A Study to Evaluate Safety, Tolerability and Pharmacokinetics of Ascending Intravenous Single Dose and Repeat Dose of GSK3342830
Condition: Infections, Bacterial
MeSH terms: Bacterial Infections
Intervention: GSK3342830; Placebo
Intervention description: A pyrogen free lyophilized formulation, white to yellowish brown powder containing 1000 mg of GSK3342830A (as free base) per vial. The reconstituted solution looks like a clear, colorless to yellow or brownish yellow liquid, free from visible particulate matter will be administered as IV infusion over 1 hour.; A clear and colorless solution containing 0.9% sodium chloride. It will administered as IV infusion over 1 hour.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 62.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Multidrug-resistant; Gram negative bacterial infection; Safety; Pharmacokinetic

Summary:

      A phase I, first-time-in-human (FTIH), randomized, double-blind, placebo controlled,
      dose-escalation study is conducted to determine the safety, tolerability, and pharmacokinetic
      (PK) profile of GSK3342830 after administration of single intravenous (IV) infusion in Part 1
      and repeat IV infusion in Part 2 in healthy subjects. Part 1 will investigate escalating
      single IV doses of GSK3342830. Part 2, will investigate escalating repeat IV doses of
      GSK3342830 with repeat dosing for 15 days as follows: a single IV infusion on Day 1, TID
      (three times a day) IV infusions on Days 2 through 14 (approximately every 8 hours), and a
      single IV infusion on Day 15. The planned starting GSK3342830 dose in Part 1 is 250 milligram
      (mg) administered as a single IV infusion. The dose is planned to increase in subsequent
      cohorts to 500, 1000, 2000, 4000, and less than or equal to (≤) 6000 mg. Part 1 will be
      divided into 6 cohorts (A-F) and each cohort will enroll 10 subjects (6 in active and 2 in
      placebo). Dose escalation will be conducted only if it is supported by the preliminary
      safety, tolerability, and PK results from the preceding dose levels in the study. The repeat
      dose escalation component (Part 2) of this study will be planned to be initiated after
      completion and evaluation of the all single dose cohorts up to and including 4000 mg.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 18 and 55 years of age, inclusive, at the time of signing the informed
             consent.

          -  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 parameter
             outside the reference range for the population being studied may be included only if
             the investigator feels and documents that the finding is unlikely to introduce
             additional risk factors and will not interfere with the study procedures.

          -  Body weight >50 kilogram (kg) (110 pounds [lb]) for men and >40 kg (99 lb) for women
             and body mass index within the range of 18.5 to 30 kg per square meter (m^2),
             inclusive.

          -  Male or Female subjects. Males: Male subjects with female partners of child-bearing
             potential must agree to use one of the highly effective contraception from the time of
             first dose of study drug until completion of the Follow-up visit, and Females: A
             female subject is eligible to participate if she is not pregnant (as confirmed by a
             negative serum human chorionic gonadotropin [hCG] test), not lactating, and considered
             to be of non-reproductive potential (non-reproductive potential is defined as:
             Pre-menopausal females with one of the following: Documented tubal ligation or
             Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of
             bilateral tubal occlusion or Hysterectomy or Documented bilateral oophorectomy).

          -  Postmenopausal defined as 12 months of spontaneous amenorrhea and in questionable
             cases a blood sample with simultaneous follicle-stimulating hormone (FSH) and
             estradiol levels consistent with menopause (refer to laboratory reference ranges for
             confirmatory levels)

          -  Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt
             will be required to use one of the highly effective contraception methods, if they
             wish to continue their HRT during the study. Otherwise, they must discontinue HRT to
             allow confirmation of post menopausal status before study enrolment.

          -  Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions.

        Exclusion Criteria:

          -  Alanine aminotransferase (ALT) not within normal limits; bilirubin >1.5× upper limit
             of normal (ULN; isolated bilirubin >1.5× ULN is acceptable if bilirubin is
             fractionated and direct bilirubin is <35%).

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Corrected QT (QTc) >450 milliseconds (msec).

          -  Any clinically significant central nervous system (e.g., seizures), cardiac,
             pulmonary, metabolic, renal, hepatic, or gastrointestinal condition or history of such
             a condition 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.

          -  Use of a systemic antibiotic within 30 days of screening.

          -  Ongoing febrile illness.

          -  Confirmed history of Clostridium difficile diarrhea

          -  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) before the first dose of study treatment, unless in the opinion of the
             Investigator, the medication will not interfere with the study procedures or
             compromise subject safety.

          -  History of regular alcohol consumption within 6 months of screening defined as an
             average weekly intake of >21 units (or an average daily intake of >3 units) for males
             or an average weekly intake of >14 units (or an average daily intake >2 units) for
             females. One unit is equivalent to 270 milliliter (mL) of full strength beer, 470 mL
             of light beer, 30 mL of spirits, or 100 mL of wine.

          -  Urinary cotinine level indicative of smoking or history or regular use of tobacco- or
             nicotine containing products within 3 months before screening.

          -  History of hypersensitivity attributed to beta-lactam antibiotics (including
             cephalosporin, carbapenem, or penicillin antibiotics) or other drugs, a history of
             multiple antibiotic intolerances, or a history of serious adverse drug reactions.

          -  Sensitivity to poison ivy or other catechol-related hypersensitivity (e.g., mango
             allergy).

          -  History of sensitivity to heparin or heparin-induced thrombocytopenia.

          -  History of latex allergy.

          -  History of sensitivity to any of the study treatments or components thereof, or a
             history of drug or other allergy that, in the opinion of the investigator,
             contraindicates participation in the study.

          -  Presence of hepatitis B surface antigen or positive hepatitis C antibody test result
             at screening or within 3 months before the first dosing day in this study.

          -  Serum creatinine >ULN.

          -  Glomerular filtration rate <90 millilter per minute per 1.73 square meter
             (mL/min/1.73m^2) as calculated by the Chronic Kidney Disease Epidemiology
             Collaboration formula

          -  Albumin to creatinine ratio (ACR) >0.03 mg/mg. In the event of an ACR above this
             threshold, eligibility may be confirmed by a second measurement.

          -  Urinalysis positive for blood without other cause identified.

          -  A positive pre-study drug or alcohol screen.

          -  A positive test for human immunodeficiency virus antibody at or before screening.

          -  Participation in the study would result in donation of blood or blood products in
             excess of 500 mL within a 56-day period.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period before the first dosing day in this 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 4 new chemical entities within 12 months before the first dosing
             day in this study.

          -  Exclusion criteria for screening and baseline 12-lead ECG: Heart rate <40 and >100
             beats per minute for males and <50 and >100 beats per minute (for females), pulse rate
             is <120 and >220 msec, QRS is <70 and >120 msec, and corrected QT interval using
             Bazett's formula (QTcB ) and corrected QT interval using Fridericia's formula (QTcF )
             >450 msec.. Also apart from this, subject having evidence of previous myocardial
             infarction, bundle branch block and Any conduction abnormality (including but not
             specific to left or right complete bundle branch block, AV block [2nd degree or
             higher], Wolf-Parkinson-White syndrome), sinus pauses more than 3 seconds,
             non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular
             ectopic beats), or any significant arrhythmia that, in the opinion of the investigator
             will interfere with the safety of the individual subject.