Safety, Antiviral Activity, and Pharmacokinetics of GSK2336805 With Peginterferon and Ribavirin in Chronic Hepatitis C Subjects

NCT01439373 | Completed Phase 2 Results

• 1 other identifier: 115519
• Study Type: interventional
• Target: 16
• Locations: 2 countries
• Sites: 10

Brief Summary

GSK2336805 is a hepatitis C virus (HCV) NS5A inhibitor being developed for the treatment of chronic hepatitis C (CHC). This study will assess the safety, antiviral activity, and pharmacokinetics of GSK2336805 alone and in combination with peginterferon alfa 2a and ribavirin in subjects with chronic hepatitis C (CHC).

Conditions

Hepatitis C, Chronic

Keywords

chronic hepatitis C; NS5A inhibitor; ribavirin; pegylated interferon; GSK2336805

Outcome Measures

Primary Outcomes (8)

• Number of Participant Achieving Rapid Virological Response (RVR) at Day 28, Nominal Analysis

  RVR was defined as the proportion of participants below the assay lower limit of detection (LOD) \<18 International units per milliliter (IU/mL) for Hepatitis C virus (HCV) ribonucleic acid (RNA) after 4 weeks of treatment (Day 28). Participants achieving RVR at Day 28 were considered treatment responders. Participants with missing HCV RNA values at Day 28 or discontinued before Day 28 were considered as treatment failure . Proportion of participants with HCV genotype 1 achieving RVR was the primary comparison of interest to show superiority of GSK2336805 over placebo in genotype 1 participants.

  Day 28

• Number of Participant Achieving RVR at Day 28, (Primary and Supportive Analyses)

  RVR was defined as the proportion of participants LOD \<18 IU/mL for HCV RNA after 4 weeks of treatment (Day 28). Participants achieving RVR at Day 28 were considered treatment responders. Participants with missing HCV RNA values at Day 28 or discontinued before Day 28 were considered as treatment failure. Proportion of participants with HCV genotype 1 achieving RVR was the primary comparison of interest to show superiority of GSK2336805 over placebo in genotype 1 participants. The primary and supportive analysis differs from the nominal analysis as supportive analysis is assessed at Day 28 ± 2 (2 days visit window) whereas, the nominal analysis was assessed at Day 28.

  Day 28

• Probability of Participants With HCV Genotype 1 Achieving RVR At Day 28, Nominal Analysis

  The primary comparison of interest was performed using a Bayesian probability model. Probability of achieving undetectable HCV RNA distribution analyzed by nominal analysis was reported.

  Day 28

• Probability of Participants With HCV Genotype 1 Achieving RVR at Day 28, Primary and Supportive Analyses

  The primary comparison of interest was performed using a Bayesian probability model. Probability of achieving undetectable HCV RNA distribution analyzed was reported.

  Day 28

• Number of Participants With HCV Genotype 1 With Virologic Response

  Serum for determination of HCV genotype was collected at the screening visit. Genotype was determined by the VERSANT HCV genotype 2.0 Assay (LiPA). Number of participants with HCV genotype 1 were reported.

  Day 7, 14 and 21

• Change From Baseline in HCV Viral Load During 24 Hour (h) Following a Single Dose of GSK2336805 on the Log 10 Scale

  Blood samples for determination of HCV RNA levels were collected at immediately prior to and 1, 2, 4, 6, and 8 and 24 h after the first dose in Part 1 (Day 1). Measurement of HCV viral load was analyzed by the central laboratory using the COBAS AmpliPrep/COBAS TaqMan HCV test. Baseline was defined as the last non-missing assessment on or before the first dose of study drug. Change from Baseline was computed as value at post Baseline specified time point minus Baseline value. Virus RNA levels reported as \<43 are undetectable levels. If the result for HCV RNA (IU/ML) was \<43, then change from Baseline was calculated using 42, and the change from Baseline on the log scale was calculated using log (42).

  Day 1 (Baseline [Pre-dose], 1, 2, 4, 6, and 8 and 24 h)

• Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Event (SAE) During Treatment Period

  AE was 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. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

  Up to Day 28

• Change From Baseline in QTcF Interval at Day 2 and 28

  Single 12-lead electrocardiogram (ECG) was obtained. The standard ECG criteria of potential clinical importance were 1) absolute QTc Interval, \> 450 milliseconds (msec), 2) absolute PR Interval, \<110 msec, 3) absolute QRS Interval, \< 75 msec and 4) increase from baseline in QTc \> 60 msec. QTc Interval was calculated using Frederica correction formula: QTcF = QT / (RR)\^1/3. Change from Baseline was calculated by subtracting the Baseline assessment value from post Baseline visit value. Baseline was defined as the last non-missing assessment on or before the first dose of study drug. The change from Baseline in QTc Interval at Day 2 and 28 were reported.

  Baseline (Day 1, Pre-dose ), Day 2 and Day 28

Secondary Outcomes (13)

• Number of Participants With Shift From Baseline to Worst Post Baseline Toxicity Grade Hematology Parameters for Day 1 to Day 28

  Baseline (Day 1) to Day 28

• Number of Participants With Shift From Baseline to Worst Post Baseline Toxicity Grade for Serum Chemistry Parameters for Day 1 to Day 28

  Baseline (Day 1) and 28

• Number of Participants With Shifts in Urinalysis Parameters From Normal at Baseline to Abnormal

  Day 14, 28, Follow-up (Day 42)

• Number of Participants With Vital Signs of Potential Clinical Concern

  Up to 42 days

• Mean Serum HCV RNA Levels at Baseline (Day 1), Day 2 and Day 28

  Baseline (Day 1, pre-dose), Day 2 (24 h, Post-dose) and Day 28

Study Arms (4)

GSK2336805

EXPERIMENTAL

Study Part 1

Drug: GSK2336805

Placebo

PLACEBO COMPARATOR

Study Part 1

Drug: GSK2336805 Matching Placebo

GSK2336805 + pegylated interferon alfa-2a + ribavrin

EXPERIMENTAL

Study Part 2

Drug: GSK2336805; Drug: Pegylated interferon alfa-2a; Drug: Ribavirin

Placebo + pegylated interferon alfa-2a + ribavirin

ACTIVE COMPARATOR

Study Part 2

Drug: Pegylated interferon alfa-2a; Drug: Ribavirin; Drug: GSK2336805 Matching Placebo

Interventions

GSK2336805 DRUG

Active Investigational Drug

GSK2336805; GSK2336805 + pegylated interferon alfa-2a + ribavrin

Pegylated interferon alfa-2a DRUG

Standard of Care drug

Also known as: Pegasys

GSK2336805 + pegylated interferon alfa-2a + ribavrin; Placebo + pegylated interferon alfa-2a + ribavirin

Ribavirin DRUG

Standard of Care drug

GSK2336805 + pegylated interferon alfa-2a + ribavrin; Placebo + pegylated interferon alfa-2a + ribavirin

GSK2336805 Matching Placebo DRUG

Placebo of Investigational Drug

Also known as: Placebo

Placebo; Placebo + pegylated interferon alfa-2a + ribavirin

Eligibility Criteria

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

You may qualify if:

• Documented chronic genotype 1 or genotype 4 HCV infection
• Naïve to all HCV antiviral treatment(s)
• Agree to IL28B genotyping
• A body mass index \>18 kg/m2 but not exceeding 36 kg/m2
• Liver biopsy obtained within 3 years (36 calendar months) prior to the Day 1 visit, with a fibrosis classification of non-cirrhotic. 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 two forms of effective contraception between them during treatment and during the 24 weeks after treatment ends
• Otherwise healthy as determined by the medical history, physical examination, ECG findings, and clinical laboratory measurements performed at Screening

You may not qualify if:

• Positive test at Screening for hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody
• History of any other clinically significant chronic liver disease
• 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 ECG corrected QT interval value greater than 450 ms and/or clinically significant ECG findings
• A personal or family history of Torsade de Pointes findings
• Pregnant or nursing women
• Males with a female partner who is pregnant
• Abnormal hematological and biochemical parameters as specified in the protocol
• History of major organ transplantation with an existing functional graft
• Thyroid dysfunction not adequately controlled
• Subjects with a history of suicide attempt or hospitalization for depression in the past 5 years and/or any current (within 6 months) severe or poorly controlled psychiatric disorder
• History or current evidence of immunologic disorder; pulmonary, cardiac, or pulmonary disease; seizure disorder; cancer or history of malignancy that in the opinion of the investigator makes the subject unsuitable for the study
• Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to first dose administration

Sponsors & Collaborators

• GlaxoSmithKline: lead
• PPD Development, LP: collaborator

Study Sites (10)

GSK Investigational Site

Anaheim, California, 92801, United States

Location

GSK Investigational Site

Chula Vista, California, 91911, United States

Location

GSK Investigational Site

Coronado, California, 92118, United States

Location

GSK Investigational Site

La Mesa, California, 91942, United States

Location

GSK Investigational Site

Oceanside, California, 92056, United States

Location

GSK Investigational Site

Miramar, Florida, 33025, United States

Location

GSK Investigational Site

Las Vegas, Nevada, 89109, United States

Location

GSK Investigational Site

Tulsa, Oklahoma, 74104, United States

Location

GSK Investigational Site

Houston, Texas, 77004, United States

Location

GSK Investigational Site

San Juan, 00927, Puerto Rico

Location

Related Publications (1)

• Gardner S, Cutrell A, Elko-Simms C, Adkison K, Hamatake R, Walker J, Rodriguez-Torres M, Hong Z. A double-blind, randomized, placebo-controlled study to assess the safety, antiviral activity and pharmacokinetics of GSK2336805 when given as monotherapy and in combination with peginterferon alfa-2a and ribavirin in hepatitis C virus genotype 1-infected treatment-naive subjects. Liver Int. 2014 Jul;34(6):e89-95. doi: 10.1111/liv.12334. Epub 2013 Oct 16.

  PMID: 24107072 DERIVED

MeSH Terms

Conditions

Hepatitis C, Chronic

Interventions

GSK2336805; peginterferon alfa-2a; Ribavirin

Condition Hierarchy (Ancestors)

Hepatitis C; Blood-Borne Infections; Communicable Diseases; Infections; 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 7, 2011
• First Posted: September 23, 2011
• Study Start: July 7, 2011
• Primary Completion: December 5, 2011
• Study Completion: December 5, 2011
• Last Updated: December 11, 2017
• Results First Posted: December 11, 2017

Record last verified: 2017-11

Locations

US (9); PR (1)