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临床试验/NCT03568942
NCT03568942已完成2 期

A Phase IIa Single-Center, Open-Label Study Evaluating the Pharmacokinetics of Repeat Oral Doses of Gepotidacin (GSK2140944) in Adult Female Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis)

GlaxoSmithKline1 个研究点 分布在 1 个国家目标入组 22 人开始时间: 2018年7月23日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
2 期
状态
已完成
入组人数
22
试验地点
1
主要终点
Area Under the Plasma Concentration-time Curve (AUC) From Zero (Pre-dose) Over the Dosing Interval (AUC[0-tau]) of Gepotidacin
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Gepotidacin (GSK2140944) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor that is being developed for the treatment of uncomplicated urinary tract infections (UTIs; acute cystitis). This Phase IIa study will evaluate plasma and urine pharmacokinetics of gepotidacin in female subjects with acute cystitis. Eligible female subjects will receive twice daily (BID) dose of gepotidacin 1500 milligram (mg) for 5 days via oral route. Pre-treatment and post-treatment samples for pharmacokinetic (PK) assessments will be collected throughout the study. The total duration of the study is approximately 28 days.

研究设计

研究类型
Interventional
分配方式
Na
干预模型
Single Group
主要目的
Treatment
盲法
None

入排标准

年龄范围
18 Years 至 65 Years（Adult, Older Adult）
性别
Female
接受健康志愿者
否

入选标准

  • •Subject must be >=18 to <=65 years of age inclusive, at the time of signing the informed consent.
  • •The subject has 2 or more of the following clinical signs and symptoms of acute cystitis with onset <=72 hours of the screening assessment: dysuria, frequency, urgency, or lower abdominal pain.
  • •The subject has pyuria (>=10 white blood cells per cubic millimeters [WBC/mm^3] or the presence of leukocyte esterase) and/or nitrite from a pretreatment clean-catch midstream urine sample based on local laboratory procedures.
  • •The subject is female. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: a) Not a woman of childbearing potential (WOCBP) OR b) A WOCBP who agrees to follow the contraceptive guidance from the Baseline Visit through completion of the Test of Cure (TOC) Visit.
  • •Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.

排除标准

  • •The subject resides in a nursing home or dependent care-type facility.
  • •The subject has a body mass index >=40.0 kilogram per square meter (kg/m^2) or a body mass index >=35.0 kg/m^2 with obesity-related health conditions such as high blood pressure or uncontrolled diabetes.
  • •The subject has a history of sensitivity to the study treatment, or components thereof, or a history of a drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates her participation.
  • •The subject is immunocompromised or has altered immune defenses that may predispose the subject to a higher risk of treatment failure and/or complications (e.g., renal transplant recipients, subjects with clinically significant persistent granulocytopenia [absolute neutrophil count <1000/microliter (µL)], and subjects receiving immunosuppressive therapy, including corticosteroid therapy [>40 mg/day prednisolone or equivalent for >1 week or >=20 milligrams per day (mg/day) prednisolone or equivalent for >6 weeks; or prednisolone or equivalent >=10 mg/day for >6 weeks]). Subjects with a known cluster of differentiation 4 (CD4) count of <200 cells/mm^3 should not be enrolled.
  • •The subject has uncontrolled diabetes, defined as a non-fasting glucose value >300 milligrams per deciliter (mg/dL) or based on investigator judgment.
  • •The subject has any of the following: A medical condition that requires medication that may be aggravated by inhibition of acetylcholinesterase, such as: a) Poorly controlled asthma or chronic obstructive pulmonary disease at Baseline and, in the opinion of the investigator, not stable on current therapy; b) Acute severe pain, uncontrolled with conventional medical management; c) Active peptic ulcer disease; d) Parkinson disease; e) Myasthenia gravis; f) A history of seizure disorder requiring medications for control (this does not include a history of childhood febrile seizures) OR Any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study drug (e.g., ileostomy or malabsorption syndrome). Subjects who have had a gastric bypass or a cholecystectomy are excluded from the study OR Hemoglobin value <12 grams per deciliter (g/dL) or a known uncorrected iron deficiency.
  • •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 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 acute cystitis that is known or suspected to be due to fungal, parasitic, or viral pathogens; or known or suspected to be due to Pseudomonas aeruginosa or Enterobacteriaceae (other than Escherichia coli [E. coli]) as the contributing pathogen.
  • •The subject has symptoms known or suspected to be caused by another disease process such as asymptomatic bacteriuria or chronic interstitial cystitis.
  • •The subject has an anatomical or physiological anomaly that predisposes the subject to UTIs or may be a source of persistent bacterial colonization, including calculi, obstruction or stricture of the urinary tract, primary renal disease (e.g., polycystic renal disease), or neurogenic bladder, or the subject has a history of anatomical or functional abnormalities of the urinary tract (e.g., chronic vesico-ureteral reflux, detrusor insufficiency).
  • •The subject has an indwelling catheter, nephrostomy, ureter stent, or other foreign material in the urinary tract.
  • •The subject who, in the opinion of the investigator, has an otherwise complicated UTI, an active upper UTI (e.g., pyelonephritis, urosepsis), signs and symptoms onset >=96 hours before the Screening assessment, or a temperature >=101 degree Fahrenheit, flank pain, chills, or any other manifestations suggestive of upper UTI.
  • •The subject has anuria, oliguria, or significant impairment of renal function (creatinine clearance <30 milliliters per minute [mL/min] or clinically significant elevated serum creatinine).
  • •The subject presents with vaginal discharge at Baseline (e.g., suspected sexually transmitted disease).
  • •The subject has congenital long QT syndrome or known prolongation of the corrected QT (QTc) interval.
  • •The subject has uncompensated heart failure, defined as New York Heart Association Class >=III.
  • •The subject has severe left ventricular hypertrophy.
  • •The subject has a family history of QT prolongation or sudden death.
  • •The subject has a recent history of vasovagal syncope or episodes of symptomatic bradycardia or bradyarrhythmia within the last 12 months.
  • •The subject is taking QT-prolonging drugs or drugs known to increase the risk of torsades de points (TdP) per the www.crediblemeds.org "Known Risk of TdP" category at the time of her Baseline Visit, which cannot be safely discontinued from the Baseline Visit to the TOC Visit; or the subject is taking a strong cytochrome P450 enzyme 3A4 (CYP3A4) inhibitor or a strong P-glycoprotein (P-gp) inhibitor.
  • •The subject has a QT interval corrected for heart rate (QTc) >450 milliseconds (msec) or a QTc >480 msec for subjects with bundle-branch block.
  • •The subject has a known ALT value >2 times upper limit of normal (ULN).
  • •The subject has a known bilirubin value >1.5 times ULN (isolated bilirubin >1.5 times 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), including symptomatic viral hepatitis or moderate-to-severe liver insufficiency (Child Pugh class B or C).
  • •The subject has received treatment with other systemic antimicrobials or systemic antifungals within 1 week before study entry.
  • •The subject must agree not to use the medications or nondrug therapies from the Baseline Visit through the TOC Visit.
  • •The subject has been previously enrolled in this study or has previously been treated with gepotidacin.
  • •The subject has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives, whichever is longer.

研究组 & 干预措施

Female subjects with acute cystitis

Experimental

Adult female subjects with suspected acute cystitis based on clinical presentation and pyuria (>=10 WBC/mm^3 or presence of leukocyte esterase) and/or nitrite will be included. Subjects will be administered 1500 mg gepotidacin BID for 5 days via the oral route.

干预措施: Gepotidacin (Drug)

结局指标

主要结局

Area Under the Plasma Concentration-time Curve (AUC) From Zero (Pre-dose) Over the Dosing Interval (AUC[0-tau]) of Gepotidacin

时间窗: Days 1 and 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose

Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. PK Parameter Population consisted of all participants who received gepotidacin 1500 mg BID through the completion of all PK collections for whom valid and evaluable plasma PK parameters were derived for gepotidacin.

Maximum Plasma Concentration (Cmax) of Gepotidacin

时间窗: Days 1 and 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose

Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.

Time of Occurrence of Cmax (Tmax) of Gepotidacin

时间窗: Days 1 and 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose

Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.

Apparent Steady State Clearance (CLss/F) of Gepotidacin

时间窗: Day 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose

Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. CLss/F was calculated as Dose divided by AUC(0-tau).

Accumulation Ratio (Ro) of Gepotidacin

时间窗: Days 1 and 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose

Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. Accumulation ratio (Ro) was calculated as ratio of AUC(0-tau) at Day 4 to AUC(0-tau) at Day 1.

Plasma Pre-dose Concentration (Ctau) of Gepotidacin

时间窗: Days 1 to 5: Pre-dose

Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.

次要结局

  • Percentage of the Given Dose of Drug Excreted in Urine (fe%) of Gepotidacin(Days 1 and 4: Pre-dose and at 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours post-dose)
  • Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious AEs (SAEs)(Up to Day 31)
  • Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Baseline, Day 2, Day 3, Day 4, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Pulse Rate(Baseline, Day 2, Day 3, Day 4, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Body Temperature(Baseline, Day 2, Day 3, Day 4, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Electrocardiogram (ECG) Parameters: PR Interval, QRS Duration, QT Interval, Corrected QT Interval Using Bazett's Formula (QTcB) and Corrected QT Interval Using Fridericia's Formula (QTcF)(Baseline; Day 1: 2 hours; Day 4: pre-dose and 2 hours)
  • Amount of Drug Excreted Over 12 Hours (Ae12hours) of Gepotidacin(Days 1 and 4: Pre-dose and at 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours post-dose)
  • Amount of Drug Excreted in Urine in a Time Interval (Ae[t1-t2]) of Gepotidacin(Days 1 and 4: Pre-dose and at 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours post-dose)
  • Renal Clearance (CLr) of Gepotidacin(Days 1 and 4: Pre-dose and at 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours post-dose)
  • Urine Pre-dose Concentration (Ctau) of Gepotidacin(Days 1 to 5: Pre-dose)
  • Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet Counts(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Hematology Parameter: Hemoglobin(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Hematology Parameter: Hematocrit(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Hemoglobin(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Volume(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Hematology Parameter: Red Blood Cell Count(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Clinical Chemistry Parameters: Creatinine and Bilirubin(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (ALP)(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Change From Baseline in Clinical Chemistry Parameters: Glucose, Calcium, Chloride, Potassium, Sodium and Urea(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Number of Participants With Urinalysis Dipstick Results: Glucose and Nitrites(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Number of Participants With Urinalysis Dipstick Results: Ketones(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Number of Participants With Urinalysis Dipstick Results: Leukocyte Esterase(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Number of Participants With Urinalysis Dipstick Results: Occult Blood(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Number of Participants With Urinalysis Dipstick Results: Protein(Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit))
  • Number of Participants With Abnormal Physical Examination Findings(Up to Day 31)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (1)

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