Clinical trial NCT01818011 (phase 1, status: terminated)
Conditions: infections, bacterial
ICD codes: A49.9, A04.9, A04.8, A49.8
Drugs: gsk1322322 initial fit for purpose tablets, gsk1322322 over granulated tablets, gsk1322322 intended commercial tablets, placebo tablets, 13c-gsk1322322 stable isotope powder, gsk1322322 for injection, placebo injection
SMILES: CC1=NC(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)=C(F)C(=N1)N1CCN2CCOC[C@@H]2C1, CC1=NC(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)=C(F)C(=N1)N1CCN2CCOC[C@@H]2C1, CC1=NC(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)=C(F)C(=N1)N1CCN2CCOC[C@@H]2C1, NC[C@H]1CC[C@@H](CC1)C(O)=O, CC1=NC(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)=C(F)C(=N1)N1CCN2CCOC[C@@H]2C1, [Na+].[Cl-]
Reason stopped: 
    emerging gsk1322322 pre-clinical data id'd potentially reactive metabolites previously not seen
    that changed the risk: benefit profile and led to a termination
  
Eligibility criteria:

        Inclusion Criteria

          -  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%) at screening and check in.

          -  Healthy as determined by a responsible and experienced physician, based on a medical
             evaluation including medical history, physical examination, laboratory tests and ECGs.
             A subject with a clinical abnormality or laboratory parameters outside the reference
             range for the population being studied may be included at the discretion of the
             Investigator only if the finding is unlikely to introduce additional risk factors and
             will not interfere with the study procedures.

          -  Part A: Male or female (of non childbearing potential) between 18 and 65 years of age
             inclusive, at the time of signing the informed consent.

          -  Part A: 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 [in
             questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)
             >40 milli international unit (MlU)/milliliter (mL) and estradiol <40 picogram [pg]/mL
             (<147 picomoles [pmol]/litre [L]) is confirmatory].

          -  Part B and C: Japanese defined as being born in Japan, having four ethnic Japanese
             grandparents, holding a Japanese passport or identity papers and being able to speak
             Japanese. Japanese subjects should also have lived outside Japan for less than 10
             years. Subjects should consume a typical Japanese diet on a regular basis.

          -  Parts B and C: Males between 20 and 65 years of age inclusive, at the time of signing
             the informed consent.

          -  Subjects with female partners of child-bearing potential must agree to use one of 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 >=45.0 kilograms and body mass index (BMI) within the range 18.5 to 29.9
             kg/meter^2 (inclusive).

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          -  QT duration corrected for heart rate by Bazett's formula (QTcB) <=450 millisecond
             (msec); or QTcB < 480 msec in subjects with Bundle Branch Block on Screening ECG.

        Exclusion Criteria

          -  A positive pre-study Hepatitis B surface antigen, positive Hepatitis C antibody, a
             positive test for human immune virus (HIV) antibody result within 3 months of
             screening.

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  A positive pre-study drug/alcohol screen.

          -  History of regular alcohol consumption within 6 months of the study defined as an
             average weekly intake of >21 units for males. One unit is equivalent to 10 gram (g) of
             alcohol: 270 mL of full strength beer (4.8%), 375mL of mid strength beer (3.5%), 470mL
             of light beer (2.7%), 250mL pre-mix full strength spirit (5%), 100mL of wine (13.5%)
             and 30mL of spirit (40%).

          -  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.

          -  Unable to refrain from the use of prescription or non-prescription drugs, including
             vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or
             14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is
             longer) prior to the first dose of study medication until completion of the follow-up
             visit, unless in the opinion of the Investigator and GSK Medical Monitor the
             medication will not interfere with the study procedures or compromise subject safety
             due to potential drug interaction. Use of antacids, H2 blockers, proton pump
             inhibitors, vitamins, and iron supplements within 7 days prior to the first dose of
             study medication and for the duration of the trial, including follow-up.

          -  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.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 day period.

          -  Parts B and C: Female subjects.

          -  Part A: Pregnant females as determined by positive [serum or urine] human chorionic
             gonadotropin (hCG) test at screening or prior to dosing.

          -  Part A: Lactating females.

          -  Part A: Cotinine levels indicative of smoking or history or regular use of tobacco- or
             nicotine-containing products within 3 months prior to screening.

          -  Part B and C: Subjects with a smoking history of >10 cigarettes per day in the last 3
             months.

          -  Unwillingness or inability to follow the procedures outlined in the protocol.

          -  Subject is mentally or legally incapacitated.

          -  History of sensitivity to heparin or heparin-induced thrombocytopenia.

          -  Unable to refrain from 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.

          -  Screening Holter monitoring shows one or more of the following: Evidence of previous
             myocardial infarction (does not include ST segment changes associated with
             repolarization) and/or Any conduction abnormality on Holter monitoring (including but
             not specific to left or right complete bundle branch block, AV block [second degree or
             higher in an awake state; similar findings in sleeping subjects would not represent
             holter based exclusion, provided that they represent physiologic rhythm variants],
             Wolf Parkinson White [WPW] syndrome), sinus pauses>3 seconds, non-sustained or
             sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats) or any
             significant arrhythmia which, in the opinion of the principal investigator and GSK
             medical monitor, will interfere with the safety of the individual subject.

          -  Exclusion criteria for screening ECG (a single repeat is allowed for eligibility
             determination): Male subjects with Heart rate <40 and >100 beats per minute (bpm), PR
             interval <120 and >220 msec, QRS duration <70 and >120 msec, QT interval corrected for
             heart rate (Bazett) >450 msec.

        Evidence of previous myocardial infarction (does not include ST segment changes associated
        with repolarization).

        Any conduction abnormality (including but not specific to left or right complete bundle
        branch block, AV block [second degree or higher], WPW syndrome, sinus pauses >3 seconds,
        non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic
        beats) or any significant arrhythmia which, in the opinion of the principal investigator
        and GSK medical monitor, will interfere with the safety of the individual subject.