Clinical trial NCT01636778: Japanese Phase II Study of SB-497115-GR in Hepatitis C Virus Infected Patients
Official title: Non-randomised, Open Label, Multi-centre Phase II Study to Assess the Efficacy and Safety of SB-497115-GR in Thrombocytopenic Subjects With Chronic Hepatitis C and Compensated Liver Cirrhosis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C, Chronic
Keywords: Thrombocytopenia
Hepatitis C, chronic
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-07-10
Enrollment: 45
Sex: ALL
Minimum age (years): 20
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the ability of SB-497115-GR to raise platelet counts in thrombocytopenic patients with hepatitis C virus (HCV) infection (platelet count \<80,000 /μL, suggestive of compensated cirrhosis) to a level desirable to initiate antiviral therapy and to assess the ability of SB-497115-GR to maintain platelet counts at a level sufficient to minimise dose reductions of pegylated interferon (Peg-IFN) and ribavirin (RBV) therapy with the expectation that a lower rate of Peg-IFN dose reduction and omission will translate to a higher rate of sustained viral response.


Eligibility criteria: Inclusion Criteria:

Subject is able to understand and comply with protocol requirements and instructions and is likely to complete the study as planned, as well as provided a written consent.

* A subject age between ≥20 and \<75 years at time of informed consent.
* A subject who applies to one of the following:

Female subject with non-childbearing potential \[i.e., physiologically incapable of becoming pregnant, who: has had a hysterectomy, or had a bilateral oophorectomy (ovariectomy), or had a bilateral tubal ligation, or is post-menopausal for greater than one year\].

Female subject with childbearing potential, has a negative urine or serum pregnancy test at screening and within the 24-hour period prior to the first dose of SB-497115-GR, and completely abstains from intercourse or agree to use two of the following acceptable methods of contraception for 14 days before exposure to SB-497115-GR, throughout the clinical trial, and for 24 weeks after completion or premature discontinuation from the study.

Intrauterine device or intrauterine system that meets the effectiveness criteria as stated in the product label.

Male partner sterilization prior to the female subject's entry into the study, and this male is the sole partner for that subject.

Double-barrier contraception (condom with spermicidal jelly, or diaphragm with spermicide).

Male subject with childbearing potential partner completely abstains from intercourse or agree to use condom and diaphragm with spermicide.

* Subjects who were diagnosed as hepatitis C or compensated liver cirrhosis (Child-Pugh class A) without hepatic encephalopathy, or ascites. If there is a clear cirrhosis, treatment should be given with care as there is a potential of progressing to liver failure.
* Subjects who, in the opinion of the investigator, are appropriate candidates for Peg-IFN and RBV combination therapy for 48 weeks.
* HCV positive by TaqMan test at screening.
* Subject who fulfil all the organ functions below.

Items Values Platelet \<80,000 /μL Haemoglobin ≥12.0 g/dL\* Absolute neutrophil count (ANC) ≥1500 /μL\* Creatinine clearance \>50 mL/minute Total bilirubin \<2.0 mg/dL Albumin \>3.0 g/dL Prothrombin time \>60%

\*If the investigators consider the values are sufficient to give Peg-IFN/RBV, then a subject can be enrolled upon consulting the Medical Monitor.

Exclusion Criteria:

* Subject who relapsed or did not respond after 48 weeks of Peg-IFN/RBV therapy had been given with sufficient dose previously.
* Subject with history of IFN (including Peg-IFN) therapy or Peg-IFN/RBV therapy, but could not been treated with optimal Peg-IFN/RBV therapy due to the reasons other than thrombocytopenia.
* Subject who received IFN therapy (including Peg-IFN), antiviral therapy (excluding oseltamivir phosphate, etc.), immuno-modulatory treatment, radiotherapy or phlebotomy within 3 months (90 days) prior to the first dose of SB-497115-GR.
* Treatment with an investigational drug within 30 days prior to the first dose of SB-497115-GR or 5 half-lives of that investigational drug (whichever is longer).
* Subject with decompensated liver disease.
* Chronic liver disease other than chronic hepatitis C (e.g., autoimmune hepatitis, alcohol-induced hepatitis, drug-induced hepatitis, etc.).
* Subject with idiopathic thrombocytopenic purpura or active autoimmune disease.
* Subject who have had a malignancy diagnosed and/or treated within the past 5 years.
* Subjects who require endoscopic treatment for varices or documented history of clinically significant bleeding from oesophageal or gastric varices.
* Any disease condition associated with active bleeding or requiring anticoagulation with heparin or warfarin.
* Subject with serious cardiac, cerebrovascular, chronic pulmonary disease or interstitial lung disease, or documented history of any of these diseases.
* Pre-existing cardiac disease (congestive heart failure in New York Heart Association Grade III/IV), or arrhythmias known to involve the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTcF \>450 msec or if with bundle brunch block, QTcF \>480 msec.
* Subject with depression, psychiatric disorder requiring treatment or suicidal ideation or suicide attempt history, or history of these.
* Subject with uncontrolled hypertension (≥160 mmHg systolic or ≥100 mmHg diastolic).
* Subject with diabetes mellitus that can not be controlled by treatment.
* Thyroid dysfunction not adequately controlled.
* Subjects with haemoglobinopathies.
* History or current condition of seizure disorder.
* Subject who was positive for Human Immunodeficiency Virus (HIV) antibody or Hepatitis B Virus (HBV) antigen.
* Subject with arterial or venous thrombosis history or evidence of portal vein thrombosis on abdominal imaging (e.g., by computerized tomography or magnetic resonance imaging) within 3 months.
* History of alcohol/drug abuse or dependence.
* History of platelet clumping that prevents reliable measurement of platelet counts.
* Subjects planning to have cataract surgery.
* History of major organ transplantation.
* Known hypersensitivity to SB-497115-GR ingredients, IFN (including Peg-IFN), nucleoside analogues or biological agents (i.e., vaccines).
* Pregnant or nursing women or a male subject with pregnant partner.

Primary outcomes:
measure: Number of Participants Whose Platelet Count Increased From a Baseline Count of < 80 Gi/L to a Count >=100 Gi/L During Part 1
timeFrame: From Baseline up to Week 9 in Part 1
measure: Number of Participants Whose Platelet Counts Maintained at >=50 Gi/L During Part 2
timeFrame: From Antiviral Baseline to up to Week 48 in Part 2
Secondary outcomes:
measure: Median Platelet Count at the Indicated Time Points in Part 1
timeFrame: Baseline, Week1, 2, 3, 4, 5, 6, 7, 8, 9, Withdrawal in Part 1
measure: Time in Weeks to Achieve Platelet Count >= 100 Gi/L
timeFrame: From Baseline up to Week 9 in Part 1
measure: Median Platelet Count at the Indicated Time Points in Part 2
timeFrame: Antiviral Baseline, Week 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, Withdrawal in Part 2
measure: Median Platelet Count at the Indicated Time Points During Follow-up Period After Part 2
timeFrame: Follow-up (FU) Baseline, FU Week 4, FU Week 12 and and FU Week 24 after Part 2
measure: Minimum Platelet Count on Antiviral Therapy
timeFrame: From Antiviral Baseline to up to Week 48 in Part 2
measure: Dose of Eltrombopag That Enabled Initiation of Antiviral Therapy
timeFrame: From Baseline up to Week 9 in Part 1
measure: Number of Antiviral Therapy Dose Reductions in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants With the Indicated Levels of Peg-IFN Alpha-2a Therapy Dose Reductions in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants With the Indicated Levels of Peg-IFN Alpha-2b Therapy Dose Reductions in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants With the Indicated Levels of RBV Therapy Dose Reductions in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Time to First Dose Reduction of Antiviral Therapy in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants Who Discontinued Antiviral Therapy in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants Who Discontinued Peg-IFN Alpha-2a Therapy in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants Who Discontinued Peg-IFN Alpha-2b Therapy in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants Achieving Adherence to Antiviral Therapy in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants Achieving Adherence to Peg-IFN Alpha 2a Antiviral Therapy in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants Achieving Adherence to Peg-IFN Alpha-2b Antiviral Therapy in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants With Sustained Virologic Response (SVR) in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants With Rapid Virological Response (RVR) and Extended RVR (eRVR) in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants With Early Virological Response (EVR) and Complete EVR (cEVR) in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants With End of Treatment Response (ETR) for Undetectable HCV RNA at the End of Peg-IFN/RBV Treatment in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Mean Serum HCV RNA at the Indicated Time Points In Part 2
timeFrame: Screening, Antviral baseline; Week 4, 12, 24, 36, 48, Withdrawal in Part 2
measure: Mean Serum HCV RNA at the Indicated Time Points During Follow-up Period After Part 2
timeFrame: FU Baseline, FU Week 12 and FU Week 24 after Part 2
measure: Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) in Part1
timeFrame: From Baseline up to week 9 in Part 1
measure: Number of Participants With Any AE and Any SAE in Part 2
timeFrame: From Antiviral Baseline up to Week 48 in Part 2
measure: Number of Participants With Any AE and Any SAE During Follow-up Period After Part 2
timeFrame: From FU Baseline up to FU Week 24 after Part 2
measure: Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points in Part 1 With Follow-up Period
timeFrame: Baseline; Week 1, 2, 3, 4, 5, 6, 7, 8, 9, Withdrawal in Part 1 and FU Week 4, FU Week 12, and FU Week 24
measure: Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points in Part 2
timeFrame: Baseline; Antiviral Baseline,Week 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, Withdrawal in Part 2
measure: Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points During Follow-up Period After Part 2
timeFrame: FU Baseline, FU Week 4, FU Week 12 and FU Week 24 after Part 2
measure: Mean Change From Baseline in Heart Rate at the Indicated Time Points in Part 1 With Follow-up Period
timeFrame: Baseline; Week 1, 2, 3, 4, 5, 6, 7, 8, 9, Withdrawal in Part 1 and FU Week 4, FU Week 12, FU Week 24
measure: Mean Change From Antiviral Baseline in Heart Rate at the Indicated Time Points in Part 2
timeFrame: Antiviral Baseline, Week 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, Withdrawal in Part 2
measure: Mean Heart Rate at the Indicated Time Points During Follow-up Period After Part 2
timeFrame: FU Baseline, FU Week 4, FU Week 12 and FU Week 24 after Part 2
measure: Mean Change From Baseline in Weight at the Indicated Time Points in Part 1 With Follow-up Period
timeFrame: Baseline; Week 1, 2, 3, 4, 5, 6, 7, 8, 9, Withdrawal in Part 1 and FU Week 4, FU Week 12, FU Week 24
measure: Mean Change From Baseline in Weight at the Indicated Time Points in Part 2
timeFrame: Baseline; Antiviral Baseline, Week 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, Withdrawal in Part 2
measure: Mean Weight at the Indicated Time Points During Follow-up Period After Part 2
timeFrame: FU Baseline, FU Week 4, FU Week 12 and FU Week 24 after Part 2
measure: Mean Change From Baseline in Body Temperature at the Indicated Time Points in Part 1 With Follow-up Period
timeFrame: Baseline; Week 1, 2, 3, 4, 5, 6, 7, 8, 9, Withdrawal in Part 1 and FU Week 4, FU Week 12, FU Week 24
measure: Mean Change From Baseline in Body Temperature at the Indicated Time Points in Part 2
timeFrame: Baseline; Antiviral Baseline,Week 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, Withdrawal in Part 2
measure: Mean Body Temperature at the Indicated Time Points During Follow-up Period After Part 2
timeFrame: FU Baseline, FU Week 4, FU Week 12 and FU Week 24 after Part 2
measure: Mean Change From Baseline in Body Mass Index (BMI) at the Indicated Time Points in Part 1 With Follow-up Periodc
timeFrame: Baseline; Week 1, 2, 3, 4, 5, 6, 7, 8, 9, Withdrawal in Part 1 and FU Week 4, FU Week 12, FU Week 24
measure: Mean Change From Baseline in BMI at the Indicated Time Points in Part 2
timeFrame: Baseline; Antiviral Baseline,Week 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, Withdrawal in Part 2
measure: Mean BMI at the Indicated Time Points During Follow-up Period After Part 2
timeFrame: FU Baseline, FU Week 4, FU Week 12 and FU Week 24 after Part 2
measure: Number of Participants With the Indicated Shift From Baseline in Severity Grades for Clinical Chemistry Parameters Per Division of Acquired Immunodeficiency Syndrome (DAIDS) in Part 1
timeFrame: From Baseline up to Week 9
measure: Number of Participants With the Indicated Shift From Baseline in Severity Grades for Clinical Chemistry Parameters Per DAIDS in Part 2
timeFrame: From Antiviral Baseline up to Week 48
measure: Number of Participants With the Indicated Shift From Baseline in Severity Grades for Clinical Chemistry Parameters Per DAIDS During Follow-up Period After Part 2
timeFrame: From FU Week 4 to FU Week 24
measure: Number of Participants With the Indicated Shifts From BL in Severity Grades for for Hematology Parameters Per DAIDS in Part 1
timeFrame: From Baseline up to Week 9
measure: Number of Participants With the Indicated Shifts From BL in Severity Grades for for Hematology Parameters Per DAIDS in Part 2
timeFrame: From Antiviral Baseline up to Week 48
measure: Number of Participants With the Indicated Shifts From BL in Severity Grades for Hematology Parameters Per DAIDS During Follow-up Period After Part 2
timeFrame: From FU Week 4 to FU Week 24
measure: Number of Participants With the Indicated Urinalysis Parameters Tested by Dipstick at the Indicated Time Points in Part1 With Follow Up Period
timeFrame: Screening, Baseline, Week 1, 2, 3, 4, 7, 8, Withdrawal, FU Week 24
measure: Number of Participants With the Indicated Urinalysis Parameters Tested by Dipstick at the Indicated Time Points in Part 2
timeFrame: Antiviral Baseline,Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, Withdrawal
measure: Number of Participants With the Indicated Urinalysis Parameters Tested by Dipstick at the Indicated Time Points During Follow-up Period After Part 2
timeFrame: FU Baseline and FU Week 24
measure: Number of Participants Assessed as Abnormal (Clinically Significant [CS] and Not Clinically Significant [NCS]) for 12-lead Electrocardiogram (ECG) at the Indicated Time Points
timeFrame: Screening, Antiviral Baseline, Week 12, 24, 36, 48, Withdrawal
measure: Number of Participants Assessed as Abnormal (Clinically Significant [CS] and Not Clinically Significant [NCS]) for 12-lead Electrocardiogram (ECG) During Follow-up After Part 2
timeFrame: FU Baseline and FU Week 24
measure: Number of Participants With Abdominal Ultrasound With Doppler at the Indicated Time Points
timeFrame: Baseline; Week 24, Week 48, Withdrawal/Completion
measure: Number of Participants With Abdominal Ultrasound With Doppler During Follow-up Period After Part 2
timeFrame: FU Week 24
measure: Spleen Measurements as Assessed by Abdominal Ultrasound With Doppler in the Study
timeFrame: Baseline; Week 24, Week 48, Withdrawal/Completion
measure: Spleen Measurements as Assessed by Abdominal Ultrasound With Doppler During Follow-up Period After Part 2
timeFrame: FU Week 24
Other outcomes:
Locations:
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Fukui
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Gunma
country: Japan
facility: GSK Investigational Site
city: Hyogo
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Kagawa
country: Japan
facility: GSK Investigational Site
city: Kagawa
country: Japan
facility: GSK Investigational Site
city: Kagoshima
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Nagasaki
country: Japan
facility: GSK Investigational Site
city: Oita
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Wakayama
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Kawaguchi T, Komori A, Fujisaki K, Nishiguchi S, Kato M, Takagi H, Tanaka Y, Notsumata K, Mita E, Nomura H, Shibatoge M, Takaguchi K, Hattori T, Sata M, Koike K. Eltrombopag enables initiation and completion of pegylated interferon/ribavirin therapy in Japanese HCV-infected patients with chronic liver disease and thrombocytopenia. Exp Ther Med. 2019 Jul;18(1):596-604. doi: 10.3892/etm.2019.7616. Epub 2019 May 24.