A Dose-Ranging Study Evaluating the Efficacy, Safety, and Tolerability of GSK2140944 in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria Gonorrhoeae

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Gonorrhea

Intervention / Treatment
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* Drug: GSK2140944


Participation Criteria
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Eligibility Criteria
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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: 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2140944 1500 mg<br>Subjects will receive single oral dose of GSK2140944 1500 mg. | Drug: GSK2140944<br>* 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).<br>|
| Experimental: GSK2140944 3000 mg<br>Subjects will receive single oral dose of GSK2140944 3000 mg. | Drug: GSK2140944<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Culture-confirmed Bacterial Eradication of Urogenital Neisseria Gonorrhoeae at the Test-of-Cure Visit | Pre-treatment urogenital, pharyngeal, and rectal swab specimens were obtained for bacteriological culture for neisseria (N.) gonorrhoeae at the Baseline visit. Test- of-Cure was defined by infection site (that is urogenital and, as appropriate, rectal and/or pharyngeal) as culture confirmed bacterial eradication of N. gonorrhoeae observed 3 to 7 days post-treatment. Pre-treatment urogenital specimens were obtained for nucleic acid amplification test (NAAT) assay to detect the presence of N. gonorrhoeae and chlamydia trachomatis at the Baseline visit. Only participants who had a pre-therapy N. gonorrhoeae isolate recovered from their urogenital specimen were evaluated. Microbiologically evaluable (ME) Population comprised of all randomized participants who had N. gonorrhoeae isolated from Baseline cultures of urogenital swab specimens, received any dose of gepotidacin, and returned for their TOC visit. | Baseline (Day 1, pre-dose) and Test-of-Cure visit (Day 4 to 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | An AE is any untoward medical occurrence in a clinical investigation participants, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinaemia (defined as alanine aminotransferase [ALT] >=3 times upper limit of normal [ULN] and bilirubin >=2 times ULN [>35 percent direct] [or ALT >=3 times ULN and international normalization ratio INR>1.5, if INR is measured]. | From start of the study treatment until Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at the Indicated Time Points | BP was measured in semi-supine position after 5 minutes rest. It was recorded at Baseline visit, 2 hour post-dose visit for participants enrolled under orignal protocol, 0.5 hour post-dose for participants enrolled under protocol amendement 1 and up to TOC visit (Day 4 to 8).Vital sign measurements were obtained prior to any scheduled blood collection visit on the same assessment day. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as TOC visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit (Day 1) and Day 4 to Day 8 | 
| Change From Baseline in Pulse Rate at the Indicated Time Points | Pulse rate was measured in semi-supine position after 5 minutes rest. It was recorded at Baseline visit, 2 hour post-dose visit for participants enrolled under orignal protocol, 0.5 hour post-dose for participants enrolled under protocol amendement 1 and up to TOC visit (Day 4 to 8). Vital sign measurements were obtained prior to any scheduled blood collection visit on the same assessment day. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as TOC visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit (Day 1) and Day 4 to Day 8 | 
| Change From Baseline in Temperature at the Indicated Time Points | Temperature was measured in semi-supine position after 5 minutes rest. It was recorded at Baseline visit, 2 hour post-dose visit for participants enrolled under orignal protocol, 0.5 hour post-dose for participants enrolled under protocol amendement 1 and up to TOC visit (Day 4 to 8). Vital sign measurements were obtained prior to any scheduled blood collection visit on the same assessment day. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as TOC visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit (Day 1) and Day 4 to Day 8 | 
| Change From Baseline in Respiratory Rate at the Indicated Time Points | Respiratory rate was measured in semi-supine position after 5 minutes rest. It was recorded at Baseline visit, 2 hour post-dose visit for participants enrolled under orignal protocol, 0.5 hour post-dose for participants enrolled under protocol amendement 1 and up to TOC visit (Day 4 to 8). Vital sign measurements was obtained prior to any scheduled blood collection visit on the same assessment day. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as TOC Visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit (Day 1) and Day 4 to Day 8 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | A single 12-lead ECGs were obtained at the Baseline, 2 hour post-dose, and at the TOC (Day 4 to 8) visit using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. ECG was obtained prior to any vital sign measurements or blood draws scheduled on the same assessment day. For participants enrolled under protocol amendment 1, ECG was measured at Baseline visit Day 1 (pre-dose) only. ECG assessments were presented as abnormal-clinically significant (CS) and abnormal-not clinically significant (NCS) at the indicated time points. Only those participants available at the specified time points were analyzed (represented by n=X , X in the category titles). | Baseline visit and up to Day 8 | 
| Number of Participants With Abnormal Physical Examination Finding | Physical examination of respiratory, cardiovascular, abdomen, gastrointestinal, urogenital systems, pharyngeal and rectal examinations with collections of microbiology specimen was performed at the Baseline and TOC (Day 4 to 8) visit. Baseline was defined as the study assessment on Day 1 (pre-dose). Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Hemoglobin, Protein and Albumin at Test-of-Cure Visit (Day 4 to 8) | Blood samples were collected at Baseline Day 1 (pre-dose) and at TOC visit (Day 4 to 8) to evaluate hemoglobin, total protein and albumin. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as value obtained at TOC visit minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Hematocrit at Test-of-Cure Visit (Day 4 to 8) | Blood samples were collected at Baseline Day 1 (pre-dose) and at TOC visit (Day 4 to 8) to evaluate hematocrit. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as value obtained at TOC visit minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Lymphocyte, Monocyte, Neutrophil Basophil, Eosinophil, Leukocyte and Platelet Count at Test-of-Cure Visit (Day 4 to 8) | Blood samples were collected at Baseline Day 1 (pre-dose) and at TOC visit (Day 4 to 8) to evaluate neutrophil, lymphocyte, basophil, eosinophil, monocyte, leukocyte and platelet count. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as value obtained at TOC visit minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Bilirubin, Direct Bilirubin and Creatinine at Test-of-Cure Visit (Day 4 to 8) | Blood samples were collected at Baseline Day 1 (pre-dose) and at TOC visit (Day 4 to 8) to evaluate bilirubin, direct bilirubin and creatinine. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as value obtained at TOC visit minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase and Alkaline Phosphatase at Test-of-Cure Visit (Day 4 to 8) | Blood samples were collected at Baseline Day 1.(pre-dose) and at TOC visit (Day 4 to 8) to evaluate alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as value obtained at TOC visit minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Chloride, Calcium, Glucose, Potassium, Sodium and Urea at Test-of-Cure Visit (Day 4 to 8) | Blood samples were collected at Baseline Day 1.(pre-dose) and at TOC visit (Day 4 to 8) to evaluate chloride, calcium, glucose, potassium, sodium and urea (blood urea nitrogen). Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as value obtained at TOC visit minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Erythrocytes at Test-of-Cure Visit (Day 4 to 8) | Blood samples were collected at Baseline Day 1 (pre-dose) and at TOC visit (Day 4 to 8) to evaluate erythrocytes (red blood cell count). Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as value obtained at TOC visit minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin at Test-of-Cure Visit (Day 4 to 8) | Blood samples were collected at Baseline Day 1 (pre-dose) and at TOC visit (Day 4 to 8) to evaluate erythrocytes mean corpuscular hemoglobin. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as value obtained at TOC Visit minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Change From Baseline in Erythrocytes Mean Corpuscular Volume at Test-of-Cure Visit (Day 4 to 8) | Blood samples were collected at Baseline Day 1 (pre-dose) and at TOC visit (Day 4 to 8) to evaluate erythrocytes mean corpuscular volume. Baseline was defined as the study assessment on Day 1 (pre-dose). Change from Baseline was calculated as value obtained at TOC Visit minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 
| Number of Participants With Abnormal Urinalysis Dipstick Results | Dipstick urinalysis was done for glucose, ketones, occult blood, protein, potential hydrogen (pH) and specific gravity at Baseline visit Day 1 (pre-dose) and Test-of-Cure visit (Day 4 to 8). Results were presented as negative (normal) or other findings reported only if observed under microscopic examination trace, 1+, 2+, 3+, 4+ and 5+ glucose, ketones, occult blood and protein. pH results were categorized as per their pH values. Baseline was defined as the study assessment on Day 1 (pre-dose). Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Baseline visit and Test-of-Cure visit (Day 4 to 8) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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uncomplicated urogenital gonorrhea, Bacterial Type II Topoisomerase Inhibitors (BTI), antibiotics, GSK2140944, N. gonorrhoeae