Dose-Ranging Study of GSK2140944 in the Treatment of Subjects With Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections
Condition: Infections, Bacterial
MeSH terms: Infections; Communicable Diseases; Bacterial Infections; Skin Diseases, Bacterial
Intervention: GSK2140944 Lyophile; GSK2140944 Capsules
Intervention description: GSK2140944 Lyophile (pale yellow to grayish yellow cake) containing 750 mg of GSK2140944 (as free base) per vial for IV infusion.; GSK2140944 500 mg capsules will be supplied as pink hard gelatin capsule with no external markings filled with slightly agglomerated pale yellow to grayish yellow powder.
Intervention MeSH terms: Gepotidacin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 126.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Dose ranging; Intravenous; Adaptive design; suspected or confirmed gram-positive acute bacterial skin and skin structure infection; Subjects; infection; Oral; GSK2140944

Summary:

      GSK2140944 belongs to a novel structural class of antibiotics - Bacterial Type II
      Topoisomerase Inhibitors (BTI). This is a Phase II, randomized, two-part, multicenter study
      designed to select the optimal dose by further characterizing the safety, tolerability and PK
      of GSK 2140944 and by evaluating efficacy in subjects requiring in-patient medical care to
      treat their suspected or confirmed Gram-positive acute bacterial skin and skin structure
      infections (ABSSSI). The selected dose will be used in future studies.
    

Eligibility criteria:

        Inclusion Criteria:

          -  The subject is an adult male at least 18 years of age or an adult female at least 18
             years of age who meets one of the following criteria: A female of child-bearing
             potential who is either 1) sexually inactive by abstinence, 2) whose sole male partner
             has been sterilized, or 3) uses a contraceptive method with a failure rate of < 1%.
             Females of child-bearing potential must not become pregnant during the study. A female
             of non child- bearing potential, which includes: Females who are surgically sterile
             with a documented hysterectomy and/or bilateral oophorectomy; Females with a
             documented tubal ligation. If the procedure was done hysteroscopically, the
             effectiveness of tubal occlusion must have been documented by hysterosalpingogram post
             procedure (typically 3 months after procedure); Females who are post-menopausal,
             defined as amenorrhoeic for greater than 1 year. For women whose menopausal status is
             in doubt, a documented previous confirmatory blood sample with follicle-stimulating
             hormone (FSH) > 40 milli-international units per milliliter (MIU/mL) and estradiol <40
             picograms per milliliter (<140 picomole per liter) would need to be confirmed or they
             will be required to use one of the contraception methods.

          -  The subject has a diagnosis of ABSSSI suspected or documented to be caused by
             Gram-positive pathogens that requires of intravenous (IV) antibiotic treatment for
             which subjects is willing to receive treatment in an in-patient setting for at least 2
             days.. ABSSSI is defined as one of the following: Wound infection (traumatic or
             post-surgical): an infection involving skin and subcutaneous tissue, characterized by
             purulent drainage from a wound with surrounding redness, edema, and/or induration of a
             minimum surface area of 75 square centimeter (cm^2) (e.g., the shortest distance of
             redness, edema, and/or induration extending at least 5 centimeter (cm) from the
             peripheral margin of the wound); Major cutaneous abscess: an infection characterized
             by a collection of pus within the dermis or deeper that is accompanied by redness,
             edema, and/or induration of a minimum surface area of 75 cm^2 (e.g., the shortest
             distance of redness, edema, and/or induration extending at least 5 cm from the
             peripheral margin of the abscess). Cellulitis: a diffuse skin infection characterized
             by a spreading area of redness, edema, and/or induration of a minimum surface area of
             75 cm^2 Note: For subjects with more than one type of eligible lesion/wound or with
             multiple lesions of the same type, the investigator must clearly identify the lesion
             to be evaluated for study purposes. The identified lesion must be consistently chosen
             for assessment (including digital imaging) throughout the study. Incision and drainage
             (I&D) of the lesion is permitted prior to the first dose of study medication and will
             be allowed, per protocol, up to 24 hours after the start of the first dose of study
             medication.

          -  The subject has at least 1 additional sign or symptom of skin infection: fluctuation,
             heat/localized warmth, and pain/tenderness.

          -  The subject has at least 1 systemic marker of infection at the time of screening:
             Lymphadenopathy (proximal to and within the drainage of the wound); Fever (>=38
             degrees Celsius); white blood cells (WBC) elevation (>10000 /cubic millimetre [mm^3]
             or >10% immature neutrophils regardless of WBC count); C-reactive protein > upper
             limit of normal (ULN). Note: Systemic markers of infection are not required for
             subjects >70 years of age or for known or suspected (based on blood glucose levels)
             diabetics.

          -  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 has an immune-compromising illness; including known human immunodeficiency
             virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), organ (including
             bone marrow) transplant recipients, hematological malignancy, and immunosuppressive
             therapy, including high-dose corticosteroids (e.g., greater than 40mg prednisone or
             equivalent per day for greater than two weeks).

          -  Body mass index (BMI)>= 40.0 kilogram per square meter.

          -  The subject has a serious underlying disease that could be imminently
             life-threatening, or 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: the subject has poorly controlled asthma
             or chronic obstructive pulmonary disease at baseline, and, in the opinion, of the
             investigator is not stable on current therapy; the subject has acute severe pain,
             uncontrolled with conventional medical management; the subject has active peptic ulcer
             disease; the subject has parkinson's disease; the subject has myasthenia gravis; the
             subject has history of seizure disorder requiring medications for control. this does
             not include a history of childhood febrile seizures; the subject has any evidence of
             mechanical obstruction of the urinary or digestive tracts.

          -  The subject has had a diagnosis of C. difficile infection (CDI) within 90 days of
             screening

          -  The subject has history of seizure disorder requiring medications for control. This
             does not include a history of childhood febrile seizures.

          -  The subject is a chronic abuser of alcohol or illicit substances such that it
             jeopardizes ability to comply with the protocol

          -  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 Medical
             Monitor, contraindicates their participation

          -  The subject has a PR Interval <120 or >220 millisecond (msec)

          -  Corrected QT interval (QTc) >450msec or QTc >480msec for subjects with bundle branch
             block. Note: The QTc is the QT interval corrected for heart rate according to either
             Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or
             manual overread. The QTc should be based on single or averaged QTc values of
             triplicate ECGs obtained over a brief recording period. It is essential that the same
             method for calculating QTc that was used at a subjects baseline visit be used for that
             subject for all subsequent visits.

          -  The subject has QRS duration <70 or >120 msec.

          -  The subject has pre-existing grade II atrioventricular block or higher, history of
             significant vasovagal and/or syncopal episodes, episodes of symptomatic bradycardia.

          -  The subject has recent acute major blood loss with signs of hemodynamic instability.

          -  The subject has liver function tests: alanine aminotransferase (ALT) >2x ULN; alkaline
             phosphatase and bilirubin >=1.5xULN (isolated bilirubin >1.5 x ULN is acceptable if
             bilirubin is fractionated and direct bilirubin <35%).

          -  The subject has a current or chronic history of liver disease, or known hepatic or
             biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic
             gallstones). Subjects with stable Hepatitis B and/or Hepatitis C will be eligible if
             they meet the liver function test criteria in criterion (ALT >2 × ULN; alkaline
             phosphatase and bilirubin ≥1.5 × ULN).

        Note: All subjects will be screened for Hepatitis B surface antigen and Hepatitis C
        ribonucleic acid (RNA), but these results will not be used to determine subject eligibility
        or subject continuation in the study after enrollment.

          -  The subject has any skin condition or skin infection listed below: Secondarily
             infected animal/human bite; Infected burn; Infections of chronic ulcerative lesions
             (including diabetic foot infections and peripheral vascular disease) that are likely
             to be polymicrobial in nature, or caused by Gram-negative or anaerobic organisms that
             are unlikely to have a Gram-positive pathogen as the causative agent, (Note: Subjects
             with diabetic foot infections or peripheral vascular disease are eligible if they have
             a qualifying ABSSSI but diabetic foot infections are not eligible lesions for
             investigation); An underlying skin disease, such as pre-existing eczematous
             dermatitis, with clinical evidence of secondary infection; Suspected or confirmed
             osteomyelitis; Suspected or confirmed septic arthritis; Uncomplicated ABSSSI such as
             simple abscess, impetiginous lesions, superficial cellulitis, furunculosis,
             carbunculosis, or folliculitis; Infected abdominal wounds unable to be surgically
             closed; Necrotizing fasciitis, rapidly necrotizing infections, gangrenous processes,
             or decubitus ulcer; An existing abscess that cannot be drained or a wound requiring
             significant surgical intervention that cannot be performed within 48 hours of
             initiation of study treatment; Skin infection known or suspected to be due to fungal,
             parasitic or viral pathogens; or known or suspected to be due to anaerobic bacterial
             pathogens or Pseudomonas aeruginosa (including ecthyma gangrenosum), or other Gram
             negative pathogens as the contributing pathogen; Skin infections complicated by the
             presence of prosthetic materials that are not to be removed such as central venous
             catheters, permanent cardiac pacemaker battery packs, or joint replacement prostheses.

          -  The subject has received treatment with a systemic and/or topical antibacterial within
             4 days of study entry; EXCEPT for any of following conditions: The subject received a
             single dose of a short-acting antibacterial (half-life less than 12 hours) drug prior
             to the first dose of study treatment; The subject has failed a previous ABSSSI regimen
             (i.e. at least 48 hours of treatment) and has documented lack of microbiological or
             clinical response to such therapy. A subject enrolled as a failure of a previous
             antibacterial treatment regimen must EITHER: Show worsening or lack of improvement or
             worsening in signs and symptoms of infection, including continued or worsening
             purulence, erythema with or without induration, fluctuation, heat/localized warmth,
             and pain/tenderness and/or continued or worsening systemic markers of infection OR
             show microbiological evidence of failure; The subject recently completed a treatment
             course with an antibacterial drug for an infection other than ABSSSI and the drug does
             not have antibacterial activity against bacterial pathogens that cause ABSSSI. (Note:
             topical antiseptics, chorhexidine, and alcohol and soaps for wound care are
             permitted). For the purposes of these criteria, the information may be obtained via a
             verbal interview with the subject or from the subject's medical records; information
             obtained via a verbal interview must be recorded in the subject's medical record.

          -  The subject has known or suspected severe impairment of renal function, including a
             calculated creatinine clearance (as calculated using the Cockroft-Gault method) of
             less than 30 millilitre per minute; requirement for peritoneal dialysis, hemodialysis,
             or hemofiltration; or oliguria (less than 20 millilitre urine output per hour over 24
             hours).

          -  The subject has known or suspected chronic neutropenia due to suppression of
             neutrophil production, or is anticipated to develop neutropenia during the course of
             the study (ie. new chemotherapy subject), with absolute neutrophil count less than
             1000 cells/mm^3 (subjects with neutrophil counts as low as 500 cell/mm^3 are eligible
             if the reduction is due entirely to the acute infectious process).

          -  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