Clinical trial NCT02503735
Conditions: Hepatitis C Chronic Kidney Disease
Keywords: CKD HCV
Sponsor: Massachusetts General Hospital
Start date: 2015-07-15; Completion date: 2019-05-01
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Treatment protocol to see if people with hepatitis C (HCV) and chronic kidney disease (CKD) who are treated with Harvoni for 12 weeks have improvements in their kidney disease.

Detailed description:
The investigators hypothesize that patients with early stage (1-3) CKD caused by HCV infection will have significantly improved proteinuria and eGFR after viral eradication with 12 weeks of treatment Harvoni (LDV/SOF). This trial data will serve as the basis to support further study of LDV/SOF in patients with early CKD. Slowing progression of CKD is a critical goal, as the increasing incidence and prevalence of advanced CKD and end stage renal disease (ESRD) places significant health burden on patients and tremendous costs on our health-care system.

Arms: arm 1: 10 patients with hepatitis C (HCV) and HCV-associated CKD that will receive 12 weeks treatment with Sofosbuvir/Ledipasvir (400mg/90mg)
Interventions: intervention 1: Sofosbuvir/Ledipasvir FDC
Intervention descriptions: intervention 1: 12 weeks treatment with Harvoni

Protocol documents:
Prot_000.pdf: 
SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
1 
 
 
Clinical Study Protocol 
 
Study Title: Effect of Ledipasvir and Sofosbuvir on Proteinuria and Estimated Glomerular 
Filtration Rate in Patients with Early Stage (1-3) Hepatitis C Associated Chronic Kidney 
Disease 
 
Sponsor: Massachusetts General Hospital 
 
Indication: Hepatitis C Virus infection and Hepatitis C related chronic kidney disease 
 
Study Principle Investigator:   
 
Dr. Raymond Chung 
Phone: 617-724-7562 
Fax: 617-724-1091 
 
Dr. Meghan Sise 
Phone: 617-643-3948 
Fax: 617-724-1122 
 
Study Center: Massachusetts General Hospital 
 
Number of Subjects planned:  24 
 
Duration of treatment: Subjects will be treated for 12 or 24 weeks 
 
Protocol Version/Date: 
 
Amendment 3  30 March 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
2 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
PROTOCOL AMENDMENT 3 
 
Study IN-US-337-1777 
Effect of Ledipasvir and Sofosbuvir on Proteinuria and Estimated Glomerular Filtration 
Rate in Patients with Early Stage (1-3) Hepatitis C Associated Chronic Kidney Disease 
 
Original Protocol 
Date: 
04 May 2015 
Amendment 1 Date: 
10 June 2015 
Amendment 2 Date: 
12 August 2015 
Amendment 3 Date: 
30 March 2017 
 
 
Rationale 
Herein is a summary of the major changes made to the protocol 
Amendment 2 dated 12 August 2015 and reflected in Amendment 3 
dated 30 March 2017: 
• 
Clarification of Inclusion/Exclusion Criteria (including those 
with resected and cured thyroid cancer and excluding those 
that are HBV surface antigen positive. 
• 
Addition of 24 weeks of therapy where this is standard of care 
per AASLD guidelines. 
• 
Addition of Appendix 2, study schedule of events for 24 week 
regimen 
 
 
 
Section: 
Appendices: Appendix 2 
Original Text: 
None 
Revised Text: 
Inclusion of Appendix 2 
Rationale: 
Schedule of events included for clarification of study specific 
procedures and sample collection for 24 week regimen. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
3 
 
 
 
 
1.1 Background 
 
Infection with hepatitis C virus (HCV) affects an estimated 180 million people, and is a 
leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma.  Chronic 
kidney disease (CKD) is common in Hepatitis C virus (HCV) infected individuals. 
Between 55-85% of HCV infected patients have glomerular disease on kidney biopsy.[1, 
2] HCV is associated with accelerated rates of progression to end-stage renal disease 
(ESRD).[3] Adjusted analyses show that patients with CKD and HCV are 34-68% more 
likely to develop ESRD than non-infected patients.[4-6]  
Historically, those with CKD who achieve SVR with interferon and ribavirin 
experience improvement in estimated glomerular filtration rate (eGFR).[7-9] The new era 
of HCV therapy allows us to test the reversibility of the association between HCV 
infection and CKD. Our preliminary data in cryoglobulinemia shows that patients treated 
with sofosbuvir-based regimens who achieve SVR had a > 70% reduction in proteinuria 
and a 12.6mL/min improvement in eGFR (Sise ME, in preparation). Reduction in 
proteinuria is an important component of the definition of clinical remission in treatment 
of glomerular diseases and an accepted surrogate for CKD progression [10, 11]. 
 
For the past 3 decades, treatment of chronic infection has centered on weekly 
injections of pegylated interferon in conjunction with weight-based dosing of oral 
ribavirin, and has been successful in achieving a sustained virologic response (SVR, 
defined as an undetectable HCV RNA level 24 weeks after the cessation of antiviral 
therapy) in 40 to 50% of patients with genotype 1[12-14]. More recently, the molecular 
characterization of the life cycle of HCV has led to the development of directly acting 
antiviral agents that have resulted in improved efficacy and tolerability. The fixed-dose 
combination ledipasvir-sofosbuvir was recently approved by the Food and Drug 
Administration (FDA) for the treatment of patients with HCV genotype 1 infection, and is 
associated with SVR rates of 93% to 95% among treatment-naïve patients receiving 8-
12 weeks of therapy. [15] Ledipasvir is a potent inhibitor of NS5A, a viral protein that 
plays an important role in viral replication, assembly, and secretion; and sofosbuvir is a 
nucleotide analog inhibitor of NS5B polymerase, which mediates HCV RNA replication.   
 
Safety  
Safety data on this combination tablet have been reported in manufacturers labeling. 
Fatigue was reported by 13-18%, headache by 11-17%. Less frequent events reported 
include Insomnia (3-6%), Nausea (6-9%), diarrhea (3-7%), increased serum lipase (3x 
ULN ≤ 3%), hyperbilirubinemia 1.5x ULN ≤3% . The most frequent (greater than or equal 
to 15% overall) adverse events (AEs) on treatment were fatigue, headache and nausea.  
 
Rationale for the current study 
We hypothesize that patients with early stage (1-3) CKD caused by HCV infection will 
have significantly improved proteinuria and eGFR after viral eradication with LDV/SOF. 
This trial data will serve as the basis to support further study of LDV/SOF in patients with 
early CKD. Slowing progression of CKD is a critical goal, as the increasing incidence 
and prevalence of advanced CKD and ESRD places significant health burden on 
patients and tremendous costs on our health-care system. 
 
2. Study Design 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
4 
 
 
This prospective single-arm intervention trial assesses the effect of ledipasvir and 
sofosbuvir on kidney function in patients with hepatitis-C associated chronic kidney 
disease. There will be a screening period of up to 60 days to assess subject eligibility to 
enroll in the trial including confirmation of proteinuria (>300mg/gram creatinine). Two 
urinary measurements above 300mg/gram creatinine will be required within 30 days of 
the first dose of ledipasvir and sofosbuvir.  There will be a treatment phase lasting 12 or 
24 weeks and a follow-up phase lasting 12 months (from treatment initiation).  
 
Treatment phase:  An open label, non-randomized, 12 (or 24) week treatment period 
performed in 24 subjects assessing efficacy, safety and tolerability of a combination 
tablet of ledipasvir dosed at 90mg per day and sofosbuvir dose at 400mg per day. If an 
SAE (Grade 3 or greater event) occurs it will be reported within 24 hours to the IRB and 
the DSMB. The data safety monitoring committee will meet once during the treatment 
trial or sooner if needed based on SAE.  
 
Study Procedures 
 
Screening 
Screening will begin with obtaining the subjects signed informed consent and will occur 
up to 60 days prior to the first dosing of study drug at Day 1.  Screening procedures will 
include the following: medical history review, physical exam, vital signs, 12-lead ECG, 
prior/concomitant medication review, urine collection for pregnancy test (females < 50), 
blood collection for chemistry and hematology and coagulation and cystatin C, urine 
collection for urine protein, albumin, B2 microglobulin and creatinine measurement.  
Presence of cirrhosis will be determined by Fibroscan obtained during the screening 
period if a fibroscan or liver biopsy has not been performed in the last 12 months. 
Cirrhosis will be defined as a liver biopsy showing cirrhosis or a Fibroscan score of > 13 
kPa.   For patients with cirrhosis, liver imaging (either ultrasound or CT scan) will be 
required within 6 months of the baseline visit to access for hepatocellular carcinoma 
(HCC).  Patients with HCC will be excluded. 
 
Patients will be eligible if blood pressure is < 140/90 and stable at both screening visits. 
If blood pressure is above goal, patients will undergo medication adjustments by treating 
clinician and are eligible to be re-screened once blood pressure is < 140/90 for two 
months. Baseline protein-to-creatinine ratio will be measured twice prior to dosing Day 1 
to assess subject baseline proteinuria prior to beginning treatment. More than 50% 
variability in baseline proteinuria measurements will results in a third measurement and 
the average of all measures will be used as study baseline. Two health-related quality of 
life questionnaires (SF-36, Fatigue Index (FACIT-F)) will be administered at baseline. 
 
Treatment  
All treatment and follow-up visits will take place at MGH.  Treatment will occur over 84 
days (12 weeks).  Subjects meeting eligibility will begin ledipasvir 90mg/sofosbuvir 
400mg oral combination tablet once daily with or without food. For missed dose(s) of 
study medication, subjects will be instructed to take the missed dose of study mediation 
as soon as possible during the same day. Subjects will be cautioned never to double the 
next dose with a missed dose of study drug under any circumstances.  
 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
5 
 
Subjects will undergo visits at 2 weeks, 4 weeks, 8 weeks and 12 weeks (24 weeks as 
well for those on 24 weeks of treatment) on treatment. Safety and efficacy assessments 
will occur on an outpatient basis including physical exam, vital signs and weight, 12-lead 
ECG, details of adverse events related to procedures, details of concomitant 
medications, collection of blood samples (for chemistry, hematology, cystatin C) and 
urine samples (pregnancy for females < 50, and proteinuria, microalbuminuria, 
creatinine, and B2 microglobulin measurements). Fasting blood samples will be taken at 
four timepoints (Baseline Visit, Week 8 Visit, SVR12 visit, and 1 year follow-up visit) in 
order to assess insulin resistance, a major contributor to kidney disease risk. Patients 
will be asked to fast after midnight for at least 8 hours on the days of the four fasting 
visits. Health related quality of life questionnaires will be administered at monthly 
intervals on treatment and during all follow-up visits. The subject should read the 
questionnaire by himself/herself and write/mark answers directly onto the questionnaire. 
Study schedule of events can be found in Appendix 1. 
 
 
Study drug dosing will continue in the absence of toxicity warranting discontinuation of 
therapy for a total of 12 or 24 weeks.  
 
Treatment Discontinuation Criteria 
1. Unacceptable toxicity, or toxicity that, in the judgment of the investigator, 
compromises the ability to continue study-specific procedures or is considered to 
not be in the subjects best interest 
2. Pregnancy of a female subject 
3. Significant protocol violation 
4. Subject request to discontinue for any reason 
5. Discontinuation of the study at the request of Gilead, regulatory agency, or an 
IRB or DSMB  
6. Virologic failure – defined below 
 
Virologic Response-Based Stopping Criteria:  
The following on-treatment virologic response-based treatment stopping criteria will be 
utilized: 
- 
Confirmed HCV RNA ≥ LLOW after 2 consecutive HCV RNA < LLOQ 
- 
Confirmed > 1 log10 increase from nadir 
- 
HCV RNA ≥ LLOQ through 8 weeks of treatment 
Confirmation should be performed as soon as possible and no later than 2 weeks after 
initial observation indicating a virologic failure during the on-treatment phase.  
 
All subjects who terminate treatment early will complete an early termination visit and will 
complete all remaining follow-up visits with study measurements on the normal timeline 
as below. 
 
Study Visit Timeline 
Baseline/Screening – Two visits in 60 days prior to treatment Day 1. Baseline visit 
fasting 
Two weeks on Treatment – W2 
Four weeks on Treatment – W4 
Eight weeks on Treatment – W8 (Fasting Visit) 
Twelve weeks on Treatment – W12 
Twenty four weeks on treatment- W24 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
6 
 
Four weeks Post Treatment – W16 (or W36) 
Twelve weeks Post Treatment – W24 (or W44) (Fasting visit) 
Twenty-four weeks Post Treatment – W36 (or W56) 
1 Year follow-up – W-52 (or W64) (Fasting visit) 
 
Subject Remuneration: 
All subjects will participate in two screening visits to confirm study eligibility.  Subjects 
will be paid $10 for the initial screening visits.  Subjects will be given a parking voucher 
for each additional study visit completed.   
 
 
3. Subject Population 
 
Number of subjects: Twenty-four patients will be enrolled in this study.  
 
Inclusion Criteria 
 
1. The subject has signed the written informed consent 
2. Male or female ≥ 18 year of age 
3. HCV genotype 1 or 4 with ribonucleic acid (HCV RNA) greater than 1000IU/mL, 
determined by HCV RNA polymerase chain reaction Roche COBAS TaqMan 
quantitative assay. If historic result is older than 24 months, genotype will be 
repeated at screening visit 1. 
4. Initial diagnosis of proteinuric chronic kidney disease occurred < 7 years prior to 
completion of screening  
5. Women of childbearing potential (i.e. women who have not undergone 
hysterectomy or bilateral oophorectomy, or no medically documented ovarian 
failure, and are ≤ 50 years of age) must agree to 1 medically approved 
contraceptive measures and have their partners agree to an additional barrier 
method of contraception for the duration of the study and for 4 weeks after the 
last administration of the study drug.  Women of childbearing potential must not 
rely on hormone-containing contraceptive as a form of birth control during the 
study but may use.  An intrauterine device, female barrier methods with cervical 
cap or diaphragm with spermicidal agent, tubal sterilization, or vasectomy in male 
partners.  
6. Male subjects must agree to consistently and correctly use a condom during 
heterosexual intercourse and avoid sperm donation for the duration of this study 
and for 90 days after the last dose of ledipasvir and sofosbuvir. Additionally, if 
their female partner is of childbearing potential (as defined above), their partner 
must agree to use either 1 of the non-hormonal methods of birth control listed 
above or a hormone-containing contraceptive for 90 days after last study drug 
date.  Hormone-containing contraceptive options for partners include implants of 
levonorgestrel, injectable progresterone, oral contraceptives, contraceptive 
vaginal ring, or transdermal contraceptive pat 
7. Adequate organ function defined as follows platelets ≥ 50 x 109/L; hemoglobin ≥ 
9 g/dL, estimated glomerular filtration rate ≥ 30mL/min/1.73m2 as estimated by 
CKD-Epi equation. 
8. Liver imaging to exclude HCC is required within 6 months in any patient with 
cirrhosis.  


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
7 
 
9. Has > 300mg/g creatinine proteinuria on average of two urine samples obtained 
within 30 days of starting ledipasvir and sofosbuvir. 
 
 
 
 
Exclusion Criteria 
 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this 
study  
 
1. History of evidence of clinically significant disorder other than hepatitis C virus 
infection or clinically significant laboratory finding that in the investigator’s 
judgment would pose a risk to subject safety, interfere with study procedures, or 
prevent completion of the study.  
2. Pregnant or lactating female 
3. Uncontrolled depression or psychiatric disease interfering with the ability to 
comply with the study procedures or complete the study 
4. History or presence of any form of cancer within 3 years prior to enrollment, with 
the exception of excised basal cell or squamous cell carcinoma of the skin, stage 
0 or 1 melanoma, resected and cured thyroid cancer, or cervical carcinoma in 
site or breast carcinoma in situ that has been excised or resected completely and 
is without evidence of local recurrence or metastasis.  
5. Experience life-threatening cryoglobulinemic vasculitis requiring initiation of 
rituximab, steroids or plasmapheresis. 
6. Concomitant use of cimetidine, trimethoprim or other drugs which can increase 
tubular creatinine reabsorption 
7. Uncontrolled cardiovascular or pulmonary disease 
8. Uncontrolled hypertension 
9. Known HIV infection.   HIV testing will be performed at screening visit 1 if no 
result is available within 6 months of informed consent. 
10. Known hypersensitivity to ledipasvir or sofosbuvir 
11. Prior HCV treatment failure using a medication in the NS5A inhibitor class 
12. Individuals who are taking the following medications and require continuation of 
the medications during the proposed study period will be excluded, given known 
interactions with ledipasvir-sofosbuvir: Carbamazepine, phenytoin, phenobarbital, 
oxcarbazepine, rifabutin, rifampin, isoniazid, rifapentine, rosuvastatin, digoxin, 
modenafinil, and St. John’s wort, milk thistle, Echinacea and amiodarone.  
Subjects with a history of gastric reflux who are taking proton pump inhibotors 
(PPI) will be asked to switch to an H2 blocker with prescribing physician 
approval.  If subject continues to have reflux refractory to H2 blocker, 20mg of 
the PPI omeprazole can be given concurrently with study drug. 
13. Having an alternate explanation of chronic kidney disease, including: 
a) Diabetic kidney disease, either by biopsy findings or duration of 
uncontrolled diabetes > 8 years without serologic evidence of immune-
complex related kidney disease 
b) Chronic hypertensive nephropathy without proteinuria 
c) Lupus nephritis 
d) Multiple myeloma 
e) Obesity related proteinuria, BMI > 35 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
8 
 
f) Ongoing nephrotoxic medication use, including NSAIDS 
g) Polycystic kidney disease 
h) Kidney biopsy showing an alternate explanation for chronic kidney 
disease 
14. Positive hepatitis B surface antigen test. 
 
 
4.   Biostatistical Analysis  
 
 
Primary endpoints of the trial include: 
 
Primary Endpoint: 
1. The percent change in proteinuria [Time Frame: 24 weeks] 
 
Secondary Endpoints(s): 
1. Mean change in eGFR as measured by creatinine and cystatin C-based estimating 
equation. [Time Frame: 24 weeks] 
2. The proportion of patients achieving at least a 25% reduction in proteinuria [Time 
Frame: 24 weeks] 
3. Mean time (in weeks) to maximum reduction in proteinuria [Time Frame: 24 weeks] 
4. Mean change in renal function (creatinine based eGFR) over 12 months [Time Frame: 
52 weeks] 
5. Change in urinary β-2microglobulin levels before and after therapy with ledipasvir and 
sofosbuvir [Time Frame: 24 weeks] 
 
Other endpoints of interest 
Additional evaluations will include health related quality of life endpoints 
 
Demographics 
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by treatment group and overall.  Demographic data will include sex, self-
identified race/ethnicity, and age. Baseline characteristic data will include body mass 
index, HCV RNA level, genotype HCV infection. 
 
Primary efficacy 
During the study period, we will measures proteinuria by a ratio of the urine protein to 
urine creatinine on spot urine samples.  We will measure serum chemistries, serum 
cystatin C and urinary B-2microglobulin levels over the course of the study. These 
measurements will take place at every study visit.  
 
Safety 
Safety will be evaluated by assessment of clinical laboratory tests, physical 
examinations, vital signs measurements at various time points during the study, and by 
the documentation of AEs.  
 
All safety data collected on or after the first dose of study drug administration up to 30 
days after the last dose of study drug will be summarized  
 
 
5. Risks and Discomforts 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
9 
 
Since patients will need blood draws for each visit,  
 
Side effects for patients taking ledipasvir-sofosbuvir include the side effects associated 
with the FDA-approved product, including fatigue, headaches, nausea, diarrhea, and 
insomnia. 
 
Participants will fill out study questionnaires, which capture information such as age, 
gender, race/ethnicity, quality of life, sources patient laboratory data (including HCV, 
HBV and HIV status).  All information will be kept confidential and will remain in a locked 
cabinet, and only study personnel will have access to the data. 
 
For standard diagnostic ultrasounds there are no known harmful effects on humans.   
For standard diagnostic CT scan, there is a risk of radiation exposure.   The total amount 
of radiation exposure patients may encounter is about 6.5 milliSieverts (mSv). 
 
 
6. Potential Benefits 
A potential benefit to subjects is that they may be cured from HCV infection by receiving 
ledipasvir-sofosbuvir treatment as recommended by the FDA.  Current data suggest the 
likelihood of cure is greater than 90%.   
 
Another potential benefit is improvement in kidney function and liver function with 
successful cure of HCV. 
 
 
7. Costs 
Routine healthcare costs will be covered by the participants insurance.  The investigator 
will absorb other costs associated with the study using discretionary funds.  The 
breakdown is as follows: 
A. Routine healthcare costs include 
1.  On treatment and post treatment:  
          - Comprehensive metabolic panel 
 
 
- Complete blood count with differential 
 
 
- HCV RNA monitoring.  
 2.  Routine HCC monitoring if cirrhotic 
 
B. Study related costs include 
1. All screening laboratory tests 
2. Screening ECG 
3. Fibroscan duringscreening 
4. On and post treatment urine protein, urine microalbumin, urine creatinine, 
urine B2 microglobulin 
5. On and post treatment serum cystatin C level  
6. On treatment ECG monitoring 
 
Monitoring and Quality Assurance 
 
Six months into the study, an independent panel made up of non-investigators will 
review all data available to that point to ensure appropriate monitoring.  These will 
include personnel from the Division of Hepatology, Infectious Diseases and Nephrology.  


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
10 
 
 
Dr. Chung and Dr. Sise will assess the conduct of the study and review all CRFs, source 
documents, and regulatory documents every six months.  They will monitor HCV RNA 
data, kidney function data, and tolerability of ledipasvir-sofosbuvir therapy.  
 
Dr. Chung and Dr. Sise will ensure that the study is conducted according to the IRB 
approved protocol and that all regulations and requirements of the IRB are followed.  
 
8. References 
1. 
Arase Y, Ikeda K, Murashima N, Chayama K, Tsubota A, Koida I, et al. 
Glomerulonephritis in autopsy cases with hepatitis C virus infection. Intern 
Med 1998,37:836-840. 
2. 
McGuire BM, Julian BA, Bynon JS, Jr., Cook WJ, King SJ, Curtis JJ, et al. Brief 
communication: Glomerulonephritis in patients with hepatitis C cirrhosis 
undergoing liver transplantation. Ann Intern Med 2006,144:735-741. 
3. 
Soma J, Saito T, Taguma Y, Chiba S, Sato H, Sugimura K, et al. High prevalence 
and adverse effect of hepatitis C virus infection in type II diabetic-related 
nephropathy. J Am Soc Nephrol 2000,11:690-699. 
4. 
Su FH, Su CT, Chang SN, Chen PC, Sung FC, Lin CC, et al. Association of 
hepatitis C virus infection with risk of ESRD: a population-based study. Am J 
Kidney Dis 2012,60:553-560. 
5. 
Tsui JI, Vittinghoff E, Shlipak MG, Bertenthal D, Inadomi J, Rodriguez RA, et al. 
Association of hepatitis C seropositivity with increased risk for developing 
end-stage renal disease. Arch Intern Med 2007,167:1271-1276. 
6. 
Lee JJ, Lin MY, Chang JS, Hung CC, Chang JM, Chen HC, et al. Hepatitis C virus 
infection increases risk of developing end-stage renal disease using 
competing risk analysis. PLoS One 2014,9:e100790. 
7. 
Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi PL, et al. 
Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C 
virus. N Engl J Med 1994,330:751-756. 
8. 
Saadoun D, Resche-Rigon M, Thibault V, Piette JC, Cacoub P. Antiviral therapy 
for hepatitis C virus--associated mixed cryoglobulinemia vasculitis: a long-
term followup study. Arthritis Rheum 2006,54:3696-3706. 
9. 
Hsu YC, Lin JT, Ho HJ, Kao YH, Huang YT, Hsiao NW, et al. Antiviral treatment 
for hepatitis C virus infection is associated with improved renal and 
cardiovascular outcomes in diabetic patients. Hepatology 2014,59:1293-
1302. 
10. 
Halbesma N, Jansen DF, Heymans MW, Stolk RP, de Jong PE, Gansevoort RT. 
Development and validation of a general population renal risk score. Clin J 
Am Soc Nephrol 2011,6:1731-1738. 
11. 
Inker LA, Levey AS, Pandya K, Stoycheff N, Okparavero A, Greene T. Early 
change in proteinuria as a surrogate end point for kidney disease 
progression: an individual patient meta-analysis. Am J Kidney Dis 
2014,64:74-85. 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
11 
 
12. 
Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Jr., et al. 
Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N 
Engl J Med 2002,347:975-982. 
13. 
Hadziyannis SJ, Sette H, Jr., Morgan TR, Balan V, Diago M, Marcellin P, et al. 
Peginterferon-alpha2a and ribavirin combination therapy in chronic 
hepatitis C: a randomized study of treatment duration and ribavirin dose. 
Ann Intern Med 2004,140:346-355. 
14. 
Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, 
et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b 
plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. 
Lancet 2001,358:958-965. 
15. 
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. 
Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without 
cirrhosis. N Engl J Med 2014,370:1879-1888. 
 
 
 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
12 
 
Appendices 
Appendix 1: Study Schedule of Events (12 week treatment) 
  
Screening  
On treatment assessments 
Post Treatment Assessments 
  
Screening Visit 
1 
Screening Visit 
2 
Baseline 
Week 2 
Week 
4 
Week 8 
Week 
12 
PT + 4 
PT+12 
PT+24 
PT+40 (1 
year 
follow-up) 
Clinical Assessments 
  
  
FASTING 
  
  
FASTING 
  
  
FASTING 
  
FASTING 
Informed consent 
x 
  
  
  
  
  
  
  
  
  
  
Determine Eligilibty 
x 
  
  
  
  
  
  
  
  
  
  
Medical History 
x 
  
  
  
  
  
  
  
  
  
  
Physical Exam 
x 
  
x 
  
  
  
x 
  
  
  
  
Height 
x 
  
  
  
  
  
  
  
  
  
  
Weight 
x 
  
x 
x 
x 
x 
x 
x 
  
  
x 
Vital Signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fibroscan1 
x 
  
  
  
  
  
  
  
  
  
  
12-Lead EKG 
x 
  
x 
x 
  
  
x 
  
  
  
  
Imaging for HCC (if needed) 
x 
  
  
  
  
  
  
  
  
  
  
AE's 
x 
  
x 
x 
x 
x 
x 
x 
  
  
  
Concomitant Medications 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Drug Dispensing 
  
  
x 
  
x 
x 
  
  
  
  
  
Quality of Life Questionnaires 
  
  
x 
  
x 
x 
x 
x 
x 
x 
x 
Laboratory Assessments 
  
  
  
  
  
  
  
  
  
  
  
Hematology (with differential) 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Complete Metabolic Panel 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation (PT/INR, PTT) 
x 
  
x 
  
  
  
x 
  
  
  
x 
Cystatin C 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
HCV RNA 
x 
  
x 
  
x 
  
x 
x 
x 
x 
  
HCV Genotyping2 
x 
  
  
  
  
  
  
  
  
  
  
HIV Ab3 
x 
  
  
  
  
  
  
  
  
  
  
Urine Pregnancy4 
x 
  
x 
  
x 
x 
x 
x 
  
  
  
HbA1c 
  
  
x 
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
13 
 
 
  
Screening  
On treatment assessments 
Post Treatment Assessments 
  
Screening Visit 
1 
Screening Visit 
2 
Baseline 
Week 2 
Week 
4 
Week 8 
Week 
12 
PT + 4 
PT+12 
PT+24 
PT+40 (1 
year 
follow-up) 
Clinical Assessments 
  
  
FASTING 
  
  
FASTING 
  
  
FASTING 
  
FASTING 
Plasma Glucose 
  
  
x 
  
  
x 
  
  
X 
  
X 
Cryocrit 
  
  
x 
  
  
X 
  
  
X 
  
X 
Rheumatoid Factor 
  
  
x 
  
  
X 
  
  
X 
  
X 
Complements C3, C4 
  
  
x 
  
  
X 
  
  
X 
  
X 
Fasting Lipid panel 
  
  
x 
  
  
  
  
  
X 
  
X 
Fasting Serum Insulin 
  
  
x 
  
  
X 
  
  
X 
  
X 
CRP 
  
  
x 
  
  
X 
  
  
X 
  
X 
Urinalysis 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine Albumin (random) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine B2 microglobin 
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total protein/creatinine ratio (random) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV Surface antigen5 
X 
  
  
  
  
  
  
  
  
  
  
Archive Plasma (10ml heparin plasma) 
  
  
x 
X 
X 
X 
x 
x 
X 
x 
X 
Archive Urine Sample (10ml) 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
1.  Fibroscan only if no results from biopsy or prior fibroscan available within 12 months prior to screening 
2.  HCV genotype only if no results available within 24 months prior to screening 
3. HIV Ab only if no results available within 6 months prior to screening 
4. Urine pregnancy testing only in WOCBP 
5. HBV surface antigen only if no result available within 6 months prior to screening 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
14 
 
 
Appendix 2: Study Schedule of Events (24 week treatment) 
  
Screening  
On treatment assessments 
 
Post Treatment Assessments 
  
Screening Visit 
1 
Screening Visit 
2 
Baseline 
Week 2 
Week 
4 
Week 8 
Week 
12 
 
 
 
Week 
24 
PT+4 
PT+12 
PT+24 
PT+40 (1 
year 
follow-up) 
Clinical Assessments 
  
  
FASTING 
  
  
FASTING 
  
 
  
FASTING 
  
FASTING 
Informed consent 
x 
  
  
  
  
  
  
 
  
  
  
  
Determine Eligilibty 
x 
  
  
  
  
  
  
 
  
  
  
  
Medical History 
x 
  
  
  
  
  
  
 
  
  
  
  
Physical Exam 
x 
  
x 
  
  
  
x 
  
  
  
  
Height 
x 
  
  
  
  
  
  
  
  
  
  
  
Weight 
x 
  
x 
x 
x 
x 
x 
x 
x 
  
  
x 
Vital Signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fibroscan1 
x 
  
  
  
  
  
  
  
  
  
  
  
12-Lead EKG 
x 
  
x 
x 
  
  
x 
  
  
  
  
Imaging for HCC (if needed) 
x 
  
  
  
  
  
  
  
  
  
  
  
AE's 
x 
  
x 
x 
x 
x 
x 
x 
x 
  
  
  
Concomitant Medications 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Drug Dispensing 
  
  
x 
  
x 
x 
3 X 
  
  
  
  
  
Quality of Life Questionnaires 
  
  
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
Hematology (with differential) 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Complete Metabolic Panel 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation (PT/INR, PTT) 
x 
  
x 
  
  
  
x 
x 
  
  
  
x 
Cystatin C 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HCV RNA 
x 
  
x 
  
x 
  
x 
x 
x 
x 
x 
  
HCV Genotyping2 
x 
  
  
  
  
  
  
  
  
  
  
  
HIV Ab3 
x 
  
  
  
  
  
  
  
  
  
  
  
Urine Pregnancy4 
x 
  
x 
  
x 
x 
x 
x 
x 
  
  
  
HbA1c 
  
  
x 
  
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 


SOF/LDV FDC 
Protocol: IN-US-337-1777 
 
Final 
Raymond Chung, MD 
 
Amendment 3: 30 March 2017 
______________________________________________________________________________________ 
15 
 
 
 
  
Screening  
 
On treatment assessments 
Post Treatment Assessments 
  
Screening Visit 
1 
Screening Visit 
2 
Baseline 
Week 2 
Week 
4 
Week 8 
Week 
12 
Week 
24 
PT + 4 
PT+12 
PT+24 
PT+40 (1 
year 
follow-up) 
Clinical Assessments 
  
  
FASTING 
  
  
FASTING 
  
  
  
FASTING 
  
FASTING 
Plasma Glucose 
  
  
x 
  
  
x 
  
  
  
X 
  
X 
Cryocrit 
  
  
x 
  
  
X 
  
  
  
X 
  
X 
Rheumatoid Factor 
  
  
x 
  
  
X 
  
  
  
X 
  
X 
Complements C3, C4 
  
  
x 
  
  
X 
  
  
  
X 
  
X 
Fasting Lipid panel 
  
  
x 
  
  
  
  
  
  
X 
  
X 
Fasting Serum Insulin 
  
  
x 
  
  
X 
  
  
  
X 
  
X 
CRP 
  
  
x 
  
  
X 
  
  
  
X 
  
X 
Urinalysis 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine Albumin (random) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine B2 microglobin 
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine Creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Total protein/creatinine ratio (random) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 HBV surface antigen5 
 X 
  
  
  
  
  
  
  
  
  
  
  
Archive Plasma (10ml heparin plasma) 
  
  
x 
X 
X 
X 
x 
x 
x 
X 
x 
X 
Archive Urine Sample (10ml) 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
1.  Fibroscan only if no results from biopsy or prior fibroscan available within 12 months prior to screening 
2.  HCV genotype only if no results available within 24 months prior to screening 
3. HIV Ab only if no results available within 6 months prior to screening 
4. Urine pregnancy testing only in WOCBP 
5. HBV surface antigen only if no result available within 6 months prior to screening