Evaluate Safety, Tolerability, and Pharmacokinetics of Single and Repeat IV Doses

NCT01615796 | Completed Phase 1

• 1 other identifier: 115198
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

Brief Summary

GSK2140944 belongs to the Bacterial Type II Topoisomerase Inhibitor (BTI) class of antibiotics. GSK2140944 has demonstrated in vitro and in vivo activity against Gram positive pathogens including methicillin resistant Staphylococcus aureus (MRSA) and Gram-negative pathogens associated with respiratory tract, skin and soft tissue infections including isolates resistant to existing classes of antimicrobials.

Conditions

Infections, Respiratory Tract

Keywords

GSK2140944; antibiotics; first time in human; pharmacokinetics; intravenous; safety; absolute bioavailability; Bacterial Type II; tolerability; infection

Outcome Measures

Primary Outcomes (10)

• Composite of pharmacokinetic (PK) parameters of GSK2140944 including area under the curve following single dose administration.

  Measurements include area under the plasma concentration curve (AUC) from time zero (pre-dose) extrapolated to infinite time (AUC(0-infinity), AUC over the dosing interval AUC(0-tau). AUC (0-12) and AUC(0-24).

  Part A up to 4 days

• Composite of PK parameters for GSK2140944 following single dose administration

  Measurements include maximum observed concentration (Cmax), systemic clearance of parent drug (CL). volume of distribution at steady state of parent drug after intravascular administration (Vdss), Mean residence time (MRT) and terminal phase half-life (t1/2)

  Part A up to 4 Days

• Composite of PK parameters for GSK2140944 including area under the curve following repeat dose administration.

  Measurements include AUC from time zero (pre-dose) extrapolated to infinite time (AUC(0-infinity), AUC over the dosing interval AUC(0-tau). AUC (0-8), AUC (0-12) and AUC(0-24).

  Part B Days 4, 7, 10 and 14

• Composite of PK parameters for GSK2140944 following repeat dose administration.

  Measurements include Cmax, CL. Vdss, MRT and t1/2.

  Part B Days 4, 7, 10 and 14

• Composite of PK parameters for GSK2140944 following repeat dose administration including maximum concentration, area under the curve, accumulation ratio and clearance of parent drub.

  Measurements include AUC(0-tau). Cmax, pre-dose (trough) concentration at the end of the dosing interval (Cτ), accumulation ratio (Ro) and CL

  Part B Days 4, 7, 10 and 14

• GSK2140944 safety parameters - adverse events

  Part A change from baseline for 15 Days. Part B change from baseline for up to 28 Days

• GSK2140944 safety parameters - telemetry

  Part A change from baseline for 15 Days. Part B change from baseline for up to 28 Days

• GSK2140944 safety parameters - absolute values and changes over time of hematology, clinical chemistry and urinalysis

  Part A change from baseline for 15 Days. Part B change from baseline for up to 28 Days

• GSK2140944 safety parameters - vital signs (blood pressure, heart rate, temperature)

  Part A change from baseline for 15 Days. Part B change from baseline for up to 28 Days

• GSK2140944 safety parameters - Electrocardiogram (ECG) measurements

  Part A change from baseline for 15 Days. Part B change from baseline for up to 28 Days

Secondary Outcomes (5)

• A composite of pharmacokinetic parameters including dose proportionality following single and repeat doses of GSK2140944.

  44 Days in Part A, 7, 10 and 14 Days in Part B

• A composite of pharmacokinetic urinary parameters to estimate the urinary excretion of unchanged GSK2140944 following a therapeutically relevant dose and higher single dose in healthy volunteers.

  4 Days in Part A

• A composite of pharmacokinetic parameters to estimate the absolute bioavailability of the oral capsule formulation of GSK2140944 as compared to the IV formulation following single equivalent doses in healthy volunteers.

  4 Days in Part A

• A composite of pharmacokinetic parameters to examine the extent of accumulation and time invariance following repeat doses of GSK2140944.

  4, 7, 10 and 14 days in Part B

• A composite of pharmacokinetic parameters to examine achievement of steady-state following repeat doses of GSK2140944.

  7, 10 and 14 days in Part B

Study Arms (12)

Cohort A1

EXPERIMENTAL

GSK2140944 200mg single dose

Drug: Part A: GSK2140944 Drug single dose of 200mg, 600mg, 1200mg, 1800 mg, and dose to be determined

Cohort A2

EXPERIMENTAL

GSK2140944 600mg single dose

Drug: Part A: GSK2140944 Drug single dose of 200mg, 600mg, 1200mg, 1800 mg, and dose to be determined

Cohort A3

EXPERIMENTAL

GSK2140944 1200mg single dose

Drug: Part A: GSK2140944 Drug single dose of 200mg, 600mg, 1200mg, 1800 mg, and dose to be determined

Cohort A4

EXPERIMENTAL

GSK2140944 1800mg single dose

Drug: Part A: GSK2140944 Drug single dose of 200mg, 600mg, 1200mg, 1800 mg, and dose to be determined

Cohort A5

EXPERIMENTAL

GSK2140944 1800mg single dose

Drug: Part A: GSK2140944 Drug single dose of 200mg, 600mg, 1200mg, 1800 mg, and dose to be determined

Cohort A6

EXPERIMENTAL

GSK2140944 dose to be determined, single dose

Drug: Part A: GSK2140944 Drug single dose of 200mg, 600mg, 1200mg, 1800 mg, and dose to be determined

Cohort B1

EXPERIMENTAL

GSK2140944 400 mg repeat dose BID up to 7 days

Drug: Part B: GSK2140944 Repeat Drug dose of 400mg, 750mg, 1000 mg, and dose to be determined

Cohort B2

EXPERIMENTAL

GSK2140944 750 mg repeat dose BID up to 7 days

Drug: Part B: GSK2140944 Repeat Drug dose of 400mg, 750mg, 1000 mg, and dose to be determined

Cohort B3

EXPERIMENTAL

GSK2140944 1000 mg repeat dose BID up to 7 days

Drug: Part B: GSK2140944 Repeat Drug dose of 400mg, 750mg, 1000 mg, and dose to be determined

Cohort B4

EXPERIMENTAL

GSK2140944 to be determined repeat dose BID up to 7 days

Drug: Part B: GSK2140944 Repeat Drug dose of 400mg, 750mg, 1000 mg, and dose to be determined

Cohort B5

EXPERIMENTAL

GSK2140944 to be determined repeat dose TID up to 14 days

Drug: Part B: GSK2140944 Repeat Drug dose of 400mg, 750mg, 1000 mg, and dose to be determined

Cohort B6

EXPERIMENTAL

GSK2140944 to be determined repeat dose TID up to 14 days

Drug: Part B: GSK2140944 Repeat Drug dose of 400mg, 750mg, 1000 mg, and dose to be determined

Interventions

Part A: GSK2140944 Drug single dose of 200mg, 600mg, 1200mg, 1800 mg, and dose to be determined DRUG

Subjects receive a single dose of GSK2140944

Cohort A1; Cohort A2; Cohort A3; Cohort A4; Cohort A5; Cohort A6

Part B: GSK2140944 Repeat Drug dose of 400mg, 750mg, 1000 mg, and dose to be determined DRUG

Subjects will receive repeat doses of GSK2140944 BID/TID for up to 14 Days

Cohort B1; Cohort B2; Cohort B3; Cohort B4; Cohort B5; Cohort B6

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• AST, ALT, alkaline phosphatase and bilirubin less than and equal to 1.5xULN (isolated bilirubin less than 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin less than 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 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) greater than 40 MlU/ml and estradiol less than 40 pg/ml (less than 147 pmol/L) is confirmatory. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until the final follow-up visit.
• Body weight greater than and equal to 50 kg and BMI within the range 19 - 31 kg/m2 (inclusive).
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

You may not qualify if:

• 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 (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• 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 positive urine test for drugs of abuse or alcohol (or alcohol breath test) at screening.
• A screening urinalysis positive for protein or glucose (greater than "trace" findings of protein or glucose).
• A serum creatinine value between screening and Day -1 visit that is increased by more than 0.2 mg/dL (or 15.25 umol/L) changes.
• History of photosensitivity to quinolones.
• Unwillingness to commit to avoid excessive exposure to sunlight (or exposure whilst on a tanning bed) which would cause a sunburn reaction from first dose up to and including the follow-up visit.
• 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.
• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of greater than 21 units (or an average daily intake of greater than 3 units) for males or an average weekly intake of greater than 14 units (or an average daily intake greater than 2 units) for females. One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer, 30 mL of spirits and 100 mL of wine.
• The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication.
• Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, or use of St. John's Wort within 14 days prior to the first dose of study medication. By exception, the volunteer may take paracetamol or acetaminophen (less than and equal to 2 grams/day) up to 48 hours prior to the first dose of study medication. However, the Investigator and GSK study team can review medication on a case by case basis to determine if its use would compromise subject safety or interfere with the study procedures or data interpretation.
• 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 GSK Medical Monitor, contraindicates their participation.
• Donation of blood in excess of 500 mL within 12 weeks prior to dosing.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Randwick, New South Wales, 2031, Australia

Location

Related Links

• Results for study 115198 can be found on the GSK Clinical Study Register.
• 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

Respiratory Tract Infections; Infections

Condition Hierarchy (Ancestors)

Respiratory Tract Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: June 7, 2012
• First Posted: June 11, 2012
• Study Start: June 4, 2012
• Primary Completion: February 21, 2014
• Study Completion: February 21, 2014
• Last Updated: May 9, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will share

Locations

AU (1)