Eltrombopag To Initiate And Maintain Interferon Antiviral Treatment To Subjects With Hepatitis C Related Liver Disease

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the ability of eltrombopag to maintain a platelet count sufficient to facilitate initiation of antiviral therapy, to minimise antiviral therapy dose reductions and to avoid permanent discontinuation of antiviral therapy. The clinical benefit of eltrombopag will be measured by the proportion of subjects who are able to achieve a Sustained Virological Response (SVR).

Official Title
-----------------
Randomised, Placebo-controlled, Multi-centre Study to Assess the Efficacy and Safety of Eltrombopag in Thrombocytopenic Subjects With Hepatitis C Virus (HCV) Infection Who Are Otherwise Eligible to Initiate Antiviral Therapy (Peginterferon Alfa-2a Plus Ribavirin

Conditions
-----------------
Hepatitis C, Chronic

Intervention / Treatment
-----------------
* Drug: eltrombopag
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female subjects, >18 years Evidence of chronic hepatitis C virus (HCV) infection Subjects who are appropriate candidates for peginterferon (pegIFN) and ribavirin antiviral therapy A platelet count of <75,000/mcL Haemoglobin >11.0g/dL for men or >10.0g/dL for women Absolute neutrophil count (ANC) >750/mm3 and no history of infections associated with neutropenia Creatinine clearance >50mL/minute All fertile males and females must use two forms of effective contraception between them during treatment and during the 24 weeks after treatment end Subject is able to understand, consent and comply with protocol requirements and instructions and is likely to complete the study as planned Exclusion criteria: Non-responders to previous treatment with pegIFN and ribavirin who failed to achieve a sustained virologic response (SVR) for reasons other than thrombocytopenia, despite an optimal course (dose and duration) of combination therapy with pegIFN and ribavirin Decompensated liver disease, e.g. Child-Pugh score >6 or history of ascites or hepatic encephalopathy or current evidence of ascites Known hypersensitivity, intolerance or allergy to interferon (IFN), ribavirin, eltrombopag or any of their ingredients Serious cardiac, cerebrovascular, or pulmonary disease that would preclude treatment with pegIFN and ribavirin Subjects with a history of any one of the following: Suicide attempt or hospitalisation for depression in the past 5 years Any current severe or poorly controlled psychiatric disorder The following subjects are eligible for study participation, but must be assessed and followed (if recommended) by a mental health professional: Subjects who have had a severe or poorly controlled psychiatric disorder more than 6 months ago but less than 5 years ago Seizure disorder that has not been well controlled History of clinically significant bleeding from oesophageal or gastric varices Subjects with haemoglobinopathies, e.g. sickle cell anaemia, thalassemia major Any prior history of arterial or venous thrombosis AND two or more of the following risk factors: hereditary thrombophilic disorders (e.g. Factor V Leiden, antithrombin III (ATIII) deficiency, etc), hormone replacement therapy, systemic contraception (containing estrogen), smoking, diabetes, hypercholesterolemia, medication for hypertension or cancer Pre-existing cardiac disease (New York Heart Association (NYHA) Grade III/IV), or arrhythmias known to involve the risk of thromboembolic events, or corrected QT interval (QTc) >450 msec Evidence of hepatocellular carcinoma Laboratory evidence of infection with human immunodeficiency virus (HIV) or active Hepatitis B Virus (HBV) infection Any disease condition associated with active bleeding or requiring anticoagulation with heparin or warfarin Therapy with any anti-neoplastic or immuno-modulatory treatment <6 months prior to the first dose of eltrombopag Subjects who have had a malignancy diagnosed and/or treated within the past 5 years, except for subjects with localised basal or squamous cell carcinoma treated by local excision or subjects with malignancies who have been adequately treated and, in the opinion of the oncologist, have an excellent chance of cancer-free survival Pregnant or nursing women Males with a female partner who is pregnant History of alcohol/drug abuse or dependence within 6 months of the study start (unless participating in a controlled rehabilitation programme) Treatment with an investigational drug or IFN within 30 days or 5 half-lives (whichever is longer) of the screening visit History of platelet clumping that prevents reliable measurement of platelet counts History of major organ transplantation with an existing functional graft Thyroid dysfunction not adequately controlled Subjects planning to have cataract surgery Evidence of portal vein thrombosis on abdominal imaging within 3 months of the baseline visit

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: eltrombopag|25, 50, 75, 100 mg tablets taken once daily orally|
|Drug: placebo|matched placebo taken once daily orally|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Sustained Virologic Response (SVR) in the Double-blind (DB) Antiviral Treatment Phase | Participants with SVR were defined as those with undetectable Hepatitis C Virus (HCV) ribonucleic acid (RNA) at 24 weeks post-completion of the treatment period of the DB Phase. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Whose Platelet Count Increased From a Baseline Count of <75 Gi/L to a Count Greater Than or Equal to (>=) 90 Giga (10^9) Cells Per Liter (Gi/L) During the Open-label (OL) Pre-Antiviral Treatment Phase | Participants were assessed for a shift from a baseline platelet count of <75 Gi/L to a count >=90 Gi/L during the OL Phase (up to 9 weeks). Local laboratories were used for platelet function tests. Platelet counts were measured by blood draw. | From Baseline up to Week 9 in the OL Phase | 
| Number of Participants Receiving the Indicated Doses of Eltrombopag in the OL Phase Who Initiated Antiviral Therapy (Peginterferon Alfa-2a and Ribavirin) in the DB Phase | In the OL Phase, participants initially received the lowest dose of eltrombopag (25 mg QD) for 2 weeks. If after this time the platelet count was <90 Gi/L, participants underwent sequential dose escalation to the next highest dose (50 mg QD for up to 2 weeks), with further dose escalations to 75 mg QD (up to 2 weeks) and 100 mg QD (up to a maximum of 3 weeks) if platelet counts remained <90 Gi/L. Participants who achieved platelet count >=90 Gi/L on any of the eltrombopag doses in the OL Phase initiated antiviral therapy in the DB Phase. | From Baseline up to Week 9 in the OL Phase | 
| Median Platelet Count at the Indicated Time Points During the OL Phase | Blood taken from peripheral blood vessels was used for the measurement of platelet counts. The Last On Treatment assessment refers to the actual last treatment assessment, not necessarily to the End of Treatment assessment entered by the Investigator. | OL Phase: Baseline; Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, and 9; Antiviral Baseline (up to Week 10); End of Treatment (up to Week 48); 4-week Follow-up (FU) (up to Week 62); 12-week FU (up to Week 70); and 24-week FU (up to Week 82) | 
| Median Platelet Count at the Indicated Time Points During the DB Phase | Blood taken from peripheral blood vessels was used for the measurement of platelet counts. | DB Phase: Baseline; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44; End of Treatment (up to Week 48); 4-week Follow-up (FU) (up to Week 52); 12-week FU (up to Week 60); and 24-week FU (up to Week 72) | 
| Number of Participants in the Indicated Categories for Minimum Platelet Count With Antiviral Therapy During the DB Phase | The minimum platelet count with antiviral therapy was categorized as follows: <25 Gi/L; >=25 to <50 Gi/L; >=50 to <90 Gi/L; >=90 to <150 Gi/L; >=150 Gi/L to <200 Gi/L; >=200 Gi/L to <400 Gi/L; and >=400 Gi/L. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 
| Number of Participants With Rapid Virological Response (RVR) and Extended RVR (eRVR) During the DB Phase | RVR is defined as the absence of detectable HCV RNA after 4 weeks of antiviral treatment. eRVR is defined as the absence of detectable HCV RNA after 4 weeks of antiviral treatment that persisted through Week 12. | From Baseline up to Week 12 | 
| Number of Participants With Early Virological Response (EVR) and Complete EVR (cEVR) During the DB Phase | EVR is defined as a clinically significant reduction from Baseline in HCV RNA (>=2 log10 decrease in HCV RNA or undetectable HCV RNA) after 12 weeks of antiviral treatment. cEVR, a subset of EVR, is defined exclusively as undetectable HCV RNA after 12 weeks of antiviral treatment. | From Baseline up to Week 12 | 
| Number of Participants With End of Treatment Response (ETR) and Sustained Virological Response at Week 12 of Follow-up (SVR12) During the DB Phase | ETR is defined as the absence of detectable HCV RNA at the end of antiviral treatment. SVR12 is defined as the absence of detectable HCV RNA at the end of antiviral treatment and the 12-week follow-up assessment. | From Baseline up to Week 36 or Week 60 (for participants with Genotype 2/3) or up to Week 60 (for participants with Non-Genotype 2/3) | 
| Number of Participants in the Indicated Categories for Antiviral Therapy Dose Reductions in the DB Phase | Participants were assigned a score equal to the number of times their dose of antiviral therapy (peginterferon or ribavirin) was reduced (0=no dose reductions [DRs]; 1=one DR; 2=two DRs; 3=three DRs; >3=more than three DRs). Where possible, every effort was made to maintain the recommended dose of antiviral therapy for the treatment duration in the DB Phase. However, where dose modification of antiviral therapy was required due to safety concerns, it was performed by the Investigator as per the region-specific product labels of peginterferon and ribavirin. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 
| Time to First Dose Reduction of Peginterferon Alfa-2a and Ribavirin Therapy in the DB Phase | Time to first dose reduction was calculated as the time period from the first dose to the first dose reduction. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 
| Number of Participants With the Indicated Levels of Peginterferon Dose Reductions in the DB Phase | The assigned dose in the DB Phase of peginterferon alfa-2a was 180 micrograms (mcg). For peginterferon dose modification, downward adjustments in one level increments was considered. The lowest dose of peginterferon alfa-2a that was allowed to be administered was 45 mcg. Where dose adjustment was required for moderate to severe adverse reactions (clinical and/or laboratory), an initial dose reduction to 135 mcg was generally adequate. In some cases, a dose reduction to 90 mcg or 45mcg was necessary. Dose increases toward the original dose were considered when the adverse reaction was resolved. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 
| Number of Participants Who Prematurely Discontinued Antiviral Therapy in the DB Phase | The following participants were considered to have discontinued from antiviral therapy: participants who were lost to follow-up; participants who withdrew for any reason; participants who died; participants who otherwise did not complete their planned course of antiviral therapy for any reason. The planned duration of antiviral therapy was 48 weeks for participants with Non-Genotype 2/3 and 24 or 48 weeks for participants with Genotype 2/3. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 
| Number of Participants (Par.) Categorized as Responders (R) and Non-responders (NR) for SVR and RVR to Antiviral Therapy in the Indicated Variants of Interleukin 28B (IL28B) (or Interferon, Lambda 3) During the DB Phase | There are two genetic variants (rs12979860 and rs8099917) mapping near IL28B associated with both interferon-induced SVR and spontaneous HCV clearance. Genotyping of the IL28B polymorphisms (rs12979860 and rs8099917) was conducted. IL28B genotype distribution by response to antiviral therapy (SVR and RVR) for both treatment arms was assessed. The effect of genotype was tested by comparing participants that carried 2 copies of the IL28B favorable response allele versus the others (recessive model). Genotypes at rs12979860 were coded as: CC=1, CT or TT=0; rs8099917 was coded as TT=1, GT or GG=0. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 
| Number of Par. With the Indicated Shift From Baseline (BL) in Severity Grades for Clinical Chemistry Parameters (Calcium, Glucose [Glu.], Potassium [Pot.], and Sodium [Sod.]), Per Division of Acquired Immunodeficiency Syndrome (DAIDS) During the DB Phase | Blood samples for the assessment of clinical chemistry parameters were taken at intervals throughout the study. Participants with the worst-case shift from BL during the DB Phase are reported, per severity grades by DAIDS, for levels of calcium (low=hypocalcemia; high=hypercalcemia), glu. (low=hypoglycemia; high=hyperglycemia), pot. (low=hypokalemia; high=hyperkalemia), and sod. (low=hyponatremia; high=hypernatremia). Per the DAIDS toxicity table, the grade ranges for each parameter are as follows: Grade (G) 1=mild; G2=moderate; G3=severe; G4=potentially life-threatening. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 
| Number of Participants With the Indicated Shifts From BL in Severity Grades for for Hematology Parameters (Hemoglobin, Lymphocytes [Lym.], Total Neutrophils [Tot Neu.], and White Blood Cells [WBC]), Per DAIDS During the DB Phase | Blood samples for the assessment of hematology parameters were taken at intervals throughout the study. Participants with the worst-case shift from BL during the DB Phase are reported, per severity grades by DAIDS, for levels of hemoglobin (low=anemia), lymphocytes (low=lymphocytopenia), total neutrophils (low=neutropenia), and white blood cells (low=leukocytopenia). Per the DAIDS toxicity table, grade ranges for each parameter are as follows: Grade (G) 1=mild; G2=moderate; G3=severe; G4=potentially life-threatening. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 
| Number of Participants in the Indicated Categories for Cataract Event During the DB Phase, Per Clinical Events Committee (CEC) Adjudication During the DB Phase | Ophthalmic (pertaining to eye) assessments were performed during the study. A cataract event is defined as an event ascertained to be a cataract (opacity or cloudiness of the lens of the eye, causing impairment of vision) by at least one of the CEC members (comprised of expert ophthalmologists who provided objective medical review of the blinded ophthalmic data). Per the CEC, cataract events were categorized as: (1) Cataract Progression (CP; progression of cataracts present at BL); and (2) Incident Cataract (IC; development of new cataracts). One eye=unilateral; both eyes=bilateral. | From Baseline up to Week 48 or Week 72 (for participants with Genotype 2/3) or up to Week 72 (for participants with Non-Genotype 2/3) | 
| Number of Participants Assessed as Normal and Abnormal (Clinically Significant [CS] and Not Clinically Significant [NCS]) for 12-lead Electrocardiogram (ECG) at the Indicated Time Points During the DB Phase | Duplicate 12-lead ECGs were required at Screening/BL, Antiviral BL, and at 12 weekly intervals during the study. The investigator assigned an ECG status of normal, abnormal, CS, or NCS; a status of abnormal alone indicates that the investigator did not determine if ECG was CS or NCS. Normal, all ECG parameters within accepted normal ranges. Abnormal, ECG finding(s) outside of normal ranges. CS, ECG with a CS abnormality that meets exclusion criteria. NCS, ECG with an abnormality not CS or meeting exclusion criteria, per Investigator, based on reasonable standards of clinical judgment. | DB Phase: Antiviral BL (up to Week 10); End of Treatment (up to Week 52); and 24-week FU (up to Week 72) | 
| Number of Participants With CS and NCS Change From Baseline for 12-lead ECG at the Indicated Time Points During the DB Phase | Duplicate 12-lead ECGs were required at Screening/BL, Antiviral BL, and at 12 weekly intervals during the study. The number of participants with a CS or a NCS change from baseline in ECG status was reported, as determined by the Investigator based on a reasonable standard of clinical judgment. Not applicable indicates that information was not provided by the investigator on whether the change from baseline ECG was CS or NCS. | End of Treatment (up to Week 52); and 24-week FU (up to Week 72) | 
| Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points During the DB Phase | Participant's blood pressure was measured at the indicated time points during the study. Systolic blood pressure is a measure of blood pressure while the heart is beating. Diastolic blood pressure is a measure of blood pressure while the heart is relaxed. Mean change from Baseline was calculated as the value at the indicated time points minus the value at Baseline. | DB Phase: Baseline; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44; End of Treatment (up to Week 48); 4-week Follow-up (FU) (up to Week 52); 12-week FU (up to Week 60); and 24-week FU (up to Week 72) | 
| Mean Change From Baseline in Heart Rate at the Indicated Time Points During the DB Phase | Heart rate was measured in participants at the indicated time points. Mean change from Baseline was calculated as the value at the indicated time points minus the value at Baseline. | DB Phase: Baseline; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44; End of Treatment (up to Week 48); 4-week Follow-up (FU) (up to Week 52); 12-week FU (up to Week 60); and 24-week FU (up to Week 72) | 
| Mean Change From Baseline in Weight at the Indicated Time Points During the DB Phase | The weight of participants was recorded at the indicated time points. Mean change from Baseline was calculated as the value at the indicated time points minus the value at Baseline. | DB Phase: Baseline; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44; End of Treatment (up to Week 48); 4-week Follow-up (FU) (up to Week 52); 12-week FU (up to Week 60); and 24-week FU (up to Week 72) | 
| Mean Change From Baseline in Body Mass Index (BMI) at the Indicated Time Points During the DB Phase | The BMI for participants was calculated at the indicated time points as body weight in kilograms divided by height in meters squared. Mean change from Baseline was calculated as the value at the indicated time points minus the value at Baseline. | DB Phase: Baseline; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44; End of Treatment (up to Week 48); 4-week Follow-up (FU) (up to Week 52); 12-week FU (up to Week 60); and 24-week FU (up to Week 72) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
thrombopoietin, hepatitis C, ribavirin, platelets, Hepatitis C-related thrombocytopenia, peginterferon alfa-2a