A Randomized, Single Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Repeat Escalating Oral Doses of GSK2140944 in Healthy Adult Subjects (BTZ116778)
Overview
- Phase
- Phase 1
- Intervention
- GSK2140944
- Conditions
- Infections, Respiratory Tract
- Sponsor
- GlaxoSmithKline
- Enrollment
- 72
- Locations
- 1
- Primary Endpoint
- GSK2140944 clinical safety data assessed as change from baseline in clinical laboratory tests
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This will be a randomized, placebo-controlled, single blind study to investigate the safety, tolerability and pharmacokinetic (PK) profile of GSK2140944 following repeat oral doses in healthy adult subjects. The study will include a Screening period (40 days), Treatment period (16 days) and a Follow-up period (26 to 30 days). A single dose will be administered on Day 1 for characterization of single dose PK, followed by twice-daily (BID) or thrice-daily (TID) dosing on Days 3 to 16. Subjects may only be randomized to one cohort per the randomization schedule. Up to 6 cohorts will be enrolled using a sequential panel. Subjects in Cohort 1 will receive GSK2140944 (6) and placebo (2). Subsequent cohorts will enroll 16 subjects such that 12 subjects will receive GSK2140944 and 4 subjects will receive placebo, per dose level according to the randomization schedule. Dose escalations are planned to run in successive weeks. Cohort 2 may begin dosing once subjects in Cohort 1 have completed 7 days of BID dosing, PK data is reviewed and safety data from at least 6 subjects is available. Each subsequent dose escalation will commence only when GSK2140944 safety data and available PK data of at least 12 subjects dosed at the previous dose level have been reviewed. The number of cohorts may be reduced or expanded if needed. The first planned dose is 400 milligram (mg) BID but may be modified based upon emergent PK, safety and tolerability data from ongoing clinical study BTZ115198 evaluating single and repeat intravenous (IV) doses of GSK2140944. The projected dose for Cohort 2 is 800 mg BID, Cohort 3 is 1500 mg BID, Cohort 4 is 2300 mg BID or 1500 mg TID and Cohort 5 and cohort 6 will be decided later. The planned maximum dose is 2500 mg TID but may be modified based upon emergent safety, tolerability and PK data. Doses of GSK2140944 or placebo will be administered following a moderate fat meal.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
- •Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. - A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GlaxSmithKline (GSK) Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- •Male or female 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; or postmenopausal defined as 12 months of spontaneous amenorrhea. To confirm post-menopausal status, a blood sample for simultaneous follicle stimulating hormone (FSH) \>40 MlU/ml and estradiol \<40 pg/ml (\<147 pmol/L) is confirmatory. Male subjects with female partners of child-bearing potential must agree to use the contraception methods. This criterion must be followed from the time of the first dose of study medication until the final follow-up visit.
- •Body weight \>=50 kg and body mass index (BMI) within the range 19 to 31 kg/m2 (inclusive).
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Exclusion Criteria
- •A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening or positive Human Immunodeficiency Virus (HIV) antibody.
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
- •Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions or history of such conditions that, in the opinion of the investigator may place the subject at an unacceptable risk as a participant in this trial or may interfere with the absorption, distribution, metabolism or excretion of drugs.
- •A screening or Day -2 urinalysis positive for protein or glucose (greater than "trace" findings of protein or glucose).
- •A serum creatinine value between screening and Day -2 visit that is increased by more than 0.2 mg/dL (or 15.25 umol/L) changes.
- •History of photosensitivity to quinolones and tendon rupture.
- •Unwillingness to commit to avoid excessive exposure to sunlight which would cause a sunburn reaction from first dose up to and including the follow-up visit.
- •A positive urine test for drugs of abuse or alcohol (or alcohol breath test) at screening or Day -
- •History of drug abuse within 6 months of the study
- •History of smoking or use of nicotine containing products within 3 months of screening, or a positive urine cotinine indicative of smoking at screening.
Arms & Interventions
Cohort 1 - GSK2140944 400 mg
Subjects will be randomized in 6:2 ratio to receive either GSK2140944 (Day 1: Single oral dose Days 3 to 16: (14 Days) BID oral doses) or placebo for approximately 15 days
Intervention: GSK2140944
Cohort 1 - Placebo
Subjects will be randomized in 6:2 ratio to receive either GSK2140944 BID or matching placebo for approximately 15 days
Intervention: Placebo
Cohort 2 - GSK2140944 800 mg
Subjects will be randomized in 12:4 ratio to receive either GSK2140944 (Day 1: Single oral dose Days 3 to 16: (14 Days) BID oral doses) or placebo for approximately 15 days. GSK2140944 dose in Cohort 2 will be decided based on the safety and PK data from six subjects in Cohort 1
Intervention: GSK2140944
Cohort 2 - Placebo
Subjects will be randomized in 12:4 ratio to receive either GSK2140944 BID or matching placebo for approximately 15 days
Intervention: Placebo
Cohort 3 - GSK2140944 1500 mg
Subjects will be randomized in 12:4 ratio to receive either GSK2140944 (Day 1: Single oral dose Days 3 to 16: (14 Days) BID oral doses) or placebo for approximately 15 days. GSK2140944 dose in Cohort 3 will be decided on the safety data and available PK data from at least 12 subjects dosed at the Cohort 2
Intervention: GSK2140944
Cohort 3 - Placebo
Subjects will be randomized in 12:4 ratio to receive either GSK2140944 bid or matching placebo for approximately 15 days
Intervention: Placebo
Cohort 4 - GSK2140944 2500 mg
Subjects will be randomized in 12:4 ratio to receive either GSK2140944 (Day 1: Single oral dose Days 3 to 16: (14 Days) BID oral doses) or placebo for approximately 15 days. GSK2140944 dose in Cohort 4 will be decided on the safety data and available PK data from at least 12 subjects dosed at the Cohort 3
Intervention: GSK2140944
Cohort 4 - Placebo
Subjects will be randomized in 12:4 ratio to receive either GSK2140944 bid or matching placebo for approximately 15 days
Intervention: Placebo
Cohort 5 - GSK2140944 TBD
Subjects will be randomized in 6:2 ratio to receive either GSK2140944 (Day 1: Single oral dose Days 3 to 16: (14 Days) TID oral doses) or placebo for approximately 15 days. GSK2140944 dose in Cohort 5 will be decided on the safety data and available PK data from at least 12 subjects dosed at the Cohort 4
Intervention: GSK2140944
Cohort 5 - Placebo
Subjects will be randomized in 6:2 ratio to receive either GSK2140944 TID or matching placebo for approximately 15 days
Intervention: Placebo
Cohort 6 - GSK2140944 TBD
Subjects will be randomized in 6:2 ratio to receive either GSK2140944 (Day 1: Single oral dose Days 3 to 16: (14 Days) TID oral doses) or placebo for approximately 15 days. GSK2140944 dose in Cohort 5 will be decided on the safety data and available PK data from at least 6 subjects dosed at the Cohort 5
Intervention: GSK2140944
Cohort 6 - Placebo
Subjects will be randomized in 6:2 ratio to receive either GSK2140944 TID or matching placebo for approximately 15 days
Intervention: Placebo
Outcomes
Primary Outcomes
GSK2140944 clinical safety data assessed as change from baseline in clinical laboratory tests
Time Frame: Day -2 and pre-morning dose on Day 2, Day 5, Day 8, Day 11, and Day 14; on the morning of Day 17 and at the Follow-up visit
Clinical laboratory assessments will include hematology, clinical chemistry, routine urinalysis and additional parameters
Pharmacokinetic parameter: Ro following repeat dose of GSK2140944
Time Frame: Day 14, Day 15 and Day 16
Pharmacokinetic data will include accumulation ratio (Ro) following repeat dose of GSK2140944
GSK2140944 clinical safety data from dual-lead cardiac monitoring
Time Frame: Day 1
Continuous dual-lead cardiac monitoring will be obtained at each timepoints using an ECG machine
GSK2140944 clinical safety data assessed as by number of adverse events (AE)
Time Frame: Up to the Follow-up visit
Safety and tolerability parameters will include recording of AEs, throughout the study
Pharmacokinetic parameter: Cmax following repeat dose of GSK2140944
Time Frame: Day 14, Day 15 and Day 16
Pharmacokinetic data will include Cmax following repeat dose of GSK2140944
Pharmacokinetic parameter: tmax following repeat dose of GSK2140944
Time Frame: Day 14, Day 15 and Day 16
Pharmacokinetic data will include tmax following repeat dose of GSK2140944
Pharmacokinetic parameter: tmax following single dose of GSK2140944
Time Frame: Up to Day 3
Pharmacokinetic data will include time of occurrence of Cmax (tmax) following single dose of GSK2140944
Pharmacokinetic parameter: t1/2 following single dose of GSK2140944
Time Frame: Up to Day 3
Pharmacokinetic data will include terminal phase half-life (t1/2) following single dose of GSK2140944
Pharmacokinetic parameter: AUC(0-tau) following repeat dose of GSK2140944
Time Frame: Day 14, Day 15 and Day 16
Pharmacokinetic data will include area under the concentration-time curve over the dosing interval (AUC(0-tau)) following repeat dose of GSK2140944
Pharmacokinetic parameter: Ctau following repeat dose of GSK2140944
Time Frame: Day 14, Day 15 and Day 16
Pharmacokinetic data will include pre-dose (trough) concentration at the end of the dosing interval (Ctau) following repeat dose of GSK2140944
Pharmacokinetic parameter: AUC(0-8) following single dose of GSK2140944
Time Frame: Day 1
Pharmacokinetic data will include area under the curve from time zero (pre-dose) to 8 hour post-dose (AUC\[0-8\]) following single dose of GSK2140944
GSK2140944 clinical safety data assessed as change from baseline in heart rate
Time Frame: Day -1, Day 1, Day 4, Day 7, Day 10, Day 13, Day 16, Day 18 and the Follow-up visit
Vital sign measurements will be done in semi-supine position and will include pulse rate
Pharmacokinetic parameter: AUC(0-12) following single dose of GSK2140944
Time Frame: Day 1
Pharmacokinetic data will include area under the curve from time zero (pre-dose) to 12 hour post-dose (AUC(0-12)) following single dose of GSK2140944
GSK2140944 clinical safety data assessed as change from baseline in 12-lead ECG
Time Frame: Day 1, Day 4, Day 7, Day 10, Day 13, Day 16, Day 18 and at the Follow-up visit
12-lead ECGs will be obtained at each timepoint using an ECG machine, after the subject has rested in a semi-supine position for at least 10 minutes
GSK2140944 clinical safety data assessed as change from baseline in blood pressure
Time Frame: Day -1, Day 1, Day 4, Day 7, Day 10, Day 13, Day 16, Day 18 and the Follow-up visit
Vital sign measurements will be done in semi-supine position and will include systolic and diastolic blood pressure
Pharmacokinetic parameter: AUC(0-infinity) following single dose of GSK2140944
Time Frame: Up to Day 3
Pharmacokinetic data will include area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC(0-infinity)) following single dose of GSK2140944
Pharmacokinetic parameter: Cmax following single dose of GSK2140944
Time Frame: Up to Day 3
Pharmacokinetic data will include maximum observed concentration (Cmax) following single dose of GSK2140944
Pharmacokinetic parameter: AUC(0-24) following single dose of GSK2140944
Time Frame: Up to Day 2
Pharmacokinetic data will include area under the curve from time zero (pre-dose) to 24 hour post-dose (AUC(0-24)) following single dose of GSK2140944
Pharmacokinetic parameter: AUC(0-t) following single dose of GSK2140944
Time Frame: Up to Day 3
Pharmacokinetic data will include area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-t)) following single dose of GSK2140944
Secondary Outcomes
- To examine extent of accumulation using PK parameter AUC(0-tau) following single dose of GSK2140944(Day 1)
- To examine the extent of time invariance using repeat dose AUC(0-tau)(Day 14, Day 15 and Day 16)
- To assess preliminary dose proportionality using PK parameter Cmax following single dose of GSK2140944(Up to Day 3)
- To assess preliminary dose proportionality using PK parameter AUC(0-tau) following repeat doses of GSK2140944(Day 14, Day 15 and Day 16)
- To assess achievement of steady-state following repeat oral doses of GSK2140944(Day 14, Day 15 and Day 16)
- To assess preliminary dose proportionality using PK parameter AUC(0-infinity) following single dose of GSK2140944(Up to Day 3)
- To assess preliminary dose proportionality using PK parameter Cmax following repeat doses of GSK2140944(Day 14, Day 15 and Day 16)
- To examine extent of accumulation using PK parameter Ro using AUC(0-tau) following repeat doses of GSK2140944(Day 14, Day 15 and Day 16)
- To examine the extent of time invariance using single dose AUC(0-infinity)(Up to Day 3)