Clinical trial NCT02045797: Dose-Ranging Study of GSK2140944 in the Treatment of Subjects With Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections
Official title: A Phase II, Randomized, Two-Part, Multicenter, Dose-Ranging Study in Adult Subjects Evaluating the Safety, Tolerability, and Efficacy of GSK2140944 in the Treatment of Subjects With Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infections, Bacterial
Keywords: Dose ranging
Intravenous
Adaptive design
suspected or confirmed gram-positive acute bacterial skin and skin structure infection
Subjects
infection
Oral
GSK2140944
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-01-27
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Number of Participants With Composite of the Cure Rate as Measured by Clinical Response and Outcome at the Early Efficacy Visit Combined With Withdrawal Rate
timeFrame: Up to Day 3
Secondary outcomes:
measure: Number of Participants With Clinical Response and Outcome at Early Efficacy Visit
timeFrame: Up to Day 3
measure: Number of Participants With Clinical Response and Outcome at the Post Therapy Visit (Day 12-18)
timeFrame: Day 12 to Day 18
measure: Number of Participants With Clinical Response and Outcome at the Final Follow up Visit (Day 21-28)
timeFrame: Day 21 to Day 28
measure: Number of Pathogens With Microbiological Response and Outcome at Early Efficacy Visit for Staphylococcus Aureus (SA) Pathogen in Lesion Sample
timeFrame: Up to Day 3
measure: Number of Pathogens With Microbiological Response and Outcome at Early Efficacy Visit for Methicillin-resistant Staphylococcus Aureus (MRSA) in Lesion Sample
timeFrame: Day 3
measure: Number of Pathogens With Microbiological Response and Outcome at Early Efficacy Visit for Methicillin-susceptible Staphylococcus Aureus (MSSA) in Lesion Sample
timeFrame: Up to Day 3
measure: Number of Pathogens With Microbiological Response and Outcome at Early Efficacy Visit for Other Gram-positive Aerobic Pathogens in Lesion Sample
timeFrame: Up to Day 3
measure: Number of Pathogens With Microbiological Response and Outcome at Early Efficacy Visit for All Gram-positive Aerobic Pathogens in Lesion Sample
timeFrame: Up to Day 3
measure: Number of Pathogens With Microbiological Response and Outcome at Early Efficacy Visit for SA, MRSA and All Gram-positive Aerobic Pathogens in Blood Sample
timeFrame: Up to Day 3
measure: Number of Pathogens With Microbiological Response and Outcome at Post Therapy Visit for SA Pathogen in Lesion Sample
timeFrame: Day 12 to Day 18
measure: Number of Pathogens With Microbiological Response and Outcome at Post Therapy Visit for MRSA in Lesion Sample
timeFrame: Day 12 to Day 18
measure: Number of Pathogens With Microbiological Response and Outcome at Post Therapy Visit for MSSA in Lesion Sample
timeFrame: Day 12 to Day 18
measure: Number of Pathogens With Microbiological Response and Outcome at Post Therapy Visit for Other Gram-positive Aerobic Pathogens in Lesion Sample
timeFrame: Day 12 to Day 18
measure: Number of Pathogens With Microbiological Response and Outcome at Post Therapy Visit for All Gram-positive Aerobic Pathogens in Lesion Sample
timeFrame: Day 12 to Day 18
measure: Number of Pathogens With Microbiological Response and Outcome at Post Therapy Visit for SA, MRSA and All Gram-positive Aerobic Pathogens in Blood Sample
timeFrame: Day 12 to Day 18
measure: Number of Pathogens With Microbiological Response and Outcome at Follow up Visit for SA Pathogen in Lesion Sample
timeFrame: Day 21 to Day 28
measure: Number of Pathogens With Microbiological Response and Outcome at Follow up Visit for MRSA in Lesion Sample
timeFrame: Day 21 to Day 28
measure: Number of Pathogens With Microbiological Response and Outcome at Follow up Visit for MSSA in Lesion Sample
timeFrame: Day 21 to Day 28
measure: Number of Pathogens With Microbiological Response and Outcome at Follow up Visit for Other Gram-positive Aerobic Pathogens in Lesion Sample
timeFrame: Day 21 to Day 28
measure: Number of Pathogens With Microbiological Response and Outcome at Follow up Visit for All Gram-positive Aerobic Pathogens in Lesion Sample
timeFrame: Day 21 to Day 28
measure: Number of Pathogens With Microbiological Response and Outcome at Follow up Visit for SA, MRSA and All Gram-positive Aerobic Pathogens in Blood Sample
timeFrame: Day 21 to Day 28
measure: Pharmacokinetic (PK) Parameters (From GSK2140944 Plasma Concentration-time Data): Maximum Observed Concentration (Cmax) on IV Therapy
timeFrame: Predose, 1, 2, 2.5, 3, 6, 12 hours post dose on Day 1 to 3
measure: PK Parameters (From GSK2140944 Plasma Concentration-time Data): Cmax on Oral Dose Therapy
timeFrame: Predose, 1, 2, 3 hours after first orally administered drug and Day 7 to 10 (predose)
measure: PK Parameters (From GSK2140944 Plasma Concentration-time Data): Time to Cmax (Tmax) on IV Therapy
timeFrame: Predose, 1, 2, 2.5, 3, 6, 12 hours post dose on Day 1 to 3
measure: PK Parameters (From GSK2140944 Plasma Concentration-time Data): Tmax on Oral Dose Therapy
timeFrame: Predose, 1, 2, 3 hours after first orally administered drug and Day 7 to 10 (predose)
measure: PK Parameters (From GSK2140944 Plasma Concentration-time Data): Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Time of the Last Quantifiable Concentration [AUC (0-t)] and AUC Over the Dosing Interval [AUC(0-tau)] on IV Therapy
timeFrame: Predose, 1, 2, 2.5, 3, 6, 12 hours post dose on Day 1 to 3
measure: PK Parameters (From GSK2140944 Plasma Concentration-time Data): AUC (0-t) and AUC(0-tau) on Oral Dose Therapy
timeFrame: Predose, 1, 2, 3 hours after first orally administered drug and Day 7 to 10 (predose)
measure: Number of Participants Demonstrating a Decrease in GSK2140944 Susceptibility When Comparing Isolates Recovered From Baseline With Those From Any Time Post-Baseline Skin Specimens
timeFrame: Up to Day 28
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 28
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Respiratory Rate
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Vital Sign: Body Temperature
timeFrame: Baseline (Day 1) up to Day 28
measure: Number of Participants With Maximum Post-Baseline Electrocardiogram (ECG) Readings
timeFrame: Up to Day 28
measure: Change From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Follicle Stimulating Hormone (FSH) and Gamma Glutamyl Transferase (GGT)
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Clinical Chemistry Parameters: Bilirubin, Creatinine, Direct Bilirubin and Urate
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Clinical Chemistry Parameters: Calcium, Carbon Dioxide, Chloride, Glucose, Magnesium, Potassium, Sodium and Urea
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Clinical Chemistry Parameters: Creatinine Clearance, Estimated
timeFrame: Baseline (Day 1) up to Day 28
measure: Estradiol Values at Baseline
timeFrame: Baseline (Day 1)
measure: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Hematology Parameters: Erythrocyte Mean Corpuscular Hemoglobin Concentration (EMCHC) and Hemoglobin
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Hematology Parameters: Erythrocyte Mean Corpuscular Hemoglobin (EMCH)
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Hematology Parameters: Erythrocyte Mean Corpuscular Volume (EMCV)
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Hematology Parameters: Erythrocytes
timeFrame: Baseline (Day 1) up to Day 28
measure: Change From Baseline in Hematology Parameters: Hematocrit
timeFrame: Baseline (Day 1) up to Day 28
measure: Number of Participants With Abnormal Urinalysis Dipstick Results
timeFrame: Up to day 28
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Anaheim
country: United States
facility: GSK Investigational Site
state: California
city: Chula Vista
country: United States
facility: GSK Investigational Site
state: California
city: La Mesa
country: United States
facility: GSK Investigational Site
state: California
city: Oceanside
country: United States
facility: GSK Investigational Site
state: California
city: Sylmar
country: United States
facility: GSK Investigational Site
state: California
city: Torrance
country: United States
facility: GSK Investigational Site
state: California
city: Miramar
country: United States
facility: GSK Investigational Site
state: Florida
city: West Palm Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Council Bluffs
country: United States
facility: GSK Investigational Site
state: Iowa
city: Hazard
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Zachary
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Carriere
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Jackson
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Butte
country: United States
facility: GSK Investigational Site
state: Montana
city: Lincoln
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Belleville
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Neptune City
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Albany
country: United States
facility: GSK Investigational Site
state: New York
city: Brooklyn
country: United States
facility: GSK Investigational Site
state: New York
city: Lima
country: United States
facility: GSK Investigational Site
state: Ohio
city: Toledo
country: United States
facility: GSK Investigational Site
state: Ohio
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Channelview
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Scangarella-Oman NE, Ingraham KA, Tiffany CA, Tomsho L, Van Horn SF, Mayhew DN, Perry CR, Ashton TC, Dumont EF, Huang J, Brown JR, Miller LA. In Vitro Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections. Antimicrob Agents Chemother. 2020 Feb 21;64(3):e01302-19. doi: 10.1128/AAC.01302-19. Print 2020 Feb 21.
citation: O'Riordan W, Tiffany C, Scangarella-Oman N, Perry C, Hossain M, Ashton T, Dumont E. Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944) in the Treatment of Patients with Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections. Antimicrob Agents Chemother. 2017 May 24;61(6):e02095-16. doi: 10.1128/AAC.02095-16. Print 2017 Jun.