records must include sufficient detail of prior treatment(s) to confirm eligibility 7) Cirrhosis Determination a) Presence of cirrhosis is defined as any one of the following: i. FibroTest score > 0.75 and AST:platelet ratio index (APRI) > 2 during Screening ii. Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score 5) iii. Transient elastography (FibroScan ) with a result of > 12.5 kpa 5

6 Patient Inclusion and Exclusion Criteria, POLARIS 2 and 3 (continued) POLARIS-2: b) Absence of cirrhosis is defined as any one of the following, unless the definition of cirrhosis has been met: i. FibroTest score 0.48 and APRI 1 performed during Screening ii. Liver biopsy within 2 years of Screening showing absence of cirrhosis iii. Transient elastography (FibroScan ) with a result of 12.5 kpa within 6 months of Day 1 POLARIS-3 had no absence of cirrhosis determination, as presence of cirrhosis was an enrollment criterion. 8) Liver imaging within 6 months prior to Day 1 is required in cirrhotic subjects to exclude hepatocellular carcinoma (HCC) 9) Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to enrollment 10) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception 11) Lactating females must agree to discontinue nursing before starting study drug. 12) Subject must be of generally good health, with the exception of chronic HCV infection, as determined by the investigator 13) Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments Exclusion Criteria Subjects who meet any of the following exclusion criteria are not to be enrolled in this study: 1) Current or prior history of any of the following: a. Clinically significant illness (other than HCV) or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol; subjects currently under evaluation for a potentially clinically significant illness (other than HCV) are also excluded b. Gastrointestinal disorder or post-operative condition that could interfere with the absorption of the study drug c. Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy d. Hepatic decompensation (e.g., clinical ascites, encephalopathy, and/or variceal hemorrhage) e. Solid organ transplantation f. Significant cardiac disease g. Unstable psychiatric condition including hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within 2 years prior to Screening h. Malignancy within the 5 years prior to Screening, with the exception of specific cancers that have been cured by surgical resection (e.g., basal cell skin cancer, etc.). Subjects under evaluation for possible malignancy are not eligible i. Significant drug allergy (e.g., hepatotoxicity) 2) Screening ECG with clinically significant abnormalities 3) Subject has the following laboratory parameters at Screening: 6

7 Patient Inclusion and Exclusion Criteria, POLARIS 2 and 3 (continued) a. ALT > 10 the upper limit of normal (ULN) b. AST > 10 ULN c. Direct bilirubin > 1.5 ULN d. Platelets < 50,000/µL e. HbA1c > 8.5% f. Creatinine clearance (Crcl) < 50 ml/min as calculated by the Cockcroft-Gault equation g. Hemoglobin < 10 g/dl h. Albumin < 3 g/dl i. International Normalized Ratio of prothrombin time (INR) > 1.5 ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR POLARIS-2: 4) HCV genotype 3, as determined by the central laboratory, and the presence of cirrhosis POLARIS-3 did not have this exclusion criterion. 5) Chronic liver disease of a non-hcv etiology (e.g., hemochromatosis, Wilson s disease, alfa-1 antitrypsin deficiency, cholangitis) 6) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV) 7) Clinically-relevant alcohol or drug abuse within 12 months of Screening. A positive drug screen will exclude subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the investigator 8) Use of any prohibited concomitant medications as described in Section 5.5 of the study protocol 9) Known hypersensitivity to the study drugs, the metabolites, or formulation excipient 7

8 Table S1. Reasons for screen failure: POLARIS-2 8

9 Figure S1. Patient disposition: POLARIS screened 173 were not randomized/enrolled 943 randomized/enrolled 502 randomized/enrolled to receive sofosbuvir-velpatasvirvoxilaprevir for 8 weeks 441 randomized to receive sofosbuvir-velpatasvir for 12 weeks 501 began treatment 440 began treatment 1 discontinued treatment due to pregnancy 3 discontinued treatment 2 due to adverse event 1 lost to follow-up 500 completed treatment 437 completed treatment 501 assessed for efficacy 440 assessed for efficacy 9

10 Table S2. Reasons for screen failure: POLARIS-3 10

11 Figure S2. Patient disposition: POLARIS screened 95 were not randomized/enrolled 220 randomized/enrolled 110 randomized/enrolled to receive sofosbuvir-velpatasvirvoxilaprevir for 8 weeks 110 randomized to receive sofosbuvir-velpatasvir for 12 weeks 110 began treatment 109 began treatment 2 discontinued treatment 1 due to adverse event 1 due to lack of efficacy 110 completed treatment 107 completed treatment 110 assessed for efficacy 109 assessed for efficacy 11

12 Table S3. Characteristics of patients who relapsed in POLARIS-2 Age Sex Race BMI (kg/m 2 ) Genotype Sofosbuvir-velpatasvir-voxilaprevir for 8 weeks Cirrhosis IL28B HCV RNA Treatment history NS3 RASs* NS5A RASs* BL Relapse BL Relapse 46 M White a No TT 7.0 Naïve Q80K Q80K None None 61 F White a No CT 6.6 Naïve Q80K Q80K None None 62 M Black a Yes CT 7.0 Naïve Q80K Q80K None None 60 M White a Yes CT 6.6 Naïve Q80K Q80K None None 59 F White a No CT 6.6 Naïve Q80K Q80K None None 55 M White a No CT 7.2 Naïve Q80K Q80K None None 68 M White a Yes CT 6.1 Naïve Q80L Q80L None None 47 F A/W a No CT 6.0 Naïve V55A V55A None None 54 M White a No CT 6.4 Naïve Q80K None None None 60 M White a No CT 7.1 Naïve None None Q30Q/H Q30R, L31M 58 F White a Yes TT 6.8 Peg/Rbv None None None None 56 M White a No CT 6.5 Peg/Rbv None None None None 62 F White a Yes CT 7.1 Peg/Rbv None None None None 62 M Black a No TT 6.8 Naïve None None None None 63 F White b No CT 6.7 Naïve None None L31M L31M 64 M Black b Yes TT 6.6 Peg/Rbv None None L31M L31M 60 M White a No CT 5.5 Naïve None None L31M L31M 72 M White c No CC 7.2 Peg/Rbv None None T24S T24S 56 F White a No CT 6.1 Peg/Rbv None None None None 53 M White d Yes CC 7.2 Naïve None None L30R L30R 63 M White a No CT 7.1 Peg/Rbv D168D/E None None None 62 a M White a Yes TT 6.2 Naive None None None None Sofosbuvir-velpatasvir for 12 weeks 60 M PI a Yes CT 6.1 Naïve None None None Y93N 55 M White b No CC 7.2 Naïve None None L31M,Y93H L31M,Y93H 74 F White a No CT 6.4 Naïve None None None None 33 b M White a No CT 5.2 Naive Q41H None M28V None A/W=Asian White; PI=Pacific Islander; Peg/Rbv=peginterferon + ribavirin; BL=baseline; BMI=body mass index. *Using a 15% reporting threshold. a This patient was observed to have HCV RNA<15 IU/mL at post-treatment week 12, and HCV RNA>15 IU/mL at post-treatment week 24. b This patient had genotype 1a at screening and was found to have genotype 3a at the post-treatment week 24 visit, which suggested a reinfection not a virologic relapse 12

13 Table S4. Characteristics of patients with virologic failure in POLARIS-3 Age Sex Race BMI Genotype Cirrhosis IL28B HCV RNA Treatment history NS3 RASs* NS5A RASs* BL Relapse BL Relapse Sofosbuvir-velpatasvir-voxilaprevir for 8 weeks 56 M White a Yes CT 5.8 Peg/Rbv None None None None 59 M White a Yes CT 6.2 Naïve None None None None Sofosbuvir-velpatasvir for 12 weeks 31 a M White a Yes CT 5.2 Peg/Rbv None None None Y93Y/H 61 F White a Yes CT 6.3 Peg/Rbv None None None Y93H Peg/Rbv=peginterferon + ribavirin; BL=baseline; BMI=body mass index. *Using a 15% reporting threshold. a This patient experienced virologic rebound (all others relapsed). 13

14 Table S5. SVR12 rates in POLARIS-2 and POLARIS-3 by baseline resistance POLARIS-2 POLARIS-3 8 Wk of Sofosbuvir, Velpatasvir and Voxilaprevir (N=498) 12 Wk of Sofosbuvir and Velpatasvir (N=435) 8 Wk of Sofosbuvir, Velpatasvir and Voxilaprevir (N=108) 12 Wk of Sofosbuvir and Velpatasvir (N=107) No NS3 or NS5A RASs 224/229 (98) 206/208 (99) 80/82 (98) 76/78 (97) Any NS3 or NS5A RASs 234/250 (94) 217/218 (>99) 23/23 (100) 23/23 (100) NS3 Only 100/110 (91) 97/97 (100) 2/2 (100) 4/4 (100) NS5A Only 114/120 (95) 90/91 (99) 20/20 (100) 19/19 (100) NS3 and NS5A 20/20 (100) 30/30 (100) 1/1 (100) 0 RASs Not Determined for Both NS3 and NS5A 19/19 (100) 9/9 (100) 3/3 (100) 6/6 (100) *Using a 15% reporting threshold. Patients who did not have observed virologic failure (ie, those who were lost to follow-up or withdrew consent) are excluded from this analysis. 14

15 Table S6. Serious adverse events in POLARIS-2 15

16 Table S7. Serious adverse events in POLARIS-3 16

17 Table S8. Grade 3 and 4 adverse events in POLARIS-2 17

18 Table S9. Grade 3 and 4 adverse events in POLARIS-3 18

19 Table S10. Grade 3 and 4 laboratory abnormalities in POLARIS-2 19

20 Table S10. Grade 3 and 4 laboratory abnormalities in POLARIS-2 (continued) 20

21 Table S11. Grade 3 and 4 laboratory abnormalities in POLARIS-3 21

22 Table S11. Grade 3 and 4 laboratory abnormalities in POLARIS-3 (continued) 22