Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Grebely J, Dalgard O, Conway B, et al. Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial. Lancet Gastroenterol Hepatol 2018; published online Jan 5.

2 Appendix Supplementary Table 1. SVR12 with 95% CIs n no SVR SVR SVR % (95% CI) Age 41 years (76, 99) >41 years (87, 99) Sex Female (88, 100) Male (83, 97) Frequency of alcohol consumption Never (77, 97) Weekly or less (86, 100) Greater than weekly (79, 100) OST and recent injecting (last month) at enrolment No OST, no recent injecting (62, 100) No OST, recent injecting (84, 100) OST, no recent injecting (68, 100) OST, recent injecting (81, 99) Current OST at baseline No (85, 99) Yes (83, 98) Recent injecting at baseline (last month) No (76, 100) Yes (87, 99) Frequency of injecting at baseline (last month) None (76, 100) Less than daily (83, 99) Daily or greater (81, 100) Heroin injecting at baseline (last month) No (82, 99) Yes (85, 99) Cocaine injecting at baseline (last month) No (86, 98) Yes (75, 100) Amphetamine injecting at baseline (last month) No (88, 99) Yes (74, 98) Injecting drug use during therapy (last month) No (73, 100) Yes (90, 99) Liver Fibrosis F0-F (88, 100) F2-F (76, 99) F (40, 97) Sofosbuvir-velpatasvir adherence <90% (76, 98) >90% (88, 99) Page 1 of 8

3 Supplementary Table 2. Unadjusted analysis of factors associated with SVR12 SVR n (%) No SVR n (%) Unadjusted OR (95% CI)* P Age 41 years 26 (93) 2 (7) >41 years 71 (95) 4 (5) 1.37 ( ) Sex Female 29 (100) 0 (0) NA NA Male 68 (92) 6 (8) NA NA Frequency of alcohol consumption Weekly or less 37 (90) 4 (10) Greater than weekly 37 (97) 1 (3) 4.00 ( ) Unknown 23 (96) 1 (4) 2.49 ( ) OST and recent injecting (last month) at enrolment No OST, no recent injecting 11 (92) 1 (8) No OST, recent injecting 32 (97) 1 (3) 2.91 ( ) OST, no recent injecting 14 (93) 1 (7) 1.27 ( ) 0.87 OST, recent injecting 40 (93) 3 (7) 1.21 ( ) Current OST at baseline No 43 (96) 2 (4) Yes 54 (93) 4 (7) 0.63 ( ) Recent injecting at baseline (last month) No 25 (93) 2 (7) Yes 72 (95) 4 (5) 1.44 ( ) Frequency of injecting at baseline (last month) Never 25 (93) 2 (7) Less than daily 46 (94) 3 (6) 1.23 ( ) Daily or greater 26 (96) 1 (4) 2.08 ( ) 0.56 Heroin injecting at baseline (last month) No 43 (93) 3 (7) Yes 54 (95) 3 (5) 1.26 ( ) Cocaine injecting at baseline (last month) No 84 (93) 6 (7) NA NA Yes 13 (100) 0 (0) NA NA Amphetamine injecting at baseline (last month) No 69 (96) 3 (4) Yes 28 (90) 3 (10) 0.41 ( ) Injecting drug use during therapy (last month) No 17 (94) 1 (6) Yes 80 (96) 3 (4) 1.57 ( ) Liver Fibrosis F0-F1 57 (97) 2 (3) F2-F3 25 (93) 2 (7) 0.44 ( ) F4 7 (78) 2 (22) 0.12 ( ) Sofosbuvir-velpatasvir adherence <90% 31 (91) 3 (9) >90% 66 (96) 3 (4) 2.13 ( ) Page 2 of 8

4 Supplementary Table 3. Enrolment Country Characteristics of Participants Country Australia 36 New Zealand 7 Canada 35 United States 5 Norway 5 Switzerland 10 United Kingdom 5 Total 103 n Page 3 of 8

5 Supplementary Table 4. Further information on participants who discontinued therapy, were lost to follow-up, or became reinfected Sex Age Region Injecting drug use prior to event Last visit week Reason for discontinuation Male 33 Australia <daily, >weekly Baseline Unknown could not be located after baseline visit Male 42 Australia <weekly, >monthly Week 3 Death illicit drug overdose Male 43 Australia <weekly, >monthly Week 8 Moved interstate and could not be located Male 38 Australia <weekly, >monthly Week 12 Unknown could not be located after week 12 visit Male 54 Australia <weekly, >monthly Week 12 Unknown could not be located after week 12 visit Male 55 Canada >3 times per day NA NA Page 4 of 8

6 Supplementary Table 5. Participant recruitment by site. Number of participants Site Country Principal Investigator enrolled Vancouver Infectious Diseases Clinic (VIDC) Canada Brian Conway 8 Coolaid Community Health Clinic Canada Chris Fraser 7 Auckland Hospital New Zealand Ed Gane 7 St. Vincent's Hospital Australia Gail Matthews 6 Royal Adelaide Hospital Australia David Shaw 5 The Alfred Hospital Australia Margaret Hellard 5 Hunter Pharmacotherapy Australia Adrian Dunlop 5 Nepean Hospital Australia Martin Weltman 5 Footscray Hospital Australia Ian Kronborg 5 Kirketon Road Centre Australia Phillip Read 5 Akershus University Hospital Norway Olav Dalgard 5 Bern Inselspital Switzerland Maria Christine Thurnheer 5 ARUD, Zurich Switzerland Philip Bruggmann 5 Ninewells Hospital UK John Dillon 5 Centre Hospitalier de l Université de Montréal (CHUM) Canada Julie Bruneau 5 Ottawa Hospital Canada Curtis Cooper 5 South Riverdale Community Health Centre Canada Jeff Powis 5 Toronto General Hospital Canada Jordan Feld 5 Einstein Wellness Centre USA Alain Litwin 5 Page 5 of 8

7 Protocol Steering Committee Gregory Dore (Chair), Philip Bruggmann (Arud Centres for Addiction Medicine, Zurich, Switzerland), Jason Grebely (UNSW Sydney, Sydney, Australia), Philippa Marks (UNSW Sydney, Sydney, Australia), Julie Bruneau (Centre Hospitalier de l'université de Montréal, Canada), Tracy Swan (Médecins Sans Frontières, New York, United States), Olav Dalgard (Akershus University Hospital, Oslo, Norway), Jude Byrne (Australian Injecting & Illicit Drug Users League), Melanie Lacalamita (Poliklinik für Infektiologie, Inselspital, Bern, Switzerland) and Adrian Dunlop (Newcastle Pharmacotherapy Service, Newcastle, Australia). Coordinating Centre Sophie Quiene (Study Co-ordinator), Evan Cunningham (PhD Student), Behzad Hajarizadeh (Lecturer), Gregory Dore (co-principal Investigator), Jason Grebely (co-principal Investigator), Philippa Marks (Clinical Trials Manager), Ineke Shaw (Systems Manager), Sharmila Siriragavan (Data Manager) and Janaki Amin (Statistician). Investigator List Philip Bruggmann (Arud Centres for Addiction Medicine, Zurich, Switzerland), Julie Bruneau (Centre Hôspitalier de l Université de Montréal, Montréal, Canada), Brian Conway (Vancouver Infectious Diseases Center, Vancouver, Canada ), Olav Dalgard (Akershus University Hospital, Oslo, Norway), Gail Matthews (St Vincent s Hospital, Sydney Australia), Adrian Dunlop (Newcastle Pharmacotherapy Service, Newcastle, Australia), Margaret Hellard (The Alfred Hospital, Melbourne, Australia), Jeff Powis (South Riverdale Community Health Centre, Toronto, Canada), David Shaw (Royal Adelaide Hospital, Adelaide, Australia), Maria Christine Thurnheer (Poliklinik für Infektiologie, Inselspital, Bern, Switzerland), Martin Weltman (Nepean Hospital, Penrith, Australia), Ian Kronborg (Footscray Hospital, Footscray, Australia), Curtis Cooper (The Ottawa Hospital, Ottawa, Canada), Jordan Feld (Toronto General Hospital, Toronto, Canada), Christopher Fraser (Coolaid Community Health Centre, Victoria, Canada), Alain Litwin (Montefiore Medical Centre, New York, United States), John Dillon (Ninewells Hospital, Dundee, United Kingdom), Ed Gane (Auckland Hospital, Auckland, New Zealand), Phillip Read (Kirketon Road Centre, Sydney, Australia). Site Co-ordinators Jessica Andreassen, Ingunn Melkeraaen and Merete Moen Tollefsen (Akershus University Hospital, Oslo, Norway), Catherine Ferguson (Royal Adelaide Hospital, Adelaide, Australia), Nargis Abram and Vincenzo Fragomeli (Nepean Hospital, Penrith, Australia), Susan Hazelwood and Michelle Hall (Newcastle Pharmacotherapy Service, Newcastle, Australia), Tina Horschik (Arud Centres for Addiction Medicine, Zurich, Page 6 of 8

8 Switzerland), Marie-Claire Chayer and Barbara Kotsoros (Centre Hôspitalier de l Université de Montréal, Montréal, Canada), Melanie Lacalamita (Poliklinik für Infektiologie, Inselspital, Bern, Switzerland), Kate Mason (South Riverdale Community Health Centre, Toronto, Canada), Alison Sevehon, Fiona Peet and Rebecca Hickey (St Vincent s Hospital, Sydney, Australia), Hannah Pagarigan (Vancouver Infectious Diseases Center, Vancouver, Canada), Michelle Hagenauer (The Alfred Hospital, Melbourne, Australia), Rachel Liddle (Footscray Hospital, Footscray, Australia), Miriam Muir and Jessica Milloy (The Ottawa Hospital, Ottawa, Canada), Diana Kaznowski and Lily Zou (Toronto General Hospital, Toronto, Canada), Rozalyn Milne (Coolaid Community Health Centre, Victoria, Canada), Linda Agyemang and Hiral Patel (Montefiore Medical Centre, New York, United States), Shirley Clearly and Linda Johnston (Ninewells Hospital, Dundee, United Kingdom), Victoria Oliver (Auckland Hospital, Auckland, New Zealand), Rebecca Lothian and Rosemary Gilliver (Kirketon Road Centre, Sydney, Australia). Page 7 of 8

9 SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 8 of 8

10 A phase II, open-label, single arm, multicentre, international trial of sofosbuvir and GS-5816 for people with chronic hepatitis C virus infection and recent injection drug use Protocol number: VHCRP1309 Protocol version: 3.0 Original protocol date: 31 March 2015 Name of sponsor: The Kirby Institute UNSW Australia Wallace Wurth Building (C27) Sydney NSW 2052 Australia Coordinating Principal Investigator (CPI): Medical Monitor: Professor Gregory Dore Dr Gail Matthews The Kirby Institute The Kirby Institute UNSW Australia UNSW Australia Wallace Wurth Building (C27) Wallace Wurth Building (C27) Sydney NSW 2052 Sydney NSW 2052 Australia Australia E: gdore@kirby.unsw.edu.au E: gmatthews@kirby.unsw.edu.au P: P: F: F: SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 1 of 39

11 Table of contents Protocol Synopsis... 4 Inclusion criteria... 6 Exclusion criteria... 7 Schedule of Assessments Background and rationale Study objectives Hypothesis Primary objective Secondary objective(s) Participant population Number of Participants and Participant Selection Inclusion criteria Exclusion criteria Study design Summary of study design Visit Schedule Virologic Response-Based Stopping Rule Treatment Discontinuation Criteria Treatment of participants Study Drug Adherence and Drug Accountability Prior and Concomitant Medications Study procedures Visits and Procedures Study Questionnaires Recording and reporting Adverse Events (AEs) Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events Adverse Event definition Serious Adverse Event (SAE) (including Serious Adverse Drug Reactions) Assessment of Adverse Events and Serious Adverse Events Assessment of Causality for Study Drugs and Procedures Assessment of Severity Reporting Requirements Suspected Unexpected Serious Adverse Reaction (SUSAR) Packaging, labeling, storage and accountability of clinical trial supplies Formulation Packaging and Labeling Storage and handling Dosage and administration SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 2 of 39

12 9.0 Biological samples Laboratory supplies and sample processing Shipping of biological samples Future use of biological samples Statistics Data Safety and Monitoring Board (DSMB) Data collection, source documents and record retention Submission of data Linkage of data Archiving Ethics committee/regulatory approval and informed consent Confidentiality of data Governance Quality Control (QC) and Quality Assurance (QA) Publication Policy List of References Abbreviations List SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 3 of 39

13 Protocol Synopsis Title SIMPLIFY A phase II, open-label, single arm, multicentre, international trial of Protocol registration no. sofosbuvir and GS-5816 for people with chronic hepatitis C virus infection and recent injection drug use ClinicalTrials.gov Identifier: NCT Background and rationale Background/Rationale: In the developed world, 50-80% of hepatitis C virus (HCV) infection occurs among people who inject drugs (PWID), both former and current 1. Hereafter, PWID will refer to people with current or "active" injecting drug use which is generally defined as use within the previous six months and to former injectors who are still active non-injecting drug users and/or on opioid substitution therapy (OST). Chronic HCV results in an increased incidence of liver cirrhosis after years; an ageing cohort of PWID means that a large burden of advanced liver disease is anticipated in the next decade 2. Initial HCV treatment guidelines excluded PWID, due to concerns about poor adherence, adverse events and re-infection 3. Successful HCV treatment studies among PWID challenged this paradigm 4-35 and guidelines have been revised to consider HCV treatment among PWID on a case-by-case basis Despite revised guidelines, few PWID have received HCV treatment Enhanced HCV assessment and treatment in PWID will be required to reduce future HCV-related morbidity and mortality 43. Treatment of chronic HCV with pegylated interferon-alfa (PEG- 4, 6-9, IFN)/ribavirin is safe and effective among those with a history of IDU and among active PWID 44, with 54-56% attaining an SVR 4, 34, 44, which is similar to results from large clinical trials among non-pwid. However, the majority of studies in this area have been limited by small sample sizes and retrospective study designs. Factors independently associated with lower SVR among PWID include poor social functioning 7, a history of untreated depression 33 and ongoing drug use during treatment 33. In 29, 35, 45, 46 addition, several studies in PWID, have shown that adherence SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 4 of 39

14 and treatment completion 45 are associated with SVR. ACTIVATE is an international network of 17 sites across seven countries with experience in the treatment of HCV infection among PWID. The first clinical trial from this collaborative network is a phase IV, open-label, multicentre, international trial of response guided treatment with directly observed pegylated interferon alfa 2b and self-administered ribavirin for 93 patients with chronic HCV genotype 2 or 3 infection and recent injection drug use or receiving OST. However, therapy with PEG- IFN and ribavirin is associated with considerable side-effects, complicating therapy among PWID. The Gilead Sciences IFN-free dual DAA regimen of sofosbuvir 400 mg once-daily (SOF, nucleotide polymerase inhibitor) and GS mg once-daily (NS5A inhibitor) has demonstrated high efficacy (95-96% SVR12) with a treatment duration of 12 weeks in treatment-naïve patients with HCV genotypes 1-6 and is currently in phase III evaluation as a 12 week regimen. The availability of a simplified IFN-free DAA-based once-daily regimen of sofosbuvir/gs-5816 should considerably enhance the capacity to scale-up HCV treatment among PWID. Hypothesis: Once-daily sofosbuvir/gs-5816 treatment will lead to sustained virological response of 90% among people with chronic HCV infection and recent injection drug use. Study objectives Primary Objective: The primary objective is to evaluate the proportion of patients with undetectable HCV RNA at 12 weeks post end of treatment (SVR12) following SOF/GS-5816 therapy for 12 weeks in people with chronic HCV infection and recent injection drug. Secondary Objectives: To evaluate the proportion adherent to therapy (both ontreatment adherence and treatment discontinuation); To evaluate the association between adherence and response to treatment [including an evaluation of the impact of early (0-3 weeks), mid (4-7 weeks) and late (8-11 weeks) missed doses on SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 5 of 39

15 response to therapy]; To evaluate factors associated with on-treatment adherence >90% and treatment discontinuation; To evaluate the proportion of participants with undetectable HCV RNA at the end of treatment (ETR); To evaluate safety and tolerability; To evaluate the change in drug use during treatment; To evaluate the change in mental health during treatment; To evaluate the change in health-related quality of life during treatment; To evaluate mixed HCV infection at baseline and among those with treatment non-response; To evaluate the rate of HCV reinfection during and up to two years following treatment; To evaluate immunovirological factors associated with treatment clearance; To evaluate the utility of dried blood spot as a simple method for monitoring HCV including treatment response. Participant population A total of 100 people with recent injection drug use will be enrolled. Inclusion criteria Subjects must meet all of the following inclusion criteria to be eligible to participate in this study. 1 Participants have voluntarily signed the informed consent form years of age or older. 3 Chronic HCV infection as defined by anti-hcv antibody or HCV RNA detection for greater than 6 months. 4 HCV RNA plasma 1000 IU/ml at Screening. 5 HCV genotypes Recent injecting drug use (previous 6 months). 7 Compensated liver disease. Enrolment of patients with cirrhosis (Fibroscan >14.6 kpa or FIB-4 > 3.25) will be capped to 40% of the total enrolment (maximum 2 per site). 8 Participants with Fibroscan >12 KPa or AFP >50 ng/ml must have an abdominal ultrasound or CT scan without evidence of hepatocellular carcinoma within 2 months prior to screening. SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 6 of 39

16 9 Negative pregnancy test at baseline (females of childbearing potential only) 10 All fertile males and females must be using effective contraception during treatment and during the 30 days after treatment end. Exclusion criteria Subjects who meet any of the exclusion criteria are not to be enrolled in this study. 1 History of any of the following: a. Clinically significant illness (other than HCV) or any other major medical disorder that may interfere with the participant treatment, assessment or compliance with the protocol; participants currently under evaluation for a potentially clinically significant illness (other than HCV) are also excluded. b. Clinical hepatic decompensation (i.e. ascites, encephalopathy or variceal haemorrhage) c. Solid organ transplant d. Malignancy within 5 years prior to screening, with exception of specific cancers that may have been cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for possible malignancy are also excluded. e. Significant drug allergy (such as anaphylaxis or hepatotoxicity). 2 Screening ECG with clinically significant abnormalities 3 Any of the following lab parameters at screening: a. ALT > 10 x ULN b. AST > 10 x ULN c. Direct bilirubin > 1.5 x ULN d. Platelets < 50,000/μL e. HbA1c > 8.5% f. Creatinine clearance (CL cr ) < 60 ml/min g. Haemoglobin < 11 g/dl for females ; < 12 g/dl for males h. Albumin < 30g/L i. INR > 1.5 ULN unless subject has known haemophilia or is SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 7 of 39

17 stable on an anticoagulant regimen affecting INR 4 Pregnant or nursing female. 5 HIV infection or HBV infection (HBcAb and HBsAg positive) 6 Use of prohibited concomitant medications as described in section Chronic use of systemically administered immunosuppressive agents (e.g. prednisone equivalent > 10 mg/day) 8 Known hypersensitivity to GS-5816, SOF or formulation excipients. 9 Therapy with any anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) *6 months prior to the first dose of study drug. 10 Any investigational drug 6 weeks prior to the first dose of study drug. 11 Previous therapy with sofosbuvir or an NS5A inhibitor prior to the first dose of study drug. 12 Ongoing severe psychiatric disease as judged by the treating physician. 13 Frequent injecting drug use that is judged by the treating physician to compromise treatment safety. 14 Inability or unwillingness to provide informed consent or abide by the requirements of the study. Study design This study will be conducted as a single arm, open-label, phase II, multicentre, international trial. There will be a maximum screening period of 6 weeks. Participants will be treated for 12 weeks with SOF/GS-5816 and then followed up for 24 weeks following their final dose of study medication. Treatment of participants Participants will receive 12 weeks of SOF/GS-5816 in an oral once-daily fixed dose combination. Therapy will be administered in weekly electronic blister packs for monitoring of adherence (a $10 incentive will be offered for the return of empty blister packs containing the electronic information). Study procedures Statistics Refer to the Study Schedule of Assessments Sample Size Assuming an SVR12 of 90%, a sample size of 100 people will provide SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 8 of 39

18 a 95% confidence interval of 82-95%. Assessments of efficacy Primary endpoints: 1. SVR12 defined as the proportion of patients with undetectable HCV RNA at 12 weeks post end of treatment (week 24). Secondary endpoints: 1. Proportion adherent to therapy (on-treatment adherence and treatment discontinuation). 2. SVR4 defined as the proportion of patients with undetectable HCV RNA at 4 weeks post end of treatment (week 16). 3. ETR defined as the proportion of patients with undetectable HCV RNA at the end of treatment (week 12) 4. SVR24 defined as the proportion of patients with undetectable HCV RNA at 24 weeks post the end of treatment (week 36). 5. Change in illicit drug use during treatment; 6. Change in mental health during treatment; 7. Change in health-related quality of life during treatment; 8. Rate of HCV reinfection during and up to two years following treatment. Assessments of safety Safety endpoints: 1. Adverse event rate and profile will be monitored for: a. Incidence of moderate or severe depression 2. Other laboratory tests will be monitored for: a. Incidence of anemia, leucopenia and thrombocytopenia b. Incidence of infections SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 9 of 39

19 Schedule of Assessments Assessment / Procedure Screening Baseline Study Treatment (weeks) Follow-up (weeks) Study weeks -6 to (Sub-study) 2 (vrvr) 4 (RVR) 8 12 Study Days -42 to Visit Window (Days) +/- 3 +/- 3 +/- 3 +/- 3 +/- 3 +/- 3 +/- 14 +/- 14 +/- 14 +/- 14 +/- 14 Informed consent, medical history x Vital signs & physical measurements x x x x x x x x x x x x HCV-RNA testing (Local Laboratory) x x x x b x x HCV genotyping Behavioural survey x x Abbreviated behavioural survey x x x x x x x x x Adherence survey and pill count x x x Mental health survey (Kessler10) x x x x Health outcomes survey (EQ-5D) x x x x Liver function tests/ Full blood count/ Biochemistry x x x x x x x x x Clotting (INR) Thyroid function tests 12-lead ECG HIV & HBV serology HbA1c x x x x x Pregnancy Test (serum or urine) x x x x x x Adverse events x x x x x x Concomitant medication x x x x x x Research Sample (EDTA plasma and Whole Blood) x a x a x x x x x x x x x x Research Sample (Dried Blood Spot) Sub-study only x S x S x S x S x S x S x S x S x S x S x S x S Research Sample (PBMCs) Sub-study only x S x S x S x S x S x S x S x r x r x r x r a Whole Blood at Screening and Baseline only, b only required if week 4 local HCV RNA >LLOQ (quantifiable), s to be conducted at sub-study sites only, r to be collected in patients with suspected relapse/reinfection at sub-study sites only (ETR) 16 (SVR4) 24 (SVR12) 36 (SVR24) 60 (FU1) 84 (FU2) 108 (FU3) SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 10 of 39

20 1.0 Background and rationale In the developed world, 50-80% of hepatitis C virus (HCV) infection occurs among people who inject drugs (PWID), both former and current 1. Hereafter, PWID will refer to people with current or "active" injecting drug use which is generally defined as use within the previous six months and to former injectors who are still active non-injecting drug users and/or on opioid substitution therapy (OST). The natural history of HCV with an increase in liver cirrhosis after years and an ageing cohort of PWID means that a large burden of advanced liver disease is anticipated in the next decade 2. Further, HCV transmission continues to occur among PWID 47. Targeted treatment to those potentially at higher risk of transmission could potentially be used to inform strategies for the implementation of public health and treatment-asprevention interventions at a population level. Initial HCV treatment guidelines excluded PWID, due to concerns about poor adherence, adverse events and re-infection 3. Successful HCV treatment studies among PWID challenged this paradigm 4-35 and guidelines have been revised to consider HCV treatment among PWID on a case-by-case basis Despite revised guidelines, few PWID have received HCV treatment Enhanced HCV assessment and treatment in PWID will be required to reduce future HCV-related morbidity and mortality 43. Treatment of chronic HCV with pegylated interferon-alfa (PEG-IFN)/ribavirin is safe and effective among those with a history of IDU 4, 6-9, and among active PWID 44, with 54-56% attaining an SVR 4, 34, 44. Factors independently associated with lower SVR among PWID include poor social functioning 7, a history of untreated depression 33 and ongoing drug use during treatment 33. Among PWID, adherence 29, 35, 45, 46 and treatment completion 45 are also associated with SVR. However, the majority of studies in this area have been limited by small sample sizes and retrospective study designs. ACTIVATE is an international network of 17 sites across seven countries with experience in the treatment of HCV infection among PWID. The first clinical trial from this collaborative network is a phase IV, openlabel, multicentre, international trial of response guided treatment with directly observed pegylated interferon alfa 2b and self-administered ribavirin for 93 patients with chronic HCV genotype 2 or 3 infection and recent injection drug use or receiving OST. However, therapy with PEG-IFN and ribavirin is associated with considerable side-effects, complicating therapy among PWID. In the next 2-5 years, simple (once-daily), tolerable, short-duration (6-12 weeks) directly acting antiviral (DAA) treatments with extremely high efficacy (cure >90%) should be the standard of care. The Gilead Sciences IFN-free dual DAA regimen of sofosbuvir 400 mg once-daily (SOF, nucleotide polymerase inhibitor) and GS mg once-daily (NS5A inhibitor) has demonstrated high efficacy SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 11 of 39

21 (95-96% SVR12) with a treatment duration of 12 weeks in treatment-naïve patients with HCV genotypes 1-6 and is currently in phase III evaluation as a 12 week regimen. The availability of a simplified IFN-free DAA-based once-daily regimen of sofosbuvir/gs-5816 should considerably enhance the capacity to scaleup HCV treatment among PWID. 2.0 Study objectives 2.1 Hypothesis Once-daily sofosbuvir/gs-5816 treatment will lead to sustained virological response of 90% among people with chronic HCV infection and recent injection drug use. 2.2 Primary objective To evaluate the proportion of patients with undetectable HCV RNA at 12 weeks post end of treatment (SVR12) following sofosbuvir/gs-5816 therapy for 12 weeks in people with chronic HCV infection and recent injection drug use. 2.3 Secondary objective(s) To evaluate the proportion adherent to therapy (both on-treatment adherence and treatment discontinuation); To evaluate the association between adherence and response to treatment [including an evaluation of the impact of early (0-3 weeks), mid (4-7 weeks) and late (8-11 weeks) missed doses on response to therapy]; To evaluate factors associated with on-treatment adherence >90% and treatment discontinuation; To evaluate the proportion of participants with undetectable HCV RNA at the end of treatment (ETR); To evaluate safety and tolerability; To evaluate the change in drug use during treatment; To evaluate the change in mental health during treatment; To evaluate the change in health-related quality of life during treatment; To evaluate mixed HCV infection at baseline and among those with treatment non-response; To evaluate the rate of HCV reinfection during and up to two years following treatment; To evaluate immunovirological factors associated with treatment clearance; To evaluate the utility of dried blood spot as a simple method for monitoring HCV including treatment response. SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 12 of 39

22 3.0 Participant population 3.1 Number of Participants and Participant Selection 100 subjects will be enrolled in this study from drug and alcohol clinics, tertiary liver and infectious diseases clinics and community health centres across the United States, Canada, Europe, New Zealand and Australia. The Kirby Institute may close or suspend screening prior at to reaching 100 participants in order to manage the total study enrolment numbers. 3.2 Inclusion criteria Subjects must meet all of the following inclusion criteria to be eligible to participate in this study. 1 Participants have voluntarily signed the informed consent form years of age or older. 3 Chronic HCV infection as defined by anti-hcv antibody or HCV RNA detection for greater than 6 months. 4 HCV RNA plasma 1000 IU/ml at Screening. 5 HCV genotypes Recent injecting drug use (previous 6 months). 7 Compensated liver disease. Enrolment of patients with cirrhosis (Fibroscan >14.6 kpa or FIB-4 > 3.25) will be capped to 40% of the total enrolment (maximum 2 per site). 8 Participants with Fibroscan >12 KPa or AFP >50 ng/ml must have an abdominal ultrasound or CT scan without evidence of hepatocellular carcinoma within 2 months prior to screening. 9 Negative pregnancy test at baseline (females of childbearing potential only). 10 All fertile males and females must be using effective contraception during treatment and during the 30 days after treatment end. 3.3 Exclusion criteria Subjects who meet any of the exclusion criteria are not to be enrolled in this study. 1 History of any of the following: a. Clinically significant illness (other than HCV) or any other major medical disorder that may interfere with the participant treatment, assessment or compliance with the protocol; participants currently under evaluation for a potentially clinically significant illness (other than HCV) are also excluded. b. Clinical hepatic decompensation (i.e. ascites, encephalopathy or variceal haemorrhage) c. Solid organ transplant d. Malignancy within 5 years prior to screening, with exception of specific cancers that may have been cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for possible malignancy are also excluded. SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 13 of 39

23 e. Significant drug allergy (such as anaphylaxis or hepatotoxicity). 2 Screening ECG with clinically significant abnormalities 3 Any of the following lab parameters at screening: a. ALT > 10 x ULN b. AST > 10 x ULN c. Direct bilirubin > 1.5 x ULN d. Platelets < 50,000/μL e. HbA1c > 8.5% f. Creatinine clearance (CL cr ) < 60 ml/min g. Haemoglobin < 11 g/dl for females ; < 12 g/dl for males h. Albumin < 30g/L i. INR > 1.5 ULN unless subject has known haemophilia or is stable on an anticoagulant regimen affecting INR 4 Pregnant or nursing female. 5 HIV infection or HBV infection (HBcAb and HBsAg positive) 6 Use of prohibited concomitant medications as described in section Chronic use of systemically administered immunosuppressive agents (e.g. prednisone equivalent > 10 mg/day) 8 Known hypersensitivity to GS-5816, SOF or formulation excipients. 9 Therapy with any anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) 6 months prior to the first dose of study drug. 10 Any investigational drug 6 weeks prior to the first dose of study drug. 11 Previous therapy with sofosbuvir or an NS5A inhibitor prior to the first dose of study drug. 12 Ongoing severe psychiatric disease as judged by the treating physician. 13 Frequent injecting drug use that is judged by the treating physician to compromise treatment safety. 14 Inability or unwillingness to provide informed consent or abide by the requirements of the study. 4.0 Study design 4.1 Summary of study design This study will be conducted as a single arm, open-label, phase II, multicentre, international trial. A total of 100 people with recent injection drug use will be enrolled. The study consists of a screening phase (6 weeks), treatment phase (12 weeks) and follow-up phase (96 weeks) to evaluate treatment response and reinfection (Figure 1). SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 14 of 39

24 Several sites will be selected to participate in the SIMPLIFY sub-study which involves the collection of additional research samples from consenting participants as specified in the schedule of assessments. Figure 1: Study schema 4.2 Visit Schedule All participants will complete screening, on-treatment and post-treatment assessments as outlined in the Schedule of Assessments and described in Section 6.0. Screening assessments must be completed within 6 weeks prior to Baseline. Following Screening and Baseline, on-treatment visits will be conducted at weeks 2 (vrvr), 4 (RVR), 8 and 12 (ETR). Post treatment visits will be conducted at weeks 16 (SVR4) 24 (SVR12), 36 (SVR24), 60 (FU1), 84 (FU2) and 108 (FU3). 4.3 Virologic Response-Based Stopping Rule The following on-treatment virologic response-based treatment stopping criteria will be used: SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 15 of 39

25 HCV RNA LLOQ (detected and quantifiable) at 8 weeks of treatment 4.4 Treatment Discontinuation Criteria Study drug must be discontinued in the following instances: Virologic failure as defined in Section 4.3 Unacceptable toxicity Pregnancy of female subject Significant protocol violation Participant request to discontinue for any reason Discontinuation of the study by the Kirby Institute, regulatory agencies or a Human Research Ethics Committee / Research Ethics Committee / Institutional Review Board All subjects who terminate early will complete the ETR visit and post-treatment weeks 4 (SVR4), 12 (SVR12), 36 (SVR24) and six-monthly post SVR follow-up visit weeks 60 (FU1), 84 (FU2) and 108 (FU3). Participants who cease study medication will, wherever possible, continue to be followed up according to the protocol study plan. Participants may revoke consent for follow-up without jeopardizing their relationship with either their doctor or the UNSW. If a participant revokes consent then, if possible, all assessments scheduled for the final visit should be completed. 5.0 Treatment of participants Participants will receive 12 weeks of open-label sofosbuvir/gs5816 (400 mg/100mg daily) in an oral oncedaily fixed dose combination. Dose modifications are prohibited. 5.1 Study Drug Adherence and Drug Accountability Therapy will be administered in weekly electronic blister packs for monitoring of adherence (a $10 incentive will be offered for the return of empty blister packs containing the electronic information). The electronic blister pack has an integrated sensor grid which allows for the recording of medication adherence. Information on compliance can then be downloaded using a specific reader following the return of the blister pack. Study drug will be reconciled using a pill count on all returned blister packs. Participants will also be required to complete an adherence questionnaire as described in Section 6.2. SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 16 of 39

26 5.2 Prior and Concomitant Medications Concomitant medication must be recorded in the source documents and ecrf from screening until the last dose of study medication. The following medications are prohibited from six weeks prior to the baseline visit through to the end of treatment: Haemotologic stimulating agents (e.g. erythropoiesis-stimulating agents (ESAs); granulocyte colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics) Chronic systemic immunosuppressants including, but not limited to, corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonals antibodies (e.g. infliximab) Investigational agents or devices for any indication Drugs disallowed per prescribing information of SOF Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of drug transporters i.e. P-gp) with study drug may result in pharmacokinetic interactions resulting in increases or decreases in exposure of study drug or these medications. The use of the Disallowed agents in Table 1 is prohibited from 21 days prior to Baseline through to the end of treatment except Amiodarone which is prohibited from 60 days prior to Baseline through to the end of treatment. Examples of representative medication which are prohibited or are used with caution are listed below: Table 1: List of Disallowed Medications Drug Class Agents Disallowed Use with Caution Acid Reducing Agents a Proton-Pump Inhibitors H2-Receptor Antagonists, Antacids Anticonvulsants b Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine Antimycobacterials b Rifabutin, Rifapentine, Rifampin Cardiac Medications c Amiodarone e Diltiazem, Verapamil, Dronedarone, Ranolazine, Bosentan, Olmesartan, Valsartan, Quinidine, Digoxin d Herbal/Natural Supplements b St. John s Wort, Echinaccea, Milk Thistle (i.e. silymarin), Chinese herb Sho-Saiko-To (or Xiao-Shai-Hu-Tang) HMG-CoA Reductase Rosuvastatin ( 10 mg/day), Atorvastatin, Inhibitors d Simvastatin, Pravastatin, Pitavastatin, Fluvastatin, Lovastatin Other Modafinil b, sulfasalazine c, methotrexate c a The 21 day washout period does not apply to Proton-Pump Inhibitors, which can be taken up to 7 days before Baseline. H2- receptor Antagonists must not exceed a dose of 20 mg famotidine or equivalent and can be taken simultaneously with SOF/GS and/or staggered by 12 hours. Antacids that directly neutralize stomach acid (i.e. Tums, Maalox) may not be taken within 4 hours (before or after) of SOF/GS-5816 administration. b May result in a decrease in the concentration of study drugs SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 17 of 39

27 c may result in an increase in the concentration of study drugs and/or concomitant medications; monitor for signs and symptoms of digoxin toxicity d Use with SOF/GS-5816 may result in an increase in the concentration of HMG-CoA Reductase Inhibitors. Monitor for signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis e 60 day washout period applies. Should any participant need to initiate treatment with any excluded concomitant medication during the study, the Medical Monitor, Dr Gail Matthews must be consulted prior to the initiation of any excluded medication. In the event that an excluded medication is initiated prior to discussion with Dr Gail Matthews, she must be made aware of the use of the excluded medication as soon as possible. Dr Gail Matthews contact details are listed on the cover of this protocol. 6.0 Study procedures 6.1 Visits and Procedures The following assessments must be conducted at study visits as per the schedule of assessments: Vital signs & physical measurements Biochemistry Sitting systolic and diastolic blood pressure, heart rate, body weight a, height a Creatinine, glucose, sodium, chloride, and potassium, creatine kinase Liver Function Tests ALT, AST, GGT, total bilirubin, albumin, alkaline phosphatase, total protein Full Blood Count Haemoglobin, haematocrit, White Blood Cells, platelets, neutrophils Clotting INR Thyroid Function Tests TSH, T4Free ECG 12-lead ECG Glycated haemoglobin HbA1c HCV RNA Must be quantitative at Screening and Week 8 HCV Genotype Within 12 months prior to screening HBV Serology Anti-HBc, HBsAg HCG Pregnancy Test For women of childbearing potential, a negative urine (or serum) HCG test at screening and baseline Questionnaires Behavioural survey, abbreviated behavioural survey, adherence questionnaire, Kessler10, EQ-5D SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 18 of 39

28 a at screening only The following assessments and procedures must be performed at each visit as specified below: Initial screening period (Week -6 to Week 0) Informed consent Medical history Vital signs and physical examination HCV RNA and genotype (Local laboratory) LFTs, FBC and biochemistry 12-lead ECG Clotting - INR Thyroid function test HIV antibody & HBV serology HbA1c Pregnancy test (females of child bearing potential only) Concomitant medication Study questionnaires (Behavioural, Kessler10 and EQ-5D) Research specimen collection (EDTA plasma & whole blood) Research specimen (PBMCs & DBS) at sub-study sites only Baseline visit (Week 0) Vital signs and physical examination HCV RNA (Local laboratory) LFTs, FBC and biochemistry Pregnancy test (females of child bearing potential only) Adverse Events Concomitant medication Study questionnaires (Abbreviated Behavioural) Research specimen collection (EDTA plasma & whole blood) Research specimen (PBMCs & DBS) at sub-study sites only On-Treatment Visits Week 1 (+/- 3 days) At Sub-study sites only Research specimen (PBMCs & DBS) at sub-study sites only Week 2 (+/- 3 days) SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 19 of 39

29 Vital signs and physical examination LFTs, FBC and biochemistry Adverse Events Concomitant medication Research specimen collection (EDTA plasma) Research specimen (PBMCs & DBS) at sub-study sites only Week 4 (+/- 3 days) Vital signs and physical examination HCV RNA (Local laboratory) LFTs, FBC and biochemistry Adverse Events Concomitant medication Study questionnaires (Abbreviated Behavioural & Adherence) Adherence Survey and pill count Research specimen collection (EDTA plasma) Research specimen (PBMCs & DBS) at sub-study sites only Week 8 (+/- 3 days) Vital signs and physical examination HCV RNA (Local laboratory) Only if Week 4 HCV RNA >LLOQ LFTs, FBC and biochemistry Adverse Events Concomitant medication Study questionnaires (Abbreviated Behavioural & Adherence) Adherence Survey and pill count Research specimen collection (EDTA plasma) SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 20 of 39

30 End of Treatment (ETR) - Week 12 (+/-3 days) Vital signs and physical examination HCV RNA (Local laboratory) LFTs, FBC and biochemistry Adverse Events Concomitant medication Study questionnaires (Abbreviated Behavioural, Adherence, EQ-5D and Kessler10) Adherence Survey and pill count Research specimen collection (EDTA plasma) Research specimen (PBMCs & DBS) at sub-study sites only Post Treatment Follow-up Visits Post Treatment Week 4 (SVR4) - Week 16 (+/- 3 days) Vital signs and physical examination LFTs, FBC and biochemistry Adverse Events Research specimen collection (EDTA plasma) Post Treatment Week 12 (SVR12) - Week 24 (+/- 14 days) Vital signs and physical examination HCV RNA (Local laboratory) LFTs, FBC and biochemistry Study questionnaires (Abbreviated Behavioural, EQ-5D and Kessler10) Research specimen collection (EDTA plasma) Research specimen (PBMCs & DBS) at sub-study sites only Post Treatment Week 24 (SVR24) - Week 36 (+/- 14 days) Vital signs and physical examination LFTs, FBC and biochemistry Study questionnaires (Abbreviated Behavioural) Research specimen collection (EDTA plasma) Research specimen (PBMCs & DBS) at sub-study sites only if suspected relapse/reinfection Post Treatment Weeks 60 (FU1), 84 (FU2) and 108 (FU3) (+/- 14 days) SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 21 of 39

31 Vital signs and physical examination Study questionnaires (Abbreviated Behavioural (all), EQ-5D (FU3 only) and Kessler10 (FU3 only)) Research specimen collection (EDTA plasma) Research specimen (PBMCs & DBS) at sub-study sites only if suspected relapse/reinfection 6.2 Study Questionnaires All subjects will undertake a number of study questionnaires at screening, baseline, and selected followup visits. The Behavioral Questionnaire The study staff will assist participants to complete this questionnaire. The SIMPLIFY behavioural survey will collect information on the following: Demographics HIV and drug treatment history Drug and alcohol usage Injecting risk behaviors Treatment acceptance and willingness (prior to treatment commencement only) Attitudes and behaviours associated with HCV reinfection An abbreviated behavioural questionnaire (follow-up) will be administered at subsequent time points during the study. Mental Health Survey (Kessler10) The Kessler (K10) measure is a 10-item self-report questionnaire intended to yield a global measure of "psychological distress" based on questions about the level of anxiety and depressive symptoms in the most recent 4-week period. Health Outcomes Survey (EQ-5D) The EQ-5D health questionnaire provides a simple descriptive profile and a single index value for health status. This information can then be translated into a health utility, which can be used for costeffectiveness analyses. SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 22 of 39

32 Adherence Survey Adherence to SOF/GS-5816 will be assessed by a weekly structured self-report adherence questionnaire and weekly pill count. 7.0 Recording and reporting Adverse Events (AEs) 7.1 Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events Adverse Event definition Adverse events and adverse drug reactions may occur in the course of this study and within the specified follow-up period. These events may also occur in screened participants during the screening period prior to enrolment as a result of protocol-specified interventions. All such events will be recorded at each study visit on the adverse event case report form. The definition of an adverse event is any untoward medical occurrence in a participant administered with a pharmaceutical product which does not necessarily have a causal relationship with the product. Pre-existing conditions or diseases that occur during the study (e.g. seasonal allergies, asthma or recurrent headaches) should not be considered as adverse events unless they change in frequency or severity. All adverse events encountered during treatment and for 4 weeks after drug discontinuation must be reported on the Adverse Event Page of the case report form (CRF). Laboratory test abnormalities as such should not be reported as adverse events unless they result in a clinically relevant condition including but not limited to modification or discontinuation of study drug. Overdoses without clinical sequelae should not be reported as an adverse event. SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 23 of 39

33 7.1.2 Serious Adverse Event (SAE) (including Serious Adverse Drug Reactions) The definition of a SAE is any untoward medical occurrence that at any dose: 1) Results in death 2) Is life-threatening (Note: the term life-threatening in the definition of serious refers to an event/reaction in which the participant was at risk of death at the time of event/reaction; it does not refer to an event/reaction which hypothetically might have caused death if it were more severe) 3) Requires in-patient hospitalisation or prolongation of existing hospitalisation 4) Results in persistent or significant disability/incapacity 5) Results in a congenital anomaly/birth defect 6) Results in a medically important event or reaction (includes infections from contaminated medicinal product/s) Medical and scientific judgment should be exercised in deciding whether other situations should be considered serious e.g. important medical events that may not be immediately life-threatening or result in death or hospitalisation, but may jeopardise the participant or may require intervention to prevent one of the outcomes listed in the definition above. 7.2 Assessment of Adverse Events and Serious Adverse Events Assessment of Causality for Study Drugs and Procedures The investigator or designee must assess each adverse event for the following: Relationship Unlikely: Possibly: Probably: An adverse event that is unlikely to be related to the use of the drug or procedures An adverse event that might be related to the use of the drug or procedures An adverse event that is likely to be related to the use of the drug or procedures Assessment of Severity The investigator or designee must assess each adverse event for the following: Severity Mild: Moderate: Discomfort noticed but no disruption of normal daily activity Discomfort sufficient to reduce or affect normal daily activity SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 24 of 39

34 Severe: Life threatening: Incapacitating with inability to work or perform normal daily activity Represents an immediate threat to life 7.3 Reporting Requirements Adverse Events All adverse events from the date of signing the consent form until four weeks after the last dose of study drug administration should be reported on the case report form. Coding Adverse events will be assigned preferred terms and categorised into system organ classes according to the Medical Dictionary for Drug Regulatory Affairs (MedDRA) classification of the WHO terminology Serious Adverse Events All serious adverse events (SAEs) should be reported within ONE WORKING DAY to the Kirby Institute and Gilead DPSH by or fax on the Serious Adverse Event Reporting Form. The appropriate Serious Event form should be used. Reports should be followed promptly by detailed, written follow-up reports when all information is not included in the initial report. Follow-up reports should be reported within ONE WORKING DAY also. The immediate and follow up reports should identify participants by unique code numbers assigned to study participants rather than personal identification. The investigator must also comply with all applicable ethical and regulatory requirement/s relating to the reporting of serious adverse events. Any serious adverse event that is ongoing at the post-study follow-up visit must be followed until resolution or until the event stabilizes (for those events that will not resolve). For deaths, the Principal Investigator will supply the sponsor and the IRB/IEC with any additional requested information (e.g. death certificate, autopsy reports and medical reports). SAE reports must be submitted to BOTH the Kirby Institute AND Gilead: Kirby Institute: Fax: Gilead DSPH: Safety_FC@gilead.com Fax: SIMPLIFY Protocol Version 3.0 dated 31 March 2015 Page 25 of 39