Study to Assess the Safety, Pharmacokinetics, and Antiviral Activity of Repeat Doses of GSK2878175 in Subjects With Chronic Hepatitis C.

NCT02014571 | Completed Phase 1

• 1 other identifier: 116976
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

GSK2878175 is a site IV NS5B non-nucleoside inhibitor (NNI) being developed for the treatment of chronic hepatitis C virus (HCV) infection. The purpose of this study is to investigate the effects of GSK2878175, at different doses in men and women infected with chronic hepatitis C virus. The study will investigate how much of the drug gets into the blood stream and how long the body takes to get rid of it. The study will also investigate if GSK2878175 has any important side effects. The study will also measure what effect GSK2878175 has on the hepatitis C virus infection after taking the study medication for 2 days. Approximately 44 people will take part in this study. Depending on the type of chronic hepatitis C infection a subject will be enrolled into 1 of 4 groups randomly. Each group will participate in one dosing session. One dosing session consists of GSK2878175 or a placebo (sugar pill) given once per day for 2 days. Group A, B, and C is made up of 8 participants per group. In each of these groups 6 participants will receive GSK2878175 and 2 participants will receive placebo. Group D is made up of 20 participants. 15 participants will receive GSK2878175 and 5 participants will receive placebo. The treatment groups will be dosed in sequence. Group A will be the first to take the study medication, then Group B, and so on. The plan is to dose subjects in Group A with 10 mg, Group B with 30 mg, Group C with 60 mg, and Group D with 60 mg of GSK2878175 or placebo. The next treatment group's actual dose will be decided after looking at the results from the previous group. The doses may therefore be higher or lower than planned depending on the previous group's results. The number of participants enrolled in the next group may also change depending on the results from the previous group.

Conditions

Hepatitis C, Chronic

Keywords

NS5B; chronic hepatitis C (CHC); antiviral activity; pharmacokinetics (PK); Safety; hepatitis C virus (HCV); GSK2878175

Outcome Measures

Primary Outcomes (7)

• Safety as assessed by the collection of adverse events (AEs).

  AEs will be collected from the start of Study Treatment and until 14 days post last-dose (at follow up).

  Screening to 14 days post last-dose

• Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, electrocardiogram (ECG) intervals, ECG rhythm telemetry, pulmonary function tests, respiratory rate and lung auscultation.

  Absolute values and changes over time of hematology, clinical chemistry, urinalysis, vital signs (blood pressure \[BP\], FSH/Estradiol (Women), Urine β-hCG (Women) temperature, and heart rate), 12 LED ECG, and Holter monitoring, ECG intervals, ECG rhythm, and telemetry will be measured. Telemetry is the continuous monitoring of a subject's heart rate and rhythm from a remote location. Pulmonary function testing includes a group of tests that measure how well the lung is functioning.

  Pre-dose to 14 days post last-dose

• Composite of PK parameters (Day 1) following repeat dose administration of GSK2878175.

  PK parameters include: AUC (0-24), Tmax, Cmax,C24, t1/2, tlag, CL/F for Day 1

  Pre Dose, 0.5hr, 1.5hr, 4hr, 6hr, 12hr

• Composite of PK parameters (Day 2) following repeat dose administration of GSK2878175.

  PK parameters include: AUC (0-t), Ct, Cmax, tmax, t1/2, CL/F for Day 2.

  Day 2 Pre Doseand Post Day 1 Dose at 24hr, 24.5hr, 25.5hr, 28hr, 30hr, 33hr, 36hr, 48hr, 72hr, 96hr, 144hr, 192hr, 240hr and 360hr

• Antiviral activity as assessed by HCV RNA viral load.

  HCV RNA viral load reduction from baseline at the 24 hr, 48 hr, and 72 hr timepoints during dosing of GSK2878175 in HCV subjects

  Baseline, 24 hr, 48 hr, and 72 hr

• Antiviral activity as assessed by HCV RNA maximum change.

  HCV RNA change from baseline to nadir (maximum change) in CHC subjects.

  Pre-dose to 14 days post last-dose.

• Antiviral activity as assessed by Time course of HCV viral load.

  Time course of HCV viral load at baseline, during, and after dosing with GSK2878175.

  Baseline, Day1, Day 2, Day 3, Day 4, Day 5, Day 7, Day 9, Day 11, and Day 16 (Follow Up Visit)

Secondary Outcomes (4)

• Viral quasi-species population.

  Pre Dose and 12hr on Day 1 and at 24hr, 30hr, 36hr, 48hr, 72hr, 96hr, 144hr, 192hr, 240hr and 360hr Post 1st Dose

• IL28B rs12979860 status on GSK2878175 pharmacokinetics.

  Day 1 Pre Dose.

• Exposure-response relationships for various safety parameters, if appropriate.

  Pre-dose to 14 days post last-dose

• Exposure-response relationship for antiviral effect.

  24, 48 and 72 hours after the first dose.

Study Arms (4)

Cohort A

EXPERIMENTAL

Eight subjects will be randomized to receive either 10 mg of GSK2878175 active treatment (4 HCV genotype 1a \[GT1a\] and 2 HCV genotype 1b \[GT1b\]) or matching placebo (1 GT1a and 1 GT1b) daily for 2 days fasted.

Drug: GSK2878175; Drug: Placebo

Cohort B

EXPERIMENTAL

Eight subjects will be randomized to receive either 30 mg of GSK2878175 active treatment (4 GT1a and 2 GT1b) or matching placebo (1 GT1a and 1 GT1b) daily for 2 days fasted.

Drug: GSK2878175; Drug: Placebo

Cohort C

EXPERIMENTAL

Eight subjects will be randomized to receive either GSK2878175 active treatment (4 GT1a and 2 GT1b) or matching placebo (1 GT1a and 1 GT1b) daily for 2 days fasted.

Drug: GSK2878175; Drug: Placebo

Cohort D

EXPERIMENTAL

Twenty subjects will be randomized to receive either 60 mg of GSK2878175 active treatment (6 GT2, 6 GT3, 3 GT4) or matching placebo (2 GT2, 2 GT3, 1 GT4).

Drug: GSK2878175; Drug: Placebo

Interventions

GSK2878175 DRUG

Round tablets (5.0mg) given once daily repeated (to 2 days), oral dose.

Cohort A; Cohort B; Cohort C; Cohort D

Placebo DRUG

Round tablets (5.0mg) given once daily repeated (to 2 days), oral dose visually matching GSK2878175.

Cohort A; Cohort B; Cohort C; Cohort D

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Has chronic genotype 1 (subtypes 1a or 1b) or genotype 2 or genotype 3 or genotype 4 (as assessed by VERSANT® HCV Genotype assay 2.0 (LiPA); VERSANT is a registered trademark of the Siemens Healthcare company.) HCV infection documented by at least 1 measurement of serum HCV RNA \>=100,000 IU/mL measured during Screening by the COBAS® High Pure/COBAS TaqMan® HCV Test v2.0 (COBAS and TaqMan are registered trademarks of the Roche Molecular Diagnostics company.) and at least one of the following:
• Documented HCV serology demonstrating the presence of anti-HCV antibodies at least 6 months before screening; or Documented presence of HCV RNA at least 6 months before screening; or Documented evidence of fibrosis on liver biopsy obtained within 3 years (\<36 calendar months) prior to the Day 1visit; or FibroSure/FibroTest \>0.28 and \<=0.58 at screening (Note: subjects with a FibroTest score \<=0.28 may be included as long as they meet any 1 of the other CHC criteria above).
• Note: Cohorts are genotype specific.
• Agrees to IL28B genotyping.
• The subject is able to understand and is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form and is likely to complete the study as planned.
• Subjects must be treatment-naïve and have not received prior treatment with any interferon, immunomodulatory agent, or DAA for HCV.
• Male or female aged between 18 and 60 years of age, inclusive, at the time of signing the informed consent.
• A female subject is eligible to participate if she is of:
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy \[for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MIU/ml and estradiol \<40 pg/ml (\<147 pmol/L) is confirmatory\].
• Child-bearing potential with negative pregnancy test as determined by serum hCG test (at Screening and Day -1) and urine hCG test on Day 1 and:
• Agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 28 days post last dose.
• OR has only same-sex partners, when this is her preferred and usual lifestyle.
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the follow up visit (14 days post last dose).
• Body weight \>50kg (110 lb) for men and \>45kg (99 lb) women and a body mass index (BMI) between 18.5-35 kg/m\^2 inclusive will be allowed.
• The subject's systolic blood pressure is inside the range of 90-140 mmHg, and diastolic blood pressure is inside the range of 45-90 mmHg. Heart rate is inside the range of 50-100 bpm for female subjects or 45-100 bpm for male subjects.

You may not qualify if:

• History of any illness that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug(s) to the subject.
• Family history of prolonged QT syndrome (Torsade de Pointes) or sudden cardiac death; first-degree relative with myocardial infarction at premature age (\<=45 years for male relative; \<=55 years for female relative).
• History or other clinical evidence of hypertension, significant or unstable cardiac disease (e.g., prolonged QT syndrome \[torsade de pointes\], angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia, coronary heart disease, and/or clinically significant ECG abnormalities).
• Evidence of cirrhosis, as determined by any 1 of the following:
• FibroSure/FibroTest score \>0.58; or Liver biopsy with a fibrosis stage indicative of cirrhosis as classified by a local pathologist (defined as Knodell \>3, Metavir \>2, Ishak \>4, or Batts and Ludwig \>2). Both incomplete and transition to cirrhosis (e.g., Metavir score 3) are considered as cirrhosis; or History of ascites, hepatic encephalopathy, or esophagogastric varices.
• Active malignant disease or history of malignant disease within 5 years before screening, with the exception of successfully treated basal cell carcinoma, squamous cell cancer of the skin, and carcinoma of the cervix in situ.
• Any other cause of significant liver disease in addition to hepatitis C, which may include but is not limited to malignancy with hepatic involvement, hepatitis B, druginduced or alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson's disease, nonalcoholic steatohepatitis, or primary biliary cirrhosis.
• Estimated creatinine clearance ≤50 mL/min using the Cockcroft-Gault equation at screening.
• A medical condition that requires frequent or prolonged use of systemic corticosteroids or immunosuppressive drugs (e.g., severe asthma; severe arthritis or autoimmune conditions; organ transplantation; or acute adrenal insufficiency).
• History of regular alcohol consumption within 1 month of the study defined as:
• an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• Unwilling to abstain from alcohol for 48 hours prior to the start of dosing until collection of the final pharmacokinetic sample during each treatment period.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that contraindicates their participation.
• Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• PPD Development, LP: collaborator

Study Sites (1)

GSK Investigational Site

San Juan, 00927, Puerto Rico

Location

Related Links

• Results for study 116976 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Hepatitis C, Chronic; Hepatitis C

Interventions

GSK2878175

Condition Hierarchy (Ancestors)

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

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2013
• First Posted: December 18, 2013
• Study Start: December 26, 2013
• Primary Completion: July 3, 2014
• Study Completion: January 15, 2015
• Last Updated: July 24, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

PR (1)