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A Phase III, Multicenter, Randomized, Active Reference, Double-blind, Double-dummy Study in Japanese Female Participants to Evaluate the Efficacy and Safety of Gepotidacin in the Treatment of Uncomplicated Urinary Tract Infection (Acute Cystitis)
(A study to investigate the efficacy and safety with gepotidacin in Japanese female participants with uncomplicated urinary tract infection (acute cystitis); Efficacy of Antibacterial Gepotidacin Evaluated in Japan (EAGLE-J))

A study to investigate the efficacy and safety with gepotidacin in Japanese female participants with uncomplicated urinary tract infection (acute cystitis); Efficacy of Antibacterial Gepotidacin Evaluated in Japan (EAGLE-J)

380

The baseline characteristics of 374 participants had an average age of 45.2 years, with 374 females (100.0%) and 374 non-Hispanic or Latino participants (100.0%) in the Intent-to-treat (ITT) population. The average age was 44.9 years in the Gepotidacin group and 46.4 years in the Nitrofurantoin group.

A total of 380 participants were enrolled in the study. Of these, 374 participants were included in the ITT population. The ITT population excluded 6 participants from a site with Good Clinical Practice (GCP) violation. The ITT analysis population included 281 participants in the Gepotidacin group and 93 participants in the Nitrofurantoin group. The microbiological ITT (micro-ITT) analysis population included 88 participants in the Gepotidacin group and 29 participants in the Nitrofurantoin group. The Micro-ITT susceptible to Nitrofurantoin (NTF-S) analysis population included 83 participants in the Gepotidacin group and 25 participants in the Nitrofurantoin group. The Micro-ITT multidrug resistant (MDR) analysis population included 18 participants in the Gepotidacin group and 3 participants in the Nitrofurantoin group. The safety population included 281 participants in the Gepotidacin group and 93 participants in the Nitrofurantoin group. The number of participants who did not complete the trial was 7 in the Gepotidacin group and 2 in the Nitrofurantoin group. The breakdown of reasons for not completing the trial included adverse events (3 in the Gepotidacin group and 0 in the Nitrofurantoin group), lack of efficacy (0 in the Gepotidacin group and 1 in the Nitrofurantoin group), lost to follow-up (1 in the Gepotidacin group and 0 in the Nitrofurantoin group), and withdrawal by subject (3 in the Gepotidacin group and 1 in the Nitrofurantoin group).

The incidence of adverse events [AEs, excluding serious adverse events (SAEs)] was 61.92% (174/281 participants) in the Gepotidacin group and 8.60% (8/93 participants) in the Nitrofurantoin group. The common AEs were diarrhoea [59.43% (167/281 participants) in the Gepotidacin group, 7.53% (7/93 participants) in the Nitrofurantoin group] and nausea [12.46% (35/281 participants) in the Gepotidacin group, 2.15% (2/93 participants) in the Nitrofurantoin group]. There were no reports of mortality in either group. The incidence of SAEs was 0.71% (2/281 participants) in the Gepotidacin group and 0.00% (0/93 participants) in the Nitrofurantoin group. The incidence of adverse events of special interest (AESIs: Clostridium difficile, cardiovascular, gastrointestinal events and potential acetylcholinesterase-inhibition events) was 68.0% (191/281 participants) in the Gepotidacin group and 12.9% (12/93 participants) in the Nitrofurantoin group.

Primary Endpoint Therapeutic Response (combined per participant Microbiological and Clinical Response) at the TOC Visit, the number and percentage of Therapeutic Successes in the Gepotidacin group were 69 participants (83.1%), and the number and percentage of Therapeutic Failures were 14 participants (16.9%). This percentage was greater than the lower 10th percentile value (48.2%) of the predictive distribution derived based on data from the global studies (Study 204989 and Study 212390) which was the success criterion, and consistency was met. Secondary Endpoints <Number of Participants with Therapeutic Response of Gepotidacin Compared to Nitrofurantoin at the TOC Visit - Micro-ITT NTF-S Population> The number and percentage of Therapeutic Successes were 69 participants (83.1%) in the Gepotidacin group and 17 participants (68.0%) in the Nitrofurantoin group. The number and percentage of Therapeutic Failures were 14 participants (16.9%) in the Gepotidacin group and 8 participants (32.0%) in the Nitrofurantoin group. <Number of Participants with Clinical Outcome at the TOC Visit - Micro-ITT NTF-S Population> The number and percentage of Clinical Resolution were 71 participants (85.5%) in the Gepotidacin group and 19 participants (76.0%) in the Nitrofurantoin group. The number and percentage of Clinical Improvement were 5 participants (6.0%) in the Gepotidacin group and 4 participants (16.0%) in the Nitrofurantoin group. The number and percentage of Clinical Worsening were 3 participants (3.6%) in the Gepotidacin group and 2 participants (8.0%) in the Nitrofurantoin group. The number and percentage of Unable to Determine were 4 participants (4.8%) in the Gepotidacin group and 0 participants (0.0%) in the Nitrofurantoin group. <Number of Participants with Clinical Response at the TOC Visit - Micro-ITT NTF-S Population> The number and percentage of Clinical Success were 71 participants (85.5%) in the Gepotidacin group and 19 participants (76.0%) in the Nitrofurantoin group. The number and percentage of Clinical Failure were 12 participants (14.5%) in the Gepotidacin group and 6 participants (24.0%) in the Nitrofurantoin group. <Number of Participants with Microbiological Outcome at the TOC Visit - Micro-ITT NTF-S Population> The number and percentage of Microbiological Eradication were 74 participants (89.2%) in the Gepotidacin group and 20 participants (80.0%) in the Nitrofurantoin group. The number and percentage of Microbiological Persistence were 0 participants (0.0%) in the Gepotidacin group and 0 participants (0.0%) in the Nitrofurantoin group. The number and percentage of Microbiological Recurrence were 1 participant (1.2%) in the Gepotidacin group and 3 participants (12.0%) in the Nitrofurantoin group. The number and percentage of Unable to Determine were 8 participants (9.6%) in the Gepotidacin group and 2 participants (8.0%) in the Nitrofurantoin group. <Number of Participants with Microbiological Response at the TOC Visit -Micro-ITT NTF-S Population> The number and percentage of Microbiological Success were 74 participants (89.2%) in the Gepotidacin group and 20 participants (80.0%) in the Nitrofurantoin group. The number and percentage of Microbiological Failure were 9 participants (10.8%) in the Gepotidacin group and 5 participants (20.0%) in the Nitrofurantoin group. <Number of Participants with Therapeutic Response at the TOC Visit- Micro-ITT MDR Population> The number and percentage of Therapeutic Success were 14 participants (77.8%) in the Gepotidacin group and 2 participants (66.7%) in the Nitrofurantoin group. The number and percentage of Therapeutic Failure were 4 participants (22.2%) in the Gepotidacin group and 1 participant (33.3%) in the Nitrofurantoin group. <Number of Participants with Clinical Outcome at the TOC Visit- Micro-ITT MDR Population> The number and percentage of Clinical Resolution were 14 participants (77.8%) in the Gepotidacin group and 2 participants (66.7%) in the Nitrofurantoin group. The number and percentage of Clinical Improvement were 2 participants (11.1%) in the Gepotidacin group and 0 participants (0.0%) in the Nitrofurantoin group. The number and percentage of Clinical Worsening were 1 participant (5.6%) in the Gepotidacin group and 1 participant (33.3%) in the Nitrofurantoin group. The number and percentage of Unable to Determine were 1 participant (5.6%) in the Gepotidacin group and 0 participants (0.0%) in the Nitrofurantoin group. <Number of Participants with Clinical Response at the TOC Visit- Micro-ITT MDR Population> The number and percentage of Clinical Success were 14 participants (77.8%) in the Gepotidacin group and 2 participants (66.7%) in the Nitrofurantoin group. The number and percentage of Clinical Failure were 4 participants (22.2%) in the Gepotidacin group and 1 participant (33.3%) in the Nitrofurantoin group. <Number of Participants with Microbiological Outcome at the TOC Visit- Micro-ITT MDR Population> The number and percentage of Microbiological Eradication were 16 participants (88.9%) in the Gepotidacin group and 2 participants (66.7%) in the Nitrofurantoin group. The number and percentage of Microbiological Persistence were 0 participants (0.0%) in the Gepotidacin group and 0 participants (0.0%) in the Nitrofurantoin group. The number and percentage of Microbiological Recurrence were 0 participants (0.0%) in the Gepotidacin group and 0 participants (0.0%) in the Nitrofurantoin group. The number and percentage of Unable to Determine were 2 participants (11.1%) in the Gepotidacin group and 1 participant (33.3%) in the Nitrofurantoin group <Number of Participants with Microbiological Response at the TOC Visit- Micro-ITT MDR Population> The number and percentage of Microbiological Success were 16 participants (88.9%) in the Gepotidacin group and 2 participants (66.7%) in the Nitrofurantoin group. The number and percentage of Microbiological Failure were 2 participants (11.1%) in the Gepotidacin group and 1 participant (33.3%) in the Nitrofurantoin group. <Number of Participants with Investigator Assessed Clinical Response- ITT Population> The number and percentage of Clinical Success were 242 participants (86.1%) in the Gepotidacin group and 86 participants (92.5%) in the Nitrofurantoin group. The number and percentage of Clinical Failure were 28 participants (10.0%) in the Gepotidacin group and 6 participants (6.5%) in the Nitrofurantoin group. The number and percentage of Unable to Determine/Missing were 11 participants (3.9%) in the Gepotidacin group and 1 participant (1.1%) in the Nitrofurantoin group. <Plasma Concentrations of Gepotidacin> Day 1, Post-dose 0-2 hours, the average concentration (SD) was 5210.23 (3428.432) ng/mL (267 participants). Day 1, Post-dose >2 hours, the average concentration (SD) was 5251.54 (2097.649) ng/mL (13 participants). Days 2-5, Pre-dose, the average concentration (SD) was 1960.14 (16752.767) ng/mL (247 participants). Days 2-5, Post-dose 0-2 hours, the average concentration (SD) was 17548.67 (124724.240) ng/mL (245 participants). Days 2-5, Post-dose >2 hours, the average concentration (SD) was 5976.40 (5142.635) ng/mL (5 participants). <Urine Concentrations of Gepotidacin> Day 1, Post-dose 0-2 hours, the average concentration (SD) was 506.988 (914.3140) microgram/milliliter (250 participants). Day 1, Post-dose >2 hours, the average concentration (SD) was 600.729 (644.2265) microgram/milliliter (28 participants). Days 2-5, Pre-dose, the average concentration (SD) was 492.096 (565.8822) microgram/milliliter (248 participants). Days 2-5, Post-dose 0-2 hours, the average concentration (SD) was 901.554 (1451.8781) microgram/milliliter (231 participants). Days 2-5, Post-dose >2 hours, the average concentration (SD) was 1138.900 (1429.7998) microgram/milliliter (19 participants). For the results of other secondary endpoints, please see 2-1 Attachment 2.

Study 214144 was a Phase III study to evaluate the efficacy and safety of Gepotidacin 1500 mg or Nitrofurantoin 100 mg, twice daily, orally for 5 days in Japanese female participants aged 12 years or older with uncomplicated urinary tract infection (acute cystitis). Please see 2-1 Attachment 1 for full version of Brief summary.

Oct. 17, 2025

https://www.sciencedirect.com/science/article/pii/S1341321X25002260

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031220467

Okawa Yasutoshi

GlaxoSmithKline K.K.

Akasaka Intercity AIR, 1-8-1 Akasaka, Minato-ku, Tokyo, Japan

jp.gskjrct@gsk.com

Okawa Yasutoshi

GlaxoSmithKline K.K.

Akasaka Intercity AIR, 1-8-1 Akasaka, Minato-ku, Tokyo, Japan

+81-120-561-007

jp.gskjrct@gsk.com

Complete

Dec. 12, 2022

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

Otherwise healthy Japanese participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. The participant must be >=12 years of age inclusive, at the time of signing the informed consent/assent and has a body weight >=40 kg.
Note: Although participants as young as 12 years may enrol in the study, study sites must follow their institutional ethics committee and enrollment will be contingent upon such approvals regarding the allowed lower age limit for clinical study participants.
Type of Participant and Disease Characteristics
2. The participant has 2 or more of the following clinical signs and symptoms of acute cystitis with onset <96 hours prior to study entry: dysuria, frequency, urgency, or lower abdominal pain (see Section 10.10).
3. The participant has nitrite or pyuria (>15 WBC/HPF or the presence of 3+/large leukocyte esterase) from a pretreatment clean-catch midstream urine sample based on local laboratory procedures.
Sex and Contraceptive/Barrier Requirements
4. The participant is female
Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
-A female participant is eligible to participate if she is a woman of childbearing potential (WOCBP) who is not pregnant as confirmed by a high sensitivity urine pregnancy test at Baseline (Day 1) regardless of current or prior contraception use or abstinence, is not breastfeeding, or is not a WOCBP.
Note: Pregnancy testing requirements, contraceptive guidance, and WOCBP definitions are provided in Section 10.4 and requirements for pregnancy testing during and after study treatment are located in Section 8.2.5.
-Additional requirements for pregnancy testing during and after study treatment are located in in section 8.2.5.
-The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent
5. The participant is capable of giving signed informed consent/assent as described in Section 10.1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) /assent form and in this protocol.

Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. The participant resides in a nursing home or dependent care type facility.
2. The participant has a body mass index >-40.0 kg/m2 or a body mass index >-35.0 kg/m2 and is experiencing obesity-related health conditions such as uncontrolled high blood pressure or uncontrolled diabetes.
3. The participant is immunocompromised or has altered immune defenses that may predispose the participant to a higher risk of treatment failure and/or complications (e.g., uncontrolled diabetes, renal transplant recipients, participants with clinically significant persistent granulocytopenia [absolute neutrophil count <1000/microlitre], and participants receiving immunosuppressive therapy, including corticosteroid therapy [>40 mg/day prednisolone or equivalent for >1 week, .20 mg/day prednisolone or equivalent for >2 weeks, or prednisolone or equivalent .10 mg/day for >6 weeks]).
Participants with a known CD4 count of <200 cells/mm3 should not be enrolled.
4. The participant has any of the following:
-Medical condition that requires medication that may be impacted by inhibition of acetylcholinesterase, such as:
Clinical Study Protocol template V16 dated 24-Jun-2021
-Poorly controlled asthma or chronic obstructive pulmonary disease at Baseline and, in the opinion of the investigator, not stable on current therapy
-Acute severe pain, uncontrolled with conventional medical management
-Active peptic ulcer disease
-Parkinson disease
-Myasthenia gravis
-A history of seizure disorder requiring medications for control (this does not include a history of childhood febrile seizures)
OR
-Known acute porphyria
-Any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study treatment
(e.g., ileostomy or malabsorption syndrome)
5. The participant has a known glucose-6-phosphate dehydrogenase deficiency.
6. The participant, in the judgment of the investigator, would not be able or willing to comply with the protocol or complete study follow-up.
7. The participant has a serious underlying disease that could be imminently lifethreatening, or the participant is unlikely to survive for the duration of the study period.
8. The participant has acute uncomplicated 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 Enterobacterales (other than E. coli) as the contributing pathogen.
9. The participant has symptoms known or suspected to be caused by another disease process, such as asymptomatic bacteriuria, overactive bladder, chronic incontinence, or chronic interstitial cystitis, that may interfere with the clinical efficacy assessments or preclude complete resolution of acute cystitis symptoms.
10. The participant has an anatomical or physiological anomaly that predisposes the participant 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 participant has a history of anatomical or functional abnormalities of the urinary tract (e.g., chronic vesicoureteral reflux, detrusor insufficiency).
11. The participant has an indwelling catheter, nephrostomy, ureter stent, or other foreign material in the urinary tract.
12. The participant who, in the opinion of the investigator, has an otherwise complicated UTI, an active upper UTI (e.g., pyelonephritis, urosepsis), signs and symptom onset >-96 hours before study entry, or a temperature .38C, flank pain, chills, or any other manifestations suggestive of upper UTI.
13. The participant has known anuria, oliguria, or significant impairment of renal function (creatinine clearance <60 mL/min or clinically significant elevated serum creatinine as determined by the investigator).
14. The participant presents with vaginal discharge at Baseline (e.g., suspected sexually transmitted disease).
15. The participant has congenital long QT syndrome or known prolongation of the corrected QT (QTc) interval.
16. The participant has uncompensated heart failure.
17. The participant has severe left ventricular hypertrophy.
18. The participant has a family history of QT prolongation or sudden death.
19. The participant has a recent history of vasovagal syncope or episodes of symptomatic bradycardia or brady arrhythmia within the last 12 months.
20. The participant is taking QT-prolonging drugs or drugs known to increase the risk of torsades de pointes (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 participant is taking a strong cytochrome P450 enzyme 3A4 (CYP3A4) inhibitor.
21. For any participant >-12 to <18 years of age, the participant has an abnormal ECG reading at Baseline.
22. The participant has a QTc >450 msec or a QTc >480 msec for participants with bundle branch block.
Note:
-The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), or Fridericia's (QTcF) formula, and/or another method. It is either machine read or manually overread.
-The specific formula used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study. In other words, several different formulas cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or
discontinue the participant from the trial.
23. The participant has a documented or recent history of uncorrected hypokalemia within the past 3 months.
24. The participant has a known alanine aminotransferase (ALT) value >2 x upper limit of normal (ULN).
25. The participant has a known total bilirubin value >1.5 x ULN (isolated bilirubin >1.5
x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
26. The participant has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice.
Note: Stable noncirrhotic chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C [e.g., presence of hepatitis B surface antigen or positive hepatitis C antibody test result]) is acceptable if the participant otherwise meets entry criteria.
27. The participant has a previous history of cholestatic jaundice/hepatic dysfunction associated with nitrofurantoin.
Prior/Concomitant Therapy
28. The participant has received treatment with other systemic antimicrobials or systemic antifungals within 1 week before study entry.
29. The participant who are expected to be non-compliant with restrictions on medications or nondrug therapies prior to the study or during the study as detailed in Section 6.8.2.
Prior/Concurrent Clinical Study Experience
30. The participant has been previously enrolled in this study or has previously been treated with gepotidacin.
31. The participant has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives, whichever is longer.
Diagnostic Assessments
32. The participant has a positive human immunodeficiency virus (HIV) antibody test
Other Exclusions
33. Current drug or alcohol abuse or dependence, or history of drug or alcohol abuse or dependence within 12 months prior to randomisation
34. The participant has a history of sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

Female

uncomplicated urinary tract infection (acute cystitis)

Participants will receive oral study treatment (gepotidacin [2 tablets] + nitrofurantoin matching placebo [1 capsule] or nitrofurantoin [1 capsule] + gepotidacin matching placebo [2 tablets]) BID (approximately every 12 hours) for 5 days.

Therapeutic response (combined perparticipant microbiological and clinical response) at the TOC Visit

Therapeutic response at the TOC Visit
Clinical outcome and response at the TOC Visit
Microbiological outcome and response at the TOC Visit
Therapeutic response at the TOC Visit
Clinical outcome and response at the TOC Visit
Microbiological outcome and response at the TOC Visit
Investigator assessment of clinical response at the TOC Visit
Occurrence of treatment-emergent adverse events (AEs), serious AEs (SAEs) and adverse events of special interest (AESIs)
Change from baseline in clinical laboratory tests
Change from baseline in electrocardiograms (ECGs)
Gepotidacin plasma and urine concentrations
Change from baseline in vital sign measurements

+81-42-648-5551

Dec. 02, 2022

none