Eltrombopag To Initiate And Maintain Interferon Antiviral Treatment To Benefit Subjects With Hepatitis C Liver Disease - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Hepatitis C, Chronic
Interventions:	Drug: eltrombopag Drug: placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Eltrombopag: Open-label Phase	Participants with a platelet count of <75 giga (10^9) cells per liter (Gi/L) initially received eltrombopag 25 milligrams (mg) once daily (QD) for 2 weeks. After 2 weeks, if the platelet count was <100 Gi/L, participants underwent dose escalation to 50 mg QD for 2 weeks. If platelet counts still remained <100 Gi/L, further dose escalations to 75 mg QD (up to 2 weeks) and 100 mg QD (up to a maximum of 3 weeks) were allowed. Participants who achieved platelet counts >=100 Gi/L during the Open-label Phase (maximum of up to 9 weeks) were eligible to enter the Double-blind (DB) Antiviral Treatment Phase, whereas those who failed to reach platelet counts >=100 Gi/L were discontinued from eltrombopag and had to attend the post-treatment follow-up visits.
Placebo+Antiviral Therapy: DB Phase	Participants completing the OL Phase were administered matching placebo tablets QD in combination with antiviral therapy (peginterferon alfa-2b and ribavirin) for a duration of either 24 or 48 weeks (for participants with Genotype 2/3) or 48 weeks (for participants with Non-Genotype 2/3).
Eltrombopag+Antiviral Therapy: DB Phase	Participants completing the OL Phase continued on the same dose of eltrombopag received in the OL Phase (dose that effectively raised platelets to >=100 Gi/L) in combination with antiviral therapy (peginterferon alfa-2b and ribavirin) for a duration of either 24 or 48 weeks (for participants with Genotype 2/3) or 48 weeks (for participants with Non-Genotype 2/3).

Participant Flow for 2 periods

Period 1: Open-label Pre-Antiviral Treatment Phase

	Eltrombopag: Open-label Phase	Placebo+Antiviral Therapy: DB Phase	Eltrombopag+Antiviral Therapy: DB Phase
STARTED	805	0	0
COMPLETED	759	0	0
NOT COMPLETED	46	0	0
Adverse Event	5	0	0
Lost to Follow-up	12	0	0
Protocol Violation	5	0	0
Physician Decision	8	0	0
Insufficient Platelet Response	13	0	0
Withdrawal by Subject	3	0	0

Period 2: Double-bilnd Antiviral Treatment Phase

	Placebo+Antiviral Therapy: DB Phase	Eltrombopag+Antiviral Therapy: DB Phase
STARTED	253	506
COMPLETED	205	404
NOT COMPLETED	48	102
Adverse Event	10	27
Protocol Violation	1	0
Lost to Follow-up	15	48
Physician Decision	5	8
Withdrawal by Subject	17	19

Baseline Characteristics

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Reporting Groups

	Description
Placebo+Antiviral Therapy: DB Phase	Participants completing the OL Phase were administered matching placebo tablets QD in combination with antiviral therapy (peginterferon alfa-2b and ribavirin) for a duration of either 24 or 48 weeks (for participants with Genotype 2/3) or 48 weeks (for participants with Non-Genotype 2/3).
Eltrombopag+Antiviral Therapy: DB Phase	Participants completing the OL Phase continued on the same dose of eltrombopag received in the OL Phase (dose that effectively raised platelets to >=100 Gi/L) in combination with antiviral therapy (peginterferon alfa-2b and ribavirin) for a duration of either 24 or 48 weeks (for participants with Genotype 2/3) or 48 weeks (for participants with Non-Genotype 2/3).

Baseline Measures

	Placebo+Antiviral Therapy: DB Phase	Eltrombopag+Antiviral Therapy: DB Phase	Total
Number of Participants [units: participants]	253	506	759
Age ^[1] [units: Years] Mean ± Standard Deviation
Years	52.0 ± 9.15	52.4 ± 8.61	52.3 ± 8.79
Gender ^[1] [units: Participants]
Female	93	185	278
Male	160	321	481
Race/Ethnicity, Customized ^[2] [units: participants]
African American (A)/African	4	8	12
American Indian or Alaska Native	0	1	1
White (W)	188	388	576
Central/South Asian	16	43	59
Japanese/East Asian /South East Asian	45	64	109
American Indian or Alaska Native and White	0	1	1
African A/African and A Indian/Alaska Native and W	0	1	1
Number of participants categorized into the indicated genotype for Hepatitic C Virus (HCV) ^[3] [units: participants]
Genotype 1	160	320	480
Genotype 2	28	40	68
Genotype 3	47	113	160
Genotype 4	17	30	47
Genotype 5	0	0	0
Genotype 6	0	1	1
Genotype 7	0	0	0
Missing	1	2	3
Number of participants categorized into the indicated Child-Pugh (CP) Class ^[4] [units: participants]
Class A	242	487	729
Class B	11	17	28
Class C	0	0	0
Missing	0	2	2
Number of participants with or without previous interferon (IFN) use ^[5] [units: participants]
Naïve	182	347	529
Experienced	71	159	230
Number of participants with the indicated FibroTest/Acti Test (FibroSURE) score ^[6] [units: participants]
Score: F0/F1/F2	19	46	65
Score: F3/F4	199	405	604
Missing	35	55	90
Number of participants with normal or elevated Baseline values for Alanine Aminotransferase (ALT) ^[7] [units: participants]
Normal	49	113	162
Elevated	204	393	597
Baseline HCV Ribonucleic Acid (RNA) ^[8] [units: International Units per milliliter] Mean ± Standard Deviation	1656788.0 ± 2564763.45	1702729.6 ± 3066411.11	1687415.8 ± 2907191.97
Baseline Platelet Count ^[9] [units: Giga (10^9) cells per liter (Gi/L)] Mean ± Standard Deviation	56.56 ± 13.571	56.85 ± 13.311	56.75 ± 13.390

[1]	Baseline characteristics were collected for the Intent-to-Treat (ITT) Population, which included all randomized participants in the Double-blind (DB) Phase of the study.
[2]	Baseline characteristics were collected for the ITT Population, which included all randomized participants in the DB Phase of the study.
[3]	Baseline characteristics were collected for the ITT Population, which included all randomized participants in the DB Phase of the study. The HCV is a small, enveloped, single-stranded, positive-sense ribonucleic acid (RNA) virus. There are seven major genotypes of HCV, which are indicated numerically from Genotype 1 to 7.
[4]	The CP score (ranging from 5 to 15, with 5 being mild and 15 being severe), calculated based on total bilirubin, serum albumin, international normalized ratio, ascites, and hepatic encephalopathy, is used to assess the severity of liver disease. A CP score of 5-6 = Class A (mild), 7-9 = Class B (moderate), and >=10 = Class C (severe).
[5]	Baseline characteristics were collected for the ITT Population, which included all randomized participants in the DB Phase of the study. Participants at Baseline were classified as not having used IFN previously (Naïve) or having used IFN previously (Experienced).
[6]	FibroSURE is a noninvasive blood test that combines the quantitative results of 6 serum biochemical markers (α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, γ-glutamyl transpeptidase [GGT], and ALT) with a participant’s age and gender to generate a measure of liver fibrosis/cirrhosis and necroinflammatory activity. It provides a numerical quantitative estimate of liver fibrosis ranging from 0.00 to 1.00, corresponding to the Metavir scoring system of stages F0 to F4 (F0, no fibrosis [F]; F1, portal F; F2, bridging F with few septa; F3, bridging F with many septa; F4=cirrhosis).
[7]	Baseline characteristics were collected for the ITT Population, which included all randomized participants in the DB Phase of the study. The normal range of ALT is 0 to 48 International Units per Liter (IU/L).
[8]	Baseline characteristics were collected for the ITT Population, which included all randomized participants in the DB Phase of the study. HCV RNA was assessed at baseline of the DB Phase. Data are missing for three participants in the Eltrombopag+Antiviral Therapy treatment group.
[9]	Baseline characteristics were collected for the ITT Population, which included all randomized participants in the DB Phase of the study. Platelet count eligibility was confirmed at the Baseline visit, prior to administration of eltrombopag, and was defined as the average of the screening and baseline counts, which must be <75 Gi/L.

Outcome Measures

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1. Primary:

Number of Participants With Sustained Virologic Response (SVR) in the Double-blind (DB) Antiviral Treatment 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) ]

Show Outcome Measure 1

2. Secondary:

Number of Participants Whose Platelet Count Increased From a Baseline Count of <75 Gi/L to a Count Greater Than or Equal to (>=) 100 Giga (10^9) Cells Per Liter (Gi/L) During the Open-label (OL) Pre-Antiviral Treatment Phase [ Time Frame: From Baseline up to Week 9 in the OL Phase ]

Show Outcome Measure 2

3. Secondary:

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 [ Time Frame: From Baseline up to Week 9 in the OL Phase ]

Show Outcome Measure 3

4. Secondary:

Median Platelet Count at the Indicated Time Points During the OL Phase [ 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) ]

Show Outcome Measure 4

5. Secondary:

Median Platelet Count at the Indicated Time Points During the DB Phase [ 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) ]

Show Outcome Measure 5

6. Secondary:

Number of Participants in the Indicated Categories for Minimum Platelet Count With Antiviral Therapy [ 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) ]

Show Outcome Measure 6

7. Secondary:

Number of Participants With Rapid Virological Response (RVR) and Extended RVR (eRVR) During 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) ]

Show Outcome Measure 7

8. Secondary:

Number of Participants With Early Virological Response (EVR) and Complete EVR (cEVR) During 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) ]

Show Outcome Measure 8

9. Secondary:

Number of Participants With End of Treatment Response (ETR) and Sustained Virological Response at Week 12 of Follow-up (SVR12) During 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) ]

Show Outcome Measure 9

10. Secondary:

Number of Participants in the Indicated Categories for Antiviral Therapy Dose Reductions in 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) ]

Show Outcome Measure 10

11. Secondary:

Time to First Dose Reduction of Peginterferon Alfa-2a and Ribavirin Therapy in 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) ]

Show Outcome Measure 11

12. Secondary:

Number of Participants With the Indicated Levels of Peginterferon Dose Reductions in 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) ]

Show Outcome Measure 12

13. Secondary:

Number of Participants Who Prematurely Discontinued Antiviral Therapy in 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) ]

Show Outcome Measure 13

14. Secondary:

Number of Participants 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) [ 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) ]

Show Outcome Measure 14

15. Secondary:

Number of Participants 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) [ 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) ]

Show Outcome Measure 15

16. Secondary:

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 [ 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) ]

Show Outcome Measure 16

17. Secondary:

Number of Participants in the Indicated Categories for Cataract Event During the DB Phase, Per Clinical Events Committee (CEC) Adjudication [ 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) ]

Show Outcome Measure 17

18. Secondary:

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 [ 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) ]

Show Outcome Measure 18

19. Secondary:

Number of Participants With CS and NCS Change From Baseline for 12-lead ECG at the Indicated Time Points During the DB Phase [ Time Frame: End of Treatment (up to Week 52); and 24-week FU (up to Week 72) ]

Show Outcome Measure 19

20. Secondary:

Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points During the DB Phase [ 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) ]

Show Outcome Measure 20

21. Secondary:

Mean Change From Baseline in Heart Rate at the Indicated Time Points During the DB Phase [ 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) ]

Show Outcome Measure 21

22. Secondary:

Mean Change From Baseline in Weight at the Indicated Time Points During the DB Phase [ 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) ]

Show Outcome Measure 22

23. Secondary:

Mean Change From Baseline in Body Mass Index (BMI) at the Indicated Time Points During the DB Phase [ 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) ]

Show Outcome Measure 23

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: GSK Response Center
Organization: GlaxoSmithKline
phone: 866-435-7343

No publications provided

Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT00529568 History of Changes
Other Study ID Numbers:	TPL108390
Study First Received:	September 12, 2007
Results First Received:	April 19, 2012
Last Updated:	May 17, 2012
Health Authority:	United Kingdom: Medicines and Healthcare Products Regulatory Agency United States: Food and Drug Administration