A Dose-Ranging Study Evaluating the Efficacy, Safety, and Tolerability of GSK2140944 in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria Gonorrhoeae
Condition: Gonorrhea
MeSH terms: Gonorrhea
Intervention: GSK2140944
Intervention description: Immediate release capsules (pink hard gelatin size 00 capsule, with no external marking, filled with slightly agglomerated pale yellowish to grayish yellow powder) containing GSK2140944 500 mg and inactive formulation excipients. GSK2140944 will be administered orally once 1500 mg (3 capsules) or 3000 mg (6 capsules).
Intervention MeSH terms: Gepotidacin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 106.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: uncomplicated urogenital gonorrhea; Bacterial Type II Topoisomerase Inhibitors (BTI); antibiotics; GSK2140944; N. gonorrhoeae

Summary:

      GSK2140944 has demonstrated in vitro activity against Neisseria (N.) gonorrhoeae, including
      ciprofloxacin resistant and susceptible strains. This study is a Phase II, randomized,
      multicenter, open-label, dose ranging study designed to inform the optimal oral dose of
      GSK2140944 by further characterizing the efficacy, safety, and tolerability in subjects with
      uncomplicated urogenital gonorrhea due to N. gonorrhoeae. Subjects will be randomly assigned
      to receive either a single 1500 milligrams (mg) or 3000 mg oral dose of GSK2140944.
      Appropriate safety and microbiological assessments will be conducted at the Baseline (Day 1)
      Visit and repeated at the Test-of-Cure (Day 4 to 8) Visit. The study duration will be
      approximately 1 week. Approximately 60 microbiologically evaluable subjects (30 subjects in
      each treatment arm) will complete the study if both arms remain active throughout the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  The subject is an adult male or female at least 18 years of age at the time of signing
             informed consent who meets one of the following criteria:

               1. A non-pregnant, non-lactating female of childbearing potential who 1) is sexually
                  inactive by abstinence, 2) has a sole male partner who has been sterilized, or 3)
                  uses a contraceptive method with a failure rate of <1% through the Test-of-Cure
                  Visit. Females of childbearing potential must not become pregnant during the
                  study.

               2. A female of non-childbearing potential, which includes the following: Females who
                  are surgically sterile with a documented hysterectomy and/or bilateral
                  oophorectomy; Females with documented tubal ligation. If the procedure was done
                  hysteroscopically, the effectiveness of tubal occlusion must have been documented
                  by hysterosalpingogram after the procedure (typically 3 months after the
                  procedure); Females who are post-menopausal, defined as amenorrhoeic for greater
                  than 1 year. For women whose menopausal status is in doubt, documented previous
                  confirmatory blood samples with follicle-stimulating hormone >40 milli
                  international units (mIU)/millilitre (mL) and estradiol <40 picograms (pg)/mL
                  (<140 picomoles [pmol]/litre [L]) will need to be confirmed, or they will be
                  required to use one of the acceptable contraception methods. Note: For the
                  purposes of these criteria, "documented" includes information obtained via a
                  verbal interview with the subject or from the subject's medical records.

          -  There is clinical suspicion that the subject has a urogenital gonococcal infection
             (e.g., prior culture, nucleic acid amplification test [NAAT] or Gram stain presumptive
             or positive for the presence of N. gonorrhoeae, or sexual contact with a partner
             diagnosed with gonorrhea within the past 14 days, as reported by the subject). Note:
             All subjects will be tested for N. gonorrhoeae, but these results will not be used to
             determine subject eligibility for enrollment in the study.

          -  The subject has provided written, dated, informed consent and is willing and able to
             comply with the study protocol.

        Exclusion Criteria:

          -  The subject is pregnant or nursing.

          -  The subject is a hysterectomized female without a cervix.

          -  The subject is a male with a current diagnosis of epididymitis or orchitis at the time
             of the Baseline Visit.

          -  The subject has a body mass index >=40.0 kilograms (kg)/square meter (m^2).

          -  The subject has a serious underlying disease that could be imminently life
             threatening, or the subject is unlikely to survive for the duration of the study
             period.

          -  The subject has a medical condition or requires medication that may be aggravated by
             inhibition of acetylcholinesterase, such as: Poorly controlled asthma or chronic
             obstructive pulmonary disease at baseline and, in the opinion of the investigator, is
             not stable on current therapy; Acute severe pain, uncontrolled with conventional
             medical management; Active peptic ulcer disease; Parkinson's disease; Myasthenia
             gravis; A history of seizure disorder requiring medications for control. This does not
             include a history of childhood febrile seizures; Any evidence of mechanical
             obstruction of the urinary or digestive tracks.

          -  The subject has had any past history or current diagnosis of Clostridium difficile
             infection at the time of the Baseline Visit.

          -  The subject, in the judgment of the investigator, would not be able or willing to
             comply with the protocol or complete study follow-up.

          -  The subject has a history of sensitivity to the study medication, or components
             thereof, or a history of a drug or other allergy that, in the opinion of the
             investigator or medical monitor, contraindicates their participation.

          -  The subject has a PR interval <120 or >220 milliseconds (msec). Note: Subjects without
             an evaluable PR interval (e.g., stable atrial fibrillation) are not eligible for this
             study.

          -  The subject has a corrected QT (QTc) >450 msec or a QTc >480 msec for subjects with
             bundle branch block. Note: The QTc is the QT interval corrected for heart rate
             according to either Bazett formula (QTcB), Fridericia formula (QTcF), machine, or
             manual overread.

          -  The subject has QRS duration <70 or >120 msec.

          -  The subject has pre-existing Grade II atrioventricular block or higher or a history of
             significant vasovagal and/or syncopal episodes or episodes of symptomatic bradycardia.

          -  The subject has a current or chronic history of liver disease (with the exception of
             Gilbert's syndrome), including symptomatic viral hepatitis and moderate to severe
             liver insufficiency (Child Pugh class B or C).

          -  The subject has been previously enrolled in this study or has previously been treated
             with GSK2140944.

          -  The subject has participated in a clinical trial and has received an investigational
             product within 30 days or 5 half-lives, whichever is longer.

          -  The subject has the following gonococcal infections: Suspected or confirmed pelvic
             inflammatory disease; Suspected or confirmed gonococcal arthritis; Other evidence of
             disseminated gonococcal infection.

          -  The subject has received treatment with a systemic or intravaginal antibacterial
             within 14 days of study entry.

          -  Subject is taking a medication that has a known risk of torsades de pointes.