Clinical trial NCT02294682: A Dose-Ranging Study Evaluating the Efficacy, Safety, and Tolerability of GSK2140944 in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria Gonorrhoeae
Official title: A Phase II, Randomized, Multicenter, Dose-Ranging Study in Adult Subjects Evaluating the Efficacy, Safety, and Tolerability of Single Doses of GSK2140944 in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria Gonorrhoeae
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Gonorrhea
Keywords: uncomplicated urogenital gonorrhea
Bacterial Type II Topoisomerase Inhibitors (BTI)
antibiotics
GSK2140944
N. gonorrhoeae
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-11-19
Enrollment: 106
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 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.

Primary outcomes:
measure: Number of Participants With Culture-confirmed Bacterial Eradication of Urogenital Neisseria Gonorrhoeae at the Test-of-Cure Visit
timeFrame: Baseline (Day 1, pre-dose) and Test-of-Cure visit (Day 4 to 8)
Secondary outcomes:
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From start of the study treatment until Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at the Indicated Time Points
timeFrame: Baseline visit (Day 1) and Day 4 to Day 8
measure: Change From Baseline in Pulse Rate at the Indicated Time Points
timeFrame: Baseline visit (Day 1) and Day 4 to Day 8
measure: Change From Baseline in Temperature at the Indicated Time Points
timeFrame: Baseline visit (Day 1) and Day 4 to Day 8
measure: Change From Baseline in Respiratory Rate at the Indicated Time Points
timeFrame: Baseline visit (Day 1) and Day 4 to Day 8
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Baseline visit and up to Day 8
measure: Number of Participants With Abnormal Physical Examination Finding
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Hemoglobin, Protein and Albumin at Test-of-Cure Visit (Day 4 to 8)
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Hematocrit at Test-of-Cure Visit (Day 4 to 8)
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Lymphocyte, Monocyte, Neutrophil Basophil, Eosinophil, Leukocyte and Platelet Count at Test-of-Cure Visit (Day 4 to 8)
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Bilirubin, Direct Bilirubin and Creatinine at Test-of-Cure Visit (Day 4 to 8)
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase and Alkaline Phosphatase at Test-of-Cure Visit (Day 4 to 8)
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Chloride, Calcium, Glucose, Potassium, Sodium and Urea at Test-of-Cure Visit (Day 4 to 8)
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Erythrocytes at Test-of-Cure Visit (Day 4 to 8)
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin at Test-of-Cure Visit (Day 4 to 8)
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Change From Baseline in Erythrocytes Mean Corpuscular Volume at Test-of-Cure Visit (Day 4 to 8)
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
measure: Number of Participants With Abnormal Urinalysis Dipstick Results
timeFrame: Baseline visit and Test-of-Cure visit (Day 4 to 8)
Other outcomes:
Locations:
city: Fountain Valley
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Palm Springs
country: United States
facility: GSK Investigational Site
state: California
city: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: New Orleans
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Omaha
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Jenkintown
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Scangarella-Oman NE, Hossain M, Dixon PB, Ingraham K, Min S, Tiffany CA, Perry CR, Raychaudhuri A, Dumont EF, Huang J, Hook EW 3rd, Miller LA. Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01221-18. doi: 10.1128/AAC.01221-18. Print 2018 Dec.
citation: Taylor SN, Morris DH, Avery AK, Workowski KA, Batteiger BE, Tiffany CA, Perry CR, Raychaudhuri A, Scangarella-Oman NE, Hossain M, Dumont EF. Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation. Clin Infect Dis. 2018 Aug 1;67(4):504-512. doi: 10.1093/cid/ciy145.