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

Hepatitis C, Chronic Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00516321
• Other study ID #: TPL103922
• Status: Completed
• Phase: Phase 3
• First received: August 13, 2007
• Last updated: October 10, 2013
• Start date: October 2007
• Est. completion date: May 2011

Study information

• Verified date: August 2012
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 687
• Est. completion date: May 2011
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic

Intervention

Drug:
• eltrombopag
25, 50, 75, 100 mg tablets taken once daily orally
• placebo
matched placebo taken once daily orally

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Camperdown	New South Wales
Australia	GSK Investigational Site	Fitzroy	Victoria
Australia	GSK Investigational Site	Garran	Australian Capital Territory
Australia	GSK Investigational Site	Heidelberg	Victoria
Australia	GSK Investigational Site	Melbourne	Victoria
Australia	GSK Investigational Site	Nedlands	Western Australia
Australia	GSK Investigational Site	Randwick	New South Wales
Belgium	GSK Investigational Site	Bruxelles
Belgium	GSK Investigational Site	Edegem
Belgium	GSK Investigational Site	Gent
Belgium	GSK Investigational Site	Leuven
Brazil	GSK Investigational Site	Campinas	São Paulo
Brazil	GSK Investigational Site	São Paulo
Canada	GSK Investigational Site	Barrie	Ontario
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Hamilton	Ontario
Canada	GSK Investigational Site	Hamilton	Ontario
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Ottawa	Ontario
Canada	GSK Investigational Site	Ottawa	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Victoria	British Columbia
Canada	GSK Investigational Site	Winnipeg	Manitoba
Czech Republic	GSK Investigational Site	Praha 4
Czech Republic	GSK Investigational Site	Praha 6
France	GSK Investigational Site	Besançon
France	GSK Investigational Site	Dijon cedex
France	GSK Investigational Site	Marseille
France	GSK Investigational Site	Montpellier
France	GSK Investigational Site	Nice
France	GSK Investigational Site	Pessac Cedex
France	GSK Investigational Site	Strasbourg
France	GSK Investigational Site	Toulouse
France	GSK Investigational Site	Toulouse cedex 9
Germany	GSK Investigational Site	Aachen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Beeskow	Brandenburg
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Bochum	Nordrhein-Westfalen
Germany	GSK Investigational Site	Bonn	Nordrhein-Westfalen
Germany	GSK Investigational Site	Deggendorf	Bayern
Germany	GSK Investigational Site	Dortmund	Nordrhein-Westfalen
Germany	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Goettingen	Niedersachsen
Germany	GSK Investigational Site	Halle	Sachsen-Anhalt
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Herne	Nordrhein-Westfalen
Germany	GSK Investigational Site	Hof/Saale	Bayern
Germany	GSK Investigational Site	Kassel	Hessen
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Leipzig	Sachsen
Germany	GSK Investigational Site	Leipzig	Sachsen
Germany	GSK Investigational Site	Leverkusen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Magdeburg	Sachsen-Anhalt
Germany	GSK Investigational Site	Mainz	Rheinland-Pfalz
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Muenster	Nordrhein-Westfalen
Germany	GSK Investigational Site	Regensburg	Bayern
Germany	GSK Investigational Site	Siegen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Germany	GSK Investigational Site	Wuerzburg	Bayern
Hong Kong	GSK Investigational Site	Pokfulam
India	GSK Investigational Site	Bangalore
India	GSK Investigational Site	Chennai
India	GSK Investigational Site	Mumbai
Israel	GSK Investigational Site	Haifa
Israel	GSK Investigational Site	Jerusalem
Israel	GSK Investigational Site	Petach Tikva
Israel	GSK Investigational Site	Safed
Israel	GSK Investigational Site	Tel Aviv
Italy	GSK Investigational Site	Avellino	Campania
Italy	GSK Investigational Site	Bari	Puglia
Italy	GSK Investigational Site	Bologna	Emilia-Romagna
Italy	GSK Investigational Site	Brescia	Lombardia
Italy	GSK Investigational Site	Catanzaro	Calabria
Italy	GSK Investigational Site	Genova	Liguria
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Palermo	Sicilia
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	San Giovanni Rotondo (FG)	Puglia
Korea, Republic of	GSK Investigational Site	Busan
Korea, Republic of	GSK Investigational Site	Incheon
Korea, Republic of	GSK Investigational Site	Seoul
Netherlands	GSK Investigational Site	Amsterdam
Netherlands	GSK Investigational Site	Nijmegen
Netherlands	GSK Investigational Site	Rotterdam
Pakistan	GSK Investigational Site	Lahore
Pakistan	GSK Investigational Site	Lahore
Poland	GSK Investigational Site	Bydgoszcz
Poland	GSK Investigational Site	Chorzow
Poland	GSK Investigational Site	Kielce
Poland	GSK Investigational Site	Szczecin
Poland	GSK Investigational Site	Wroclaw
Puerto Rico	GSK Investigational Site	Ponce
Puerto Rico	GSK Investigational Site	San Juan
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Constanta
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Mosocow
Russian Federation	GSK Investigational Site	Smolensk
Slovakia	GSK Investigational Site	Bratislava
Slovakia	GSK Investigational Site	Bratislava
Slovakia	GSK Investigational Site	Kosice
Slovakia	GSK Investigational Site	Martin
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Granada
Spain	GSK Investigational Site	L'Hospitalet de Llobregat. Barcelona
Spain	GSK Investigational Site	La Coruña
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	San Sebastián
Spain	GSK Investigational Site	Sevilla
Spain	GSK Investigational Site	Valencia
Taiwan	GSK Investigational Site	Kaohsiung
Taiwan	GSK Investigational Site	Taichung
Taiwan	GSK Investigational Site	Tainan
Taiwan	GSK Investigational Site	Taipei
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Chiangmai
Thailand	GSK Investigational Site	Khon Kaen
Thailand	GSK Investigational Site	Songkla
Ukraine	GSK Investigational Site	Donetsk
Ukraine	GSK Investigational Site	Kyiv
Ukraine	GSK Investigational Site	Kyiv
Ukraine	GSK Investigational Site	Vinnytsia
United Kingdom	GSK Investigational Site	Glasgow	Lanarkshire
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Plymouth
United States	GSK Investigational Site	Ann Arbor	Michigan
United States	GSK Investigational Site	Asheville	North Carolina
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Bradenton	Florida
United States	GSK Investigational Site	Bronx	New York
United States	GSK Investigational Site	Burlington	Massachusetts
United States	GSK Investigational Site	Charlottesville	Virginia
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Fairfax	Virginia
United States	GSK Investigational Site	Gainsville	Florida
United States	GSK Investigational Site	Galveston	Texas
United States	GSK Investigational Site	Hershey	Pennsylvania
United States	GSK Investigational Site	Honolulu	Hawaii
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Jackson	Tennessee
United States	GSK Investigational Site	Jackson	Mississippi
United States	GSK Investigational Site	La Jolla	California
United States	GSK Investigational Site	Little Rock	Arkansas
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Louisville	Kentucky
United States	GSK Investigational Site	Manhasset	New York
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	New Haven	Connecticut
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Rochester	New York
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	San Clemente	California
United States	GSK Investigational Site	St. Louis	Missouri
United States	GSK Investigational Site	Syracuse	New York
United States	GSK Investigational Site	Tucson	Arizona
United States	GSK Investigational Site	Tulsa	Oklahoma
United States	GSK Investigational Site	Valhalla	New York
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Czech Republic,  France,  Germany,  Hong Kong,  India,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Pakistan,  Poland,  Puerto Rico,  Romania,  Russian Federation,  Slovakia,  Spain,  Taiwan,  Thailand,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	No
Secondary	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	No
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	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	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
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	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
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 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)	No
Secondary	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)	No
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	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No