Clinical trial NCT03144635
Conditions: Hepatitis C Viral Chronic Kidney Disease stage3
Keywords: Direct Acting Antivirals Grazoprevir Elbasvir
Sponsor: Kyushu University
Start date: 2017-04-01; Completion date: 2018-09-20
Enrollment: 80 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The regimen using grazoprevir plus elbasvir treatment is promising in Japan, because it may safely be used for the elderly patients with renal dysfunction. Grazoprevir and elbasvir are metabolized in the liver and do not require dose-adjustment for patients with renal dysfunction. However, no data related to efficacy and safety of the grazoprevir plus elbasvir treatment for Japanese elderly patients with renal dysfunction (eGFR\<60 mL/min/1.73m2) have been reported. Therefore, physicians are at a loss whether or not to treat the patients with renal dysfunction due to no evidence.

The aim of this study is to investigate the improvement of serum endostatin level of Japanese patients with CKD stage 3 after grazoprevir (NS3/4A protease inhibitor) plus elbasvir (NS5A replication complex inhibitor) treatment by a prospective, multicenter cohort study.

Detailed description:

Arms: arm 1: Grazoprevir 100 mg plus Elbasvir 50 mg per day for 12 weeks.
Interventions: intervention 1: Grazoprevir plus Elbasvir
Intervention descriptions: intervention 1: An oral dose of 100 mg/day of grazoprevir as well as an oral dose of 50 mg/day of elbasvir for 12 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
 
 Investigator Studies ProgramProtocol Template
Requirements for Submitting a Full Proposal 
Section #1 - Protocol Identification 
Study Title: 
A prospective multicenter observational study for characterization of renal 
function G1b CHC patients with CKD-3 treated with grazoprevir plus elbasvir: 
New monitoring system of chronic kidney disease stage using by serum 
endostatin level 
Document Date: 
September 20, 2018 
Institution Name 
Norihiro Furusyo, MD. PhD. 
Investigator 
Contact 
Information: 
- Full address  
- Phone No. 
- Fax  No. 
- e-mail address 
Associate Professor,  
Department of General Internal Medicine, Kyushu University Hospital,  
3-1-1, Maidashi, Higashi-Ku, Fukuoka, Japan, 812-8582  
TEL: +81-92-642-5909 
FAX: +81-92-642-5916 
e-mail: furusyo@gim.med.kyushu-u.ac.jp 
 
 
 


 
2 
 
 
Section #2- Core Protocol 
 
2.1 Objectives & 
Hypotheses  
 
 
 
 
2.1.1 List the objectives.  
Primary Endpoints:  
No worsening of renal function of serum endostatin level at 12 weeks after the 
treatment    
Secondary Endpoints:  
1. Improvement of serum creatinine level at 12 weeks after the treatment  
2. Sustained virological response-12 (SVR12) (negative for serum HCV RNA at 
12 weeks after the completion of administration)  
3. Virological responses at time points other than the primary time point  
4. Effect on decrease of serum alanine aminotransferase (ALT) levels 
(normalization of serum ALT levels [<30 U/L] at 12 weeks after the completion 
of administration)  
5. Completion/discontinuation of therapy, and incidence of adverse events  
6. Relationship between SVR12 and drug resistance mutations in NS3/4A and 
NS5A regions of HCV genome 
2.1.2 List the clinical hypotheses.  
Hypothesis-1: The grazoprevir plus elbasvir treatment might cause an 
improvement of renal dysfunction (serum endostatin level) of patients with 
reduced kidney function. 
Hypothesis-2: The grazoprevir plus elbasvir treatment might be tolerable and 
show high virological outcomes even for the patients with reduced kidney 
function. 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
Our Kyushu University Liver Disease Study (KULDS) Group has reported results 
on a cohort study of over 1,200 chronic hepatitis C (CHC) patients treated with a 
dual therapy of pegylated interferon alpha (PEG-IFNα) plus ribavirin (RBV) [1-11] 
and that of over 850 CHC patients treated with a telaprevir (TVR)- or simeprevir 
(SMV)-based triple therapy with PEG-IFNα plus RBV [12-29]. Although sustained 
virological response (SVR) rate has dramatically been improved by using direct-
acting antiviral agent (DAA) such as TVR or SMV, treatment discontinuation due to 
adverse effects has been observed at high rate in elderly patients. In Japan, patients 
with CHC are getting older year by year. In fact, over 55% of patients receiving the 
first oral IFN-free DAA dual therapy of asunaprevir (ASV) and daclatasvir (DCV) 
were aged 70 or over in our cohort study [Ogawa E, et al. Hepatol Res., 2016]. 
Moreover, they were frequently suffering from chronic kidney disease (CKD) due to 
hypertension, diabetes mellitus, acute kidney injury by medications, and/or aging. 
Among our 400 patients treated with ASV/DCV, approximately 25% patients were 


 
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suffering from moderate CKD (estimated glomerular filtration rate (eGFR): 30-59 
mL/min/1.73 m2) [Furusyo N, et al. EASL 2016, SAT-225, in Barcelona]. Thus, it is 
very important whether new regimens for HCV infection are safely used for patients 
with renal dysfunction.  
   The regimen using grazoprevir plus elbasvir treatment is promising in Japan, 
because it may safely be used for the elderly patients with renal dysfunction. Indeed, 
grazoprevir and elbasvir are metabolized in the liver and do not require dose-
adjustment for patients with renal dysfunction [Roth D, et al. EASL 2015]. However, 
no data related to efficacy and safety of the grazoprevir plus elbasvir treatment for 
Japanese elderly patients (age 76 or older) with renal dysfunction (eGFR<60 
mL/min/1.73m2) have been reported. Therefore, physicians are at a loss whether or 
not to treat the patients with renal dysfunction due to no evidence.     
   Higher serum endostatin level is associated with lower GFR and higher 
albuminuria and independently predicts incident CKD in elderly individuals [30] 
[Ruge T, American Journal of Nephrology, 2014]. No data was found on 
improvement of serum endostatin level of chronic hepatitis C patients with renal 
dysfunction after sustained HCV viremia clearance by antiviral treatment.    
   The aim of this study is to investigate the improvement of serum endostatin level 
of Japanese patients with CKD stage 3 after grazoprevir (NS3/4A protease inhibitor) 
plus elbasvir (NS5A replication complex inhibitor) treatment by a prospective, 
multicenter cohort study. Furthermore, we evaluate efficacy and safety of the 
treatment in the same patients and address the data gap described above.   
(See attachment on References 1-30) 
2.3 Study Design 
 
A prospective multicenter observational study  
Target Patients: Japanese patients with CKD stage 3  
Target patient number: 80  
This study is performed by the Kyushu University Liver Disease Study (KULDS) Group. 
The members are: 
Kyushu General Internal Medicine Center, Haradoi Hospital (Jun Hayashi, MD.) 
Kajiwara Clinic (Eiji Kajiwara, MD.) 
Department of Gastroenterology, Kyushu Medical Center (Makoto Nakamuta, MD.) 
Center for Liver Disease, Shin-Kokura Hospital (Hideyuki Nomura, MD.) 
Center for Liver Disease, Kokura Medical Center (Takeaki Satoh, MD.) 
Department of Hepatology, Hamanomachi Hospital (Kazuhiro Takahashi, MD.) 


 
4 
 
Department of Internal Medicine, Kitakyushu Municipal Medical Center (Akira Kawano, 
MD.) 
Department of Internal Medicine, Fukuoka City Hospital (Toshimasa Koyanagi, MD.) 
Department of Internal Medicine, Chihaya Hospital (Kazufumi Dohmen, MD.) 
Liver Unit, Department of Internal Medicine, Kyushu Central Hospital (Koichi Azuma, 
MD.) 
Department of Medicine and Biosystemic Science, Kyushu University Hospital (Shinji 
Shimoda, MD.) 
Department of Medicine and Bioregulatory Science, Kyushu University Hospital (Masaki 
Kato, MD.) 
2.4 Study Flowchart 
 
Observation and Test Parameters and Methods 
The following items will be conducted. Items 7) Serum endostatin level is a main 
study-specific parameter and require a blood sample volume of 30 mL for each 
measurement. Items 1) to 6) are performed routinely in clinical settings. 
[Patient characteristics] 
gender, age, height, liver histology, prior treatments, allergic history, medical 
history, and any complications 
[Hematological parameters] 
1) Routine blood test (white blood cell count, neutrophil count, platelet count, 
hemoglobin level) 
2) Coagulation (PT-INR) 
3) Biochemistry (LDH, BUN, total bilirubin, direct bilirubin, total protein, albumin, 
creatinine, Na, K, Cl, amylase, and lipase) 
4) Liver function tests (AST, ALT, γ-GTP, ALP) 
5) Lipid metabolism (TC, HDL-C, LDL-C, TG) 
6) Fibrosis markers (hyaluronic acid, type IV collagen, M2BP, and AFP) 
7) Endostatin level 
8) HCV genotype 
9) HCV gene mutation test 
10) HCV RNA level (PCR assay: both TaqMan HCV test and AccuGene m-HCV) 
11) IL28B SNPs 
12) Liver biopsy/FibroScan 
Timing 
 
Items 
Baseline 
On treatment 
Follow up 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 4 
Week 8 
Week 12 


 
5 
 
Whole blood test* 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
 
 
 
 
 
 
 
 
Biochemistry 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
AST/AST, γ-GTP, ALP 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
Lipid metabolism 
(TC, HDL-C, LDL-C, TG) 
x 
 
 
 
 
 
x 
 
 
x 
Fibrosis markers (AFP, 
hyaluronic acid, type IV 
collagen, M2BP) 
x 
 
x 
 
x 
 
x 
 
 
x 
Endostatin level 
x 
x 
x 
 
x 
 
x 
x 
 
x 
HCV Genotype 
x 
 
 
 
 
 
 
 
 
 
HCV gene mutation test 
x 
 
 
 
 
 
 
 
 
 
HCV RNA level 
(PCR assay: 
TaqMan+AccuGene) 
x 
 
x 
 
x 
 
x 
x 
x 
x 
IL28B SNPs 
x 
 
 
 
 
 
 
 
 
 
Liver biopsy or 
FibroScan 
x 
 
 
 
 
 
 
 
 
 
 
*: Whole blood test includes white blood cell count, neutrophil count, platelet count, 
and hemoglobin level 
2.5 Study 
Procedures 
Patients who have received sufficient explanation for participation in the study, and 
who have submitted a written form of informed consent by their own freewill after 
thorough understanding. 
Inclusion Criteria:  
1. Subjects aged 20 years or older.  
2. Patients positive for HCV RNA for over 6 months and infected with genotype 1b 
chronic hepatitis C, including compensated cirrhosis.  
3. Patients without co-infection of hepatitis B virus.  
4. Patients without co-infection of human immunodeficiency virus  
5. Patients with moderate chronic kidney disease (CKD stage 3) (eGFR: 30-59 
mL/min/1.73m2). A diagnosis of CKD is only confirmed if repeated eGFR tests 
for at least 90 days.  
Exclusion Criteria:  
1. Patients with decompensated cirrhosis (Child Pugh B and C)  
2. Patients with albumin <3.0 g/dL and platelets <75,000 /μL 
3. Patients with autoimmune hepatitis 
4. Constant heavy alcohol drinkers (converted to ethanol ≥60 g/day) 5. Patients who 
have a history of hypersensitivity to grazoprevir and elbasvir 


 
6 
 
6. Patients who are pregnant females, or females who may become pregnant, or 
females who are breastfeeding  
7. Patients with heart disease that is hard to control (e.g., very recent cardiac 
infarction, severe heart failure, unstable arrhythmia)  
8. Patients who are under medication with drugs listed as contraindication in a 
package insert of grazoprevir plus elbasvir treatment  
9. Patients judged (by the physician in charge of research) to be inappropriate as 
subjects for the study for any other reasons.   
  After informed consent is obtained, administration is to be conducted according to 
the following dose/injection route: An oral dose of 100 mg/day of grazoprevir as well 
as an oral dose of 50 mg/day of elbasvir for 12 weeks. During the study, therapy 
shall be conducted safely after confirmation of the presence or absence of adverse 
events, results of serologic tests, and the blood cell count. Each patient is followed 
up every 2 to 4 weeks until 12 weeks after completion of therapy.  
Discontinuation criteria:  
Serologic tests, including liver function and blood cell counts (white blood cell count, 
neutrophil count, platelet count, hemoglobin level), should be conducted during 
therapy, more than twice a week within 1 week after initial administration and 
regularly every week thereafter to consider the necessity of discontinuation. The 
patient may be discontinued from the study at the discretion of the investigator 
according to the status of the patient if adverse events develop.  
2.6 Study Duration 
From the time of approval of the IRB to 31 March, 2020 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
State who will be responsible for analyzing the study data (Investigator, contract 
CRO, etc.). When appropriate state how the blind will be maintained during the 
study, as appropriate, and when the data will be un-blinded. For the purpose of the 
final analysis, the official clinical database will not be un-blinded until 
medical/scientific review has been completed, protocol violators have been identified 
(if appropriate), and data has been declared complete.   
Variables/Time Points of Interest: All variables (primary and secondary) that are 
listed in the study hypotheses, and the time points at which they will be analyzed, 
need to be described in detail. Efficacy variables discussed in this section should 
have been included as part of an objective or hypothesis section. These variables 
and the time points at which they are to be analyzed should be consistent with the 
primary and secondary hypotheses, i.e., primary variables and time points should 
relate to the primary hypotheses.  
Statistical Method: Statistical analyses will be conducted using SPSS Statistics 
version 22.0 (IBM SPSS Inc., Chicago, IL, USA). A P value less than 0.05 will be 
regarded as statistically significant in all analyses. Variables with P value <0.10 in 
univariate analysis will be evaluated using multivariate logistic regression to identify 


 
7 
 
variables significantly associated with SVR12. The results will be expressed as odds 
ratios and their 95% confidence interval (CI). Each endpoint such as SVR12, 
Adverse event frequency, tolerability, ALT normalization will be summarized with 
mean and 95% CI. Drug concentration will be summarized with trough concentration 
and 95% CI.  
Power/Sample Size: Although there is no report (or literature) on the improvement of 
serum endostatin levels after eradication of HCV, we hypothesize that endostatin 
levels would be improved in 50% of patients with SVR and 5% of patients without 
SVR. According to Japanese Phase 3 trial, the SVR rate of this regimen is 90%. We 
estimate the proportion of SVR would be 97%. In this case, 76 patients are 
necessary and sufficient to detect differences between two groups with 2-side 
alpha=5% and power=80%. Since the dropout rate of patients is approximately 5%, 
the estimated sample size should be 80. We set the sample size based on the 
feasibility of this exploratory study.  
2.8 Specific Drug 
Supply 
Requirements  
None (Obtain from market by PI) 
2.9 Adverse 
Experience 
Reporting 
The Investigator-Sponsor will report Serious Adverse Experiences to Merck Global 
Safety and any local regulatory agency (as applicable) as per the study agreement.  
 
Adverse Event 
An adverse event means any unfavorable and unintended change in the structure, 
function, or chemistry of the body temporally associated with any use of the Merck 
product whether or not considered related to the use of the product.  Any worsening 
(i.e., any clinically significant adverse change in frequency and/or intensity) of a 
preexisting condition which is temporally associated with the use of the product, is 
also an adverse experience. 
 
Serious Adverse Event 
A serious adverse event (SAE) is any adverse event occurring at any dose that: 
• Results in death 
• Is life threatening (places the subject/patient, in the view of the investigator, at 
immediate risk of death from the experience as it occurred) 
• Results in a persistent or significant disability/incapacity 
• Results in or prolongs an existing inpatient hospitalization 
• Is a congenital anomaly/birth defect 
Other important medical events that may not result in death, not be life threatening, 
or not require hospitalization may be considered a serious adverse experience when, 
based upon appropriate medical judgment, the event may jeopardize the 


 
8 
 
subject/patient and may require medical or surgical intervention to prevent one of the 
outcomes listed above.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that did not require hospitalization, or development 
of drug dependency or drug abuse. 
• Is an overdose (whether accidental or intentional) 
• Cancer (that is not the condition under the study)* 
 
*If disease progression is noted during a protocol-specified reevaluation of the status 
of a patient’s cancer and the progression is manifested solely by results of tumor 
markers and/or radiologic imaging, that occurrence of progressive disease will NOT 
be recorded as an adverse experience. 
 
All Serious Adverse Event, regardless of causal relationship to the investigational 
product, must be forwarded  via Fax to MSD KK Pharmacovigilance group via fax 
(81-3-6238-9191) within 2 working days of the investigator becoming aware of the 
event 
 
Non-Serious Adverse Event 
All Non-Serious Adverse Event, regardless of causal relationship to the 
investigational product, must be forwarded via Fax to MSD KK Pharmacovigilance 
group via fax (81-3-6238-9191) annually and the due date for the reporting will be 
defined in the CTRA. 
2.10 Itemized Study 
Budget  
A preliminary study budget must be provided with the initial proposal submitted to give 
guidance to the MISP Review Committee as to the expected study costs.   A refined 
itemized budget detailing the costs associated with the study should be provided with 
the final protocol or included in the study agreement as Exhibit B.  
2.11 References 
References related to this study    
 
[1] Furusyo N, Kajiwara E, Takahashi K, Nomura H, Tanabe Y, Masumoto A, 
Maruyama T, Nakamuta M, Enjoji M, Azuma K, Shimono J, Sakai H, Shimoda S, 
Hayashi J: Association between the treatment length and cumulative dose of 
pegylated interferon alpha-2b plus ribavirin and their effectiveness as a combination 
treatment for Japanese chronic hepatitis C patients: A project of the Kyushu University 
Liver Disease Study Group. Journal of Gastroenterology and Hepatology 23 (7): 1094-
1104, 2008.    
 
[2] Ogawa E, Furusyo N, Toyoda K, Takeoka H, Maeda S, Hayashi J: The longitudinal 
quantitative assessment by transient elastography of chronic hepatitis C patients 
treated with pegylated interferon alpha-2b and ribavirin. Antiviral Research 83 (2): 127-
134, 2009.    
 
[3] Ogawa E, Furusyo N, Toyoda K, Taniai H, Otaguro S, Kainuma M, Murata M, 
Sawayama Y, Hayashi J: Excellent superiority and specificity of COBAS TaqMan HCV 


 
9 
 
assay in an early viral kinetic change during pegylated interferon-alpha 2b plus 
ribavirin treatment. BMC Gastroenterology 10: 38, 2010.    
 
[4] Kainuma M, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Tanabe T, Satoh T, 
Maruyama T, Nakamuta M, Kotoh K, Azuma K, Shimono J, Shimoda S, Hayashi J: 
Pegylated interferon α-2b plus ribavirin for older patients with chronic hepatitis C. 
World Journal of Gastroenterology 16 (35): 4400-4409, 2010.    
 
[5] Furusyo N, Murata M, Ogawa E, Toyoda K, Ihara T, Ikezaki H, Hayashi T, Koga T, 
Kainuma M, Hayashi J: Ribavirin concentration in the later stages of 48-week 
pegylated interferon-alfa 2b plus ribavirin therapy for chronic hepatitis C is useful for 
predicting virological response. Journal of Antimicrobial Chemotherapy 66 (5): 1127-
1139, 2011.    
 
[6] Kainuma M, Furusyo N, Azuma K, Kajiwara E, Takahashi K, Nomura H, Tanabe Y, 
Satoh T, Maruyama T, Nakamuta M, Kotoh K, Shimoda S, Hayashi J, The Kyushu 
University Liver Disease Study Group: Pegylated interferon alpha-2b plus ribavirin for 
Japanese chronic hepatitis C patients with normal alanine aminotransferase. 
Hepatology Research 42 (1): 33-41, 2012.    
 
[7] Ogawa E, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Tanabe Y, Satoh T, 
Maruyama T, Nakamuta M, Kotoh K, Azuma K, Dohmen K, Shimoda S, Hayashi J: An 
evaluation of the adverse effect of premature discontinuation of pegylated interferon 
alpha-2b and ribavirin treatment for chronic hepatitis C virus infection: Results from 
Kyushu University Liver Disease Study (KULDS). Journal of Gastroenterology and 
Hepatology 27 (7): 1233-1240, 2012.    
 
[8] Ogawa E, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Tanabe Y, Satoh T, 
Maruyama T, Nakamuta M, Kotoh K, Azuma K, Dohmen K, Shimoda S, Hayashi J, 
The Kyushu University Liver Disease Study Group: An inadequate dosage of ribavirin 
is related to virological relapse by chronic hepatitis C patients treated with pegylated 
interferon alpha-2b and ribavirin. Journal of Infection and Chemotherapy 18 (5): 689-
697, 2012.    
 
[9] Ogawa E, Furusyo N, Murata M, Ikezaki H, Ihara T, Hayashi T, Toyoda K, Taniai 
H, Okada K, Kainuma M, Hayashi J: Insulin resistance undermines the advantages of 
IL28B polymorphism in the pegylated interferon alpha-2b and ribavirin treatment of 
chronic hepatitis C patients with genotype 1. Journal of Hepatology 57 (3): 534-540, 
2012.    
 
[10] Ogawa E, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Maruyama T, Tanabe 
Y, Satoh T, Nakamuta M, Kotoh K, Azuma K, Dohmen K, Shimoda S, Hayashi J: 
Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of 
hepatocellular carcinoma of patients with chronic hepatitis C: A prospective, 
multicenter study. Journal of Hepatology 58 (3): 495-501, 2013.    
 
[11] Ogawa E, Furusyo N, Murata M, Ikezaki H, Ihara T, Hayashi T, Toyoda K, Okada 
K, Kainuma M, Kajiwara E, Takahashi K, Satoh T, Hayashi J: Valuable antiviral 
therapeutic options for the treatment of thrombocytopenia of patients with chronic 
hepatitis C. Journal of Viral Hepatitis 20 (12): 838-846, 2013.    
 
[12] Furusyo N, Ogawa E, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi 
K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J, The 
Kyushu University Liver Disease Study (KULDS) Group: Telaprevir can be 
successfully and safely used to treat older patients with genotype 1b chronic hepatitis 
C. Journal of Hepatology 59 (2): 206-212, 2013.    
 
[13] Ogawa E, Furusyo N, Murata M, Toyoda K, Eiraku E, Shimizu M, Harada Y, 
Mitsumoto F, Takayama K, Okada K, Kainuma M, Hayashi J: Early phase viral kinetics 


 
10 
 
of chronic hepatitis C patients receiving telaprevir-based triple therapy: A comparison 
of two real-time PCR assays. Antiviral Research 99 (2): 119-124, 2013.    
 
[14] Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi 
K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J, The 
Kyushu University Liver Disease Study (KULDS) Group: Clinical milestones for the 
prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based 
triple therapy. Journal of Hepatology 59 (4): 667-674, 2013.    
 
[15] Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi 
K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J, The 
Kyushu University Liver Disease Study (KULDS) Group: Telaprevir-based triple 
therapy for chronic hepatitis C patients with advanced fibrosis: A prospective clinical 
study. Alimentary Pharmacology and Therapeutics 38 (9): 1076-1085, 2013.    
 
[16] Furusyo N, Ogawa E, Murata M, Toyoda K, Ohnishi H, Eiraku K, Shimizu M, 
Harada Y, Mitsumoto F, Takayama K, Kainuma M, Okada K, Hayashi J: Therapeutic 
drug monitoring of telaprevir in chronic hepatitis C patients receiving telaprevir -based 
triple therapy is useful for predicting virological response. Journal of Antimicrobial 
Chemotherapy 69 (2): 483-490, 2014.    
 
[17] Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi 
K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J, The 
Kyushu University Liver Disease Study (KULDS) Group: Influence of low-density 
lipoprotein cholesterol on virological response to telaprevir-based triple therapy for 
chronic HCV genotype 1b infection. Antiviral Research 104:102-109, 2014.    
 
[18] Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi 
K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Akahoshi T, 
Maehara M, Hayashi J; The Kyushu University Liver Disease Study (KULDS) Group: 
Efficacy and safety of splenectomy in telaprevir-based triple therapy for chronic 
hepatitis C patients with thrombocytopenia and advanced fibrosis. Journal of 
Gastroenterology and Hepatology 29(9): 1728-35, 2014.    
 
[19] Ogawa E, Furusyo N, Shimizu M, Ihara T, Hayashi T, Harada Y, Toyoda K, Murata 
M, Hayashi J: Non-invasive fibrosis assessment predicts sustained virological 
response to telaprevir with pegylated interferon and ribavirin for chronic hepatitis C. 
Antiviral Therapy 20(2): 185-192, 2015.   
 
[20] Kawano A, Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Dohmen K, Nomura 
H, Takahashi K, Satoh T, Azuma K, Tanabe Y, Shimoda S, Kotoh K, Hayashi J , The 
Kyushu University Liver Disease Study (KULDS) Group: Bacterial infection as an 
adverse effect of telaprevir-based triple therapy for chronic hepatitis C infection. 
Internal Medicine 54(6): 567-572, 2015.    
 
[21] Takayama K, Furusyo N, Ogawa E, Ikezaki H, Shimizu M, Masayuki M, Hayashi 
J: Direct acting antiviral agent-based therapy effectively decreases the serum alpha 
fetoprotein level of chronic hepatitis C patients. World Journal of Gastroenterology 
21(15): 4696-4706, 2015.    
 
[22] Ogawa E, Furusyo N, Kajiwara E, Nomura H, Kawano A, Takahashi K, Dohmen 
K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J, The 
Kyushu University Liver Disease Study (KULDS) Group: Comparative safety study on 
severe anemia by simeprevir- versus telaprevir-based triple therapy for chronic 
hepatitis C. Journal of Gastroenterology and Hepatology 30 (8): 1309-1316, 2015.    
 
[23] Ogawa E, Furusyo N, Dohmen K, Kajiwara E, Kawano A, Nomura H, Takahashi 
K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J, The 
Kyushu University Liver Disease Study (KULDS) Group: Effectiveness of triple therapy 


 
11 
 
with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure. 
Journal of Viral Hepatitis 22 (12): 992-1001, 2015.    
 
[24] Ogawa E, Furusyo N, Dohmen K, Kajiwara E, Kawano A, Nomura H, Takahashi 
K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J; The 
Kyushu University Liver Disease Study (KULDS) Group: Comparative effectiveness 
and safety study of triple therapy with simeprevir or telaprevir for non-cirrhotic patients 
with chronic hepatitis C virus genotype 1b infection. Journal of Gastroenterology and 
Hepatology 30 (12): 1759-1767, 2015.    
 
[25] Hiramine S, Sugiyama M, Furusyo N, Uto H, Ido A, Tsubouchi H, Watanabe H, 
Ueno Y, Korenaga M, Murata K, Masaki N, Hayashi J, Thomas DL, Mizokami M. A 
thymine-adenine dinucleotide repeat polymorphism near IL28B is associated with 
spontaneous clearance of hepatitis C virus. Journal of Gastroenterology 50 (10): 1069-
1077, 2015.  
 
[26] Hiramine S, Furusyo N, Ogawa E, Nakamuta M, Kajiwara E, Nomura H, Dohmen 
K, Takahashi K, Satoh T, Azuma K, Kawano A, Koyanagi T, Kotoh K, Shimoda S, 
Hayashi J. Importance of virological response in the early stage of telaprevir-based 
triple therapy World Journal of Hepatology 7 (26): 2688-2695, 2015.  
 
[27] Ura K, Furusyo N, Ogawa E, Hayashi T, Mukae H, Shimizu M, Toyoda K, Murata 
M, Hayashi J. Serum WFA+-M2BP is a non-invasive liver fibrosis marker that can 
predict the efficacy of direct acting antiviral-based triple therapy for chronic hepatitis 
C. Alimentary Pharmacology & Therapeutics 43 (1): 114-124, 2016. 
 
[28] Ogawa E, Furusyo N, Murata M, Hayashi T, Shimizu M, Mukae H, Toyoda K, 
Hotta T, Uchiumi T, Hayashi J. Impact of HCV kinetics on treatment outcome differs 
by the type of real-time HCV assay in NS3/4A protease inhibitor-based triple therapy. 
Antiviral Research 126: 35-42, 2016.  
 
[29] Hayashi T, Ogawa E, Furusyo N, Murata M, Hayashi J. Influence of insulin 
resistance on the development of hepatocellular carcinoma after antiviral treatment for 
non-cirrhotic patients with chronic hepatitis C. Infectious Agents and Cancer 11: 9, 
2016.  
 
[30] Shimizu M, Furusyo N, Tanaka Y, Kato Y, Mitsumoto-Kaseida F, Takayama K, 
Ura K, Hiramine S, Hayashi T, Ikezaki H, Ihara T, Mukae H, Ogawa E, Toyoda K, 
Kainuma M, Murata M, Hayashi J. The relation of postprandial plasma glucose and 
serum endostatin to the urinary albumin excretion of residents with pre-diabetes: 
Results from the Kyushu and Okinawa Population Study (KOPS). International 
Urology and Nephrology 2016 (in press). 
2.12 Publication 
Plan 
Hepatology, Journal of Hepatology, Journal of Gastroenterology 
(72 weeks after the start of study) 
AASLD, EASL, APASL 
(2017-2018) 
2.13 Curriculum 
Vitae 
 
Attached 
2.14 Protocol 
Submission for 
Investigator-
Initiated Studies  
Non U.S. protocols should be submitted to the MSD office by the investigators.