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)

JRCT ID: jRCT2031220467

Registered date:26/11/2022

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: uncomplicated urinary tract infection (acute cystitis)
• Date of first enrollment: 11/01/2023
• Target sample size: 374
• Study type: Interventional
• Intervention(s): 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.

Outcome(s)

• Primary Outcome: Therapeutic response (combined perparticipant microbiological and clinical response) at the TOC Visit

Secondary Outcome

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

Key inclusion & exclusion criteria

• Age minimum: >= 12age old
• Age maximum: Not applicable
• Gender: Female

Include criteria

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.

Exclude criteria

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.

Related Information

• Primary Sponsor: Okawa Yasutoshi