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

NCT ID: NCT01615796

Last Updated: 2017-05-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 86 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-06-04
• Study Completion Date: 2014-02-21

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.

Detailed Description

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 issue infections including isolates resistant to existing classes of antimicrobials. This study will be the first administration of GSK2140944 as an intravenous (IV) formulation in humans and will be conducted in two (2) parts. Single IV doses will be explored in Part A and repeat IV doses will be explored in Part B. In addition, this study will evaluate the absolute bioavailability of an oral capsule formulation as compared to the IV formulation in Part A. Both study parts will investigate the safety, tolerability and pharmacokinetic profile of GSK2140944 in healthy adult subjects.

Conditions

Infections, Respiratory Tract

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: SINGLE

Study Groups

Cohort A1

GSK2140944 200mg single dose

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

Subjects receive a single dose of GSK2140944

Cohort A2

GSK2140944 600mg single dose

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

Subjects receive a single dose of GSK2140944

Cohort A3

GSK2140944 1200mg single dose

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

Subjects receive a single dose of GSK2140944

Cohort A4

GSK2140944 1800mg single dose

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

Subjects receive a single dose of GSK2140944

Cohort A5

GSK2140944 1800mg single dose

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

Subjects receive a single dose of GSK2140944

Cohort A6

GSK2140944 dose to be determined, single dose

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

Subjects receive a single dose of GSK2140944

Cohort B1

GSK2140944 400 mg repeat dose BID up to 7 days

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Cohort B2

GSK2140944 750 mg repeat dose BID up to 7 days

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Cohort B3

GSK2140944 1000 mg repeat dose BID up to 7 days

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Cohort B4

GSK2140944 to be determined repeat dose BID up to 7 days

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Cohort B5

GSK2140944 to be determined repeat dose TID up to 14 days

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Cohort B6

GSK2140944 to be determined repeat dose TID up to 14 days

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Interventions

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

Subjects receive a single dose of GSK2140944

Intervention Type: DRUG

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

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

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 (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.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• History of tendon rupture.
• Subject is mentally or legally incapacitated.
• History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency).
• Consumption of red wine, seville oranges, grapefruit or grapefruit juice, pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices containing such products from 7 days prior to the first dose of study medication.
• Screening holter monitoring shows one or more of the following: Any symptomatic arrhythmia (except isolated extra systoles); Sustained cardiac arrhythmias (such as atrial fibrillation or flutter, SVT (greater than 10 consecutive beats)); Sinus tachycardia (or supraventricular tachycardia) greater than 150 bpm; Non-sustained or sustained ventricular tachycardia (defined as greater than and equal to 3 consecutive ventricular ectopic beats); Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree or higher in an awake subject], WPW syndrome, other pre-excitation syndromes); Symptomatic sinus pause or sinus pause >3 seconds - unless patient is straining, vomiting, or having some other type of hypervagal response; 300 or more supraventricular ectopic beats in 24 hours; 250 or more ventricular ectopic beats in 24 hours; Ischemia, diagnosed by a sequence of EKG changes that include flat or downsloping ST-segment depression greater than 0.1 mV, with a gradual onset and offset that lasts for a minimum period of 1 minute. Each episode of ischemia must be separated by a minimum duration of at least 1 minute, during which the ST segment returns back to baseline (1x1x1 rule).
• Neutrophil count <2000 cells per microliter (a single repeat is allowed for eligibility determination).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Randwick, New South Wales, Australia

Countries

Australia

Study Documents

Document Type: Dataset Specification

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Study Protocol

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Statistical Analysis Plan

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Informed Consent Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Clinical Study Report

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Individual Participant Data Set

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Annotated Case Report Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Related Links

https://www.clinicalstudydatarequest.com

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Other Identifiers

115198

Identifier Type: -

Identifier Source: org_study_id