Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single and Repeat Escalating Doses of GSK1325756 Solution for Infusion, and Absolute Bioavailability Relative of an Oral Dose, in Healthy Adult Subjects

NCT02169583 | Completed Phase 1

• 1 other identifier: 201022
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This will be the first time GSK1325756 Solution for Infusion formulation that has been administered to humans. Prior studies have been performed with oral GSK1325756. The primary objectives of this study are to obtain information on the safety, tolerability, and pharmacokinetics (PK) of single and twice daily intravenous (IV) administration of GSK1325756 in healthy subjects. In Part A, single, escalating doses will be given in the same cohort of subjects after a seven day washout. In addition, the study will evaluate the absolute bioavailability of a single dose of the current oral tablet formulation as compared to the IV formulation in Part A. In Part B, twice daily (BID) intravenous dose administration will be given for 5 days (9 total doses) in two separate cohorts of subjects. Data from this study will provide understanding of the safety, tolerability, and PK of intravenously administered GSK1325756 twice daily to guide dose selection in future clinical studies in patients with viral respiratory tract infections

Conditions

Infections, Respiratory Tract

Keywords

GSK1325756; Safety; Bioavailability; Pharmacokinetics

Outcome Measures

Primary Outcomes (6)

• Number of subjects with adverse events (AEs)

  An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

  Part A and Part B: from Day -1 until 7 to 10 days post-last dose

• Changes over time in clinical laboratory evaluations from pre-dose values

  Clinical laboratory assessments will include hematology, clinical chemistry, urinalysis parameters

  Part A and Part B: from Day -1 until 7 to 10 days post-last dose

• Changes over time in vital signs from pre-dose values

  Vital sign measurements will include systolic and diastolic blood pressure and pulse rate

  Part A and Part B: from Day -1 until 7 to 10 days post-last dose

• Changes over time in electrocardiogram (ECG) parameters from pre-dose values

  12-lead ECGs will be obtained at each timepoint

  Part A and Part B: from Day -1 until 7 to 10 days post-last dose

• GSK1325756 PK parameters following single dose administration in Part A and on Day 1 of Part B

  PK parameters will include area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time \[AUC(0-infinity)\], area under the concentration-time curve from time zero (pre-dose) to time t \[AUC(0-t)\], area under the concentration-time curve from time zero (pre-dose) to 24 hours \[AUC(0-24)\], maximum observed concentration (Cmax), time to maximum observed concentration (tmax), observed concentration at 24 hours post-dose (C24), terminal half-life (t1/2), time of last measurable concentration (tlast), clearance (CL) and volume of distribution (Vz)

  Part A: Pre-dose, 0.5 hour (hr), 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose in each treatment period.

• GSK1325756 PK parameters following repeat dose administration (Part B, Day 5)

  PK parameters will include area under the concentration-time curve from time zero (pre-dose) to the end of the dosing interval \[AUC(0-tau)\], concentration at the end of the dosing interval (Ctau), Cmax, tmax, t1/2, Volume of distribution at steady-state (Vdss), and oral clearance (CL/F)

  Part B: Day 5 at pre-dose, 0.5, 1hr (end of infusion), 1.5, 2, 3, 4, 8, 12 and 24 hrs post-dose

Secondary Outcomes (6)

• GSK1325756 PK parameters following single and repeat IV dose administration to assess dose proportionality

  Part A: Pre-dose, 0.5hr, 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose. Part B: Day 1 and Day 5: pre-dose, 0.5, 1hr (end of infusion), 1.5, 2, 3, 4, 8, 12 and (Day 5 only) 24 hrs post-dose. Day 2-4: pre-dose (each dose)

• GSK1325756 PK parameters following single IV and oral dose administration of a given dose of GSK1325756 (Part A) to determine the absolute bioavailability

  Part A: Pre-dose, 0.5hr, 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose

• GSK1325756 accumulation ratio

  Part A: Pre-dose, 0.5hr, 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose Part B: Day 1 and Day 5: pre-dose, 0.5, 1hr (end of infusion), 1.5, 2, 3, 4, 8, 12 and (Day 5 only) 24 hrs post-dose. Day 2-4: pre-dose (each dose)

• GSK1325756 time invariance

  Part A: Pre-dose, 0.5hr, 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose Part B: Day 1 and Day 5: pre-dose, 0.5, 1hr (end of infusion), 1.5, 2, 3, 4, 8, 12 and (Day 5 only) 24 hrs post-dose. Day 2-4: pre-dose (each dose)

• GSK1325756 Pre-dose concentrations (C12/Ctau) on Day 2 through 4

  Part B: Day 2 to Day 4 (pre-dose; each dose)

Study Arms (2)

Part A (Cohort 1)

EXPERIMENTAL

Approximately 8 subjects (6 Active, 2 Placebo) will be randomized to receive single escalating IV doses i.e.10 milligrams (mg), 25 mg and 100 mg, plus one oral 100 mg dose (on the last occasion) of GSK1325756 or matching placebo, with a 7-days washout between doses. Dose escalations will be based on review of PK and safety data from preceding dose level. The projected doses for each group are subject to modification based upon PK and safety data from preceding cohorts. Pharmacokinetic parameters will be reviewed from at least 4 active subjects from preceding dose before dose escalating to the next dose level. The maximum dose administered will be 100 mg. Additional subjects/Cohorts may be enrolled.

Drug: GSK1325756 Solution; Drug: GSK1325756 Solution Matching Placebo; Drug: GSK1325756 Tablet; Drug: GSK1325756 Tablet Matching Placebo

Part B (Cohorts 2 and 3)

EXPERIMENTAL

Approximately 8 subjects (6 Active, 2 Placebo) per cohort will be randomized to receive escalating repeated IV doses of GSK1325756 or matching placebo (Cohort 2: 25 mg, Cohort 3: 50 mg) for 5 days. Repeated (BID) doses of GSK1325756 will begin the morning of Day 1 and continue through the morning of Day 5 (9 total doses). Dose escalations will be based on review of PK and safety data from preceding dose level. The projected doses for each group are subject to modification based upon PK and safety data from preceding cohorts. Pharmacokinetic parameters will be reviewed from at least 4 active subjects from preceding dose before dose escalating to the next dose level. The maximum dose administered will be 50 mg BID. Additional subjects/Cohorts may be enrolled.

Drug: GSK1325756 Solution; Drug: GSK1325756 Solution Matching Placebo

Interventions

GSK1325756 Solution DRUG

Solution containing 2 mg/mL GSK1325756 in sterile water for injection, to be administered intravenously.

Part A (Cohort 1); Part B (Cohorts 2 and 3)

GSK1325756 Solution Matching Placebo DRUG

Solution containing sterile water for injection matching GSK1325756 solution, to be administered intravenously.

Part A (Cohort 1); Part B (Cohorts 2 and 3)

GSK1325756 Tablet DRUG

A white film coated tablet containing 50 mg GSK1325756 to be administered orally.

Part A (Cohort 1)

GSK1325756 Tablet Matching Placebo DRUG

A white film coated tablet matching GSK1325756 tablet, to be administered orally.

Part A (Cohort 1)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males/females aged between 18 and 65 years of age inclusive, at the time of signing the informed consent.

You may not qualify if:

• Body weight \>=60 kilograms (kg) for men and \>=45 kg for women; and Body Mass Index (BMI) within the range 19 to 32 kg/square meter (m\^2) (inclusive).
• 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 milli-international unit (MIU)/milliliter (mL) and estradiol \<40 picograms (pg)/mL (\<147 picomoles \[pmol\]/liter \[L\]) is confirmatory\].
• Male subjects with female partners of child-bearing potential must agree to use one of the acceptable contraception methods. This criterion must be followed from the time of the first dose of study medication until 90 days following the last dose.
• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5 x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Based on a single ECG obtained over a brief recording period: corrected QT interval (QTc) \<450 milliseconds (msec); or QTc \<480 msec in subjects with Bundle Branch Block.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• History of regular alcohol consumption within 6 months 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 grams (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.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation.
• Part A only: Subjects currently or likely to take antacids (H2 receptor antagonists, proton pump inhibitors \[PPI\] blockers, etc.) at any point during the study.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• Urinary cotinine levels indicative of smoking history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
• A positive pre-study drug/alcohol screen.
• A positive test for human immunodeficiency virus (HIV) antibody.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

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.
• Results for study 201022 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Respiratory Tract Infections

Interventions

danirixin

Condition Hierarchy (Ancestors)

Infections; Respiratory Tract Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2014
• First Posted: June 23, 2014
• Study Start: June 12, 2014
• Primary Completion: August 28, 2014
• Study Completion: August 28, 2014
• Last Updated: May 15, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will share

Locations

US (1)