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A Single Center Four Part Study in Healthy Adult Subjects to Evaluate: the Safety, Tolerability and Pharmacokinetics of a Single Oral Dose and Repeat Escalating Oral Doses of GSK945237; the Effect of Linezolid on Hematology Safety Parameters; and the Effects of GSK945237 and Moxifloxacin on QTc.

This study has been terminated.
(Internal decision to progress alternate molecule with more preferable profile)
Sponsor:
Information provided by:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01039610
First received: December 23, 2009
Last updated: May 12, 2011
Last verified: May 2011
  Purpose

GSK945237 belongs to the Bacterial Type II Topoisomerase Inhibitor (BTI) class of antibiotics. GSK945237 has demonstrated in vitro and in vivo activity against Gram positive [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. This study will be conducted in four (4) parts, with a single oral dose being explored in Part A (2400 mg) and repeat oral doses (b.i.d. and q.d.) being explored in Part B. Parts C and D will be optional evaluations of repeat oral doses of linezolid and a comparative evaluation of the effect of GSK945237 and moxifloxacin, respectively. Parts A and B will be single-blind, randomized, placebo-controlled, dose-rising (Part B only) studies of healthy subjects to evaluate the safety, tolerability and pharmacokinetics of GSK945237. The proposed doses range from 400 mg to 2400 mg. Part C will be a single-blind, randomized, and placebo-controlled repeat dose evaluation of 600 mg (b.i.d.) of linezolid. Part D will be a single-blind, randomized, placebo-controlled, two period crossover study. The proposed doses for Part D will be 1200 mg GSK945237 and 400 mg moxifloxacin.


Condition Intervention Phase
Infections, Bacterial
Drug: GSK945237
Drug: Placebo
Drug: Linezolid
Drug: Moxifloxacin
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: A Single Center Four Part Study in Healthy Adult Subjects to Evaluate: the Safety, Tolerability and Pharmacokinetics of a Single Oral Dose and Repeat Escalating Oral Doses of GSK945237; the Effect of Linezolid on Hematology Safety Parameters; and the Effects of GSK945237 and Moxifloxacin on QTc.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Safety and tolerability assessments, consisting of AEs, ECGs, vital signs, clinical laboratory tests. [ Time Frame: duration of dosing ] [ Designated as safety issue: Yes ]
  • Plasma AUC(0-t), AUC(0-inf), Cmax, tmax, and t1/2 of GSK945237 [ Time Frame: duration of dosing ] [ Designated as safety issue: No ]
  • Amount excreted in urine (Ae) and renal clearance of GSK945237 [ Time Frame: duration of dosing ] [ Designated as safety issue: No ]
  • Saliva PK parameters [ Time Frame: duration of dosing ] [ Designated as safety issue: No ]
  • QT interval and heart rate [ Time Frame: duration of dosing ] [ Designated as safety issue: Yes ]
  • Change from baseline in QTc for GSk945237, moxifloxacin, and placebo [ Time Frame: duration of dosing ] [ Designated as safety issue: Yes ]

Enrollment: 0
Study Start Date: November 2009
Study Completion Date: August 2010
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A
GSK945237 2400mg single dose
Drug: GSK945237
Dose detailed in Arm description
Drug: Placebo
matching placebo tablet
Experimental: Part B Cohort 1
GSK945237 400 mg QD, 7 Days 4 subjects GSK945237:2 subjects Placebo
Drug: GSK945237
Dose detailed in Arm description
Drug: Placebo
matching placebo tablet
Experimental: Part B Cohort 2
GSK945237 400 mg QD, 14 Days 4 subjects GSK945237:2 subjects Placebo
Drug: GSK945237
Dose detailed in Arm description
Drug: Placebo
matching placebo tablet
Experimental: Part B Cohort 3
GSK945237 400 mg BID, 14 Days 4 subjects GSK945237:2 subjects Placebo
Drug: GSK945237
Dose detailed in Arm description
Drug: Placebo
matching placebo tablet
Experimental: Part B Cohort 4
GSK945237 800 mg BID, 14 Days 9 subjects GSK945237:3 subjects Placebo
Drug: GSK945237
Dose detailed in Arm description
Drug: Placebo
matching placebo tablet
Experimental: Part B Cohort 5
GSK945237 1200 mg BID, 14 Days 9 subjects GSK945237:3 subjects Placebo
Drug: GSK945237
Dose detailed in Arm description
Drug: Placebo
matching placebo tablet
Experimental: Part B Cohort 6
GS945237 1600 mg QD, 14 Days 9 subjects GSK945237:3 subjects Placebo
Drug: GSK945237
Dose detailed in Arm description
Drug: Placebo
matching placebo tablet
Active Comparator: Part C
Linezolid 600 mg BID, 14 Days 9 subjects Linezolid:3 subjects Placebo
Drug: Placebo
matching placebo tablet
Drug: Linezolid
600 mg BID, 14 Days
Active Comparator: Part D

2 period crossover Period 1: Placebo 1 day; GSK945237 dose to be determined, 5 Days Period 2: Placebo 5 days; moxifloxacin 400 mg single dose

16 subjects

Drug: GSK945237
Dose detailed in Arm description
Drug: Placebo
matching placebo tablet
Drug: Moxifloxacin
40 mg single dose

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy as determined by a responsible physician, based on a medical evaluation including history, physical examination, laboratory tests, cardiac monitoring. A subject with a non-clinically significant abnormality or laboratory parameters outside the reference range may be included only if the investigator considers that the finding will not introduce additional risk factors and will not interfere with the study procedures or data interpretation.
  • Male or female between 18 and 60 years of age.
  • A female subject is eligible to participate if she is of:
  • Non-childbearing potential defined as pre-menopausal females with a documented bilateral tubal ligation, hysterectomy, or bilateral oophorectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory].
  • Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until at least 90 days post-last dose.
  • Body weight greater than 50 kg and BMI within the range 19 - 32 kg/m2 (inclusive).
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  • QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.

Exclusion Criteria:

  • 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.
  • Any preexisting retinal condition or finding on baseline examination 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 interpretation of ophthalmologic safety results during the conduct of the trial.
  • The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
  • A positive test for HIV antibody.
  • 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 (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine.
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • Use of prescription or non-prescription drugs, including vitamins above the recommended daily intake 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 acetaminophen (< or equal to 2 grams/day) or ibuprofen (1600 mg/day) up to 48 hours prior to the first dose of study medication. However, the investigator and study team can review medication use on a case by case basis to determine if its use would compromise subject safety or interfere with 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.
  • The subject has donated blood within 2 months prior to dosing and/or donated plasma within 1 week prior to dosing.
  • An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactating women, or an unwillingness of male subjects to use a condom and spermicide, in addition to having their female partner use another form of contraception such as an IUD, diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal implants or a tubal ligation, if engaging in sexual intercourse with a female partner who could become pregnant. This criterion must be followed from the time of study medication administration and until 90 days after study medication administration.
  • Lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
  • Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.
  • For Part C and Part D only: Contraindications to the use of linezolid or moxifloxacin, respectively as per the package insert [Avelox Product Information, 2008; Zyvox Product Information, 2008].
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01039610

Locations
United States, Texas
GSK Investigational Site
Dallas, Texas, United States, 75247
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: E.D. Derilus; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier: NCT01039610     History of Changes
Other Study ID Numbers: 107895
Study First Received: December 23, 2009
Last Updated: May 12, 2011
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
GSK945237
bacterial type II topoisomerase Inhibitors (BTI)
repeat dose
tolerability
single dose
antibiotics
pharmacokinetics
safety
linezolid
QTc
moxifloxacin

Additional relevant MeSH terms:
Bacterial Infections
Linezolid
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Antineoplastic Agents
Contraceptive Agents
Contraceptive Agents, Female
Contraceptives, Oral
Contraceptives, Oral, Combined
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Synthesis Inhibitors
Reproductive Control Agents
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on November 27, 2014