Axitinib For The Treatment Of Advanced Hepatocellular Carcinoma

Hepatocellular Carcinoma Clinical Trial

Official title:

A MULTICENTER, GLOBAL, RANDOMIZED, DOUBLE-BLIND STUDY OF AXITINIB PLUS BEST SUPPORTIVE CARE VERSUS PLACEBO PLUS BEST SUPPORTIVE CARE IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA FOLLOWING FAILURE OF ONE PRIOR ANTIANGIOGENIC THERAPY

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01210495
• Other study ID #: A4061058
• Secondary ID: 2010-021590-37
• Status: Completed
• Phase: Phase 2
• Start date: December 6, 2010
• Est. completion date: December 20, 2016

Study information

• Verified date: December 2018
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study is designed to demonstrate that axitinib plus best supportive care is superior to placebo plus best supportive care in prolonging survival in patients with advanced hepatocellular carcinoma.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 224
• Est. completion date: December 20, 2016
• Est. primary completion date: March 3, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Locally advanced or metastatic HCC

• Failure of one prior antiangiogenic therapy including sorafenib, bevacizumab and brivanib.

• Child-Pugh Class A or B (score 7 only) disease.

Exclusion Criteria:

• Prior treatment of advanced HCC with more than one prior first-line systemic therapy.

• Any prior local therapy within 2 weeks of starting the study treatment.

• Presence of hepatic encephalopathy and/or clinically relevant ascites.

• Presence of main portal vein invasion by HCC.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Drug:
• Axitinib (AG-013736)
Axitinib [tablet, 1 mg, 5 mg] will be given twice daily [BID] with continuous dosing; duration is approximately 3-6 months; starting dose is 5 mg BID

Other:
• Best Supportive Care
BSC may include medications and supportive measures deemed necessary to palliate disease related symptoms and improve quality of life.

Drug:
• Placebo
Placebo [tablet, 1 mg, 5 mg] will be given twice daily [BID] with continuous dosing; duration is approximately 3-6 months; starting dose is 5 mg BID

Other:
• Best Supportive Care
BSC may include medications and supportive measures deemed necessary to palliate disease related symptoms and improve quality of life.

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	CHC Clinique Saint-Joseph	Liège
China	The PLA 307 Hospital	Beijing
China	Guangdong General Hospital	Guangzhou	Guangdong
China	Sir Run Run Shaw Hospital of College of Medicine of Zhejiang University	Hangzhou	Zhejiang
China	The First Affiliated Hospital of Anhui Medical University	Hefei	Anhui
China	Nanjing Bayi Hospital	Nan Jing	Jiangsu
China	Jiang Su Cancer Hospital	Nanjing	Jiangsu
China	Zhongshan Hospital Fudan University	Shanghai
France	Centre Hospitalier Universitaire d'Amiens	Amiens
France	Hopital Saint André	Bordeaux Cedex
France	CHU Cote de Nacre	Caen, cedex 05
France	Bichat-Beaujon Service Inter Hospitalier De Cancerologie	Clichy
France	Hopital De La Croix-Rousse	Lyon Cedex 04
France	UPCET-CIC Timone	Marseille
France	CHRU Montpellier-Hopital Saint Eloi - Departement Oncologie Medicale	Montpellier Cedex 05
France	Hôpital L'Archet Ii	Nice
France	Hôpital Saint Antoine	Paris
France	Centre Eugène Marquis	Rennes
France	CHRU de Purpan.	Toulouse Cedex
Germany	Medizinische Klinik mit Schwerpunkt	Berlin
Germany	Universitätsklinikum Bonn	Bonn
Germany	Klinikum der Ludwig-Maximilians-Universitaet , Campus Grosshadern	München
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	Prince of Wales Hospital	Shatin, N.T.
Hungary	Semmelweis Egyetem I.sz. Belgyógyászati Klinika	Budapest
Hungary	Szegedi Tudományegyetem Onkoterápiás Klinika	Szeged
Italy	Istituto di Ematologia ed Oncologia Medica, Lorenzo ed Ariosto Seragnoli,	Bologna
Italy	Policlinico S.Orsola-Malpighi Dipartimento di Ematologia e Scienze Oncologiche "L. E A. Seragnoli"	Bologna
Italy	Ospedale Versilia,Oncologia Medica	Lido Di Camaiore (LU)
Italy	Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori IRST	Meldola (FC)
Italy	Unita Operativa Oncologia Medica IRCCS Fondazione Salvatore Maugeri	Pavia
Italy	Policlinico Universitario Agostino Gemelli	Roma
Italy	Unità Operativa Oncologica Medica	Roma
Italy	Azienda Ospedaliera Universitaria Senese Policlinico Santa Maria aile Scotte	Siena
Japan	Chiba University Hospital	Chiba City	Chiba
Japan	Sasaki Foundation Kyoundo Hospital	Chiyoda-Ku	Tokyo
Japan	Gifu Municipal Hospital	Gifu-shi	Gifu
Japan	Nihon University Itabashi Hospital	Itabashi-Ku	Tokyo
Japan	Kanazawa University Hospital	Kanazawa	Ishikawa
Japan	Yamanashi Prefectural Central Hospital	Kofu-Shi
Japan	Aichi Cancer Center Central Hospital, Diagnostic and Interventional Radiology	Nagoya	Aichi
Japan	Kinki University Hospital	Osaka-Sayama	Osaka
Japan	Shizuoka Cancer Center	Suntou-gun	Shizuoka
Korea, Republic of	National Cancer Center/ Center for Liver Cancer	Goyang-si
Korea, Republic of	Asan Medical Center, Division of Oncology, Department of Internal Medicine	Seoul
Korea, Republic of	Samsung Medical Center, Division of Hematology-Oncology, Department of Medicine	Seoul
Slovakia	Fakultna nemocnica s poliklinikou F. D. Roosevelta Banska Bystrica	Banska Bystrica
Slovakia	Narodny onkologicky ustav	Bratislava
Slovakia	Nemocnica Poprad, a.s.	Poprad
Slovakia	POKO Poprad s.r.o.	Poprad
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Chang Gung Medical Foundation - Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	Chi-Mei Medical Center LiouYing	Tainan
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Chang Gung Medical Foundation Linkou Branch	Taoyuan
United Kingdom	Clatterbridge Centre for Oncology NHS Foundation Trust	Liverpool
United Kingdom	Royal Liverpool and Broadgreen University Hospital	Liverpool
United Kingdom	Hammersmith Hospital	London
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	Royal Free Hospital	London
United Kingdom	The Christie NHS Foundation Trust	Withington	Manchester
United States	University of Michigan	Ann Arbor	Michigan
United States	Alta Bates Summit Comprehensive Cancer Center	Berkeley	California
United States	Moores UCSD Cancer Center	La Jolla	California
United States	UCSD Medical Center- La Jolla	La Jolla	California
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	University of California Irvine Medical Center	Orange	California
United States	Florida Hospital Transplant Center, Liver Unit	Orlando	Florida
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania
United States	UCSD Medical Center- Hillcrest	San Diego	California
United States	Moffitt Cancer Center & Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Belgium,  China,  France,  Germany,  Hong Kong,  Hungary,  Italy,  Japan,  Korea, Republic of,  Slovakia,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS) - Stratified Analysis, Randomized Portion	OS was defined as the time from the date of randomization to the date of death due to any cause. OS (in months) was calculated as (date of death - first randomization date +1)/30.4. For participants still alive at the time of the analysis, the OS time was censored on the last date they were known to be alive. All participants were followed up for survival at least every 3 months after discontinuing study treatment until at least two years after randomization of the last participant.	From randomization until at least two years after the last participant has been randomized (up to 6 years)
Secondary	Progression-Free Survival (PFS) - Stratified Analysis, Randomized Portion	PFS was defined as time from randomization to first documented objective tumor progression or to death due to any cause, whichever occurred first. PFS (in months) was calculated as (first event date - first randomization date +1)/30.4. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was death). As per response evaluation criteria in solid tumors (RECIST) 1.1, progression was defined as greater than or equal to (>=) 20% increase in sum of longest dimensions of target lesions or appearance of one or more new target lesions and unequivocal progression of existing non-target lesions, or appearance of 1 new non-target lesions. Participants discontinuing study treatment without documented evidence of PD were to be followed up at least every 8 weeks after discontinuing study treatment until disease progression, or initiation of another anticancer treatment.	Every 8 weeks until disease progression/death or start of new treatment or until at least two years after the last participant has been randomized, whatever occurs first
Secondary	Objective Response Rate (ORR) - Percentage of Participants With Objective Response by Stratified Analysis, Randomized Portion	ORR was defined as the percentage of participants with confirmed complete response (CR) or confirmed partial response (PR) according to the RECIST 1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis <10 millimetres [mm]). PR was defined as a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.	Every 8 weeks until at least two years after the last participant has been randomized
Secondary	Time to Tumor Progression (TTP) - Stratified Analysis, Randomized Portion	TTP was defined as the time from randomization to first documentation of objective tumor progression. If tumor progression data included more than 1 date, the first date was used. TTP (in months) was calculated as (first event date - first randomization date +1)/30.4.	Every 8 weeks until disease progression/death or start of new treatment or until at least two years after the last participant has been randomized, whatever occurs first
Secondary	Duration of Response (DR) by Unstratified Analysis, Randomized Portion	DR was defined as the time from the first documentation of objective tumor response (CR or PR) that was subsequently confirmed to the first documentation of PD or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, the first date was to be used. DR (in months) was to be calculated as (the end date for DR - first CR or PR that was subsequently confirmed +1)/30.4.	From objective response to date of progression or death
Secondary	Percentage of Participants With Overall Clinical Benefit Response (CBR) - Stratified Analysis, Randomized Portion	CBR was defined as the percentage of participants with confirmed CR or confirmed PR or a best response of stable disease >=8 weeks according to RECIST 1.1 criteria, relative to all randomized participants who had baseline measurable disease. Confirmed responses were defined as those that persisted on repeat imaging study >=4 weeks after the initial documentation of response. Participants who did not have on study radiographic tumor re-evaluation or who died, progressed, or dropped out for any reason prior to reaching a CR, PR, or stable disease were counted as non-responders in the assessment of CBR. A participant who initially met the criteria for a PR and then subsequently became a confirmed CR was to be assigned a best response of CR.	From Baseline up to end of treatment
Secondary	Axitinib Steady-State Pharmacokinetic (PK) Parameter - Maximum Observed Plasma Concentration (Cmax), Non-Randomized Portion	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing.	Cycle 1 Day 15
Secondary	Axitinib Steady-State PK Parameter - Area Under the Plasma Concentration Versus Time Curve From 0 to 24 Hour (AUC0-24), Non-Randomized Portion	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. In the below table, 4 participants in Child-Pugh A and 1 participant in Child-Pugh B were not reported due to nonestimable half-life.	Cycle 1 Day 15
Secondary	Axitinib Steady-State Pharmacokinetic Parameter - Time to First Occurrence of Cmax (Tmax), Non-Randomized Portion	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing.	Cycle 1 Day 15
Secondary	Axitinib Steady-State Pharmacokinetic Parameter - Apparent Oral Clearance (CL/F), Non-Randomized Portion	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. In the below table, 4 participants in Child-Pugh A and 1 participant in Child-Pugh B were not reported due to nonestimable half-life.	Cycle 1 Day 15
Secondary	Axitinib Steady-State Pharmacokinetic Parameter - Terminal Plasma Elimination Half-Life (t1/2), Non-Randomized Portion	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. In the below table, 4 participants in Child-Pugh A and 1 participant in Child-Pugh B were not reported due to nonestimable half-life.	Cycle 1 Day 15
Secondary	Axitinib Steady-State Pharmacokinetic Parameter - Apparent Oral Volume of Distribution of the Drug During the Elimination Phase (Vz/F), Non-Randomized Portion	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. The PK parameter, Vz/F has been presented in this outcome measure. In the below table, 4 participants in Child-Pugh A and 1 participant in Child-Pugh B were not reported due to nonestimable half-life.	Cycle 1 Day 15
Secondary	Concentration of Soluble Proteins at Baseline in Randomized Portion	Plasma soluble proteins interleukin-6 (IL-6), E-Selectin, interleukin-8 (IL-8), hepatocyte growth factor (HGF), matrix metalloproteinase-2 (MMP-2), stem cell factor (SCF), angiopoietin-2 (Ang-2), vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor-C (VEGF-C), soluble vascular endothelial growth factor receptor 2 (sVEGFR2), soluble vascular endothelial growth factor receptor 3 (sVEGFR3), stromal cell-derived factor-1 (SDF1), neutrophil gelatinase-associated lipocalin (NGAL), migration inhibitory factor (MIF), c-MET, regulated upon activation normal T cell expressed and presumably secreted (RANTES), and monocyte chemotactic protein-3 (MCP-3) were only measured in randomized participants.	Baseline
Secondary	Percentage of Participants With Specific Micro-Ribonucleic Acid (miRNA) Transcript Present in Circulation in Randomized Portion	A 5 millilitres (mL) whole blood sample was collected from all randomized participants to evaluate the miRNA transcripts.	Baseline
Secondary	Functional Assessment of Cancer Therapy - Hepatobiliary Questionnaire (FACT-Hep) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model	FACT-Hep consists of 27-item FACT-G, and 18-item Hepatobiliary Subscale. FACT-Hep questionnaire uses 5-point Likert rating scale, range '0'-not at all to '4'. FACT-Hep total score ranges from 0 to 180, where highest score represents maximum achievable quality of life. Domains of FACT-G include Physical Well-Being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB). Hepatobiliary disease specific items include: swelling or cramps, losing weight, gastrointestinal (GI)-related questions, lack of energy, side effects, pain, fatigue, usual activities, jaundice, fevers, itching, taste of food and chills. Eight of the items (pain, back pain, stomach pain/discomfort, lack of energy, fatigue, nausea, weight loss and jaundice) make up FACT-Hepatobiliary Symptom Index (FHSI-8), and are considered to be symptoms specific to hepatobiliary cancer. Table below included mixed effect model estimated average based on all observed values/time points.	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
Secondary	Functional Assessment of Cancer Therapy - General (FACT-G) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model	FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate QoL in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): PWB, SWB, EWB and FWB; each ranging from 0 (not at all) to 4 (very much). FACT-G ranged between 0 and 108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
Secondary	Functional Assessment of Cancer Therapy (FACT)-Hepatobiliary Symptom Index-8 (FHSI-8) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model	The FACT-Hep includes the FACT-G and a hepatobiliary module. The hepatobiliary disease specific items include: swelling or cramps, losing weight, GI related questions, lack of energy, side effects, pain, fatigue, usual activities, jaundice, fevers, itching, taste of food and chills. Eight of the items (pain, back pain, stomach pain/discomfort, lack of energy, fatigue, nausea, weight loss, and jaundice) make up the FHSI-8, and are considered to be symptoms specific to hepatobiliary cancer. FHSI-8 total score ranges from 0 to 32 where "0" is a severely symptomatic participant and the highest score indicates an asymptomatic participant. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
Secondary	Functional Assessment of Cancer Therapy-G (FACT-G) Subscales in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model	FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate QoL in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general HRQoL: PWB, SWB, EWB and FWB. Each of the individual subscale, except EWB has 7 items and each integer scored 0 to 4 making a maximum possible score of 28 (range 0 to 28). EWB has 6 items and each integer scored 0 to 4 making a maximum possible score of 24 (range 0 to 24). For all the 4 scales, higher values correspond to better health. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
Secondary	Functional Assessment of Cancer Therapy - Hepatobiliary Cancer Subscale (FACT Hep-CS18) Questionnaire in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model	This subscale consists of 18 items rated on a scale from '0' - not at all to '4' - very much regarding how much each item was present in the last 7 days. FACT-Hep-CS18 total score ranges from 0 to 72. The higher score reflects better QoL or fewer symptoms. The 18 items of this scale are associated with hepatocellular carcinoma. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
Secondary	Functional Assessment of Cancer Therapy - Hepatobiliary Cancer Trial Outcome Index (FACT Hep-TOI) Questionnaire in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model	The trial outcome index is defined to be the sum (PWB+FWB+HepCS), making it 32 items altogether. Each ranges from '0' - not at all to '4' - very much regarding how much each item was present in the last 7 days. FACT Hep -TOI total score ranges from 0 to 128, where the highest score represents a maximum achievable quality of life. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
Secondary	Time to Deterioration (TTD) Based on the Composite Endpoint in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model	TTD analysis was performed for FHSI-8. Time to deterioration was defined as the time between date of randomization and date of the event.	From randomization to death or tumor progression or FHSI-8 mean score decrease >=3 points, whichever comes first
Secondary	EuroQoL (EQ-5D)- Health State Profile Utility Score in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model	EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state. Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
Secondary	EuroQoL Visual Analogue Scale (EQ-VAS) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model	EQ-5D VAS in rates the participant's overall health status using values from 0 (worst imaginable) to 100 (best imaginable). The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
Secondary	Number of Participants With Dose-Limiting Toxicities (DLTs) in Non-Randomized Portion	Number of Child-Pugh Class B (score 7) participants with DLT was evaluated during Cycle 1 of treatment in the non-randomized portion of the study.	Cycle 1 (4 weeks)
Secondary	Number of Participants With Treatment-Emergent Adverse Events (AEs) in Non-Randomized Portion	An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. The grade of an AE was determined according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.	Up to 28 days after last dose of study drug (up to 6 years)
Secondary	Number of Participants With Treatment-Related Adverse Events (AEs) in Non-Randomized Portion	Treatment-related AE was any untoward medical occurrence in a participant with causal relationship to the study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The grade of an AE was determined according to CTCAE Version 3.0.	Up to 28 days after last dose of study drug (up to 6 years)
Secondary	Number of Participants With Treatment-Emergent Adverse Events (AEs) in Randomized Portion	An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. The grade of an AE was determined according to CTCAE Version 3.0.	Up to 28 days after last dose of study drug (up to 6 years)
Secondary	Number of Participants With Treatment-Related Adverse Events (AEs) in Randomized Portion	Treatment-related AE was any untoward medical occurrence in a participant with causal relationship to the study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The grade of an AE was determined according to CTCAE Version 3.0.	Up to 28 days after last dose of study drug (up to 6 years)

External Links

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