Clinical trial NCT02874066
Conditions: Hepatitis Viruses
Keywords: Hepatitis C virus Hemodialysis Direct acting antiviral agents
Sponsor: National Taiwan University Hospital
Start date: 2017-03-13; Completion date: 2018-12-25
Enrollment: 46 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Hepatitis C virus (HCV) infection is common in patients receiving hemodialysis. The uptake of antiviral therapy for these patients is limited in the era of interferon (IFN) plus ribavirin (RBV), probably because the sustained virologic response (SVR) rates are low and the risk of treatment-related adverse events (AEs) are high. In the era of IFN-free direct acting antiviral agents (DAAs), several studies have indicated high rates of SVR and excellent safety profiles to treat patients with severe renal impairment. With regard to ombitasvir/paritaprevir/ritonavir plus dasabuvir (PrOD) treatment, a phase 2 study (RUBY-1) study has shown 90% of SVR in treatment-naive HCV-1 patients with chronic kidney disease (CKD) stage 4 or 5. Among the HCV-1b patients, who received PrOD for 12 weeks, all 7 patients achieved SVR. Although the data confirmed the excellent safety and efficacy in HCV-1b patients with severe renal impairment, the patient number was small and the data with regard to treatment-experienced patients was lacking. Therefore, we aimed to evaluated the safety and efficacy of ProD for 12 weeks in treatment-naive and treatment-experienced HCV-1b patients receiving hemodialysis.

Detailed description:
Overview Hepatitis C virus (HCV) infection remains a major co-morbidity in hemodialysis patients. The incidence and prevalence rates of HCV infection in hemodialysis patients are much higher than those in the general population, and are attributed to high rates of nosocomial HCV transmission. With regard to HCV genotype distribution, HCV genotype 1 (GT-1) infection is the most prevalent type of infection worldwide and the genotype distribution in HCV-infected individuals receiving hemodialysis (HD) is similar to that observed in HCV-infected individuals with normal renal function.Compared to non-HCV infected hemodialysis patients, HCV-infected patients have increased risks of liver-related morbidity and mortality.10 Although HCV-infected hemodialysis patients who receive renal transplantation have survival advantages over those who remain on maintenance dialysis, these patients still have poor patient and graft survival, as well as have poor responses to interferon (IFN)-based therapy. In contrast, hemodialysis patients who eradicate HCV infection have improved biochemical, virologic and histologic responses, whether on maintenance dialysis or after renal transplantation.

Clinical experience of IFN-based Therapy Approximately one third of hemodialysis patients with chronic HCV infection achieve sustained virological response (SVR) by conventional IFN or peginterferon monotherapy. In addition 18-30% of patients receiving IFN-based monotherapy prematurely discontinued treatment due to adverse events (AEs). Although the addition of ribavirin to IFN further improves the SVR rate in HCV-infected patients with normal renal function, ribavirin has been considered contraindicated to treat HCV-infected hemodialysis patients because of concern for life-threatening hemolytic anemia. Recently, pilot studies have indicated the feasibility of adding low-dose ribavirin (200 mg three times per week to daily 400 mg, adjusted to achieve a target concentration of 10-15 μmol/L), to IFN for treatment of HCV-infected hemodialysis patients. Generally, the SVR rate and the premature discontinuation rate due to null-response, severe anemia, and/or heart failure for combination therapy are 56% and 22%, respectively.Based on these small-scale studies, low-dose ribavirin (daily 200 mg) was approved in August 2011 by the U.S. Food and Drug Administration to treat HCV-infected hemodialysis patients.Two recent well-conducted randomized control studies to compare the efficacy and safety of combination therapy with peginterferon alfa-2a (135 μg/week) plus low-dose ribavirin (RBV) (200 mg/day) or monotherapy with peginterferon (135 μg/week) for 48 and 24 weeks in treatment-naïve HCV GT-1 and GT-2 infected individuals receiving hemodialysis showed that the SVR rates of combination therapy groups were greater than those of monotherapy groups (64% versus 34%, p \< 0.001 for HCV GT-1; 74% versus 44%, p \< 0.001 for HCV GT-2), respectively. Although the SVR rate of combination therapy with peginterferon plus low-dose ribavirin is higher than that of peginterferon monotherapy. About 70-75% of these patients experienced clinically significant anemia which needed high dose of erythropoiesis stimulating agents (ESAs) to keep the hemoglobin level within the safety range. Although telaprevir (TVR)-based triple therapy has been used to treat 4 HCV-1 patients receiving hemodialysis who were not responsive to prior peginterferon plus RBV with good efficacy, the added on-treatment adverse events (AEs) and the pill burden precluded the widespread use of this agent.

Clinical experience of IFN-free therapy by ombitasvir/paritaprevir/ritonavir plus dasabuvir in HCV GT-1 patients The recent introduction of IFN-free direct acting antiviral agents (DAAs) has made a paradigm shift with regard to the medical treatment for HCV-infected individuals, based on the excellent efficacy and safety in ordinary patients. Among the various IFN-free DAA regimens, treatment with ombitasvir/paritaprevir/ritonavir plus dasabuvir (PrOD) has been approved in 2014 to treat patients with chronic HCV GT-1 infection. Treatment with PrOD plus weight-based ribavirin for 12 weeks achieved an SVR12 rate of 96.2% and 96.3% in treatment-naïve and treatment-experienced non-cirrhotic HCV GT-1 patients, respectively (SAPPHIRE-I and SAPPHIRE-II). Furthermore, the SVR12 rates in those with GT-1a and GT-1b were 95.3% and 98.0% in treatment-naïve patents, and 96.0% and 96.7% in treatment-experienced patients, respectively. Among treatment-experienced HCV-1 patients, the SVR rates of PrOD plus RBV were comparable in those with various prior treatment responses by peginterferon plus RBV (relapse: 95.3%; partial response: 100%, null response: 95.2%).36 Among treatment-naïve and treatment-experienced compensated cirrhotic HCV GT-1 patients, treatment with PrOD plus RBV for 12 or 24 weeks achieved and SVR rate of 91.8% and 95.%, respectively (TURQUOISE-II).37 The SVR12 rates in HCV GT-1b cirrhotic patients were similar in those receiving 12 and 24 weeks of treatment (98.5% versus 100%); the SVR12 rate in HCV GT-1a cirrhotic patients receiving 24 week of treatment was greater than those receiving 12 weeks of treatment (94.2% versus 88.6%), particularly for prior non-responders to peginterferon plus RBV (92.9% versus 80%). The PEARL-III and PEARL-IV studies compared the SVR12 rates in treatment-naïve non-cirrhotic HCV GT-1b and HCV GT-1a patients receiving PrOD with/without RBV for 12 weeks.37 The SVR12 rate of PrOD without RBV was similar to that of PrOD with RBV in HCV GT-1b patients (99.0% versus 99.5%). However, the SVR12 rate in HCV GT-1a patients receiving PrOD with RBV was marginally higher than those receiving PrOD without RBV (97.0% versus 90.2%). The PEARL-II study further confirmed that in treatment-experienced non-cirrhotic HCV GT-1b patients, treatment with PrOD without RBV for 12 weeks had comparable SVR12 rate to PrOD with RBV therapy (100% versus 96.6%). In TURQUOISE-III study, PrOD without RBV for 12 weeks achieved an SVR12 rate of 100% in treatment-naïve and treatment-experienced compensated cirrhotic HCV GT-1b patients. With regard to safety, PrOD with/without RBV showed excellent safety profiles with few patients experiencing serious adverse events (SAEs) and prematurely treatment discontinuation. The constitutional AEs in patients receiving PrOD based treatment showed were slightly higher than those receiving placebo. Furthermore, most of these symptoms were mild in grades. About 5% of the non-cirrhotic patients and about 8% of the cirrhotic patients receiving PrOD plus RBV had an on-treatment hemoglobin level of \< 10 g/dL; and none of the non-cirrhotic patients and about 2% of the compensated cirrhotic patients receiving PrOD had an on-treatment hemoglobin level of \< 10 g/dL, respectively.35-40 In addition, the on-treatment AST/ALT elevation of more than 5 times the upper limit of normal (ULN) were 0.6%-1.7% and 0.5% in non-cirrhotic patients receiving PrOD with and without RBV; and were 2.9% and 2.0% in compensated cirrhotic patients receiving PrOD with and without RBV, respectively. The on-treatment total bilirubin elevation of more than 3 times ULN were 2.4%-5.7% and 0.5% in non-cirrhotic patients receiving PrOD with and without RBV; 13.5% and 0% in compensated cirrhotic patients receiving PrOD with and without RBV, respectively.35-40 Based on the above evidence, treatment with PrOD for 12 weeks is recommended for treatment-naïve and treatment-experienced HCV GT-1b patients, regardless of cirrhosis or not. Treatment with PrOD plus RBV for 12 weeks is recommended for HCV GT-1a patients, except for compensated cirrhotic HCV GT-1a null responders to prior therapy where treatment with PrOD plus RBV for 24 weeks is recommended.

Clinical experience of IFN-free therapy by ombitasvir/paritaprevir/ritonavir plus dasabuvir in HCV GT-1 patients with severe renal impairment or end-stage renal disease (ESRD) The pharmacokinetic (PK) study of ombitasvir, paritaprevir, ritonavir, and dasabuvir was evaluated in 24 subjects with normal renal function, and with mild, moderate or severe renal impairment (each arm 6 patients). Compared to subjects with normal renal function, the area under the curves (AUCs) in subjects with mild renal impairment were comparable for ombitasvir, 20% higher for paritaprevir and dasabuvir, and 42% higher for ritonavir; the AUCs in subjects with moderate renal impairment were comparable for ombitasvir, 37% higher for paritaprevir and dasabuvir, and 80% higher for ritonavir; the AUCs in subjects with severe renal impairment were comparable for ombitasvir, 50% higher for paritaprevir and dasabuvir, and 114% higher for ritonavir. All patients were well tolerated for PrOD treatment except for mild AEs, including nausea, myalgia, and catheter-site erythema, encountered in 1 subject with moderate renal impairment. Based on the PK study, the changes of the drug exposure were not clinically relevant and the doses of PrOD do not require adjustment.

The phase 3b RUBY-I study evaluated the safety and efficacy of PrOD with RBV and PrOD without RBV for 12 weeks in 13 and 7 HCV GT-1a and HCV GT-1b treatment-naïve non-cirrhotic patients with severe renal impairment or ESRD. The interim safety analysis showed that no patients had study drug discontinuation, no treatment-related serious adverse events (SAEs) and no clinically significant changes in markers of liver or kidney function. With regard to efficacy, 14 of the 20 patients completed 12 weeks of treatment and all of them achieved end-of-treatment virologic response (EOTVR). Ten patients (8 in GT-1a and 2 in GT-1b) completed post-treatment follow-up for 4 weeks and all achieved SVR4. Furthermore, 2 HCV GT-1a patients completed post-treatment follow-up for 12 weeks and all achieved SVR12.

Rationale of the study design Although peginterferon monotherapy and combination therapy with peginterferon plus low-dose RBV for 24-48 weeks have been evaluated in many studies, the efficacy for the treatment regimens were only modest (SVR rate about 60%). In addition, the on-treatment AEs and SAEs by IFN-based therapies were frequently encountered in HCV-infected patients receiving hemodialysis. Of note was the pronounced on-treatment hemoglobin level decrease in patients receiving combination therapy by peginterferon plus low-dose RBV, necessitating significant RBV dose reduction and high-dose erythrocyte stimulating agent (ESA) support.

By receiving IFN-free DAA therapies, HCV-infected patients have excellent SVR rates, low on-treatment SAE and AE rates, shorter treatment duration, and low pill burdens. The PK study of ombitasvir, paritaprevir, ritonavir and dasabuvir proves the excellent safety profiles and dose adjustment are not needed for PrOD regimen in subjects with various degrees of renal impairment. The interim analysis of RUBY-I study showed the excellent on-treatment and off-therapy antiviral effects in HCV GT-1a and GT-1b infected patients receiving PrOD plus low-dose RBV and PrOD, respectively. However, all the patients enrolled in the RUBY-I study were treatment-naïve and were non-cirrhotic. Furthermore, only 7 patients in the RUBY-I study were HCV GT-1b patients. Based on the excellent safety and efficacy profiles of PrOD treatment for HCV GT-1b infected patients with normal renal function, we aim to evaluate the safety and efficacy of PrOD for 12 weeks in treatment-naïve and treatment-experienced HCV GT-1b non-cirrhotic patients receiving hemodialysis.

Arms: arm 1: Paritaprevir/ritonavir/ombitasvir (PTV/r/OBV, 75mg/50mg/12.5mg per tablet, Viekirax): 2 tablets per os per day Dasabuvir (DSV, 250 mg per tablet, Exviera): 1 tablet per os twice per day Treatment duration: 12 weeks
Interventions: intervention 1: PTV/r/OBV/DSV
Intervention descriptions: intervention 1: Viekirax/Exviera for 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
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Paritaprevir/Ritonavir/Ombitasvir1plus1Dasabuvir1for1Treatment7Naive1
and1Treatment7Experienced1Non7Cirrhotic1Patients1with1Hepatitis1C1
Virus1Genotype11b1Receiving1Hemodialysis1(PIVOTAL)1
1
Version1
1.0"
Protocol1Date1
24"April,"2016"
Investigational1
Product1
Ombitasvir,"paritaprevir/ritonavir,"dasabuvir"
Development1phase1 3b"
Study1Design1
Prospective,"multicenter,"open>label,"interventional"trial"
Sponsor1
1 Abbvie"
Medical1Monitor1
Department"Ministry"of"Health"and"Welfare,"Executive"Yuan,"
Taiwan"
Taiwan"Joint"Institutional"Review"Board"
Study1Coordinator1
Chen>Hua"Liu,"MD,"PhD"
Contact"Information:"+886>2>23123456"ext"63572"
E>mail:"jacque_liu@mail2000.com.tw"


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SPONSOR1SIGNATURE1PAGE1
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Protocol1No.:" "
Title:1 Ombitasvir/Paritaprevir/Ritonavir" plus" Dasabuvir" for" Treatment>Naive" and"
Treatment>Experienced" Non>Cirrhotic" Patients" with" Hepatitis" C" Virus" Genotype" 1b"
Receiving"Hemodialysis"
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Sponsor"
Abbvie"
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Name:"
" " " " " " " " " " " " " " " " " " " " " "
" " " " " " " " " " " " " " " " " " " " " "
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Signature:"
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Date:"
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INVESTIGATOR1SIGNATURE1PAGE1
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Protocol1No.:" "
Title:1 Ombitasvir/Paritaprevir/Ritonavir" plus" Dasabuvir" for" Treatment>Naive" and"
Treatment>Experienced" Non>Cirrhotic" Patients" with" Hepatitis" C" Virus" Genotype" 1b"
Receiving"Hemodialysis"
"
I,"the"undersigned,"have"reviewed"this"protocol,"and"I"agree"to"conduct"this"study"
with"the"information"contained"in"this"protocol,"and"in"accordance"with"the"principles"
of" Declaration" of" Helsinki" and" the" International" Conference" on" Harmonization" for"
Good"Clinical"Practice."
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Name:" " " " " " " " " " " " " " " " " " " " " " " " " " " " Signature:" " " " " " " " " " " " " " " " " " " " " " " " "
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Date:" " " " " " " " " " " " " " " " " " " " " " " " " " "
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Affiliation"&"Address:" " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " "
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PROTOCOL1SYNOPSIS1
Version1
1.0"
Protocol1Date1
24"April,"2016"
Protocol1No.1
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Title1
Ombitasvir/Paritaprevir/Ritonavir"plus"Dasabuvir"for"
Treatment>Naive"and"Treatment>Experienced"Non>Cirrhotic"
Patients"with"Hepatitis"C"Virus"Genotype"1b"Receiving"Hemodialysis"
Diagnosis1
Chronic"hepatitis"C,"genotype"1b"
Participating1Center1
National"Taiwan"University"Hospital,"Taipei,"Taiwan"
National"Taiwan"University"Hospital,"Yun>Lin"Branch,"Yun>Lin,"
Taiwan"
Taipei"City"Hospital,"Ren>Ai"Branch,"Taipei,"Taiwan"
Tri>Service"General"Hospital,"National"Defense"Medical"Center,"
Taipei,"Taiwan"
China"Medical"University"Hospital,"Taichung,"Taiwan"
Taichung"Veterans"General"Hospital,"Taichung,"Taiwan"
Tung’s"Taichung"MetroHarbor"Hospital,"Taichung,"Taiwan"
Ditmanson"Medical"Foundation"Chia>Yi"Christian"Hospital,"Chia>Yi,"
Taiwan"
National"Cheng"Kung"University"Hospital,"Tainan,"Taiwan"
Phase1of1Trial1
3b"
Investigational1
Product1
Ombitasvir/paritaprevir/ritonavir"12.5"mg/75"mg/50"mg"tablet"
Dasabuvir"250"mg"tablet"
Acronym:"PrOD"
Dose1
Ombitasvir/paritaprevir/ritonavir"25/150/100"mg"QD"(2"tablet"once"
daily)"
Dasabuvir"250"mg"BID"(1"tablet"twice"daily)"
Duration1
12"weeks"
Treatment1
allocation1
Open>label"
Estimated1Sample1
Size1
Treatment>naïve:"35"
Treatment>experienced:"15"
Main1Inclusion1
Criteria1
1.!
Ages"of"20"to"70"yeas"
2.!
Male"or"female"
3.!
Body"mass"index"(BMI)"18.5>35.0"kg/m2"
4.!
Chronic"HCV"infection,"defined"as"patients"who"meet"as"least"
one"of"the"two"following"criteria:" "


5"
"
•!
Anti>HCV"antibody"(Abbott"HCV"EIA"2.0,"Abbott"
Laboratories,"Abbott"Park,"Illinois,"USA)"or"HCV"RNA">"
1,000"IU/mL"for"at"least"6"months"before"screening"
•!
Positive"HCV"RNA">"1,0000"IU/mL"(Cobas"TaqMan"HCV"
Test"v2.0,"Roche"Diagnostics"GmbH,"Mannheim,"
Germany,"low"limit"of"quantification"(LLOQ):"25"IU/mL)"
at"the"time"of"screening"with"a"liver"biopsy"consistent"
with"chronic"HCV"infection"
5.!
HCV"genotype"1b"(HCV"GT>1b)"infection"(Abbott"RealTime"
HCV"genotype"II,"Abbott"Molecular"Inc."Illinois,"USA)"
6.!
Treatment>naïve"or"treatment>experienced"(including"patients"
who"relapsed,"who"had"virological"breakthrough,"or"who"were"
null>responsive"to"IFN>based"therapies)"
7.!
HCV"RNA">"10,000"IU/mL"at"screening"
8.!
Absence"of"cirrhosis"with"documented"results"of"one"of"the"
following"criteria:"
•!
Liver"biopsy"within"24"months"prior"to"or"during"
screening"demonstration"the"absence"of"cirrhosis,"e.g."
METAVIR"score"≤"3"or"Ishak"score"≤"4."
•!
A"screening"transient"elastography"(Fibroscan)"result"of"<"
12.5"kPa"
•!
A"screening"Fibrosis"Index"Based"on"4"markers"(FIB>4)"of"≤"
1.45"and"Aspartate"Aminotransferase"to"Platelet"Ratio"
Index"(APRI)"of"≤"2"
•!
Subjects"with"non>qualifying"FIB>4/APRI"or"Fibroscan"
result"may"only"be"enrolled"if"they"have"a"qualifying"liver"
biopsy"within"24"months"prior"to"or"during"screening"
9.!
Estimated"glomerular"filtration"(eGFR)"rate"<"15"
mL/min/1.73m2"as"assessed"by"modified"of"diet"in"renal"
disease"(MDRD)"equation,"and"receiving"regular"hemodialysis"
Main1Exclusion1
Criteria1
1.!
HCV"infection"other"than"HCV"GT>1b"
2.!
HBV"or"HIV"coinfection"
3.!
Presence"of"cirrhosis"(Child>Pugh"class"A,"B"or"C)"
4.!
Any"primary"cause"of"liver"disease"other"than"chronic"HCV"
infection,"including"but"not"limited"to"the"following"
•! Hemochromatosis"
•! Alfa>1"antitrypsin"deficiency"
•! Wilson’s"disease"


6"
"
•! Autoimmune"hepatitis"
•! Alcoholic"liver"disease"
•! Drug>induced"hepatitis"
5.!
Screening"laboratory"analyses"showing"any"of"the"following"
results"
•! Hemoglobin"(Hb)"level"<"10"g/dL"
•! Absolute"neutrophil"count"(ANC)"<"1,500"cells/μL"
•! Platelet"count"<"60,000"cells/mm3"
•! International"normalized"ratio"(INR)">"2.0"
•! Albumin"(Alb)"<"2.8"g/dL"
•! Bilirubin"(Bil)">"3.0"mg/dL"
•! Alanine"aminotransferase"(ALT)">"5X"upper"limit"of"normal"
(ULN)"
•! Aspartate"aminotransferase"(AST)">"5X"upper"limit"of"
normal"(ULN)"
•! Serum"alfa>fetoprotein"(AFP)">"100"ng/mL"
6.!
Presence"of"hepatocellular"carcinoma"(HCC)"on"imaging"
studies"such"as"computed"tomography"(CT)"scan"or"magnetic"
resonance"imaging"(MRI)"
7.!
History"of"malignancy"(except"cutaneous"melanoma)"within"5"
years"at"the"screening"
8.!
Organ"transplantation"other"than"cornea"and"hair"(prior"renal"
transplantation"with"graft"failure"not"included)"
9.!
Prior"exposure"to"investigational"agents"for"HCV"(direct"acting"
antiviral"agents,"host>targeting"agents,"or"therapeutic"
vaccines)"
10.! Pregnancy"
11.! Unwilling"to"have"contraception"during"the"study"period"
12.! Unwilling"to"provide"informed"consent"
Primary1endpoint1
1.!
Sustained"virological"response"(SVR12):"HCV"RNA"level"<LLOQ" "
12"weeks"after"the"completion"of"therapy"(Cobas"TaqMan"
HCV"Test"v2.0,"Roche"Diagnostics"GmbH,"Mannheim,"
Germany,"low"limit"of"quantification"(LLOQ):"25"IU/mL)"
2.!
Treatment>emergent"adverse"event"(AE)>related"withdrawal"
rate"
Secondary1endpoint1
1.!
Sustained"virological"response"(SVR24):"HCV"RNA"level"<"LLOQ"
24"weeks"after"the"completion"of"therapy"(Cobas"TaqMan"
HCV"Test"v2.0,"Roche"Diagnostics"GmbH,"Mannheim,"


7"
"
Germany,"low"limit"of"quantification"(LLOQ):"25"IU/mL)"
2.!
Rapid"virological"response"(RVR):"HCV"RNA"level"<"LLOQ"at"
week"4"of"treatment(Cobas"TaqMan"HCV"Test"v2.0,"Roche"
Diagnostics"GmbH,"Mannheim,"Germany,"low"limit"of"
quantification"(LLOQ):"25"IU/mL)"
3.!
End>of>treatment"virological"response"(EOTVR):"HCV"RNA"
level"<"LLOQ"at"the"end"of"treatment"(Cobas"TaqMan"HCV"Test"
v2.0,"Roche"Diagnostics"GmbH,"Mannheim,"Germany,"low"
limit"of"quantification"(LLOQ):"25"IU/mL)"
4.!
Fibrosis"Index"Based"on"4"markers"(FIB>4):"changes"of"FIB>4"
before"treatment"and"at"the"end>of>follow>up"
5.!
FibroScan:"changes"of"liver"stiffness"before"treatment"and"at"
the"end>of>follow>up"
Resistance1
1.!
Resistance"information"will"be"analyzed"for"any"subjects"who"
has"sequencing"performed"on"baseline"samples:" "
•! The"resistance>associated"variants"(RAVs)"at"signature"
amino"acid"position"at"baseline"identified"by"population"
nucleotide"sequencing"and"comparison"to"the"appropriate"
prototype"reference"standard"sequence"
2.!
Resistance"information"will"be"analyzed"for"subjects"who"fail"
to"achieve"SVR12"and"who"have"on>treatment"HCV"RNA"≥"
1,000"IU/mL"
•! The"RAVs"at"signature"amino"acid"position"at"baseline"
identified"by"population"nucleotide"sequencing"
comparison"to"the"appropriate"prototypic"reference"
sequence"
•! The"RAVs"in"available"post>baseline"samples"identified"by"
population"and/or"clonal"nucleotide"sequencing"and"
comparison"to"the"baseline"sequencing"
•! The"RAVs"in"available"post>baseline"samples"identified"by"
population"and/or"clonal"nucleotide"sequencing"and"
comparison"to"the"appropriate"prototypic"reference"
sequence"
3.!
The"most"prevalent"amino"acid"RAVs"identified"by"population"
sequencing"and"those"emerging"or"becoming"enriched"in"
isolates"from"at"least"2"subjects"in"the"study"will"be"
summarized."Furthermore,"the"persistence"of"the"detected"
amino"acid"RAVs"will"also"be"reported."


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Proposed1Statistical1
Analysis1
Variables/Time"Points"of"Interest:"sustained"virological"response"
(SVR12):"HCV"RNA"level"<"LLOQ"12"weeks"after"the"completion"of"
therapy"(Cobas"TaqMan"HCV"Test"v2.0,"Roche"Diagnostics"GmbH,"
Mannheim,"Germany,"low"limit"of"quantification"(LLOQ):"25"IU/mL)"
Statistical"Methods"
1.!
Treatment>naïve:"
•! Alfa>error:"0.05,"beta>error:"0.20,"two>tailed"statistics"
•! Controlled"arm"(null>hypothesis):"peginterferon"alfa>2a"
plus"low>dose"ribavirin"for"48"weeks"(SVR24:"64%)"(Liu"CH,"
et"al."Pegylated"interferon>α2a"with"or"without"low>dose"
ribavirin"for"treatment>naive"patients"with"hepatitis"C"virus"
genotype"1"receiving"hemodialysis:"a"randomized"trial."Ann"
Intern"Med"2013;159:729>38.)"
•! PrOD"arm:"estimated"to"be"94%"
•! Sample"estimation"in"PrOD"arm:"35"
2.!
Treatment>experienced:"not"designed"to"evaluate"formal"
statistical"hypotheses,"and"no"sample"size"calculation"
performed"because"of"the"lack"of"SVR12"rate"data"by"
peginterferon"alfa>2a"plus"low>dose"ribavirin"retreatment."


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Flow%Chart%
%
Study%Visit%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
11%
12%
Procedure%
Screening%
Treatment%
EOT%
FollowEup%
EOF%
Extended%
followEup%
Study%Week%
E4%to%E1%
Day%1%
1%
2%
4%
6%
8%
10%
12%
16%
20%
24%
36%
Informed%Consent%
X%
%
%
%
%
%
%
%
%
%
%
%
%
Inclusion/Exclusion%
X%
%
%
%
%
%
%
%
%
%
%
%
%
Demographic%
X%
%
%
%
%
%
%
%
%
%
%
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Height%
X%
%
%
%
%
%
%
%
%
%
%
%
%
Weight%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
Medical%History%
X%
%
%
%
%
%
%
%
%
%
%
%
%
Physical%Examination%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
Vital%Signs%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
Adverse%Event%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
%
%
%
Abdominal%US%
X%
%
%
%
%
%
%
%
X%
%
%
X%
%
ECG%
X%
X%
%
%
%
%
%
%
X%
%
%
X%
X%
Pregnancy%test1%
X%
X%
%
%
X%
%
X%
%
X%
X%
%
%
%
Hemogram2%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
Coagulation%profile3%
X%
X%
%
%
%
%
%
%
X%
%
%
X%
X%
Biochemistry%
X4%
X4%
X%
X%
X%
X%
X%
X%
X4%
X%
X%
X4%
X4%
Serology%
X5%
X%
%
%
%
%
%
%
X%
%
%
X%
X%


10"
"
Virology%
X6%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
Urinalysis%
X%
X%
%
%
X%
%
X%
%
X%
%
%
X%
X%
Human%genetics7%
X%
%
%
%
%
%
%
%
%
%
%
%
%
FibroScan%or%Liver8%
biopsy%
X%
%
%
%
%
%
%
%
X%
%
%
X%
%
Resistant%variants9%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
Archive%serum%sample%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
X%
EOT:"end"of"treatment,"EOF:"end"of"follow6up"
1%For"pre6menopausal"women"with"child"birth"potential,"testing"for"urine"beta"human"chorionic"gonadotropin"(β6HCG)."If"the"urine"sample"is"unable"to"collect,"consider"
serum"β6HCG"test"
2"Including"hemoglobin"level,"white"blood"cell"count,"absolute"neutrophil"count,"platelet"count."
3"Including"prothrombin"time,"activated"partial"thromboplastin"time."
4% Including" albumin," total" bilirubin" (T6Bil)," direct" bilirubin" (D6Bil)," aspartate" aminotransferase" (AST)," alanine" aminotransferase" (ALT)," alkaline" phosphatase" (ALP),"
gamma6glutaryl" transpeptidase" (6GT)," creatinine" (Cre)," blood" urea" nitrogen" (BUN)," sodium" (Na)," potassium" (K)," chloride" (Cl)," calcium" (Ca)," inorganic" phosphorus" (P),"
magnesium"(Mg),"uric"acid"(UA),"fasting"glucose"(GluAC),"glycated"hemoglobin"(HbA1c),"triglyceride"(TG),"cholesterol"(CHO),"low"density"lipoprotein"(LDL),"high"density"
lipoprotein"(HDL),"iron"(Fe),"total"iron"binding"capacity"(TIBC),"ferritin."Others"include"AST,"ALT"with/without"T6Bil,"D6Bil,"ALP/r6GT."
5%Including"anti6HCV,"HBsAg,"anti6HBs,"anti6HBc,"anti6HIV."Others"include"anti6HCV."
6"Including"HCV"RNA,"HCV"genotype/subgenotype."Others"include"HCV"RNA."
7"Including"interleukin"28B"(IL28B)"genotypes."
8"For"patients"with"failed"or"unreliable"Fibroscan"evaluation,"liver"biopsy"to"stage"the"hepatic"fibrosis"is"suggested"and"is"optional."In"patients"who"receive"liver"biopsy"to"
stage"the"hepatic"fibrosis,"the"EOF"liver"biopsy"is"also"optional."
9"All"samples"tested"were"stored"until"the"completion"of"the"study."Tests"for"all"subjects"for"resistant"associated"variants"(RVAs)"of"interests"at"NS3,"NS5A,"and"NS5B"regions"
at"the"screening"time"point."Others"were"tested"for"subjects"who"fail"to"achieve"SVR12"or"who"have"on6treatment"HCV"RNA"≥"1,000"IU/mL."


11"
"
ABBREVIATIONS+
ADL"
Activities"of"Daily"Living"
AE"
Adverse"Event"
AFP"
Alfa"Fetoprotein"
AIDS"
Acquired"Immune"Deficiency"Syndrome"
ALB"
Albumin"
ALP"
Alkaline"Phosphatase"
ALT"
Alanine"aminotransferase"
ANC"
Absolute"Neutrophil"Count"
ANTIEHBc"
Hepatitis"B"Virus"Core"Antigen"Antibody"
ANTIEHBs"
Hepatitis"B"Virus"Surface"Antigen"Antibody"
ANTIEHCV"
Hepatitis"C"Virus"Antibody"
ANTIEHIV"
Human"Immunodeficiency"Virus"Antibody"
aPTT"
Activated"Partial"Thromboplastin"Time"
AST"
Aspartate"aminotransferase"
AUC"
Area"Under"the"Curve"
BID"
Twice"Daily"Dose"
BIL"
Bilirubin"
BMI"
Body"Mass"Index"
BP"
Blood"Pressure"
BT"
Body"Temperature"
Ca"
Calcium"
CBC"
Complete"Blood"Count"
CHC"
Chronic"Hepatitis"C"
CHO"
Cholesterol"
CI"
Confidence"Interval"
CL"
Chloride"
CRF"
"
Case"Report"Form"
CT"
Computed"Tomography"
CYP"
Cytochrome"P"
DAA"
Direct"Acting"Antiviral"
DEBil"
Direct"Bilirubin"
DDI"
Drug"Drug"Interaction"
DNA"
Deoxyribonucleic"Acid"
EC"
Ethics"Committee"
ECG"
Electrocardiogram"
eGFR"
Estimated"Glomerular"Filtration"Rate"


12"
"
EIA"
Enzyme"Immune"Assay"
EOF"
End"of"FollowEup"
EOT"
End"of"Treatment"
EOTVR"
EndEofEtreatment"Virologic"Response"
ESA"
Erythrocyte"Stimulating"Agent"
ESRD"
End"Stage"Renal"Disease"
FDA"
Food"and"Drug"Administration"
FE"
Iron"
GCP"
Good"Clinical"Practice"
GLUAC"
Fasting"Glucose"
GT"
Genotype"
Hb"
Hemoglobin"
HbA1c"
Glycated"Hemoglobin"
HBsAg"
Hepatitis"B"Surface"Antigen"
HBV"
Hepatitis"B"Virus"
HCC"
Hepatocellular"Carcinoma"
HCT"
Hematocrit"
HCV"
Hepatitis"C"Virus"
HD"
Hemodialysis"
HDL"
High"Density"Lipoprotein"
HIV"
Human"Immunodeficiency"Virus"
IFN"
Interferon"
IL28B"
Interleukin"28B"
INR"
International"Normalized"Ratio"
IRB"
Institutional"Review"Board"
IU"
International"Unit"
K"
Potassium"
L"
Liter"
LDL"
Low"Density"Lipoprotein"
LLOQ"
Lower"Limit"of"Quantification"
MCH"
Mean"Corpuscular"Hemoglobin"
MCHC"
Mean"Corpuscular"Hemoglobin"Concentration"
MDRD"
Modified"of"Diet"in"Renal"Disease"Equation"
mg"
Milligram"
Mg"
Magnesium"
mL"
Milliliter"
MRI"
Magnetic"Resonance"Imaging"
NA"
Sodium"


13"
"
PI"
Principle"Investigator"
PK"
Pharmacokinetics"
PO"
Per"Os"
PR"
Pulse"Rate"
PrOD"
Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir"
PT"
Prothrombin"Time"
QD"
Once"Daily"Dose"
RAV"
Resistance"Associated"Variant"
RBV"
Ribavirin"
RBC"
Red"Blood"Cell"Count"
RNA"
Ribonucleic"Acid"
RR"
Relative"Risk"
RR"
Respiratory"Rate"
RVR"
Rapid"Virologic"Response"
SAE"
Serious"Adverse"Event"
SD"
Standard"Deviation"
SUSAR"
Suspected"Unexpected"Severe"Adverse"Reaction"
SVR"
Sustained"Virologic"Response"
TEBil"
Total"Bilirubin"
TG"
Triglyceride"
TIBC"
Total"Iron"Binding"Capacity"
TVR"
Telaprevir"
UA"
Uric"Acid"
ULN"
Upper"Limit"of"Normal"
US"
Ultrasonography"
WBC"
White"Blood"Cell"count"
ΒEHCG"
Beta"Human"Chorionic"Gonadotropin"
γEGT"
GammaEGlutaryl"Transpeptidase"
μg"
Microgram"


14"
"
Table+of+Contents+
TITLE+PAGE"………………………………………………………………………………………………………."
1"
SPONSOR+SIGNATURE+PAGE+…………………………………………………………………………….+
2"
INVESTIGATOR+SIGNATURE+PAGE+…………………………………………………………………….+
3"
PROTOCOL+SYNOPSIS+………………………………………………………………….……………………+
4"
FLOW+CHARTS+…………….……………………………………………………………………………………+
9"
ABBREVIATIONS+……………………………………………………………………………………………….+
11"
TABLE+OF+CONTENTS+………………………………………………………………………………………..+
14"
1.! INTRODUCTION+………………………………………………………………………………………….+
18"
1.1+Overview+………………………………………………………………………………………………"
18"
1.2+Clinical+experience+of+IFNIbased+Therapy+……………………………..……………."
18"
1.3+Clinical+experience+of+IFNIfree+therapy+by+ombitasvir/paritaprevir/+
ritonavir+plus+dasabuvir+in+HCV+GTI1+patients"……………………………………………"
"
19"
1.4+Clinical+experience+of+IFNIfree+therapy+by+ombitasvir/paritaprevir/+
ritonavir+plus+dasabuvir+in+HCV+GTI1+patients+with+severe+renal+
impairment+or+endIstage+renal+disease+(ESRD)"…………………………………………."
"
"
21"
1.5+Rationale+for+the+study+design+………………………………………..……………………+
22"
2.! STUDY+DESIGN+……………………………………………………………………………………………+
24"
2.1+Study+population"………………………….…………………………………………………….."
24"
" " 2.1.1"Inclusion"criteria"………………………………………………….…………………………"
24"
" " 2.1.2"Exclusion"criteria"……….………………………………………………………..…………"
25"
" " 2.1.3"Definition"of"the"criteria"…….……………………….……………………………….…"
26"
2.1.4"Prior"or"concomitant"HCV"therapy"…………………………………………………."
28"
2.1.4.1"Prior"therapy"………………………………………………………………………….."
28"
2.1.4.2"Concomitant"therapy"………………………………………………………………"
28"
2.1.4.3"Prohibited"therapy"…………………………………………………………………"
29"
2.1.4.4"Concomitant"therapy"requiring"dosage"adjustment,"altered"
timing"or"additional"monitoring"………………………………………………"
"
29"
2.2+Intervention"……………………..…………………………………………………………………."
30"
2.2.1"Identity"of"investigational"drugs"……………………………………………………."
30"
" " 2.2.2"Packing"and"labeling"………………………………………………………………………"
31"
2.2.3"Storage"and"disposition"of"investigational"drugs"……………………………."
31"


15"
"
" " 2.2.4"Shipment"of"investigational"drugs"……………..………………………………..…"
31"
2.2.5"Blinding"…………………………………………………………………………………………."
31"
" " 2.2.6"Dispensing"of"investigational"drugs"…….……………………….…………………"
31"
" " 2.2.7"Dosage"and"duration"of"interventional"drugs"…………………………………"
32"
" " 2.2.8"Dosage"adjustment"…………………………………………………………..……………"
32"
2.2.9"Treatment"compliance"……………………………………………………………………"
32"
" " 2.2.10"Drug"accountability"……………………………………………………..………………."
33"
2.3+Objective"…………………………………………….…………………..…….……………………."
33"
" " 2.3.1"Primary"objectives"………………….…………………………..……………..…….……"
33"
" " 2.3.2"Secondary"objectives"………………………………………………………………..……"
34"
" " 2.3.3"Outcome"measures"…………………………………………..…….……………………."
34"
2.4+Study+schedule"……………….………………………………..……..…….……………………."
34"
" " 2.4.1"Study"windows"and"rounding"principles"……….….……………………………."
34"
" " 2.4.2"Screening"visit"…………………………………………………..…….……………………."
35"
2.4.3"Rescreening"visit"……………………………………………………………………………."
35"
" " 2.4.4"Treatment"visit"……….………………………………………..…….………….…………."
36"
" " 2.4.5"FollowEup"visit"……….………………………………………..………….………..………."
36"
2.4.6"End"of"followEup"visit"…………………………………………………………………….."
37"
" " 2.4.7"Extended"followEup"visit"……….……………………………..…….….………………"
37"
2.5+Study+procedures/evaluations"………………………….…..…….….……….…………."
37"
2.5.1"Informed"consent"………………………………………………………………………….."
37"
" " 2.5.2"Demographics,"baseline"values,"medical"history"….….………….…………."
38"
" " 2.5.3"Clinical"evaluations"……………………………..…………..…….….……….…………."
38"
" " " " " 2.5.3.1"Vital"signs,"weight,"height"……………………..………………………..……."
38"
" " " " " 2.5.3.2"Physical"examination"…………….………………..…….….……….…………."
38"
" " " " " 2.5.3.3"Adverse"events"………………..……………………..…….….……….…………."
38"
" " 2.5.4"Laboratory"evaluations"……………….…………………..…….….……….…………."
39"
" " " " " 2.5.4.1"Routine"laboratory"panels"…………………………….….……….…………."
39"
" " " " " 2.5.4.2"Human"genetic"analysis"……………………………….……………………….."
40"
" " " " " 2.5.4.3"Virology"analyses"……………….…………………..…….….……….…………."
40"
" " " " " 2.5.4.4"Abdominal"ultrasonography"…………………………….……………………"
42"
2.5.4.5"Electrocardiogram"(ECG)"………………………………………………………."
42"
" " " " " 2.5.4.6"FibroScan"and"liver"biopsy"………………..……………………..…….….…."
42"


16"
"
2.5.4.7"Archive"serum"sample"………………………………………………………….."
43"
3.! ADVERSE+EVENT+MANAGEMENT+&+REPORTING+………………….……..….………….+
47"
" 3.1+Adverse+event"…………………………………………………………….….……….…………."
47"
" 3.2+Serious+adverse+event"……………………..……………………….….……..……………."
47"
" 3.3+Reporting+and+classification+procedures"……………………..….……….…….…."
48"
3.3.1"Severity"of"adverse"event"……………………………………………………………."
48"
3.3.2"Relationship"to"investigational"drug"…………………………………………….."
49"
3.3.3"Pregnancy"……………………………………………………………………………………."
49"
3.3.4"Toxicity"management"………………………………………………………………….."
50"
3.3.4.1"Grade"1"or"2"adverse"events"and"laboratory"abnormalities"…."
50"
3.3.4.2"Grade"3,"or"higher"adverse"events"and"laboratory"
abnormalities"………………………………………………………………………"
"
50"
3.3.4.3"Management"of"transaminase"elevations"……………………………"
51"
4.! DOSE+INTERRUPTION,+DISCONTINUATION+RULES+…………..….………….………….+
54"
" 4.1+Dose+interruption"……….………………………..…..………..…….….….…….…………."
54"
" 4.2+Dose+discontinuation"……….…………………..…….….……………….….….…………."
54"
" 4.3+Subject+withdrawal+and+replacement"……….……………………….…..…………."
54"
5.! PROTOCOL+DEVIATION+………………………………………………….……………………………+
55"
6.! STATISTICAL+CONSIDERATIONS+……….…………………………..…….….……….………….+
56"
" 6.1+Sample+size+determination"……….………..…………..…..…….….……….…………."
56"
" 6.2+Definition+of+primary+endpoints"……….……………..……………....…….….…….."
56"
" 6.3+Analyses+for+primary+efficacy+endpoint"…………………………………………….."
56"
" 6.4+Analysis+for+primary+safety+endpoint"………………………………..……..…..……"
57"
" 6.5+Sensitivity+analysis+for+the+primary+efficacy+endpoint"………………..…….."
57"
6.6+Subgroup+analyses+…………………………………………………………………………….."
57"
6.7+Additional+efficacy+endpoint+…………………………………………………………….."
58"
6.8+Resistance+analyses"……………………………………………………………………………"
58"
6.9+Adverse+events"………………………………………………………………………………….."
60"
6.10+Clinical+laboratory+data"……………………………………………………………………."
60"
7.! STUDY+ADMINISTRATION+………………………….……………………….….……….………….+
62"
" 7.1+Regulatory+and+ethical+consideration"……….…………..…….…..…….…………."
62"
" " " 7.1.1"Institutional"review"board/ethics"committee"approval"…………………"
62"
7.1.2"Ethical"conduct"of"the"study"…………………………………………………………"
62"


17"
"
" " " 7.1.3"Subject"informed"consent"……………………………..…….….……….…………."
63"
" 7.2+Data+collection"…………………………………………………....…….….……….…………."
64"
7.2.1"Source"documents"……………………………………………………………………...."
64"
7.2.2"Case"report"forms"……………………………………………………………………….."
64"
" 7.3+Record+retention"……………………………..……………………..….….……….…………."
64"
" 7.4+Information+disclosure"……………………………………………….….……….…………."
64"
" " " 7.4.1"Confidentiality"……………………………………………….…….….……….…………."
65"
7.4.2"Completion"of"the"study"………………………………………………………………"
65"
" " " 7.4.2"Publication"policy"………………………………..…………..….….……….…………."
65"
8.! REFERENCES+………..……………………………………………….………..….….……….………….+
66"
9.! APPENDIX+………………………………………………………………………….….……….………….+
70"
"
"


18"
"
1.! INTRODURCTION+
1.1!Overview+
Hepatitis" C" virus" (HCV)" infection" remains" a" major" coEmorbidity" in"
hemodialysis"patients.1E3"The"incidence"and"prevalence"rates"of"HCV"infection"
in" hemodialysis" patients" are" much" higher" than" those" in" the" general"
population," and" are" attributed" to" high" rates" of" nosocomial" HCV"
transmission.4E6"With"regard"to"HCV"genotype"distribution,"HCV"genotype"1"
(GTE1)" infection" is" the" most" prevalent" type" of" infection" worldwide" and" the"
genotype"distribution"in"HCVEinfected"individuals"receiving"hemodialysis"(HD)"
is" similar" to" that" observed" in" HCVEinfected" individuals" with" normal" renal"
function.7E9"
Compared"
to"
nonEHCV"
infected"
hemodialysis"
patients,"
HCVEinfected" patients" have" increased" risks" of" liverErelated" morbidity" and"
mortality.10" Although" HCVEinfected" hemodialysis" patients" who" receive" renal"
transplantation" have" survival" advantages" over" those" who" remain" on"
maintenance"dialysis,"these"patients"still"have"poor"patient"and"graft"survival,"
as" well" as" have" poor" responses" to" interferon" (IFN)Ebased" therapy.11E13" In"
contrast,"hemodialysis"patients"who"eradicate"HCV"infection"have"improved"
biochemical," virologic" and" histologic" responses," whether" on" maintenance"
dialysis"or"after"renal"transplantation.14,15"
+
1.2!Clinical+experience+of+IFNIbased+Therapy+
Approximately"one"third"of"hemodialysis"patients"with"chronic"HCV"infection"
achieve" sustained" virological" response" (SVR)" by" conventional" IFN" or"
peginterferon" monotherapy.16E18" In" addition" 18E30%" of" patients" receiving"
IFNEbased"monotherapy"prematurely"discontinued"treatment"due"to"adverse"
events"(AEs)."Although"the"addition"of"ribavirin"to"IFN"further"improves"the"
SVR" rate" in" HCVEinfected" patients" with" normal" renal" function," ribavirin" has"
been"considered"contraindicated"to"treat"HCVEinfected"hemodialysis"patients"
because" of" concern" for" lifeEthreatening" hemolytic" anemia." Recently," pilot"
studies" have" indicated" the" feasibility" of" adding" lowEdose" ribavirin" (200" mg"
three" times" per" week" to" daily" 400" mg," adjusted" to" achieve" a" target"
concentration" of" 10E15" μmol/L)," to" IFN" for" treatment" of" HCVEinfected"
hemodialysis" patients.19E28" Generally," the" SVR" rate" and" the" premature"


19"
"
discontinuation"rate"due"to"nullEresponse,"severe"anemia,"and/or"heart"failure"
for" combination" therapy" are" 56%" and" 22%," respectively.29" Based" on" these"
smallEscale"studies,"lowEdose"ribavirin"(daily"200"mg)"was"approved"in"August"
2011" by" the" U.S." Food" and" Drug" Administration" to" treat" HCVEinfected"
hemodialysis" patients.30" Two" recent" wellEconducted" randomized" control"
studies" to" compare" the" efficacy" and" safety" of" combination" therapy" with"
peginterferon" alfaE2a" (135" μg/week)" plus" lowEdose" ribavirin" (RBV)" (200"
mg/day)" or" monotherapy" with" peginterferon" (135" μg/week)" for" 48" and" 24"
weeks" in" treatmentEnaïve" HCV" GTE1" and" GTE2" infected" individuals" receiving"
hemodialysis"showed"that"the"SVR"rates"of"combination"therapy"groups"were"
greater"than"those"of"monotherapy"groups"(64%"versus"34%,"p"<"0.001"for"
HCV" GTE1;" 74%" versus" 44%," p" <" 0.001" for" HCV" GTE2)," respectively.31,32"
Although" the" SVR" rate" of" combination" therapy" with" peginterferon" plus"
lowEdose"ribavirin"is"higher"than"that"of"peginterferon"monotherapy."About"
70E75%" of" these" patients" experienced" clinically" significant" anemia" which"
needed" high" dose" of" erythropoiesis" stimulating" agents" (ESAs)" to" keep" the"
hemoglobin" level" within" the" safety" range." Although" telaprevir" (TVR)Ebased"
triple"therapy"has"been"used"to"treat"4"HCVE1"patients"receiving"hemodialysis"
who"were"not"responsive"to"prior"peginterferon"plus"RBV"with"good"efficacy,"
the"added"onEtreatment"adverse"events"(AEs)"and"the"pill"burden"precluded"
the"widespread"use"of"this"agent.33,34"
+
1.3!Clinical+experience+of+IFNIfree+therapy+by+ombitasvir/paritaprevir/ritonavir+
plus+dasabuvir+in+HCV+GTI1+patients+
The"recent"introduction"of"IFNEfree"direct"acting"antiviral"agents"(DAAs)"has"
made"a"paradigm"shift"with"regard"to"the"medical"treatment"for"HCVEinfected"
individuals," based" on" the" excellent" efficacy" and" safety" in" ordinary" patients."
Among"
the"
various"
IFNEfree"
DAA"
regimens,"
treatment"
with"
ombitasvir/paritaprevir/ritonavir"plus"dasabuvir"(PrOD)"has"been"approved"in"
2014"to"treat"patients"with"chronic"HCV"GTE1"infection."Treatment"with"PrOD"
plus"weightEbased"ribavirin"for"12"weeks"achieved"an"SVR12"rate"of"96.2%"and"
96.3%"in"treatmentEnaïve"and"treatmentEexperienced"nonEcirrhotic"HCV"GTE1"
patients," respectively" (SAPPHIREEI" and" SAPPHIREEII).35,36" Furthermore," the"


20"
"
SVR12" rates" in" those" with" GTE1a" and" GTE1b" were" 95.3%" and" 98.0%" in"
treatmentEnaïve" patents," and" 96.0%" and" 96.7%" in" treatmentEexperienced"
patients,"respectively."Among"treatmentEexperienced"HCVE1"patients,"the"SVR"
rates" of" PrOD" plus" RBV" were" comparable" in" those" with" various" prior"
treatment" responses" by" peginterferon" plus" RBV" (relapse:" 95.3%;" partial"
response:" 100%," null" response:" 95.2%).36" Among" treatmentEnaïve" and"
treatmentEexperienced"compensated"cirrhotic"HCV"GTE1"patients,"treatment"
with"PrOD"plus"RBV"for"12"or"24"weeks"achieved"and"SVR"rate"of"91.8%"and"
95.%,"respectively"(TURQUOISEEII).37"The"SVR12"rates"in"HCV"GTE1b"cirrhotic"
patients"were"similar"in"those"receiving"12"and"24"weeks"of"treatment"(98.5%"
versus" 100%);" the" SVR12" rate" in" HCV" GTE1a" cirrhotic" patients" receiving" 24"
week"of"treatment"was"greater"than"those"receiving"12"weeks"of"treatment"
(94.2%"versus"88.6%),"particularly"for"prior"nonEresponders"to"peginterferon"
plus"RBV"(92.9%"versus"80%).37"The"PEARLEIII"and"PEARLEIV"studies"compared"
the"SVR12"rates"in"treatmentEnaïve"nonEcirrhotic"HCV"GTE1b"and"HCV"GTE1a"
patients"receiving"PrOD"with/without"RBV"for"12"weeks.37"The"SVR12"rate"of"
PrOD"without"RBV"was"similar"to"that"of"PrOD"with"RBV"in"HCV"GTE1b"patients"
(99.0%" versus" 99.5%)." However," the" SVR12" rate" in" HCV" GTE1a" patients"
receiving" PrOD" with" RBV" was" marginally" higher" than" those" receiving" PrOD"
without" RBV" (97.0%" versus" 90.2%).38" The" PEARLEII" study" further" confirmed"
that" in" treatmentEexperienced" nonEcirrhotic" HCV" GTE1b" patients," treatment"
with" PrOD" without" RBV" for" 12" weeks" had" comparable" SVR12" rate" to" PrOD"
with" RBV" therapy" (100%" versus" 96.6%).39" In" TURQUOISEEIII" study," PrOD"
without"RBV"for"12"weeks"achieved"an"SVR12"rate"of"100%"in"treatmentEnaïve"
and" treatmentEexperienced" compensated" cirrhotic" HCV" GTE1b" patients.40"
With" regard" to" safety," PrOD" with/without" RBV" showed" excellent" safety"
profiles" with" few" patients" experiencing" serious" adverse" events" (SAEs)" and"
prematurely" treatment" discontinuation." The" constitutional" AEs" in" patients"
receiving" PrOD" based" treatment" showed" were" slightly" higher" than" those"
receiving"placebo."Furthermore,"most"of"these"symptoms"were"mild"in"grades."
About"5%"of"the"nonEcirrhotic"patients"and"about"8%"of"the"cirrhotic"patients"
receiving"PrOD"plus"RBV"had" " an"onEtreatment"hemoglobin"level"of"<"10"g/dL;"
and" none" of" the" nonEcirrhotic" patients" and" about" 2%" of" the" compensated"


21"
"
cirrhotic"patients"receiving"PrOD"had"an"onEtreatment"hemoglobin"level"of"<"
10"g/dL,"respectively.35E40"In"addition,"the"onEtreatment"AST/ALT"elevation"of"
more"than"5"times"the"upper"limit"of"normal"(ULN)"were"0.6%E1.7%"and"0.5%"
in"nonEcirrhotic"patients"receiving"PrOD"with"and"without"RBV;"and"were"2.9%"
and"2.0%"in"compensated"cirrhotic"patients"receiving"PrOD"with"and"without"
RBV,"respectively."The"onEtreatment"total"bilirubin"elevation"of"more"than"3"
times"ULN"were"2.4%E5.7%"and"0.5%"in"nonEcirrhotic"patients"receiving"PrOD"
with" and" without" RBV;" 13.5%" and" 0%" in" compensated" cirrhotic" patients"
receiving"PrOD"with"and"without"RBV,"respectively.35E40"Based"on"the"above"
evidence," treatment" with" PrOD" for" 12" weeks" is" recommended" for"
treatmentEnaïve" and" treatmentEexperienced" HCV" GTE1b" patients," regardless"
of" cirrhosis" or" not." Treatment" with" PrOD" plus" RBV" for" 12" weeks" is"
recommended"for"HCV"GTE1a"patients,"except"for"compensated"cirrhotic"HCV"
GTE1a"null"responders"to"prior"therapy"where"treatment"with"PrOD"plus"RBV"
for"24"weeks"is"recommended."
"
1.4!Clinical+experience+of+IFNIfree+therapy+by+ombitasvir/paritaprevir/ritonavir+
plus+ dasabuvir+ in+ HCV+ GTI1+ patients+ with+ severe+ renal+ impairment+ or+
endIstage+renal+disease+(ESRD)+
The" pharmacokinetic" (PK)" study" of" ombitasvir," paritaprevir," ritonavir," and"
dasabuvir"was"evaluated"in"24"subjects"with"normal"renal"function,"and"with"
mild,"moderate"or"severe"renal"impairment"(each"arm"6"patients)."Compared"
to"subjects"with"normal"renal"function,"the"area"under"the"curves"(AUCs)"in"
subjects" with" mild" renal" impairment" were" comparable" for" ombitasvir," 20%"
higher"for"paritaprevir"and"dasabuvir,"and"42%"higher"for"ritonavir;"the"AUCs"
in"subjects"with"moderate"renal"impairment"were"comparable"for"ombitasvir,"
37%"higher"for"paritaprevir"and"dasabuvir,"and"80%"higher"for"ritonavir;"the"
AUCs" in" subjects" with" severe" renal" impairment" were" comparable" for"
ombitasvir,"50%"higher"for"paritaprevir"and"dasabuvir,"and"114%"higher"for"
ritonavir.41"All"patients"were"well"tolerated"for"PrOD"treatment"except"for"mild"
AEs,"including"nausea,"myalgia,"and"catheterEsite"erythema,"encountered"in"1"
subject"with"moderate"renal"impairment."Based"on"the"PK"study,"the"changes"
of"the"drug"exposure"were"not"clinically"relevant"and"the"doses"of"PrOD"do"


22"
"
not"require"adjustment."
The" phase" 3b" RUBYEI" study" evaluated" the" safety" and" efficacy" of" PrOD" with"
RBV"and"PrOD"without"RBV"for" 12" weeks"in"13"and"7"HCV"GTE1a"and"HCV"
GTE1b"treatmentEnaïve"nonEcirrhotic"patients"with"severe"renal"impairment"or"
ESRD.42"The"interim"safety"analysis"showed"that"no"patients"had"study"drug"
discontinuation,"no"treatmentErelated"serious"adverse"events"(SAEs)"and"no"
clinically" significant" changes" in" markers" of" liver" or" kidney" function." With"
regard"to"efficacy,"14"of"the"20"patients"completed"12"weeks"of"treatment"and"
all" of" them" achieved" endEofEtreatment" virologic" response" (EOTVR)." Ten"
patients"(8"in"GTE1a"and"2"in"GTE1b)"completed"postEtreatment"followEup"for"4"
weeks"and"all"achieved"SVR4."Furthermore,"2"HCV"GTE1a"patients"completed"
postEtreatment"followEup"for"12"weeks"and"all"achieved"SVR12."
"
1.5!Rationale+of+the+study+design+
Although" peginterferon" monotherapy" and" combination" therapy" with"
peginterferon" plus" lowEdose" RBV" for" 24E48" weeks" have" been" evaluated" in"
many"studies,"the"efficacy"for"the"treatment"regimens"were"only"modest"(SVR"
rate"about"60%)."In"addition,"the"onEtreatment"AEs"and"SAEs"by"IFNEbased"
therapies" were" frequently" encountered" in" HCVEinfected" patients" receiving"
hemodialysis." Of" note" was" the" pronounced" onEtreatment" hemoglobin" level"
decrease" in" patients" receiving" combination" therapy" by" peginterferon" plus"
lowEdose" RBV," necessitating" significant" RBV" dose" reduction" and" highEdose"
erythrocyte"stimulating"agent"(ESA)"support."
By"receiving"IFNEfree"DAA"therapies,"HCVEinfected"patients"have"excellent"SVR"
rates,"low"onEtreatment"SAE"and"AE"rates,"shorter"treatment"duration,"and"
low" pill" burdens." The" PK" study" of" ombitasvir," paritaprevir," ritonavir" and"
dasabuvir"proves"the"excellent"safety"profiles"and"dose"adjustment"are"not"
needed" for" PrOD" regimen" in" subjects" with" various" degrees" of" renal"
impairment." The" interim" analysis" of" RUBYEI" study" showed" the" excellent"
onEtreatment" and" offEtherapy" antiviral" effects" in" HCV" GTE1a" and" GTE1b"
infected"patients"receiving"PrOD"plus"lowEdose"RBV"and"PrOD,"respectively."
However,"all"the"patients"enrolled"in"the"RUBYEI"study"were"treatmentEnaïve"
and" were" nonEcirrhotic." Furthermore," only" 7" patients" in" the" RUBYEI" study"


23"
"
were"HCV"GTE1b"patients."Based"on"the"excellent"safety"and"efficacy"profiles"
of" PrOD" treatment" for" HCV" GTE1b" infected" patients" with" normal" renal"
function,"we"aim"to"evaluate"the"safety"and"efficacy"of"PrOD"for"12"weeks"in"
treatmentEnaïve"and"treatmentEexperienced"HCV"GTE1b"nonEcirrhotic"patients"
receiving"hemodialysis."


24"
"
2.! STUDY+DESIGN+
2.1!Study+population+
We" will" conduct" a" phase" 3b," multicenter," openElabel" trial" at" 9" academic"
centers" in" Taiwan." TreatmentEnaïve" and" treatmentEexperienced" HCV" GTE1b"
nonEcirrhotic" patients" who" receive" maintenance" hemodialysis" due" to" ESRD"
and" who" are" 20E70" years" old" are" consecutively" enrolled" in" the" study." The"
protocol" will" be" approved" by" Central" Institutional" Review" Board" (CEIRB)" of"
Taiwan"and"will"be"conducted"in"accordance"with"the"principles"of"Declaration"
of" Helsinki" and" the" International" Conference" on" Harmonization" for" Good"
Clinical" Practice." Each" patient" provides" written" informed" consent" before"
enrollment."
+
2.1.1!Inclusion+criteria+
[1]!Ages"of"20"to"70"yeas"
[2]!Male"or"female"
[3]!Body"mass"index"(BMI)"18.5E35.0"kg/m2"
[4]!Chronic"HCV"infection,"defined"as"patients"who"meet"as"least"one"of"the"
two"following"criteria"
•!
AntiEHCV" antibody" (Abbott" HCV" enzyme" immunoassay" [EIA]" 2.0,"
Abbott"Laboratories,"Abbott"Park,"Illinois,"USA)"or"HCV"RNA">"1,000"
IU/mL"for"at"least"6"months"before"screening"
•!
Positive"HCV"RNA">"1,0000"IU/mL"(Cobas"TaqMan"HCV"Test"v2.0,"
Roche" Diagnostics" GmbH," Mannheim," Germany," low" limit" of"
quantification"(LLOQ):"25"IU/mL)"at"the"time"of"screening"with"a"
liver"biopsy"consistent"with"chronic"HCV"infection"
[5]!HCV" GTE1b" infection" (Abbott" RealTime" HCV" genotyping" II," Abbott"
Molecular"Inc."Illinois,"USA)"
[6]!TreatmentEnaïve" or" treatmentEexperienced" (including" patients" who"
relapsed,"who"had"virological"breakthrough,"or"who"were"nullEresponsive"
to"IFNEbased"therapies)"
[7]!HCV"RNA">"10,000"IU/mL"at"screening"
[8]!Absence" of" cirrhosis" with" documented" results" of" one" of" the" following"
criteria:"


25"
"
•!
Liver" biopsy" within" 24" months" prior" to" or" during" screening"
demonstration"the"absence"of"cirrhosis,"e.g."METAVIR"score"≤"3"or"
Ishak"score"≤"4."
•!
A"screening"transient"elastography"(Fibroscan)"result"of"<"12.5"kPa"
•!
A"screening"Fibrosis"Index"Based"on"4"markers"(FIBE4)"of"≤"1.45"and"
Aspartate"Aminotransferase"to"Platelet"Ratio"Index"(APRI)"of"≤"2"
•!
Subjects" with" nonEqualifying" FIBE4/APRI" or" Fibroscan" result" may"
only" be" enrolled" if" they" have" a" qualifying" liver" biopsy" within" 24"
months"prior"to"or"during"screening"
[9]!Estimated" glomerular" filtration" (eGFR)" rate" <" 15" mL/min/1.73m2" as"
assessed" by" modified" of" diet" in" renal" disease" (MDRD)" equation," and"
receiving"regular"hemodialysis"
"
2.1.2!Exclusion+criteria+
[1]! HCV"infection"other"than"HCV"GTE1b"
[2]! HBV"or"HIV"coinfection"
[3]! Presence"of"cirrhosis"(ChildEPuge"class"A,"B"or"C)"
[4]! Any" primary" cause" of" liver" disease" other" than" chronic" HCV" infection,"
including"but"not"limited"to"the"following"
•!
Hemochromatosis"
•!
AlfaE1"antitrypsin"deficiency"
•!
Wilson’s"disease"
•!
Autoimmune"hepatitis"
•!
Alcoholic"liver"disease"
•!
DrugEinduced"hepatitis"
[5]! Screening"laboratory"analyses"showing"any"of"the"following"results"
•!
Hemoglobin"(Hb)"level"<"10"g/dL"
•!
Absolute"neutrophil"count"(ANC)"<"1,500"cells/μL"
•!
Platelet"count"<"60,000"cells/mm3"
•!
International"normalized"ratio"(INR)">"2.0"
•!
Albumin"(Alb)"<"2.8"g/dL"
•!
Bilirubin"(Bil)">"3.0"mg/dL"
•!
Alanine"aminotransferase"(ALT)">"5X"upper"limit"of"normal"(ULN)"
•!
Aspartate"aminotransferase"(AST)">"5X"upper"limit"of"normal"(ULN)"


26"
"
•!
Serum"alfaEfetoprotein"(AFP)">"100"ng/mL"
[6]! Presence"of"hepatocellular"carcinoma"(HCC)"on"imaging"studies"such"as"
computed"tomography"(CT)"scan"or"magnetic"resonance"imaging"(MRI)"
[7]! History"of"malignancy"(except"cutaneous"melanoma)"within"5"years"at"the"
screening"
[8]! Organ" transplantation" other" than" cornea" and" hair" (prior" renal"
transplantation"with"graft"failure"not"included)"
[9]! Prior" exposure" to" investigational" agents" for" HCV" (direct" acting" antiviral"
agents,"hostEtargeting"agents,"or"therapeutic"vaccines)"
[10]!Pregnancy"
[11]!Unwilling"to"have"contraception"during"the"study"period"
[12]!Unwilling"to"provide"informed"consent"
"
2.1.3! Definition+of+the+criteria+
[1]! Stage"of"the"hepatic"fibrosis:"diagnosis"of"the"hepatic"fibrosis"by"one"
of"the"following"methods"
•!
Liver"biopsy:"graded"by"METAVIR"fibrosis"score"F0EF4."
•!
Fibroscan"score:"F0"(≤"6"KPa),"F1"(6.1"to"7.0"KPa),"F2"(7.1"to"9.4"
KPa),"F3"(9.5"to"12.5KPa),"F4"(≥"12.5"KPa)."
•!
Subjects" with" a" nonEqualifying" Fibroscan" results" (including"
failure" to" measure" [zero" valid" measurement]," unreliable"
measurement" [less" than" 10" valid" measurement," a" successful"
rate"of"less"than"60%"or"the"interquartile"range"more"than"30%"
of"the"median"FibroScan"score])"are"suggested"to"receive"liver"
biopsy"to"confirm"the"severity"of"hepatic"fibrosis."Liver"biopsy"is"
not"optional"and"is"not"compulsive."
[2]! Compensated"cirrhosis:"cirrhotic"patients"with"ChildEPugh"score"of"<"
7"(See"below"Table)."
[3]! Decompensated"cirrhosis:"cirrhotic"patients"with"ChildEPugh"score"of"
≥"7"(See"Table"below)."
"
Parameter+
Points+assigned+for+Observed+Findings+
1+
2+
3+


27"
"
Total"bilirubin"(mg/dL)"
<"2"
2E3"
>"3"
Serum"albumin"(g/dL)"
>"3.5"
2.8E3.5"
<"2.8"
Prothrombin"time"(INR)"
<"1.7"
1.7E2.3"
>"2.3"
Ascites1"
None"
Mild"
Moderate"to"severe"
Hepatic"encephalopathy2"
Grade"0"
Grade"IEII"(or"suppressed"
with"medication)
Grade"IIIEIV"(or"
refractory
1"Mild"="ascites"detectable"only"by"ultrasound"examination;"moderate"to"severe"="ascites"
manifested"by"moderate"symmetrical"distention"of"the"abdomen"
2"Grade"0"="normal"consciousness,"personality,"neurological"examination,"
electroencephalogram;"grade"I"="restless,"sleep"disturbed,"irritable/agitated,"tremor,"
impaired"handwriting,"triphasic"wave"(5"Hz);"grade"II"="lethargic,"timeEdisoriented,"
inappropriate"behavior,"asterixis,"ataxia,"slow"triphasic"wave;"grade"III"="somnolent,"
stuporous,"placeEdisoriented,"hyperactive"reflexes,"rigidity,"slower"triphasic"wave;"
grade"IV"="unarousable"coma,"no"personality/behavior,"decerebrate,"slow"delta"wave"
(2E3"Hz)"
[4]! Definition"of"treatmentEexperienced"patients"
•!
Relapser:" patients" receiving" IFNEbased" therapy" (IFN" or"
peginterferon"with/without"RBV)"for"the"treatment"of"HCV"and"
with"undetectable"HCV"RNA"at"or"after"the"end"of"treatment,"
but"subsequently"having"detectable"HCV"RNA"within"24"weeks"
of"offEtherapy"followEup."
•!
Viral" breakthrough:" patients" receiving" IFNEbased" therapy" (IFN"
or"peginterferon"with/without"RBV)"for"the"treatment"of"HCV"
and"
with"
onEtreatment"
undetectable"
HCV"
RNA,"
but"
subsequently" having" detectable" HCV" RNA" with" ongoing"
treatment."
•!
Null" responder:" patients" receiving" at" least" 12" weeks" of"
IFNEbased"therapy"(IFN"or"peginterferon"with/without"RBV)"for"
the"treatment"of"HCV"and"failing"to"achieve"at"least"2"log"HCV"
RNA"decline"from"the"baseline"to"week"12"of"therapy,"or"with"
continuous"detectable"HCV" " RNA"after"24"weeks"of"treatment."
•!
Intolerance:"patients"who"discontinue"IFNEbased"therapy"(IFN"
or" peginterferon" with/without" RBV)" during" the" treatment" for"
HCV" due" to" intolerance" to" any" of" the" components" of" the"
IFNEbased"therapy."


28"
"
"
2.1.4!Prior+or+concomitant+HCV+therapy+
Any"medication"or"vaccine"(including"overEtheEcounter"or"prescription"
medicines," vitamins," traditional" medicines," and/or" herbal" medicines)"
taken"by"the"subjects"from"the"timing"of"signing"the"informed"consent"
through"the"treatment"period"and"28"days"after"the"study"drugs"are"
stopped,"must"be"recorded"in"the"case"report"form"(CRF)"along"with"
the" reason" for" use," date(s)" of" administration" including" the" start" and"
end" dates," and" dosage" information" (including" route," dosage" and"
frequency)." The" investigators" should" review" all" concomitant"
medications"for"any"potential"drugEdrug"interactions"(DDIs)."
"
2.1.4.1!Prior+therapy+
TreatmentEnaïve"patients"must"not"have"prior"or"current"use"of"
the" investigational" or" commercially" available" agents" for" HCV,"
including"IFN,"peginterferon,"telaprevir,"boceprevir,"asunaprevir,"
daclatasvir,"PrOD,"sofosbuvir,"ledipasvir,"simeprevir"or"RBV."
TreatmentEexperienced" patients" must" have" previously" received"
IFNEbased"therapy,"including"IFN"or"peginterferon"monotherapy,"
or" combination" therapy" with" IFN/peginterferon" plus" RBV" and"
failed"treatment."These"patients"should"have"documentation"of"
the"types"and"duration"of"prior"therapy,"as"well"as"the"type"of"
treatment" failure" and/or" the" reason" for" premature" treatment"
discontinuation"due"to"intolerance."
"
2.1.4.2!Concomitant+therapy+
The" investigator" should" confirm" than" concomitant" medications"
can"be"administered"with"PrOD."Some"medications"may"require"
dose" adjustment" due" to" potential" for" DDIs." The" investigator"
should"also"review"the"label(s)"for"the"concomitant"medication(s)"
for"additional"information."
The"use"of"hepatic"protective"medications,"such"as"milk"thistle,"
ursodeoxycholic"acid,"glycyrrhizin"acid,"SAM,"ShoEsaikoEto"etc.,"is"


29"
"
allowed," provided" that" the" drug" does" not" meet" any" other"
exclusion"criteria."The"dose"of"these"drugs"should"be"kept"stable"
while"the"subjects"are"during"the"PrOD"treatment."
During" the" postEtreatment" period," the" investigator" should"
reassess" concomitant" medications" and" subjects" may" resume"
previously"prohibited"medications"or"revert"to"preEstudy"doses"2"
weeks"following"the"last"dose"of"the"study"drugs,"if"applicable."
"
2.1.4.3!Prohibited+therapy+
The" prohibited" therapy" in" subjects" receiving" PrOD" therapy" is"
listed"below:"
"
Alfuzocin"
Etravirine"
Propafenone"
Aliskiren"
Flecamide"
Propoxyphene"
Amiodarone"
Flurazepam"
Quetiapine"
Astemizole"
Fusidic"acid"
Quinidine"
Atorvastatin"
Gemfibrozil"
Rifabutin"
Bepredil"
Hormone"contraceptives"
Rifampin"
Carbamazepine"
Lovastatin"
Saquinavir"
Cisapride"
Lopinavir"
Sildenafil"
Clorazepate"
Midazolam"
Simvastatin"
Clozapine"
Nevirapine"
St."John’s"Wort"
Diazepam"
Pethidine"
Terfenadine"
Efavirenz"
Phenobarbital"
Trizolam"
Elvitegravir/cobicstat"
Phenytoin"
Voriconazole"
Encainide"Ergot"Derivatives"
Pimozide"
"
Estazolam"
Piroxicam"
"
+
2.1.4.4!Concomitant+ therapy+ requiring+ dosage+ adjustment,+ altered+
timing+or+additional+monitoring+
The" concomitant" therapy" than" requires" dosage" adjustment,"
altered" timing," or" additional" monitoring" in" subjects" receiving"
PrOD"therapy"is"listed"below:"


30"
"
+
Amlodipine"
Doxazocin"
Risperidone"
Amitriptyline"
Enalapril"
Rouvastatin"
Aripiprazole"
Ezetimibe"
Sertraline"
Bisoprolol"
Flupentixol"
Sirolimus"
Chlorpromazine"
Fluvastatin"
Tacrolimus"
Candesartan"
Haloperidol"
Trazodone"
Clopidogrel"
Mycophenolate"
Venlafaxine"
Cyclosporine"
Olanzapine"
Verapamil"
Dabigatran"
Pitavastatin"
Vernakalant"
Digoxin"
Pravastatin"
"
"
In" addition" to" the" medications" listed" above," the" use" of" known"
strong"inducers"of"cytochrome"P3A"(CYP3A)"or"strong"inhibitors"
of"CYP2C8"are"prohibited"within"2"weeks"or"within"10"halfElives,"
whichever"is"longer,"prior"to"the"initial"dose"of"PrOD"and"through"
the"first"2"weeks"after"the"subjects"has"completed"PrOD"in"the"
treatment"period."
Refer"to"the"ritonavir"labeling"for"a"list"of"prohibited"medications."
AntiEHCV"medications"other"than"those"specified"in"the"protocol"
will"not"be"allowed"during"the"treatment"period."
Management" of" hematological" toxicity," including" leukopenia,"
and" thrombocytopenia," by" hematological" growth" factor" is" not"
allowed."The"ESA"can"be"allowed"during"the"treatment"period"for"
renal" anemia." However," the" Sponsor" will" not" reimburse" the"
expense"of"ESA"usage."
"
2.2!Intervention+
2.2.1! Identity+of+investigational+drugs+
+
Investigational+Drugs+
Manufacturer+
Route+of+
Administration+
Dosage+
Form+
Strength+
Ombitasvir/paritaprevir/
Abbvie"
Oral"
Tablet"
12.5"mg/75mg"


31"
"
ritonavir"
/50mg"
Dasabuvir"
Abbvie"
Oral"
Tablet"
250"mg"
"
2.2.2!Packing+and+labeling+
Ombitasvir/paritaprevir/ritonavir"will"be"supplied"in"bottles"containing"
64"tablets."Dasabuvir"will"be"supplied"in"bottles"containing"64"tablets."
Each"bottle"will"be"labeled"as"required"by"local"requirement."
"
2.2.3!Storage+and+disposition+of+investigational+drugs+
+
Investigational+Drugs+
Storage+Condition+
Ombitasvir/paritaprevir/ritonavir"
15°"to"25°C"(59°F"to"77°F)"
Dasabuvir"
15°"to"25°C"(59°F"to"77°F)"
"
The"investigational"drugs"are"for"investigational"use"only"and"must"be"
used"within"the"context"of"the"study."The"study"drugs"supplied"for"this"
study" must" be" maintained" under" adequate" security" and" stored" under"
appropriate"conditions"specified"on"the"label"until"dispensed"for"subject"
use"or"returned"to"the"Sponsor."
"
2.2.4!Shipment+of+the+investigational+drugs+
A" supply" of" investigational" drugs" will" be" sent" to" the" each" clinical"
pharmacology"department"of"each"participating"center"by"the"Sponsor"
following"the"approval"of"the"site"by"the"Department"Ministry"of"Health"
and"Welfare,"Executive"Yuan,"Taiwan."Because"this"is"an"openElabel"trial,"
all"the"study"medications"are"supplied"with"an"openEcode."
"
2.2.5!Blinding+
This"is"an"openElabel"study."
"
2.2.6!Dispensing+of+the+investigational+drugs+
Ombitasvir/paritaprevir/ritonavir" and" dasabuvir" are" taken" Per" Os" (PO)"
with" food" to" increase" the" bioavailability." Subjects" should" comply" with"


32"
"
the"investigators’"instructions"and"receive"adequate"dosage"of"the"study"
drugs" to" secure" the" efficacy" and" safety." Furthermore," if" the" subject"
misses"the"scheduling"timing"for"the"study"drugs,"he/she"should"replace"
the" dose" within" 12" hours;" otherwise" he/she" should" not" receive" the"
study"drugs"and"be"considered"as"missed"dosage."
"
2.2.7!Dosage+and+duration+of+interventional+drugs+
[1]! Ombitasvir/paritaprevir/ritonavir"(12.5"mg/75mg/50mg"per"tablet)"
will"be"dosed"2"tablets"QD."
[2]! Dasabuvir"(250"mg"per"tablet)"will"be"dosed"1"tablet"BID."
[3]! All"study"drugs"should"be"dosed"together"and"administered"with"
food"i.e.,"the"AM"dose"of"ombitasvir/paritaprevir/ritonavir"and"
dasabuvir"should"be"taken"together"with"food"and"the"PM"dose"of"
dasabuvir"should"be"taken"with"food."
"
2.2.8!Dosage+adjustment+
The"dosage"and"dosing"frequency"adjustments"of"the"study"drugs"are"
generally" not" allowed." The" study" drugs" can" be" discontinued" under"
protocolEdefined"conditions."
"
2.2.9!Treatment+compliance+
The"investigator"or"his/her"designated"and"qualified"representatives"will"
administer" and" dispense" investigational" drugs" for" subjects" enrolled" in"
this" study." The" study" drugs" must" not" be" dispensed" for" reasons" other"
than"that"described"in"the"protocol."Furthermore,"all"study"drugs"will"be"
dispensed"to"subjects"by"studyEsite"personnel"under"the"instruction"of"
the"investigator."
At" the" start" of" the" study," each" subject" should" be" instructed" the"
importance"of"the"dosing"adherence"to"the"assigned"treatment"regimen"
with" regard" to" virologic" responses" and" potential" development" of"
resistance"
associated"
variants"
(RAVs)."
Subjects"
will"
receive"
investigational"drugs"from"Day"1"visit"to"the"EOT."In"addition,"subjects"
will"be"instructed"to"return"all"bottles"of"investigational"drugs"to"the"site"


33"
"
staff"at"the"appropriate"visits."During"the"onEtreatment"visits,"the"site"
staff"will"inspect"the"content"of"the"bottles"and"record"the"status"of"each"
one"as"well"as"the"exact"number"of"remaining"tablets"of"investigational"
drugs."
Investigational"drugs"should"not"be"interrupted"for"toxicity"management"
or"any"other"reason"for"more"than"7"consecutive"days."If"investigational"
drugs" must" be" interrupted" for" more" than" 7" consecutive" days," the"
investigator"should"note"the"attributed"reason"in"case"report"form"(CRF),"
and"should"consider"discontinue"the"subject."
"
2.2.10! Drug+accountability+
The" investigator" or" his/her" designated" and" qualified" representatives"
will"verify"that"the"investigational"drug"supplies"are"well"received"and"
in"the"correct"amount."An"overall"accountability"of"the"investigational"
drugs"will"be"performed"and"verified"by"Abbvie"monitor"throughout"
the" treatment" period." Final" accountability" will" be" verified" by" the"
monitor"at"the"end"of"the"study"drug"treatment"at"each"site."
During" the" study," should" the" subject" misplace" or" damage" the"
investigational"drug"bottle,"the"investigator"should"contact"the"study"
coordinator" as" well" as" Abbvie" for" the" replacement" of" the" drugs." An"
explanation"of"the"reason"of"the"misplaced"or"damaged"study"drug(s)"
should"be"documented"in"CRF."Upon"completion"of"or"discontinuation"
from" the" treatment" period," all" original" investigational" drug" bottles"
should"be"counted"and"returned"to"the"Sponsor"or"destroyed"at"site."
The" site" will" maintain" the" records" of" the" study" drugs" including" the"
amount"of"drugs"received,"and"return"as"well"as"disposal."
"
2.3!Objective+
2.3.1!Primary+objectives+
[1]! Sustained"virological"response"(SVR12):"HCV"RNA"level"<"LLOQ"12"
weeks"after"the"completion"of"therapy"(Cobas"TaqMan"HCV"Test"
v2.0,"Roche"Diagnostics"GmbH,"Mannheim,"Germany,"low"limit"of"
quantification"(LLOQ):"25"IU/mL)"
[2]! TreatmentEemergent"adverse"event"(AE)Erelated"withdrawal"rate"


34"
"
"
2.3.2!Secondary+objectives+
[1]! Sustained" virological" response" (SVR24):" HCV" RNA" level" <" LLOQ" 24"
weeks" after" the" completion" of" therapy" (Cobas" TaqMan" HCV" Test"
v2.0,"Roche"Diagnostics"GmbH,"Mannheim,"Germany,"low"limit"of"
quantification"(LLOQ):"25"IU/mL)"
[2]! Rapid"virological"response"(RVR):"HCV"RNA"level"<"LLOQ"at"week"4"
of" treatment" (Cobas" TaqMan" HCV" Test" v2.0," Roche" Diagnostics"
GmbH,"Mannheim,"Germany,"low"limit"of"quantification"(LLOQ):"25"
IU/mL)"
[3]! EndEofEtreatment" virological" response" (EOTVR):" HCV" RNA" level" <"
LLOQ" at" end" of" treatment" (Cobas" TaqMan" HCV" Test" v2.0," Roche"
Diagnostics"GmbH,"Mannheim,"Germany,"low"limit"of"quantification"
(LLOQ):"25"IU/mL)"
[4]! Fibrosis"Index"Based"on"4"markers"(FIBE4):"changes"of"FIBE4"before"
treatment"and"at"the"endEofEfollowEup"
[5]! FibroScan:" changes" of" liver" stiffness" before" treatment" and" at" the"
endEofEfollowEup"
"
2.3.3!Outcome+measures+
[1]! Efficacy:"sustained"virologic"response"(SVR12),"defined"as"HCV"RNA"<"
LLOQ" 12" weeks" after" the" completion" of" therapy" (Cobas" TaqMan"
HCV"Test"v2.0,"Roche"Diagnostics"GmbH,"Mannheim,"Germany,"low"
limit"of"quantification"(LLOQ):"25"IU/mL)"for"subjects"who"receive"at"
least"one"dose"of"the"study"medications."
[2]! Safety:"treatmentEemergent"AEErelated"withdrawal"rate"for"subjects"
who"receive"at"least"one"dose"of"the"study"drugs."
"
2.4!Study+schedule+
2.4.1!Study+windows+and+rounding+principles+
The"time"windows"allowed"in"the"study"are"listed"below"and"should"be"
followed"unless"otherwise"specified"in"this"protocol."
"
Timeframe+
Allowable+Windows+


35"
"
Screening"visit"
0"
Rescreening"visit"
±"28"days"
Treatment"visits"
±"2"days"
FollowEup"visits"
±"7"days"
End"of"followEup"visit"
±"14"days"
Extended"followEup"visit"
±"14"days"
"
Data" for" the" analyses" will" be" rounded" following" the" standard"
mathematical" or" scientific" principles" where" values" <" 5" will" be" round"
down"whereas"values"≥"5"will"be"round"up"to"the"next"significant"digit."
"
2.4.2!Screening+visit+
At"the"screening"visit,"subjects"who"provide"signed"and"dated"written"
informed"consent"will"undergo"the"study"procedure"identified"in"Section"
2.5" associated" with" the" screening" visit." The" investigator" will" evaluate"
whether"the"subject"meets"all"of"the"eligibility"criteria"during"the"period"
from" the" screening" visit" through" the" start" of" the" treatment" period."
Subjects" who" meet" all" eligibility" criteria" with" the" exception" of"
nonEevaluable" FibroScan" should" undergo" a" liver" biopsy." Liver" biopsy"
should" be" performed" during" the" screening" period" if" all" the" inclusion"
criteria"and"one"of"the"exclusion"criteria"are"met."The"screening"visit"will"
be" conducted" up" to" 28" days" before" the" start" of" the" drug" treatment."
Subjects"who"fail"to"fulfill"initial"screening"can"have"another"rescreening"
which"would"be"spanned"within"28"days"of"the"first"screening."The"study"
is"designed"to"enroll"35"treatmentEnaïve"and"15"treatmentEexperienced"
eligible" subjects" to" meet" the" scientific" objectives." Therefore," if" the"
target"number"of"subjects"has"been"enrolled,"there"is"a"possibility"that"
additional"subjects"undergoing"screening"will"not"be"enrolled."
"
2.4.3!Rescreening+visit+
Subjects"who"meet"all"eligibility"criteria"with"the"exception"of"up"to"3"
exclusionary" laboratory" parameters" may" rescreen" once" within" the"
28Eday" screening" period." However," subjects" with" any" of" the" following"


36"
"
exclusionary"values"will"not"be"allowed"to"rescreen:"
[1]! Positive"hepatitis"B"surface"antigen"
[2]! Positive"HIV"antibody"
[3]! Confirmed"pregnancy"
Subjects"who"fail"to"enroll"within"28"days"of"screening,"regardless"of"the"
reason"for"falling"outside"the"28Eday"screening"window,"may"be"allowed"
to" rescreen" only" once." These" subjects" must" be" rescreened" for" all"
laboratory"and"eligibility"criteria,"not"just"those"that"were"exclusionary"
at"the"first"screening"attempt."
"
2.4.4!Treatment+visit+
After" meeting" the" eligibility" criteria," 35" treatmentEnaïve" and" 15"
treatmentEexperienced" patients" will" be" enrolled" and" assigned" to" 12"
weeks"of"PrOD"treatment."Subjects"will"receive"instructions"about"the"
investigational" drugs" and" the" dosing" schedule" at" the" week" 0" (i.e." day"
1/baseline)" visit." Ombitasvir/paritaprevir/ritonavir" will" be" dosed" orally"
daily" and" dasabuvir" will" be" dosed" orally" twice" daily" as" described" in"
Section" 2.2.7." All" subjects" will" continue" to" return" to" the" site" on" an"
outpatient"basis"up"to"12"weeks"for"the"study"procedures."Sites"should"
ensure"that"subjects"adhere"to"the"study"visits"listed"in"the"flow"chart."
Subjects"who"cannot"complete"the"study"visits"should"ensure"they"do"
not" run" out" of" the" investigational" drugs" prior" to" the" next" study" visit."
Compliance" is" critical" to" ensure" adequate" drug" exposure." Safety" and"
tolerability" of" the" treatment" will" be" assessed" throughout" the" study."
Laboratory" tests" will" include" hematology," biochemistry," coagulation"
profiles," virological," serological" test," and" urinalysis" when" appropriate."
Blood"samples"for"the"RAVs"will"be"collected"as"detailed"in"flow"chart."
Virologic"failure"criteria"will"be"evaluated"and"applied"by"the"investigator"
as" detailed" in" Section" 2.5.4.3." Subjects" who" prematurely" discontinue"
from"the"treatment"should"return"for"a"treatment"discontinuation"visit"
and"undergo"the"study"procedures"as"described"(See"Section"4.2)."
"
2.4.5!FollowIup+visit+


37"
"
All" subjects" who" receive" at" least" one" of" investigational" drugs" after"
treatment" visits" and" either" complete" treatment" or" prematurely"
discontinue" treatment" will" be" monitored" in" the" postEtreatment"
followEup" for" safety," efficacy" and" the" emergence" and" persistence" of"
RAVs"for"additional"24"weeks"following"the"last"dose"of"investigational"
drugs."The"postEtreatment"followEup"will"begin"the"day"following"the"last"
dose"of"investigational"drugs."Subjects"with"HCV"RNA"<LOD"at"the"EOT"
(i.e." endEofEtreatment" virologic" response," EOTVR)" and" who" have" a"
confirmed"HCV"RNA"≥"LOD"at"any"point"in"the"postEtreatment"followEup"
till"12"weeks"after"the"completion"of"therapy"will"be"considered"to"have"
relapsed."
"
2.4.6!End+of+followIup+visit+
Subjects"should"return"to"the"site"for"the"end"of"followEup"visit"at"week"
12"offEtherapy."If"the"subject"prematurely"discontinues"treatment,"then"
he/she"should"have"all"end"of"followEup"visit"during"the"last"site"visit."
The" site" staff" should" contact" the" subjects" who" fail" to" receive" end" of"
followEup"visit"whining"7"days"to"confirm"the"availability"of"efficacy"and"
safety"endpoints."
+
2.4.7!Extended+followIup+visit+
Subjects"are"suggested"return"to"the"site"for"the"extended"followEup"visit"
at" week" 24" offEtherapy." If" the" subject" prematurely" discontinues"
treatment,"then"he/she"should"have"all"end"of"followEup"visit"during"the"
last"site"visit."
"
2.5!Study+ procedures/evaluations+ (See+ summary+ Table+ at+ the+ end+ of+ the+
section)+
The"study"procedures"are"outlined"and"discussed"in"detail"in"this"section"with"
the"exception"of"assessment"of"concomitant"medications"(See"Section"2.1.4.2),"
monitoring" of" treatment" compliance" (See" Section" 2.2.9)," and" collection" of"
adverse"event"(AE)"information"(Section"3)."All"study"data"will"be"recorded"in"
the"subject’s"source"documentation"and"then"the"appropriate"CRF."


38"
"
"
2.5.1!Informed+consent+
Written"informed"consent"will"be"obtained"from"the"subject"before"any"
study"procedures"are"commenced."
"
2.5.2!Demographics,+baseline+values,+medical+history+
Demographics" and" baseline" characteristics" including" the" age," gender,"
race," and" medical" history" will" be" obtained" from" each" patient" who"
provides"written"informed"consent."The"medical"history"will"be"obtained"
by" consulting" the" subjects." If" there" is" uncertainty" with" regard" to" the"
subject’s" medical" history," he/she" may" be" requested" to" provide" the"
related" medical" records" from" the" primary" care" physicians" or" other"
healthEcare" providers," if" appropriate." Methods" of" contraception," if"
applicable,"should"also"be"documented"in"the"source"documents."
"
2.5.3!Clinical+evaluations+
2.5.3.1!Vital+signs,+weight,+height+
Vital" signs" will" include" ear" temperature," pulse" rate" (PR),"
respiratory"rate"(RR)"and"blood"pressure"(BP)."The"subject"should"
wear"lightweight"clothing"and"no"shoes"during"weighing."Height"
will"only"be"measured"at"screening"visit,"and"the"subject"will"not"
wear"shoes."
"
2.5.3.2!Physical+examination+
The"site"investigators"will"perform"the"physical"examination"for"
each"subject"at"the"defined"clinic"visits."The"complete"physical"
examination" will" include" examination" of" all" pertinent" body"
systems" (head" &" neck," chest," heart," abdomen," genitourinary,"
extremities," skin," and" nervous" system)." Furthermore," the" site"
investigators" should" document" the" specific" changes" from"
previous"medical"status."
"
2.5.3.3!Adverse+events+


39"
"
The" site" investigators" are" responsible" for" the" detection" and"
documentation"of"any"event"meeting"the"criteria"and"definition"
of"adverse"events"(AEs)"or"serious"adverse"events"(SAEs)."All"AEs"
and"SAEs"should"be"recorded"by"a"preEspecific"checklist"in"the"
source" documents." The" severity" of" all" constitutional" AEs" is"
graded" according" to" the" Common" Terminology" Criteria" for"
Adverse" Events" (CTCAE)," version" 4.0." Furthermore," the" site"
investigators"should"assess"the"causality"between"the"allocated"
treatment"and"the"AEs"or"SAEs."
"
2.5.4!Laboratory+evaluations+
2.5.4.1!Routine+laboratory+panels+
Hematology," coagulation" profile," biochemistry," serology" and"
urinalysis"panels"performed"at"the"assigned"visits"will"be"shown"
below."
"
Classification+
Item+
Hematology"
Hemoglobin" (Hb)," hematocrit" (HCT)," white" blood" cell"
count"(WBC),"platelet"count"(PLT),"differential"WBC"count,"
mean" corpuscular" volume" (MCV)," mean" corpuscular"
hemoglobin" (MCH)," mean" corpuscular" hemoglobin"
concentration"(MCHC),"red"blood"cell"count"(RBC)"
Coagulation"profile"
Prothrombin" time" (PT)," activated" partial" thromboplastin"
time"(aPTT),"international"normalized"ratio"(INR)"
Biochemistry"
Albumin" (ALB)," total" bilirubin" (TEBIL)," direct" bilirubin"
(DEBIL),"
aspartate"
aminotransferase"
(AST),"
alanine"
aminotransferase" (ALT)," alkaline" phosphatase" (ALP),"
gammaEglutaryl"
transpeptidase"
(γEGT),"
blood"
urea"
nitrogen"(BUN),"creatinine"(CRE),"sodium"(NA),"potassium"
(K),"chloride"(CL),"calcium"(Ca),"inorganic"phosphorus"(P),"
magnesium"(Mg),"uric"acid"(UA),"fasting"glucose"(GLUAC),"
glycated"
hemoglobin"
(HbA1c),"
triglyceride"
(TG),"
cholesterol" (CHO)," low" density" lipoprotein" (LDL)," high"


40"
"
density" lipoprotein" (HDL)," iron" (FE)," total" iron" binding"
capacity"(TIBC),"ferritin"
Serology"
Hepatitis"B"virus"surface"antigen"(HBsAg),"hepatitis"B"virus"
surface"antigen"antibody(antiEHBs),"hepatitis"B"core"
antigen"antibody"(antiEHBc),"hepatitis"C"virus"antibody"
(AntiEHCV),"human"immunodeficiency"virus"antibody"
(AntiEHIV),"alfaEfetoprotein"(AFP)"
Pregnancy"test"
Urine"or"serum"beta"human"chorionic"gonadotropin"
(βEHCG)"
Fibrosis"index"based"on"4"markers"(FIBE4):"an"index"to"assess"the"
severity"of"fibrosis"stages"by"using"age,"platelet"count,"AST,"and"
ALT"levels."The"formula"of"FIBE4"is"shown"as"below:"
"
FIBI4+="
Age"(years)"
x" AST"(IU/L)"
"
"
"
Platelet"count"(109"cells/L)" x"
ALT"(IU/L)1/2"
"
FIBE4"≤"1.45"denotes"a"fibrosis"stage"of"<"F3"
FIBE4">"3.25"denotes"a"fibrosis"stage"of"≥"F3"
"
2.5.4.2!Human+genetic+analysis+
Human" genetic" study" will" be" performed" by" testing" the" single"
nucleotide" polymorphism" (SNP)" at" the" locus" of" rs8099917" for"
interleukin"28B"(IL28B)"gene"(ABI"TaqMan"allelic"discrimination"
kit" and" ABI7900HT" Sequence" Detection" System," Applied"
Biosystems,"Life"Technologies"Corporation,"Grand"Island,"NY)"at"
screening"visit."Subjects"who"do"not"have"available"but"who"can"
be" reached" before" the" trial" completion" will" be" required" to"
perform"this"genetic"study."
"
2.5.4.3!Virology+analyses+
Virology"analyses"performed"at"the"assigned"site"visits"are"shown"
below."
"


41"
"
Classification+
Item+
Virology"
Hepatitis"C"virus"RNA"(HCV"RNA)"
Virology"
Hepatitis"C"virus"genotype"(HCV"genotype)"
Virology"
Resistance"associated"variants"(RAVs)"
"
[1]! HCV" RNA" will" be" tested" by" Cobas" TaqMan" HCV" Test" v2.0"
(Roche"Diagnostics"GmbH,"Mannheim,"Germany,"low"limit"of"
quantification"(LLOQ):"25"IU/mL)"
[2]!
HCV" genotype" will" be" tested" by" Abbott" RealTime" HCV"
genotype"II"(Abbott"Molecular"Inc."Illinois,"USA)"
[3]!
RAV"analysis:"specific"instruction"for"preparation"and"storage"
of"samples"will"be"provided"by"the"central"laboratory,"and"
RAVs"will"be"performed"by"populationEbased"sequencing"at"
sites"of"interest"for"HCV"NS"regions"
The" virological" responses" during" treatment" and" virologic"
outcome"are"listed"below:"
"
Parameter+
Definition"
Very"rapid"virologic"response"(vRVR)"
HCV"RNA"<"LLOQ"at"week"2"of"treatment"
Rapid"virologic"response"(RVR)"
HCV"RNA"<"LLOQ"at"week"4"of"treatment"
EndEofEtreatment"virologic"response"
(EOTVR)"
HCV"RNA"<"LLOQ"at"the"end"of"treatment"
(EOT)"
Sustained"virologic"response"(SVR4)"
HCV"RNA"<"LLOQ"4"weeks"after"the"
completion"of"treatment"
Sustained"virologic"response"(SVR12)"
HCV"RNA"<"LLOQ"12"weeks"after"the"
completion"of"treatment"
Sustained"virologic"response"(SVR24)"
HCV"RNA"<"LLOQ"24"weeks"after"the"
completion"of"treatment"
Virologic"failure"
Failure"to"achieve"SVR"
Relapse"
HCV"RNA"<"LLOQ"at"the"endEofEtreatment,"
but"becoming"detectable"after"the"cessation"
of"treatment"
NullEresponse"
Failure"to"achieve"HCV"RNA"<"LLOQ"by"week"


42"
"
6"
Viral"breakthrough"
HCV"RNA"≥"LLOQ"(defined"as"2"consecutive"
HCV"RNA"measurement"≥"LOD)"at"any"time"
point"after"HCV"RNA"<"LLOQ"during"
treatment"
Increased"from"nadir"HCV"RNA"(defined"as"2"
consecutive"HCV"RNA"measurement"of">"1"
log10"IU/mL"above"nadir)"at"any"time"point"
during"treatment"
Non"virologic"failure"
Subjects"who"fail"to"achieve"SVR"and"who"
cannot"be"categorized"to"relapse,"null"
response"or"viral"breakthrough"
"
Except"for"subjects"with"relapse"or"subjects"who"meet"the"non"
virologic" failure," those" who" meet" the" criteria" for" viral"
breakthrough" or" viral" nullEresponse" should" discontinue" study"
treatment."
"
2.5.4.4!Abdominal+ultrasonography+
GrayEscale" abdominal" ultrasonography" (US)" will" be" recorded" at"
the"time"points"of"screening"visit,"and"EOT"and"EOF."
"
2.5.4.5!Electrocardiogram+(ECG)+
Resting" 12Elead" ECG" will" be" recorded" at" the" time" points" of"
screening"visit,"day"1"of"treatment,"EOT,"EOF"and"the"extended"
followEup."
"
2.5.4.6!FibroScan+and+liver+biopsy+
FibroScan"is"required"at"the"screening"visit"for"all"subjects"who"
are" willing" to" participate" in" the" study." Subjects" with" a"
nonEqualifying" Fibroscan" results" (including" failure" to" measure"
[zero"valid"measurement],"unreliable"measurement"[less"than"10"
valid" measurement," a" successful" rate" of" less" than" 60%" or" the"


43"
"
interquartile" range" more" than" 30%" of" the" median" FibroScan"
score])" are" suggested" to" receive" liver" biopsy" to" confirm" the"
severity"of"hepatic"fibrosis."Liver"biopsy"is"not"optional"and"is"not"
compulsive."FollowEup"Fibroscan"will"be"performed"at"EOT"and"
EOF" for" all" subjects" who" participate" in" the" study," even" if" the"
subject" with" nonEqualifying" FibroScan" evaluation" at" the"
screening"visit."Furthermore,"liver"biopsy"to"stage"the"severity"of"
hepatic"fibrosis"at"EOF"is"also"optional."
"
2.5.4.7!Archive+serum+sample+
Archive" serum" samples" will" be" collected" at" the" study" visits."
Archive" serum" samples" are" being" collected" for" possible"
additional"analyses,"including"but"not"limited"to,"study"drug"or"
metabolite"measurements,"viral"load,"safety/efficacy"assessment,"
HCV"gene"sequencing,"HCV"resistance"testing,"and"other"possible"
predictors"for"treatment"responses."
The" preparation," transport," and" storage" of" the" archive" serum"
samples"will"be"provided"by"the"central"laboratory."


44"
"
Summary'Tables'for'Study'Procedures/Evaluations'
"
Study'Visit'
0'
1'
2'
3'
4'
5'
6'
7'
8'
9'
10'
11'
12'
Procedure'
Screening'
Treatment'
EOT'
FollowGup'
EOF'
Extended'followGup'
Study'Week'
G4'to'G1'
Day'1'
1'
2'
4'
6'
8'
10'
12'
16'
20'
24'
36'
Informed'Consent'
X'
'
'
'
'
'
'
'
'
'
'
'
'
Inclusion/Exclusion'
X'
'
'
'
'
'
'
'
'
'
'
'
'
Demographic'(age,'gender,'race)'
X'
'
'
'
'
'
'
'
'
'
'
'
'
Height'
X'
'
'
'
'
'
'
'
'
'
'
'
'
Weight'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
Medical'History'
X'
'
'
'
'
'
'
'
'
'
'
'
'
Physical'Examination'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
Vital'Signs'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
Adverse'Event'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
'
'
'
Abdominal'US'
X'
'
'
'
'
'
'
'
X'
'
'
X'
'
12Glead'ECG'
X'
X'
'
'
'
'
'
'
X'
'
'
X'
X'
Pregnancy'test'
X'
X'
'
'
X'
'
X'
'
X'
X'
'
'
'
FibroScan'or'Liver'biopsy'
X'
'
'
'
'
'
'
'
X'
'
'
X'
'


45"
"
Study'Visit'
0'
1'
2'
3'
4'
5'
6'
7'
8'
9'
10'
11'
12'
Procedure'
Screening'
Treatment'
EOT'
FollowGup'
EOF'
Extended'followGup'
Study'Week'
G4'to'G1'
Day'1'
1'
2'
4'
6'
8'
10'
12'
16'
20'
24'
36'
Complete'blood'count'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
PT/aPTT'
X'
X'
'
'
'
'
'
'
X'
'
'
X'
X'
Alb'
X'
X'
'
'
'
'
'
'
X'
'
'
X'
X'
TGBil/DGBil'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
AST/ALT'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
ALP/rGGT'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
BUN/Cre'
X'
X'
'
'
'
'
'
'
X'
'
'
X'
X'
Na/K/Cl/Ca/P/Mg'
X'
X'
'
'
X'
'
X'
'
X'
'
'
X'
X'
Uric'acid'
X'
X'
'
'
X'
'
X'
'
X'
'
'
X'
X'
GluAC'
X'
X'
'
'
X'
'
X'
'
X'
'
'
X'
X'
HbA1c'
X'
X'
'
'
'
'
'
'
X'
'
'
X'
X'
TG/TGCHO/HDL/LDL'
X'
X'
'
'
X'
'
X'
'
X'
'
'
X'
X'
Fe/TIBC/ferritin'
X'
X'
'
'
'
'
'
'
X'
'
'
X'
X'
AFP'
X'
X'
'
'
'
'
'
'
X'
'
'
X'
X'
AntiGHCV'
X'
X'
'
'
'
'
'
'
X'
'
'
X'
X'
HBsAg/antiGHBs/antiGHBc/antiGHIV'
X'
'
'
'
'
'
'
'
'
'
'
'
'
HCV'RNA'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
HCV'genotype'
X'
'
'
'
'
'
'
'
'
'
'
'
'
Resistant'variants'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'


46"
"
Archive'serum'sample'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'
X'


47#
#
3.! ADVERSE)EVENT)MANAGEMENT)&)REPORTING)
3.1!Adverse)event) )
An#adverse#event#(AE)#is#defined#as#any#untoward#medical#occurrence#in#a#
patient# or# clinical# investigational# subject# administered# a# pharmaceutical#
product#and#which#does#not#necessarily#have#a#causal#relationship#with#this#
treatment.# An# AE# can# therefore# be# any# unfavorable# and# unintended# sign#
(including# abnormal# laboratory# tests),# symptom,# or# disease# temporally#
associated#with#the#use#of#a#medicinal#or#investigational#product,#whether#or#
not#the#event#is#considered#causally#related#to#the#use#of#the#product.#
An#AE#can#result#from#the#use#of#drugs#stipulated#in#the#protocol#or#labeling,#
as# well# as# from# accidental# or# intentional# overdose,# drug# abuse,# or# drug#
withdrawal.# Any# worsening# of# a# subject’s# preAexisting# health# status# is#
considered# an# AE.# Laboratory# abnormalities# and# changes# in# vital# signs# are#
considered#to#be#AEs#only#if#they#result#in#treatment#discontinuation#or#drug#
dosage#reduction,#necessitate#additional#medical#intervention,#and/or#if#the#
practitioner/investigator#considers#them#to#be#an#AE.#
An#elective#surgery/procedure#scheduled#to#occur#during#a#study#will#not#be#
considered# an# AE# even# if# the# surgery/procedure# is# being# performed# for# a#
preAexisting#condition#and#the#surgery/procedure#has#been#planned#prior#to#
the#study,#and#then#the#deterioration#of#the#condition#for#which#the#elective#
surgery/procedure#is#being#done#will#be#considered#an#AE.#
#
3.2!) Serious)adverse)event)
A# serious# adverse# event# (SAE)# is# any# adverse# event# occurring# for# treated#
patients# during# the# study# period# that# will# results# in# any# of# the# following#
outcomes:#
[1]! Death#
[2]! LifeAthreatening#(subject#at#immediate#risk#of#death)#
[3]! InApatients#hospitalization#or#prolongation#of#existing#hospitalization#
[4]! Congenital#anomaly#or#birth#defect#
[5]! Persistent#or#significant#disability#or#incapacity#
[6]! Important# medical# event# requiring# medical# or# surgical# intervention# to#
prevent#serious#outcome#


48#
#
For#SAEs#with#the#outcome#of#death,#the#date#and#the#cause#of#death#will#be#
recorded#on#the#appropriate#CRF.#
#
3.3!Reporting)and)classification)procedures)
All#constitutional#and#laboratory#AEs#of#the#study#are#graded#according#to#the#
Common#Terminology#Criteria#for#Adverse#Events#(CTCAE),#version#4.0,#which#
can#
be#
available#
by#
visiting#
the#
following#
website#
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010A06A14_QuickReference
_5x7.pdf).#If#the#subject#experiences#the#same#AE#with#more#than#one#grade#
of# intensity,# the# highest# grade# of# intensity# should# be# recorded# in# CRF.# In#
addition# to# grade# the# severity,# the# investigator# should# also# determine# the#
causalArelationship# between# each# AE# or# SAEs# and# the# administered#
investigational#drug(s).#When#assessing#the#relationship#to#the#investigational#
drug(s),#the#most#conservative#evaluation#should#be#adopted.# #
If#a#SAE#occurs#during#the#study#period,#the#investigator#should#immediately#
notify#the#Data#Monitor#and#Safety#Board#(DMSB),#Institutional#Review#Board#
(IRB)/Ethics# Committee# (EC),# and# local# regulatory# authorities.# The# site#
investigator#must#complete#a#SAE#Report#Form#and#is#responsible#to#report#
the# event# to# the# regulatory# authorities# mentioned# above# by# faxing# the#
required#documents.#
)
3.3.1!Severity)of)adverse)event)
The#investigator#will#use#the#following#definition#to#grade#the#severity#of#
each#AE:#
#
Severity*)
Definition)
Grade)1)
Mild;# asymptomatic# or# mild# symptoms;# clinical# or# diagnostic#
observations#only;#intervention#not#indicated#
Grade)2)
Moderate;# minimal,# local# or# noninvasive# intervention# indicated;#
limiting#ageAappropriate#instrumental#activities#of#daily#living#(ADL)#
Grade)3)
Severe# or# medically# significant# but# not# immediate# lifeAthreatening;#
hospitalization# or# prolongation# of# hospitalization# indicated;# disabling;#
limiting#selfAcare#ADL#


49#
#
Grade)4)
LifeAthreatening#consequences;#urgent#intervention#indicated#
Grade)5)
Death#related#to#AE#
*#Not#all#grades#are#appropriate#for#all#AEs.#Therefore,#some#AEs#are#listed#in#CTCAE#v.4.0#with#
fewer#than#five#options#for#Grade#selection.#
)
3.3.2!Relationship)to)investigational)drug)
The# investigator# will# use# the# following# definition# to# assess# the#
relationship#of#the#AE#to#the#use#of#PrOD#
#
Relationship)
Definition)
Reasonable)possibility)
An# AE# where# there# is# evidence# to# suggest# a# causal#
relationship#between#the#study#drug#and#the#AE#
No)reasonable)possibility)
An#AE#where#there#is#no#evidence#to#suggest#a#causal#
relationship#between#the#study#drug#and#the#AE#
#
For# causality# assessments,# events# assessed# as# having# a# reasonable#
possibility#of#being#related#to#the#investigational#drug#will#be#considered#
“associated”.# Events# assessed# as# having# no# reasonable# possibility# of#
being# related# to# the# investigational# drug# will# be# considered# “not#
associated”.# An# AE# will# be# considered# to# be# associated# to# the#
investigational#drug#if#the#investigator#has#not#reported#a#causality#or#
deemed#it#not#assessable.#
)
3.3.3!Pregnancy)
Subjects#and#their#partners#should#avoid#pregnancy#and#males#should#
avoid#sperm#donation#throughout#the#course#of#the#study,#starting#with#
study#day#1#and#for#28#days#after#the#EOT#by#PrOD.#
Information# regarding# a# pregnancy# occurrence# in# a# study# subject# and#
the# outcome# of# the# pregnancy# will# be# collected# for# pregnancies#
occurring#up#to#28#days#after#the#EOT#by#PrOD.#
Subjects#who#discontinue#investigational#drugs#due#to#pregnancy#will#be#
monitored#for#SVR#in#postAtreatment#period.#
Pregnancy# in# a# study# subject# is# not# considered# an# AE.# However,# the#


50#
#
medical# outcome# of# an# elective# or# spontaneous# abortion,# stillbirth# or#
congenital#anomaly#is#considered#a#SAE.#
)
3.3.4!Toxicity)management)
For# the# purpose# of# medical# management,# all# AEs# and# laboratory#
abnormalities#that#occurring#during#the#study#must#be#evaluated#by#the#
investigator.# Toxicity# is# deemed# “clinically# significant”# based# on# the#
judgement# of# the# investigator.# Laboratory# abnormalities# will# be#
managed# as# deemed# clinically# appropriate# by# the# investigator# until#
resolved.#
The#investigator#should#avoid#interruption#investigational#drugs#for#>#7#
consecutive# days.# The# investigator# should# ensure# that# the# study# drug#
interruptions# and# the# associated# AEs# are# promptly# entered# into#
appropriate#CRF.#
#
3.3.4.1!Grade)1)or)2)adverse)events)and)laboratory)abnormalities)
Subjects# who# develop# Grade# 1# or# 2# AEs# or# laboratory#
abnormalities#may#continue#investigational#drugs#with#followAup#
per#study#protocol#and#in#accordance#with#local#standard#of#care.#
(See#Appendix#A)#
#
3.3.4.2!Grade)3,)or)higher)adverse)events)and)laboratory)abnormalities)
[1]! Grade# 3,# or# higher# adverse# events# (severe# or# serious#
adverse#events)#
If# a# subject# experiences# a# severe# or# serious# AE# that# the#
investigator# considers# to# be# a# reasonable# possibility# of#
relationship# to# the# study# drug,# investigator# should# assess#
whether# the# AE# can# be# managed# medically# without#
interruption#of#study#drug,#or#whether#study#drug#should#be#
interrupted# until# it# improves,# or# study# drugs# should# be#
permanently# discontinued.# If# study# drugs# are# interrupted#
and#restarted#and#the#AE#recurs,#then#study#drug#should#be#
permanently#discontinued.#
If# a# subject# experiences# a# severe# or# serious# AE# that# is#
considered# unrelated# (no# reasonable# possibility)# to# the#
study# drugs,# it# is# not# necessary# to# interrupt# study# drugs#
unless#an#interruption#is#required#because#of#the#nature#of#
the# event# (e.g.# unable# to# take# oral# medications).# If# an#


51#
#
interruption#is#required,#it#should#not#exceed#7#days.#
The#investigator#should#ensure#that#all#SAEs#are#reported#to#
DMSB,#IRB/EC,#local#regulatory#authorities#and#the#Sponsor#
within# 24# hours# of# awareness.# SAE# followAup# information,#
including# associated# dose# interruption# or# discontinuation,#
must#also#be#reported#to#these#institutes#within#24#hours#of#
awareness# and# the# information# should# be# promptly#
recorded#in#CRF.#
#
[2]! Grade#3,#or#higher#laboratory#abnormalities#(See#Appendix#
A)#
With#the#exception#of#Grade#3#or#higher#abnormalities#of#
total# bilirubin,# uric# acid,# phosphorous,# total# cholesterol,#
triglyceride,# or# glucose# (in# subjects# with# a# diagnosis# of#
diabetes# mellitus),# if# the# subject# a# Grade# 3# or# higher#
laboratory# parameter# during# the# treatment# period,# the#
abnormal#laboratory#test#should#be#repeated.#If#the#Grade#3#
or#higher#abnormality#is#confirmed,#the#investigator#should#
assess#whether#the#abnormality#can#be#managed#medically#
without#interruption#of#the#study#drugs,#or#whether#study#
drugs# should# be# interrupted# or# permanently# discontinued#
and#the#laboratory#parameter#followed#until#it#improves.#If#
study# drugs# are# interrupted# and# restarted# and# the#
abnormality#
recurs,#
then#
study#
drugs#
should#
be#
permanently#discontinued.#
Elevations# of# serum# AST# or# ALT# should# be# managed#
according# to# the# guidance# in# Section# 3.3.4.3.# Grade# 3# or#
higher#
abnormalities#
of#
total#
bilirubin,#
uric#
acid,#
phosphorus,# total# cholesterol,# triglyceride,# or# glucose# (in#
subjects# with# a# diagnosis# of# diabetes# mellitus)# should# be#
managed# medically# as# appropriate# and# do# not# require#
conformation# or# study# drug# interruption# unless# deemed#
necessary#by#the#investigator.#
#
3.3.4.3!Management)of)transaminase)elevations)
Transient#asymptomatic#Grade#3#or#higher#ALT#elevations#have#
been# observed# in# approximately# 1%# of# subjects# receiving#
paritaprevir/ritonavirAcontaining#
regimens.#
If#
a#
subject#


52#
#
experiences#an#increase#in#ALT#>#10X#ULN,#or#to#>#5X#ULN#which#
was#increased#from#previous#measurement,#the#subject#should#
have# a# confirmatory# ALT# measurement# performed# in# a# timely#
fashion.# If# the# ALT# increase# in# confirmed,# the# management#
guideline# should# be# followed# (See# Table# “Management# of#
Confirmed#
ALT#
Elevations”).#
Subject#
using#
an#
estrogenAcontaining# product# should# discontinue# use# of# that#
product.#
#
Management)of)Confirmed)ALT)Elevations#
ALT#≥#20X#ULN#
•!
Permanently#discontinue#study#drugs.#
•!
Manage#the#subject#as#medically#appropriate.#
ALT#≥#10X#ULN#
or#
ALT# ≥# 5X# ULN# and# increased#
from# previous# measurement#
with# symptoms# and# signs# of#
hepatitis#present#
•!
If# using# and# estrogenAcontaining# product:#
discontinue# estrogenAcontaining# product# and#
repeat#ALT#testing,#preferably#within#1#week.#
•!
Repeat# ALT,# AST,# TABil,# DABil,# ALP,# and# INR,#
preferably#within#1#week#
•!
Evaluate# for# alterative# etiology# of# ALT#
elevation:#
update#
medical#
history#
and#
concomitant# medications# CRF# (if# applicable),#
and#obtain#appropriate#testing#as#appropriate.#
•!
Manage#the#subject#as#medically#appropriate.#
•!
Permanently#discontinue#study#drugs#for#any#
of# the# following:# ALT# level# increase# to# 20X#
ULN,#increasing#DABil,#increasing#INR,#or#new#
symptoms/signs#of#hepatitis.#
ALT# ≥# 5X# ULN# and# increased#
from# previous# measurement,#
but# <# 10X# ULN# and# without#
symptoms#or#signs#of#hepatitis#
•!
Continue#study#drugs.#
•!
As# soon# as# possible,# measure# ALT,# AST,# TABil,#
DABil,#ALP#and#INR.#Repeat#liver#chemistry#as#
indicated#
until#
resolution.#
Evaluate#
for#
alternative# etiology# of# ALT# elevation:# update#
medical#history#and#concomitant#medications#
CRF# (if# applicable),# and# obtain# additional#
testing#as#appropriate.#
•!
Manage#the#subject#as#medically#appropriate.#
•!
Permanently#discontinue#study#drugs#for#any#
of# the# following:# ALT# level# increase# to# 20X#
ULN,#increasing#DABil,#increasing#INR,#or#new#


53#
#
symptoms/signs#of#hepatitis.#


54#
#
4.! DOSE)INTERRUPTION,)DISCONTINUATION)RULES)
4.1!Dose)interruption)
If#a#subject#cannot#take#his/her#study#drugs#according#to#protocol#specific#day#
due#to#AE,#the#subject#should#be#treated#for#the#event#when#appropriate.#In#
addition,#the#subject#should#return#to#the#clinic#as#soon#as#possible#to#receive#
the#scheduled#dosing#within#the#timeframe#(See#Section#2.4.1).#If#the#subject#
fails#to#receive#the#assigned#study#drugs#within#the#timeframe,#he/she#should#
skip#this#dosing#and#return#to#the#clinic#for#the#next#protocol#specific#dosing#
day.#If#an#interruption#is#required,#it#should#not#exceed#7#days.#
#
4.2!Dose)discontinuation)
Subjects#who#meet#the#one#of#the#following#criteria#will#be#discontinued#from#
the#study#
[1]! Serious#adverse#events#(SAEs)#
[2]! Subjectively#wish#to#discontinue#further#treatment#
[3]! Pregnancy#
[4]! Null#response#to#treatment#
[5]! Viral#breakthrough#under#treatment#
[6]! Subject’s#nonAcompliance#with#the#protocol#
At#any#time,#if#the#site#investigator#thinks#that#the#study#is#no#longer#in#the#
best# interest# for# the# patient,# then# the# patients# should# be# discontinued# for#
further#treatment.#
#
4.3!Subject)withdrawal)and)replacement)
Subjects# may# withdrawal# from# the# trials# at# any# time# for# any# reasons.# Any#
subjects# who# are# withdrawn# from# the# trials# are# encouraged# to# receive#
offAtherapy# study# visits# to# assess# the# efficacy# and# safety.# The# timing# and#
reasons#for#treatment#withdrawal#should#be#documented#by#investigator#in#
the#CRF.#
Eligible#subjects#who#are#scheduled#for#treatment#but#who#do#not#receive#any#
study# drugs# will# be# replaced# and# will# not# be# considered# in# the# analyses# of#
efficacy#and#safety#endpoints.#Subjects#who#receive#at#least#one#dose#of#the#
study#drugs#and#who#prematurely#discontinue#treatment#will#not#be#replaced.#


55#
#
5.! PROTOCOL)DEVIATION)
The#investigator#should#not#implement#any#deviation#from#the#protocol#without#
prior#review#and#agreement#by#the#Sponsor#and#in#accordance#with#EC#and#local#
regulatory#authorities,#except#when#necessary#to#eliminate#an#immediate#hazard#
to#study#subjects.#When#a#deviation#from#the#protocol#is#deemed#necessary#for#
an#individual#subject,#the#investigator#must#contact#the#Sponsor#and#the#study#
coordinator.# Any# significant# protocol# deviations# affecting# the# subject# eligibility#
and/or#safety#must#be#reviewed#and/or#approved#by#IRB/EC#and#local#regulatory#
authorities,#as#applicable,#prior#to#implementation.#


56#
#
6.! STATISTICAL)CONSIDERATION)
6.1!Sample)size)determination)
[1]! TreatmentAnaïve#HCV#GT1b#patients:# #
Based# on# the# assumption# that# the# SVR# rate# of# treatmentAnaïve# HCV#
GTA1b#patients#who#receive#48#weeks#of#peginterferon#alfaA2a#plus#low#–
dose#RBV#group#is#64%,#we#estimate#that#a#total#of#35#patients#would#
provide# 90%# power# to# detect# an# absolute# increase# in# SVR# with# PrOD#
therapy#of#30%#points#or#more#(2Asided#alpha#=#0.05).31#
[2]! TreatmentAexperienced#HCV#GTA1b#patients:# #
It# is# not# designed# to# evaluate# formal# statistical# hypotheses,# and# no#
sample#size#calculation#performed#because#of#the#lack#of#SVR#rate#data#
by#peginterferon#alfaA2a#plus#lowAdose#RBV#retreatment.#The#estimated#
sample#size#in#treatmentAexperienced#subjects#is#15.#
[3]! Estimated#timeframe#for#completing#the#enrollment:#24#weeks#
#
6.2!Definition)of)primary)endpoints)
[1]! Primary# efficacy# endpoint:# SVR12# rate,# defined# as# subjects# with# serum#
HCV#RNA#<LOD#12#weeks#after#the#cessation#of#treatment#by#a#sensitive#
HCV#RNA#test#(Abbott#RealTime#HCV,#Limit#of#detection#(LOD):#12#IU/mL;#
Abbott#Park,#Illinois,#USA)#divided#by#total#enrolled#subjects#in#each#arm#
for#subjects#who#receive#at#least#one#dose#of#the#study#medication.#
[2]! Primary#safety#endpoint:#adverse#event#(AE)Arelated#withdrawal#rate#for#
subjects#who#receive#at#least#one#dose#of#the#study#medication.#
#
6.3!Analyses)for)primary)efficacy)endpoint)
The#efficacy#endpoint#is#SVR12,#and#subjects#who#do#not#meet#the#criteria#for#
SVR#are#considered#not#to#achieve#SVR12.#The#clinical#scenarios#for#subjects#
who# fail# to# achieve# SVR12# include:# virologic# failure,# including# relapse,#
nullAresponse,# viral# breakthrough,# and# non# virologic# failure# (See# Section#
2.5.4.3).#
Subjects# who# are# categorized# as# nullAresponse# or# viral# breakthrough# are#
considered#nonASVR#regardless#of#the#availability#of#the#end#of#followAup#HCV#
RNA#data.#


57#
#
Subjects#(except#nullAresponse#and#viral#breakthrough)#are#considered#failure#
to#achieve#SVR12#even#if#they#do#not#have#available#end#of#followAup#HCV#RNA#
data.#
To#test#the#hypothesis#that#the#SVR12#rate#of#treatmentAnaïve#patients#who#
receive#PrOD#for#12#weeks#is#superior#to#those#who#receive#peginterferon#plus#
lowAdose# RBV# for# 48# weeks,# the# percentages# of# subjects# with# SVR12# in#
patients#will#be#calculated#with#a#2Asided#95%#confidence#interval#(CI)#using#
Wilson#score#method,#and#the#lower#confidence#bound#will#be#compared#to#
the#defined#threshold.#The#lower#confidence#bound#must#be#greater#than#64%#
in#order#for#the#regimen#to#be#considered#superior.#
#
6.4!Analysis)for)primary)safety)endpoint)
The# safety# endpoint# is# treatmentAemergent# adverse# event# (AE)Arelated#
withdrawal# rate# for# subjects# who# receive# at# least# one# dose# of# the# study#
medication.#The#proportions#of#AEArelated#withdrawal#rate#in#the#study#are#
reported# by# number# (percentage)# as# appropriate.# We# will# not# report# the# P#
value#because#the#estimated#sample#sizes#in#this#trial#are#aimed#to#detect#the#
differences# of# efficacy# endpoint,# rather# than# the# differences# of# safety#
endpoint.#
)
6.5!Sensitivity)analysis)for)the)primary)efficacy)endpoint)
In#addition#to#presenting#the#primary#efficacy#endpoint#(SVR12),#SVR12#will#be#
presented# using# the# following# other# methods# to# impute# missing#
postAtreatment#virologic#results:#
[1]! Imputing#any#missing#HCV#RNA#values#in#the#SVR12#window#by#carrying#
forward#the#last#nonAmissing#(postAbaseline)#HCV#RNA#value#prior#to#the#
SVR12#window#
[2]! Imputing# as# any# missing# HCV# RNA# values# in# the# SVR12# window# but#
exclude# the# subjects# who# are# categorized# as# “prematurely# discontinue#
study# drugs# with# no# noAtreatment# virologic# failure”# and# “missing#
followAup#data#in#the#postAtreatment#period”#
#
6.6!Subgroup)analyses)


58#
#
The# SVR12# will# be# presented# in# percentage# with# 2Asided# 95%# CI# in# the#
following#subgroups:#
[1]! Age#(<#55#versus#≥#55#yeas)#
[2]! Sex#(male#versus#female)#
[3]! BMI#(<#25#versus#≥#25#kg/m2)#
[4]! Baseline#HCV#RNA#level#(<#800,000#versus#≥#800,000#IU/mL)#
[5]! IL28B#genotype#rs8099917#(TT#versus#nonATT)#
[6]! Fibrosis#stage#(<#F2#versus#≥#F2)#by#FibroScan#and/or#liver#biopsy#
#
6.7!Additional)efficacy)endpoint)
[1]!
SVR24:#HCV#RNA#level#<#LLOQ#24#weeks#after#the#completion#of#therapy#
(Cobas# TaqMan# HCV# Test# v2.0,# Roche# Diagnostics# GmbH,# Mannheim,#
Germany,#low#limit#of#quantification#(LLOQ):#25#IU/mL)#
[2]!
Rapid#virological#response#(RVR):#HCV#RNA#level#<#LLOQ)#at#week#4#of#
treatment(Cobas# TaqMan# HCV# Test# v2.0,# Roche# Diagnostics# GmbH,#
Mannheim,#Germany,#low#limit#of#quantification#(LLOQ):#25#IU/mL)#
[3]!
EndAofAtreatment#virological#response#(EOTVR):#HCV#RNA#level#<#LLOQ#
at# the# end# of# treatment# (Cobas# TaqMan# HCV# Test# v2.0,# Roche#
Diagnostics# GmbH,# Mannheim,# Germany,# low# limit# of# quantification#
(LLOQ):#25#IU/mL)#
[4]!
Fibrosis# index# based# on# 4# markers# (FIBA4):# changes# of# FIBA4# before#
treatment#and#at#the#endAofAfollowAup#
[5]!
FibroScan:# changes# of# liver# stiffness# before# treatment# and# at# the#
endAofAfollowAup#
)
6.8!Resistance)analyses)
Only# samples# with# an# HCV# RNA# level# of# ≥# 1,000# IU/mL# will# undergo#
population# sequence# analysis# in# order# to# allow# accurate# assessment# of# the#
product# amplification.# For# subjects# who# experience# virologic# failure,# the#
sample#closest#in#time#after#with#an#HCV#RNA#level#of#≥#1,000#IU/mL#will#be#
used# if# the# HCV# RNA# level# at# the# time# of# failure# is# <# 1,000# IU/mL.# The#
prototype# reference# strain# with# its# associated# GenBank# Accession# ID# for#
sequence#analyses#is#1bACon1#(AJ238799)#


59#
#
For#PrOD#treatment,#resistanceAassociated#signature#amino#acid#variants#will#
be# identified# as# appropriate.# Amino# acid# positions# where# RAVs# have# been#
identified#in%vitro#and/or#in%vivo#in#HCV#GTA1b#are#shown:#
#
Direct)Acting)Antiviral)
Amino)Acid)Position)for)HCV)GTW1b)RAVs)
Paritaprevir#(NS3)#
56,#155,#156,#168#
Ombitasvir#(NS5A)#
28,#29,#30,#31,#32,#58,#93#
Dasabuvir#(NS5B)#
316,#368,#411,#414,#445,#448,#453,#553,#556,#558,#559#
#
The#following#definition#will#be#used#in#the#resistance#analyses:#
[1]! Baseline#sample:#sample#collected#before#the#first#dose#of#PrOD.#
[2]! Baseline# variant:# a# variant# (by# population# sequencing)# in# a# baseline#
sample#determined#by#comparison#of#the#amino#acid#sequence#of#the#
baseline# sample# to# the# appropriate# prototypic# reference# amino# acid#
sequence#for#a#given#target#at#the#NS3,#NS5A#and#NS5B#region.#
[3]! PostAbaseline#variant#by#population#sequencing:#an#amino#acid#variant#in#
a#postAbaseline#time#point#sample#that#is#not#detected#at#baseline#in#the#
subject#and#is#detectable#by#population#sequencing.#
[4]! Emerged#variant#by#population#sequencing:#a#postAbaseline#variant#that#
is# observed# in# 2# or# more# subjects# of# the# same# subgenotype# by#
population#sequencing.#
[5]! Linked# variant# by# population# sequencing:# 2# or# more# signature# or#
emerged#amino#acid#variants#identified#within#a#sample#by#population#
sequencing#where#at#least#one#of#the#variants#is#at#a#signature#position,#
and#no#mixture#amino#acids#is#detected#at#either#position.#
For#those#samples#to#be#evaluated,#a#listing#by#subject#of#all#baseline#variants#
relative#
to#
the#
prototypic#
reference#
sequence#
at#
signature#
resistanceAassociated#amino#acid#positions#will#be#provided#for#each#target#of#
PrOD#regimen.#Furthermore,#the#HCV#amino#acid#sequence#at#postAbaseline#
time#points#with#an#HCV#RNA#level#of#≥#1,000#IU/mL#that#are#analyzed#will#be#
compared#to#the#baseline#and#prototypic#reference#amino#acid#sequences.#A#
listing#by#subject#and#time#point#of#all#postAbaseline#variants#relative#to#the#
baseline# amino# acid# sequences# will# be# provided# for# paritaprevir# (NS3),#


60#
#
ombitasvir#(NS5A)#and#dasabuvir#(NS5B).#In#addition,#a#listing#by#subject#and#
time# point# of# all# postAbaseline# variants# at# signature# resistanceAassociated#
amino# acid# positions# relative# to# the# prototypic# reference# amino# acid#
sequences# will# be# provided.# Furthermore,# the# number# and# percentage# of#
subjects#with#emerged#variants#by#amino#acid#position#and#variant#within#a#
DAA#target#as#compared#to#baseline#will#be#summarized.#
The# number# and# percentage# of# subjects# with# linked# variants# by# population#
sequencing#within#paritaprevir,#ombitasvir#and#dasabuvir#will#be#summarized.#
In# addition# to# a# listing# of# linked# variants# by# subject# and# time# point# will# be#
provided#for#each#DAA#target.#
The# persistence# of# resistanceAassociated# substitutions# that# emerged# for#
paritaprevir,# ombitasvir,# and# dasabuvir# will# be# assessed# by# population#
sequencing#at#selected#postAtreatment#time#point.#Listing#by#subject#and#time#
point# of# all# postAtreatment# variants# relative# to# the# baseline# amino# acid#
sequence#will#be#provided#for#each#DAA#target.#
#
6.9!Adverse)events)
The#number#and#percentage#of#subjects#with#treatmentAemergent#AEs#after#
initiation#of#study#drugs#through#28#days#after#the#last#dose#of#study#drugs#will#
be#tabulated#and#provided#according#to#definition#provided#by#CTCAE,#version#
4.0.# In# addition,# the# number# and# percentage# of# subjects# with# SAEs# ad# the#
number#and#the#number#of#percentage#of#subjects#with#treatmentAemergent#
AEs#leading#to#treatment#discontinuation#will#also#be#provided.#
Subjects# with# more# than# one# AE# defined# by# CTCAE,# version# 4.0,# will# be#
counted# only# once# for# that# term# using# the# most# severe# incidence# for# the#
severity#rating#table#and#the#most#related#for#the#relationship#to#study#drug#
table.#
#
6.10! Clinical)laboratory)data)
Clinical#laboratory#tests#will#be#summarized#in#each#study#visit.#The#baseline#
value# will# be# the# last# measurement# prior# to# the# initial# dose# of# study# drug.#
Laboratory# data# values# collected# during# the# treatment# period# will# be#
categorized# as# low,# normal,# or# high# based# on# reference# ranges# of# the#


61#
#
laboratory#used#in#this#study.#The#number#and#percentage#of#subjects#who#
experience# postAbaseline# changes# during# treatment# in# clinical# laboratory#
values#from#low/normal#to#high#and#high/normal#to#low#based#in#the#normal#
range#will#be#summarized.#
Additional#analyses#will#be#performed#if#useful#and#appropriate.#
#


62#
#
7.! STUDY)ADMINISTRATION)
7.1!Regulatory)and)ethical)consideration)
7.1.1! Institutional)review)board/ethics)committee)approval)
It# is# the# investigator’s# responsibility# to# ensure# that# the# protocol# is#
reviewed#and#approved#by#an#appropriate#Institutional#Review#Board#
(IRB)#or#Ethics#Committee#(EC).#The#investigator#must#also#submit#the#
informed#consent#form,#any#other#written#documents#for#the#subject,#
and#all#advertisements#that#may#be#used#for#subject#recruitment#to#
the#IRB/EC#for#review#and#approval#before#commencing#studyAspecific#
activities.#If#there#would#be#any#protocol#amendment#during#the#study,#
it#is#the#investigator’s#responsibility#to#submit#the#related#documents#
to#
IRB/EC#
and#
ensure#
to#
obtain#
IRB/EC#
approval#
before#
implementation# of# any# amended# procedures.# It# is# also# the#
investigator’s#responsibility#to#submit#any#SAE#report,#regular#progress#
report#to#IRB/EC,#and#receive#scheduled#or#unAscheduled#monitoring#
from#IRB/EC.#
#
7.1.2! Ethical)conduct)of)the)study)
The# study# will# be# conducted# in# accordance# with# the# protocol,#
International#
Conference#
on#
Harmonization#
(ICH)#
guidelines,#
applicable#regulations#and#guidelines#governing#clinical#study#conduct#
and#the#ethical#principle#that#have#their#origin#in#the#Declaration#of#
Helsinki.# Responsibilities# of# the# clinical# investigator# are# specified# as#
followed:#
[1]! Conducting# the# study# in# accordance# with# the# relevant,# current#
protocol,# making# changes# in# a# protocol# only# after# notifying#
IRB/EC,# local# regulatory# authorities,# and# the# Sponsor,# except#
when# necessary# to# protect# the# safety,# rights# or# welfare# of#
subjects#
[2]! Personally#
conducting#
or#
supervising#
the#
described#
investigation(s)#
[3]! Informing# all# subjects# that# the# drugs# are# being# used# for#
investigational# purposes# and# complying# with# the# requirements#


63#
#
relating#to#informed#consent#and#IRB/EC#review#and#approval#of#
the#protocol#and#amendments#
[4]! Reporting# adverse# experiences# that# occur# in# the# course# of# the#
investigation(s)# to# the# principle# investigator,# IRB/EC,# local#
regulatory#authorities,#and#the#Sponsor#
[5]! Reading# the# safety# information# in# the# protocol,# including# the#
instructions#for#use#and#the#potential#risks#and#side#effects#of#the#
investigational#product(s)#
[6]! Informing# all# associates,# colleagues,# and# employees# assisting# in#
the#conduct#of#the#study#about#their#obligations#in#meeting#the#
above#commitments#
[7]! Maintaining# adequate# and# accurate# records# of# the# conduct#
during#the#study,#making#those#records#available#for#inspection#by#
IRB/EC,#local#regulatory#authorities,#and#the#Sponsor#
[8]! Maintaining# records# demonstrating# that# an# EC# reviews# and#
approves#the#initial#clinical#investigation#and#all#amendments#
[9]! Reporting# promptly,# all# changes# in# the# research# activity# and# all#
unanticipated# problems# involving# risks# to# human# subjects# or#
others,# to# the# appropriate# individuals# and/or# directly# to# the#
IRB/EC,#local#regulatory#authorities#and#the#Sponsor#
[10]!Following#the#protocol#and#not#make#any#changes#in#the#research#
without# IRB/EC# approval,# except# where# necessary# to# eliminate#
the#apparent#immediate#hazards#to#human#subjects#
#
7.1.3! Subject)informed)consent)
Before#enrollment,#the#subject#must#provide#written#informed#consent#
form#to#the#investigator#in#accordance#to#ethical#regulations.#A#copy#of#
the# informed# consent# form# will# be# given# to# the# subject# and# the#
original# one# will# be# placed# in# the# subject’s# medical# record.# The#
International# Conference# on# Harmonization# (ICH)# required# elements#
and# Health# Insurance# Portability# and# Accountability# Act# (HIPAA)#
authorization#in#language#that#is#readable#an#understandable#to#the#
subject.#


64#
#
#
7.2!Data)collection)
7.2.1!Source)documents)
Source# documents# are# defined# as# original# documents,# data# and#
records.#This#may#include#hospital#records,#clinical#and#office#charts,#
laboratory#
data/information,#
evaluation#
checklist,#
pharmacy#
dispensing# and# other# records,# recorded# data# from# automated#
instruments,# microfiches,# photographic# negatives,# microfilm# or#
magnetic#media#and/or#XArays.#Data#collected#during#the#study#must#
be#recorded#by#the#investigator#on#the#appropriate#source#documents.#
The#investigator(s)/institution(s)#will#permit#studyArelated#monitoring,#
IRB/EC#audit,#and#regulatory#inspection(s),#providing#direct#access#to#
source#documents.#
#
7.2.2!Case)report)forms)
Case#report#form#(CRF)#must#be#completed#for#each#subject#screened#
or# enrolled# in# this# study.# These# forms# will# be# used# to# transmit#
information#collected#during#the#study#to#the#Sponsor#and#the#local#
regulatory#authorities,#as#applicable.#An#electronic#CRF#(eCRF)#will#be#
provided#for#the#study.#All#data#should#be#entered#into#eCRF#within#3#
days#after#the#subject’s#visit.#After#the#subject#has#completed#the#trial,#
the#principle#investigator#in#each#site#must#review#the#eCRF#and#sign#
the#signature#page#of#the#eCRF#to#confirm#he/she#has#reviewed#all#the#
data#in#eCRF#that#are#pertinent#to#the#subject.# #
#
7.3!Record)retention)
The#site#should#retain#a#copy#of#all#the#study#records#for#the#study#subjects#in#
a# secure# and# accessible# location# for# a# minimum# of# 10# years# after# the#
completion# of# the# study.# Study# records# will# contain# the# appropriate#
documents# which# are# conformed# to# the# recommendation# by# International#
Conference#on#Harmonization#for#Good#Clinical#Practice#(ICHAGCP).#
#
7.4!Information)disclosure)


65#
#
7.4.1! Confidentiality)
The#name#of#each#subject#will#be#kept#confidential.#The#subject’s#code#
number,#subject’s#initial,#and#date#of#birth#will#be#recorded#in#eCRF.#All#
the#findings#in#the#study#will#be#stored#in#electronic#database.#Subject#
will# be# informed# that# all# personal# information# made# available# for#
inspection#will#be#protected#in#strict#confidence.#
#
7.4.2! Completion)of)the)study)
The# investigator# will# conduct# the# study# in# compliance# with# the#
protocol#and#complete#the#study#within#the#timeframe#specified#in#the#
contract# between# the# investigator# and# the# Sponsor.# Continuation# of#
this#study#beyond#this#date#must#be#mutually#agreed#upon#writing#by#
both#the#investigator#and#the#Sponsor.#The#investigator#will#provide#a#
final#report#to#the#IRB/EC#following#completion#of#the#study,#and#will#
forward#a#copy#of#this#report#to#the#Sponsor.#
#
7.4.3! Publication)policy)
The# investigators# are# intended# to# publish# the# results# in# the# form# of#
interim#analysis#or#final#completion#report#to#the#conference#meeting#
or#related#journals#as#appropriate#within#a#reasonable#period#of#time#
after#completion#of#the#study.#The#Sponsor#will#determine#the#timing#
for#data#disclosure#when#appropriate.#


66#
#
8.! REFERENCES)
1.! Berenguer# M.# Treatment# of# chronic# hepatitis# C# in# hemodialysis# patients.#
Hepatology#2008;48:1690A9.#
2.! Martin# P,# Fabrizi# F.# Hepatitis# C# virus# and# kidney# disease.# J# Hepatol#
2008;49:613A24.#
3.! Liu# CH,# Kao# JH.# Treatment# of# hepatitis# C# virus# infection# in# patients# with#
endAstage#renal#disease.#J#Gastroenterol#Hepatol#2011;26:228A39.#
4.! Fabrizi# F,# Messa# P,# Martin# P.# Transmission# of# hepatitis# C# virus# infection# in#
hemodialysis:#current#concepts.#Int#J#Artif#Organs#2008;31:1004A16.#
5.! Mohd#Hanafiah#K,#Groeger#J,#Flaxman#AD,#Wiersma#ST.#Global#epidemiology#
of#hepatitis#C#virus#infection:#new#estimates#of#ageAspecific#antibody#to#HCV#
seroprevalence.#Hepatology#2013;57:1333A42.#
6.! Liu#CH,#Liang#CC,#Liu#CJ,#et#al.#Pegylated#interferon#alfaA2a#monotherapy#for#
hemodialysis#patients#with#acute#hepatitis#C.#Clin#Infec#Dis#2010;51:541A9.#
7.! Messina#JP,#Humphreys#I,#Flaxman#A,#et#al.#Global#distribution#and#prevalence#
of#hepatitis#C#virus#genotypes.#Hepatology#2015;61:77A87.#
8.! Pol# S,# Thiers# V,# Nousbaum# JB,# et# al.# The# changing# relative# prevalence# of#
hepatitis# C# virus# genotypes:# evidence# in# hemodialyzed# patients# and# kidney#
recipients.#Gastroenterology#1995;108:581A3.#
9.! Azevedo#HA,#VillelaANogueira#CA,#Perez#RM,#et#al.#Similar#HCV#viral#load#levels#
and# genotype# distribution# among# endAstage# renal# disease# patients# on#
hemodialysis#and#HCVAinfected#patients#with#normal#renal#function.#J#Nephrol#
2007;20:609A16.#
10.!Fabrizi# F,# Takkouche# B,# Lunghi# G,# Dixit# V,# Messa# P,# Martin# P.# The# impact# of#
hepatitis# C# virus# infection# on# survival# in# dialysis# patients:# metaAanalysis# of#
observational#studies.#J#Viral#Hepat#2007;14:697A703.#
11.!Ingsathit#A,#Kamanamool#N,#Thakkinstian#A,#Sumethkul#V.#Survival#advantage#
of# kidney# transplantation# over# dialysis# in# patients# with# hepatitis# C:# a#
systematic#review#and#metaAanalysis.#Transplantation#2013;95:943A8.#
12.!Rostami#Z,#Nourbala#MH,#Alavian#SM,#Bieraghdar#F,#Jahani#Y,#Einollahi#B.#The#
impact#of#hepatitis#C#virus#infection#on#kidney#transplantation#outcomes:#a#
systematic# review# of# 18# observational# studies:# the# impact# of# HCV# on# renal#
transplantation.#Hepat#Mon#2011;11:247A54.#


67#
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Am#Soc#Nephrol#2011;6:2226A34.#
15.!Huraib#S,#Iqbal#A,#Tanimu#D,#Abdullah#A.#Sustained#virological#and#histological#
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with#chronic#viral#hepatitis#C.#Am#J#Nephrol#2001;21:435A40.#
16.!Russo#MW,#Goldsweig#CD,#Jacobson#IM,#Brown#RS#Jr.#Interferon#monotherapy#
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efficacy#and#safety.#Am#J#Gastroenterol#2003;98:1610A5.#
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systematic# review# of# the# literature# and# metaAanalysis# of# treatment# efficacy#
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patients#with#chronic#hepatitis#C#virus#infectionAAa#pilot#study.#J#Viral#Hepat#
2001;8:287A92.#
20.!Tan#AC,#Brouwer#JT,#Glue#P,#et#al.#Safety#of#interferon#and#ribavirin#therapy#in#
haemodialysis# patients# with# chronic# hepatitis# C:# results# of# a# pilot# study.#
Nephrol#Dial#Transplant#2001;16:193A5.#
21.!Mousa#DH,#Abdalla#AH,#AlAShoail#G,#AlASulaiman#MH,#AlAHawas#FA,#AlAKhader#
AA.#AlphaAinterferon#with#ribavirin#in#the#treatment#of#hemodialysis#patients#
with#hepatitis#C.#Transplant#Proc#2004;36:1831A4.#
22.!Bruchfeld# A,# Lindahl# K,# Reichard# O,# Carlsson# T,# Schvarcz# R.# Pegylated#
interferon#and#ribavirin#treatment#for#hepatitis#C#in#haemodialysis#patients.#J#
Viral#Hepat#2006;13:316A21.#
23.!Rendina# M,# Schena# A,# Castellaneta# NM,# et# al.# The# treatment# of# chronic#
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68#
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patients#awaiting#renal#transplant.#J#Hepatol#2007;46:768A74.#
24.!Carriero# D,# Fabrizi# F,# Uriel# AJ,# Park# J,# Martin# P,# Dieterich# DT.# Treatment# of#
dialysis# patients# with# chronic# hepatitis# C# using# pegylated# interferon# and#
lowAdose#ribavirin.#Int#J#Artif#Organs#2008;31:295A302.#
25.!van#Leusen#R,#Adang#RP,#de#Vries#RA,#et#al.#Pegylated#interferon#alfaA2a#(40#kD)#
and#ribavirin#in#haemodialysis#patients#with#chronic#hepatitis#C.#Nephrol#Dial#
Transplant#2008;23:721A5.#
26.!Hakim#W,#Sheikh#S,#Inayat#I,#et#al.#HCV#response#in#patients#with#end#stage#
renal# disease# treated# with# combination# pegylated# interferon# alphaA2a# and#
ribavirin.#J#Clin#Gastroenterol#2009;43:477A81.#
27.!Liu# CH,# Liang# CC,# Liu# CJ,# et# al.# Pegylated# interferon# alfaA2a# plus# low# dose#
ribavirin# for# the# retreatment# of# dialysis# chronic# hepatitis# C# patients# who#
relapsed#from#prior#interferon#monotherapy.#Gut#2009;58:314A6.#
28.!Deltenre#P,#Moreno#C,#Tran#A,#et#al.#AntiAviral#therapy#in#haemodialysed#HCV#
patients:#efficacy,#tolerance#and#treatment#strategy.#Aliment#Pharmacol#Ther#
2011;34:454A61.#
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2011;18:e263A9.#
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31.!Liu# CH,# Huang# CF,# Liu# CJ,# et# al.# Pegylated# interferonAα2a# with# or# without#
lowAdose# ribavirin# for# treatmentAnaive# patients# with# hepatitis# C# virus#
genotype# 1# receiving# hemodialysis:# a# randomized# trial.# Ann# Intern# Med#
2013;159:729A38.#
32.!Liu#CH,#Liu#CJ,#Huang#CF,#et#al.#Peginterferon#alfaA2a#with#or#without#lowAdose#
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receiving#haemodialysis:#a#randomised#trial.#Gut#2015;64:303A11.#
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telaprevir# in# haemodialysed# HCV# patients:# is# it# feasible?# J# Clin# Virol#
2013;56:146A9.#
34.!Wiegand#J,#Maasoumy#B,#Buggisch#P,#et#al.#Letter:#Telaprevir#triple#therapy#in#


69#
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chronic# hepatitis# C# genotype# 1# patients# receiving# haemodialysis.# Aliment#
Pharmacol#Ther#2014;39:1342A4.#
35.!Feld# JJ,# Kowdley# KV,# Coakley# E,# et# al.# Treatment# of# HCV# with#
ABTA450/rAombitasvir# and# dasabuvir# with# ribavirin.# N# Engl# J# Med#
2014;370::1594A603.#
36.!Zeuzem# S,# Jacobson# IM,# Baykal# T,# et# al.# Retreatment# of# HCV# with#
ABTA450/rAombitasvir# and# dasabuvir# with# ribavirin.# N# Engl# J# Med#
2014;370:1604A14.#
37.!Poordad#F,#Hezode#C,#Trinh#R,#et#al.#ABTA450/rAombitasvir#and#dasabuvir#with#
ribavirin#for#hepatitis#C#with#cirrhosis.#N#Engl#J#Med#2014;370:1973A82.#
38.!Ferenci# P,# Bernstein# D,# Lalezari# J,# et# al.# ABTA450/rAombitasvir# and# dasabuvir#
with#or#without#ribavirin#for#HCV.#N#Engl#J#Med#2014;370:1983A92.#
39.!Andreone# P,# Colombo# MG,# Enejosa# JV,# et# al.# ABTA450,# ritonavir,# ombitasvir,#
and#dasabuvir#achieves#97%#and#100%#sustained#virologic#response#with#or#
without# ribavirin# in# treatmentAexperienced# patients# with# HCV# genotype# 1b#
infection.#Gastroenterology#2014;147:359A365.e1.#
40.! Feld# JJ,# et# al.# ABTA450/rAOmbitasvir# and# Dasabuvir# without# Ribavirin# for#
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Germany,#2015.#
41.! Khatri#A,#Dutta,#S,#Marbury#T,#et#al.#The#pharmacokinetics#and#safety#of#the#
direct# acting# antiviral# regimen# of# ABTA450/r,# ombitasvir,# with/without#
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compared#to#subjects#with#normal#renal#function.#AASLD#65th#Annual#Meeting,#
Boston,#MA,#2014.#
42.! Pockros#
PJ,#
Reddy#
KR,#
Mantry#
PS,#
et#
al.#
Safety#
of#
ombitasvir/paritaprevir/ritonavir#plus#dasabuvir#for#treating#HCVA1#infection#in#
patient#with#severe#renal#impairment#or#endAstage#renal#disease:#the#RUBYA1#
study.#EASL#50th#Annual#Meeting,#Vienna,#Austria,#2015.


70#
#
9.! APPENDIX*
Appendix*A:*Grading*for*Laboratory*Abnormalities*(Adapted*from*CTCAE,*version*4.0)*
*
Hematology*
Grade*1*
Grade*2*
Grade*3*
Grade*4*
Grade*5*
Hemoglobin*decreased*
<LLN#'#10.0#g/dL#
<LLN#'#6.2#mmol/L#
<LLN#–#100#g/L#
10.0#'#8.0#g/dL#
6.2#'#4.9#mmol/L#
100#–#80#g/L#
8.0#–#6.5#g/dL#
4.9#–#4.0#mmol/L#
80#–#65#g/L#
<#6.5#g/dL#
<#4.0#mmol/L#
<#65#g/L#
'#
White*blood*cell*count*
decreased*
<#LLN#–#3,000/mm3#
<#LLN#–#3.0#x#109/L#
<#3,000#–#2,000/mm3#
<#3.0#x#109#–#2.0#x#109/L#
<#2,000#–#1,000/mm3#
<#2.0#x#109#–#1.0#x#109/L#
<#1,000/mm3#
<#1.0#x#109/L#
'#
Neutrophil*count*decreased*
<#LLN#–#1,500/mm3#
<#LLN#–#1.5#x#109/L#
<#1,500#–#1,000/mm3#
<#1.5#x#109#–#1.0#x#109/L#
<#1,000#–#500/mm3#
<#1.0#x#109#–#0.5#x#109/L#
<#500/mm3#
<#0.5#x#109/L#
'#
Lymphocyte*count*decreased*
<#LLN#–800/mm3#
<#LLN#–#0.8#x#109/L#
<#800#–#500/mm3#
<#0.8#x#109#–#0.5#x#109/L#
<#500#–#200/mm3#
<#0.5#x#109#–#0.2#x#109/L#
<#200/mm3#
<#0.2#x#109/L#
'#
Lymphocyte*count*increased*
'#
>#4,000#–#20,000/mm3# #
>#20,000/mm3#
'#
'#
Platelet*count*decreased*
<#LLN#–#75,000/mm3#
<#LLN#–#75.0#x#109/L#
75,000#–#50,000/mm3#
75.0#x#109#–#50.0#x#109/L#
50,000#–#25,000/mm3#
50.0#x#109#–#25.0#x#109/L#
<#25,000/mm3#
<#25.0#x#109/L#
'#
INR*increased*
>#1#–#1.5#x#ULN;#>#1#–#1.5#
times#above#baseline#if#
on#anticoagulation#
>#1.5#–#2.5#x#ULN;#>#1.5#–#
2.5#times#above#baseline#if#
on#anticoagulation#
>#2.5#x#ULN;#>#2.5#times#
above#baseline#if#on#
anticoagulation#
'#
'#
Activated*partial*
thromboplastin*time*
prolonged*
>#ULN#–#1.5#x#ULN#
>#1.5#'2.5#x#ULN#
>#2.5#x#ULN#
'#
'#


71#
#
*
Biochemistry*
Grade*1*
Grade*2*
Grade*3*
Grade*4*
Grade*5*
Albumin,*serum,*low*
<#LLN#–#3#g/dL#
<#LLN#–#30#g/L#
<#3#'#2#g/dL#
<#30#'#20#g/L#
<#2#g/dL#
<#20#g/L#
Life'threatening#
consequences;#urgent#
intervention#indicated#
'#
Blood*bilirubin*increased*
>#ULN#–#1.5#x#ULN#
>#1.5#–#3.0#x#ULN#
>#3.0#–#5.0#x#ULN#
>#5.0#x#ULN#
#
Alanine*aminotransferase*
increased*
>#ULN#–#3.0#x#ULN#
>#3.0#–#5.0#x#ULN#
>#5.0#–#20.0#x#ULN#
>#20.0#x#ULN#
'#
Aspartate*aminotransferase*
increased*
>#ULN#–#3.0#x#ULN#
>#3.0#–#5.0#x#ULN#
>#5.0#–#20.0#x#ULN#
>#20.0#x#ULN#
'#
Alkaline*phosphatase*
increased*
>#ULN#–#2.5#x#ULN#
>#2.5#–#5.0#x#ULN#
>#5.0#'#20.0#x#ULN#
>#20.0#x#ULN#
'#
rTGT*increased*
>#ULN#–#2.5#x#ULN#
>#2.5#–#5.0#x#ULN#
>#5.0#'#20.0#x#ULN#
>#20.0#x#ULN#
'#
Glucose,*serum,*low*
<#LLN#–#55#mg/dL#
<#LLN#–#3.0#mmol/L#
<#55#–#40#mg/dL#
<#3.0#–#2.2#mmol/L#
<#40#'#30#mg/dL#
<#2.2#–#1.7#mmol/L#
Hospitalization#indicated#
<#30#mg/dL#
<#1.7#mmol/L#
Life'threatening#
consequences#
Death#
Glucose,*serum,*high*(fasting)*
>#ULN#–#160#mg/dL#
>#ULN#–#8.9#mmol/L#
>#160#'#250#mg/dL#
>#8.9#–#13.9#mmol/L#
>#250#'500#mg/dL#
>#13.9#–#27.8#mmol/L#
Hospitalization#indicated#
>#500#mg/dL#
>#27.8#mmol/L#
Life'threatening#
consequences#
Death#
Triglyceride,*high*(fasting)*
>#150#–#300#mg/dL#
>#300#'#500#mg/dL#
>#500#–#1,000#mg/dL#
>#1,000#mg/dL#
'#


72#
#
>#1.71#'3.42#mmol/L#
>#3.42#'5.7#mmol/L#
>#5.7#'11.4#mmol/L#
>#11.4#mmol/L#
Cholesterol,*high*
>#ULN#–#300#mg/dL#
>#ULN#–#7.75#mmol/L#
>#300#'#400#mg/dL#
>#7.75#–#10.34#mmol/L#
>#400#'#500#mg/dL#
>#10.34#–#12.92#mmol/L#
>#500#mg/dL#
>#12.92#mmol/L#
'#
Uric*acid,*serum,*high*
>#ULN#–#10.0#mg/dL#(0.59#
mmol/L)#without#
physiologic#
consequences#
'#
>#ULN#–#10.0#mg/dL#(0.59#
mmol/L)#with#physiologic#
consequences#
>#10.0#mg/dL#(#>#0.59#
mmol/L)#
Life'threatening#
consequences#
'#
Sodium,*serum,*high*
>#ULN#–#150#mmol/L#
>#150#–#155#mmol/L#
>#155#–#160#mmol/L#
Hospitalization#indicated#
>#160#mmol/L#
Life'threatening#
consequences#
Death#
Sodium,*serum,*low*
<#LLN#–#130#mmol/L#
'#
<#130#–#120#mmol/L#
<#120#mmol/L#
Life'threatening#
consequences#
Death#
Potassium,*serum,*high*
>#ULN#–#5.5#mmol/L#
>#5.5#–#6.0#mmol/L#
>#6.0#–#7.0#mmol/L#
Hospitalization#indicated#
>#7.0#mmol/L#
Life'threatening#
consequences#
Death#
Potassium,*serum,*low*
<#LLN#–#3.0#mmol/L#
<#LLN#–#3.0#mmol/L#
Symptomatic;#intervention#
indicated#
<#3.0#–#2.5#mmol/L#
Hospitalization#indicated#
<#2.5#mmol/L#
Life'threatening#
consequences#
Death#
Calcium,*serum,*high*
>#ULN#–#11.5#mg/dL#
>#ULN#–#2.9#mmol/L#
>#11.5#–#12.5#mg/dL#
>#2.9#–#3.1#mmol/L#
Symptomatic#
>#12.5#–#13.5#mg/dL#
>#3.1#–#3.4#mmol/L#
Hospitalization#indicated#
>#13.5#mg/dL#
>#3.4#mmol/L#
Life'threatening#
Death#


73#
#
consequences#
Calcium,*ionized,*high*
>#ULN#–#1.5#mmol/L#
>#1.5#–#1.6#mmol/L#
Symptomatic#
>#1.6#–#1.8#mmol/L#
Hospitalization#indicated#
>#1.8#mmol/L#
Life'threatening#
consequences#
Death#
Calcium,*serum,*low*
<#LLN#–#8.0#mg/dL#
<#LLN#–#2.0#mmol/L#
<#8.0#–#7.0#mg/dL#
<#2.0#–#1.75#mmol/L#
<#7.0#–#6.0#mg/dL#
<#1.75#–#1.5#mmol/L#
Hospitalization#indicated#
<#6.0#mg/dL#
<#1.5#mmol/L#
Life'threatening#
consequences#
Death#
Calcium,*ionized,*low*
<#LLN#–#1.0#mmol/L#
<#1.0#–#0.9#mmol/L#
Symptomatic#
<#0.9#–#0.8#mmol/L#
Hospitalization#indicated#
<#0.8#mmol/L#
Life'threatening#
consequences#
Death#
Phosphate,*serum,*low*
<#LLN#–#2.5#mg/dL#
<#LLN#–#0.8#mmol/L#
<#2.5#–#2.0#mg/dL#
<#0.8#–#0.6#mmol/L#
<#2.0#–#1.0#mg/dL#
<#0.6#–#0.3#mmol/L#
<#1.0#mg/dL#
<#0.3#mmol/L#
Life'threatening#
consequences#
Death#
Magnesium,*serum,*high*
>#ULN#–#3.0#mg/dL#
>#ULN#–#1.23#mmol/L#
'#
>#3.0#–#8.0#mg/dL#
>#1.23#–#3.30#mmol/L#
>#8.0#mg/dL#
>#3.30#mmol/L#
Life'threatening#
consequences#
Death#
Magnesium,*serum,*low*
<#LLN#–#1.2#mg/dL#
<#LLN#–#0.5#mmol/L#
<#1.2#–#0.9#mg/dL#
<#0.5#–#0.4#mmol/L#
<#0.9#–#0.7#mg/dL#
<#0.4#–#0.3#mmol/L#
<#0.7#mg/dL#
<#0.3#mmol/L#
Life'threatening#
Death#


74#
#
consequences#
Lipase*increased*
>#ULN#–#1.5#x#ULN#
>#1.5#–#2.0#x#ULN#
>#2.0#–#5.0#x#ULN#
>#5.0#x#ULN#
'#
Serum*amylase*increased*
>#ULN#–#1.5#x#ULN#
>#1.5#–#2.0#x#ULN#
>#2.0#–#5.0#x#ULN#
>#5.0#x#ULN#
'#
Iron*overload*
'#
Moderate#symptoms;#
intervention#not#indicated#
Severe#symptoms;#
intervention#indicated#
Life'threatening#
consequences;#urgent#
intervention#indicated#
Death#
*
Cardiac*Investigation*
Grade*1*
Grade*2*
Grade*3*
Grade*4*
Grade*5*
Electrocardiogram*QT*
corrected*interval*prolonged*
QTc#450'480#ms#
QTc#481'500#ms#
QTc#≥#501#ms#at#least#two#
separate#ECGs#
QTc#≥#501#ms#and#>#60#ms#
change#from#baseline#and#
Torsade#de#pointes#or#
polymorphic#ventricular#
tachycardia#or#
signs/symptoms#of#serious#
arrhythmia#
'#
LLN:#lower#limit#of#normal;#ULN:#upper#limit#of#normal#