Dose Ranging of GSK2336805 in Combination Therapy

NCT01648140 | Completed Phase 2 Results

• 1 other identifier: 115879
• Study Type: interventional
• Target: 286
• Locations: 6 countries
• Sites: 34

Brief Summary

GSK2336805 is a novel hepatitis C virus (HCV) non-structural 5A (NS5A) inhibitor being developed for the treatment of chronic HCV infection. This Phase II, multicenter, parallel-group, randomized, dose-ranging study will assess the safety and tolerability, antiviral activity, and pharmacokinetics of GSK2336805 at 2 dose levels (40 and 60 mg) in combination with pegylated interferon alfa-2a (PEG) and ribavirin (RIBA) in approximately 100 treatment-naïve subjects with chronic genotype 1 HCV infection. In a separate nonrandomized single-arm cohort, up to 15 treatment-naïve subjects with genotype 4 chronic HCV infection will be enrolled in parallel at the dose level of 60 mg of GSK2336805.

Conditions

Hepatitis C, Chronic

Keywords

Genotype 4; GSK2336805; pegylated interferon; telaprevir; Genotype 1; chronic hepatitis C; ribavirin; NS5A inhibitor; hepatitis C virus (HCV) infection

Outcome Measures

Primary Outcomes (17)

• Number of Participants Achieving eRVR

  eRVR is defined as plasma HCV ribonucleic acid (RNA) \<lower limit of quantification (LLOQ) and target not detected at Weeks 4 and 12. Participants who discontinued prior to Week 12 assessments or had missing HCV RNA values at Weeks 4 and 12 were treated as non-responders.

  Week 4 and Week 12

• Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) up to Week 12

  An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign(including an abnormal laboratory finding), symptom, or disease(new or exacerbated) temporally associated with the use of a medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect, important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.

  From the start of study treatment up to Week 12

• Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points up to Week 12

  Blood pressure measurements were taken to observe vital signs and included SBP and DBP at the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and Post-treatment (PT) Follow Up (FU) Weeks 4, 12 and 24. Change from Baseline in SBP and DBP is summarized for each post-Baseline assessment up to Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) up to 12-week treatment period

• Mean Change From Baseline in Heart Rate at the Indicated Time Points up to Week 12

  Vital sign monitoring included heart rate, measured at the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4, 12 and 24. Change from Baseline in heart rate is summarized for each post-Baseline assessment upto Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Day 2, Weeks 1, 2, 4, 6, 8, and 12

• Mean Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell Count at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and white blood cell count at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the basophils, eosinophils, lymphocytes, total neutrophils, platelet count and white blood cell count values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Mean Change From Baseline in Red Blood Cell Count at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of red blood cell count at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the red blood cell count values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Mean Change From Baseline in Hemoglobin at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of hemoglobin at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the hemoglobin values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Mean Change From Baseline in Hematocrit at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of hematocrit at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the hematocrit values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Mean Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of mean corpuscle volume at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the mean corpuscle volume values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Mean Change From Baseline in Albumin at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of albumin at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the albumin values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Mean Change From Baseline in Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Creatine Kinase (CK) and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of ALP, ALT, AST, CK and GGT at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4 Change from Baseline in the ALP, ALT, AST, CK and GGT values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Mean Change From Baseline in Direct Bilirubin, Total Bilirubin and Creatinine at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of direct bilirubin, total bilirubin and creatinine at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the direct bilirubin, total bilirubin and creatinine values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Mean Change From Baseline in Chloride, Bicarbonate, Glucose, Potassium, Sodium, Inorganic Phosphorus and Urea/Blood Urea Nitrogen (BUN) at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of Chloride, bicarbonate, glucose, potassium, sodium, inorganic phosphorus and urea/BUN at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the chloride, bicarbonate, glucose, potassium, sodium, inorganic phosphorus and urea/BUN values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Mean Change From Baseline in Creatinine Clearance at the Indicated Time Points up to Week 12

  Blood samples were collected for the measurement of Creatinine Clearance at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. It is estimated by Cockcroft-Gault Equation. Change from Baseline in the Creatinine Clearance values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

• Number of Participants With Shift From Baseline in Urinalysis Data up to Week 12

  Urine samples were collected for urinalysis at Baseline, Weeks 2, 12, 18, 24, 48 and PT FU Weeks 4. Number of participants with shift from Baseline in urinalysis to normal (NL), abnormal (ANL) and missing (MIS) data up to Week 12 are summarized. Urine bilirubin (UBIL), urine glucose (UGLU), urine ketones (UKET), urine leukocyte esterase test (ULET) for detecting WBC, urine nitrite (UNIT), urine occult blood (UOB) were performed with dipstick method. Urine microscopy (UM) is performed to detect bacteria (BAC), red blood cells (RBC) and white blood cells (WBC). Other urinalysis parameter included urine pH (UpH) and urine specific gravity (USG). Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0), Weeks 2 and 12

• Mean Change From Baseline in Electrocardiographic (ECG) Heart Rate Values at the Indicated Time Points up to Week 12

  The ECG parameter heart rate was measured at Baseline, Weeks 1 and 12. Change from Baseline in ECG heart rate is summarized for each post-Baseline assessment up to Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1 and 12

• Mean Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval and QT Interval Corrected Bazett's Formula (QTcB), QT Interval Corrected Using Fridericia's Formula (QTcF) Values at the Indicated Time Points up to Week 12

  The ECG parameters including PR interval, QRS duration, uncorrected QT interval, QTcB, QTcF were measured at Baseline, Weeks 1 and 12. Change from Baseline in ECG parameters are summarized for each post-Baseline assessment up to Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

  Baseline (Week 0) and Weeks 1 and 12

Secondary Outcomes (28)

• Number of Participants With Any AEs and Any SAEs After Week 12

  From Week 12 up to PT Week 24 FU

• Number of Participants Achieving Very Rapid Virologic Response (vRVR), Rapid Virologic Response (RVR), Complete Early Virologic Response (cEVR), Sustained Virologic Response 12 and 24 (SVR12 and SVR24) With Response Guided Treatment (RGT)

  From the start of the treatment up to PT FU Week 24

• Mean GSK2336805 Plasma Concentrations on Day 1, Day 2, Week 4, and Week 12

  Day 1, Day 2, Week 4, and Week 12

• Maximum Plasma Concentration (Cmax) and Concentration at the End of the Dosing Interval (Ctau) of GSK2336805 at Week 4

  Week 4 (24 h post dose)

• Time of Maximal Plasma Concentration (Tmax) of GSK2336805 at Week 4

  Week 4 (24 h post dose)

Study Arms (4)

T40

EXPERIMENTAL

Hepatitis C virus (HCV) genotype 1 GSK2336805 40 mg, pegylated interferon alpha-2a, and ribavirin arm

Drug: GSK2336805 40 mg; Drug: Pegylated interferon alpha-2a; Drug: Ribavirin

T60

EXPERIMENTAL

Hepatitis C virus (HCV) genotype 1 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm

Drug: GSK2336805 60 mg; Drug: Pegylated interferon alpha-2a; Drug: Ribavirin

PRT

ACTIVE COMPARATOR

Hepatitis C virus (HCV) genotype 1 Telaprevir, pegylated interferon alpha-2a, and ribavirin arm

Drug: Pegylated interferon alpha-2a; Drug: Ribavirin; Drug: Telaprevir

G4

EXPERIMENTAL

Hepatitis C virus (HCV) genotype 4 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm

Drug: GSK2336805 60 mg; Drug: Pegylated interferon alpha-2a; Drug: Ribavirin

Interventions

GSK2336805 40 mg DRUG

20 mg tablet, round, 10-mm diameter, white to off-white, no markings

T40

GSK2336805 60 mg DRUG

30 mg tablet, round, 10-mm diameter, white to off-white, no markings

G4; T60

Pegylated interferon alpha-2a DRUG

180 microgram per 0.5 mL prefilled syringe for single use

Also known as: Pegasys

G4; PRT; T40; T60

Ribavirin DRUG

200-mg tablet, capsule-shaped, light blue, film-coated, and debossed with "200" on 1 side and the logo "3RP" on the other side

Also known as: Ribasphere

G4; PRT; T40; T60

Telaprevir DRUG

375 mg film-coated tablet

Also known as: Incivek (United States), Incivo (European Union)

PRT

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Male or female aged 18 to 70 years of age, inclusive, at Screening.
• Genotype 1 or genotype 4 hepatitis C virus (HCV) infection as assessed by Versant HCV Genotype assay 2.0 (LiPA).
• Chronic HCV infection documented by at least 1 measurement of serum HCV RNA greater than or equal to 100,000 IU/mL measured during Screening by the COBAS High Pure/COBAS TaqMan HCV Test v2.0 and at least one of the following:
• A positive anti-HCV antibody, HCV RNA, or HCV genotype test at least 6 months prior to Baseline (Day 1) together with positive HCV RNA and anti-HCV antibody tests at the time of Screening; or
• A positive HCV RNA test and anti-HCV antibody test at the time of Screening together with either a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of chronic hepatitis C disease, such as the presence of fibrosis).
• Naïve to all HCV antiviral treatment(s), including, but not limited to, immunomodulatory and nucleoside/nucleotide treatments for chronic HCV infection.
• Agree to interleukin 28B (IL28B) genotyping.
• A subject, who, in the opinion of the investigator, is an appropriate candidate for pegylated interferon alpha-2a (PEG)/ribavirin (RIBA)/protease inhibitor combination therapy for genotype 1 subjects and PEG/RIBA combination therapy for genotype 4 subjects.
• Body mass index \>18 kg/m2 but not exceeding 36 kg/m2.
• A liver biopsy obtained within 3 years (36 calendar months) prior to the Day 1 visit, with a fibrosis classification of noncirrhotic as judged by a local pathologist (defined as Knodell less than or equal to 3, Metavir less than or equal to 2, Ishak less than or equal to 4, or Batts and Ludwig less than or equal to 2). Both incomplete and transition to cirrhosis (e.g., Metavir score 3) are considered as cirrhosis. If no recent (\<36 months) liver biopsy is available, a study-qualifying biopsy must be performed prior to Baseline (Day 1).
• All fertile males and females must use 2 forms of effective contraception between them during treatment and during the 24 weeks after treatment ends.
• Females, is eligible to enter and participate in the study if of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) and includes any female who has had a hysterectomy or has had a bilateral oophorectomy (ovariectomy) or has had a bilateral tubal ligation or is postmenopausal (demonstrate total cessation of menses for greater than 1 year).
• Females, is eligible to enter and participate in the study if of childbearing potential and has a negative urine or serum pregnancy test at Screening and within the 24-hour period prior to the first dose of study medication and completely abstains from intercourse for 2 weeks before exposure to the study medication, throughout the clinical study, and for 24 weeks after completion or premature discontinuation from this study or uses 2 of the following acceptable methods of contraception throughout the clinical study and for 24 weeks after completion or premature discontinuation from this study:
• Any intrauterine device with a documented failure rate of \<1% per year

You may not qualify if:

• Positive test at Screening visit for hepatitis B surface antigen (HBsAg) or antihuman immunodeficiency virus antibody
• History of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions consistent with decompensated liver disease
• Positive results on urine screen for drugs of abuse test at Screening (unless used as medical treatment, e.g., with a prescription)
• History of alcohol/drug abuse or dependence within 6 months of the study start (unless participating in a controlled rehabilitation program)
• Screening visit electrocardiogram corrected QT (QTc) interval value \>450 ms and/or clinically significant electrocardiogram findings
• Personal or family history of Torsade de Pointes findings
• Pregnant or nursing
• Male with a female partner who is pregnant
• Abnormal hematological and biochemical parameters, including:
• Neutrophil count \<1500 cells/mm3 (or \<1250 cells/mm3 for African American/Black subjects)
• Hemoglobin \<11 g/dL in females or \<12 g/dL in males
• Creatinine greater than or equal to 1.5 × the upper limit of normal (ULN)
• Estimated creatinine clearance less than or equal to 50 mL/min (as calculated using the Cockcroft-Gault formula)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase greater than or equal to 5 × ULN
• Total bilirubin greater than or equal to 2.0 × ULN (except subjects with Gilbert's syndrome)

Sponsors & Collaborators

• GlaxoSmithKline: lead
• PPD Development, LP: collaborator

Study Sites (34)

GSK Investigational Site

Dothan, Alabama, 36305, United States

Location

GSK Investigational Site

Anaheim, California, 92801, United States

Location

GSK Investigational Site

Los Angeles, California, 90017, United States

Location

GSK Investigational Site

DeLand, Florida, 32720, United States

Location

GSK Investigational Site

Orlando, Florida, 32806, United States

Location

GSK Investigational Site

Columbus, Georgia, 31904, United States

Location

GSK Investigational Site

Savannah, Georgia, 31405, United States

Location

GSK Investigational Site

Baltimore, Maryland, 21229, United States

Location

GSK Investigational Site

Brockton, Massachusetts, 02302, United States

Location

GSK Investigational Site

Springfield, Massachusetts, 01105, United States

Location

GSK Investigational Site

Las Vegas, Nevada, 89109, United States

Location

GSK Investigational Site

New York, New York, 10016, United States

Location

GSK Investigational Site

Asheville, North Carolina, 28801, United States

Location

GSK Investigational Site

Fayetteville, North Carolina, 28304, United States

Location

GSK Investigational Site

Jenkintown, Pennsylvania, 19046, United States

Location

GSK Investigational Site

Houston, Texas, 77074, United States

Location

GSK Investigational Site

Annandale, Virginia, 22003, United States

Location

GSK Investigational Site

Norfolk, Virginia, 23502, United States

Location

GSK Investigational Site

Brussels, 1070, Belgium

Location

GSK Investigational Site

Liège, 4000, Belgium

Location

GSK Investigational Site

Sofia, 1407, Bulgaria

Location

GSK Investigational Site

Sofia, 1431, Bulgaria

Location

GSK Investigational Site

Sofia, 1606, Bulgaria

Location

GSK Investigational Site

Varna, 9010, Bulgaria

Location

GSK Investigational Site

Lyon, 69317, France

Location

GSK Investigational Site

Paris, 75651, France

Location

GSK Investigational Site

Pessac, 33604, France

Location

GSK Investigational Site

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

GSK Investigational Site

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

GSK Investigational Site

Würzburg, Bavaria, 97080, Germany

Location

GSK Investigational Site

Berlin, 13353, Germany

Location

GSK Investigational Site

Hamburg, 20099, Germany

Location

GSK Investigational Site

Ponce, 00716, Puerto Rico

Location

GSK Investigational Site

San Juan, 00927, Puerto Rico

Location

Related Publications (1)

• Protocol contains no citations

  BACKGROUND

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Hepatitis C, Chronic; Hepatitis C; Infections

Interventions

GSK2336805; peginterferon alfa-2a; Ribavirin; telaprevir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2012
• First Posted: July 24, 2012
• Study Start: August 1, 2012
• Primary Completion: July 1, 2014
• Study Completion: July 16, 2014
• Last Updated: June 2, 2017
• Results First Posted: June 2, 2017

Record last verified: 2016-11

Data Sharing

• IPD Sharing: Will share

Locations

US (18); BU (4); DE (5); BE (2); FR (3); PR (2)