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

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.

Time frame: 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)

Population: Intent-to-Treat (ITT) Population: all participants randomized in 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.

Time frame: 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)

Population: Safety DB Population. Only those participants contributing data at the indicated time points were analyzed.

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.

Time frame: 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)

Population: Safety DB Population. Only those participants contributing data at the indicated time points were analyzed.

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.

Time frame: 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)

Population: Safety DB Population. Only those participants contributing data at the indicated time points were analyzed.

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.

Time frame: 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)

Population: Safety DB Population. Only those participants contributing data at the indicated time points were analyzed.

Blood taken from peripheral blood vessels was used for the measurement of platelet counts.

Time frame: 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)

Population: ITT Population. Only those participants contributing data at the indicated time points were analyzed. The Last On Treatment assessment refers to the actual last treatment assessment, not necessarily to the End of Treatment assessment entered by the Investigator.

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.

Time frame: 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)

Population: Safety Population. Only those participants contributing data at the indicated time points were analyzed.

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.

Time frame: DB Phase: Antiviral BL (up to Week 10); End of Treatment (up to Week 52); and 24-week FU (up to Week 72)

Population: Safety DB Population. Only those participants contributing data at the indicated time points were analyzed. Worst ECG post-BL is the worst ECG assessment reported for a participant at a post-BL assessment and could be Normal, Abnormal - NCS, Abnormal - CS, or Abnormal (NCS or CS not given).

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.

Time frame: 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)

Population: ITT Population

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.

Time frame: 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)

Population: Safety DB Population

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.

Time frame: 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)

Population: ITT Population

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.

Time frame: 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)

Population: Pharmacogenetic (PGx) Sub-Population: participants enrolled in this study who provided written informed consent for PGx research with a blood sample for genotyping and who were successfully genotyped for at least one of the two genetic markers under study

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.

Time frame: From Baseline up to Week 9 in the OL Phase

Population: Safety Population. Participants with a platelet count \>=90 Gi/L and who initiated antiviral therapy during the DB Phase were analyzed.

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.

Time frame: 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)

Population: ITT Population

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.

Time frame: From Baseline up to Week 9 in the OL Phase

Population: Safety Population: all participants who had received study drug in the OL 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.

Time frame: End of Treatment (up to Week 52); and 24-week FU (up to Week 72)

Population: Safety DB Population. Only those participants contributing data at the indicated time points were analyzed.

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.

Time frame: From Baseline up to Week 12

Population: ITT Population

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.

Time frame: 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)

Population: ITT Population

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.

Time frame: From Baseline up to Week 12

Population: ITT Population

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.

Time frame: 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)

Population: ITT Population. One participant could have had more than one dose reduction.

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.

Time frame: 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)

Population: Safety DB Population

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.

Time frame: 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)

Population: Safety DB Population: all randomized participants who had received study drug in the DB Phase

Time to first dose reduction was calculated as the time period from the first dose to the first dose reduction.

Time frame: 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)

Population: ITT Population. Only those participants with dose reductions were analyzed.