| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Urinary Tract Infection (Acute Cystitis) |
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| E.1.1.1 | Medical condition in easily understood language |
| Acute Cystitis in adolescent and adult females |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011781 |
| E.1.2 | Term | Cystitis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the combined clinical and microbiological efficacy of gepotidacin compared to nitrofurantoin, at the Test of Cure (TOC) Visit, in female
articipants with acute cystitis with qualifying bacterial uropathogen(s) at Baseline that all are susceptible to nitrofurantoin.
|
|
| E.2.2 | Secondary objectives of the trial |
- To assess the clinical efficacy of gepotidacin compared to nitrofurantoin, at the TOC and Follow up Visits, in female participants with acute cystitis with qualifying bacterial uropathogen(s) at Baseline that all are susceptible to nitrofurantoin
- To assess microbiological efficacy of gepotidacin compared to nitrofurantoin, at the TOC and Follow-up Visits,in female participants with acute cystitis with qualifying bacterial uropathogen(s) at Baseline that all are susceptible to nitrofurantoin
- To assess the combined clinical and microbiological efficacy of gepotidacin compared to nitrofurantoin, at Follow-up Visit,in female participants with acute cystitis with qualifying bacterial uropathogen(s) at Baseline that all are susceptible to nitrofurantoin
-To determine plasma and urine pharmacokinetic(PK) concentrations of gepotidacin infemale participants with acute cystitis
-To assess safety and tolerability of gepotidacin compared to nitrofurantoin |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- The participant is ≥12 years of age 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 enroll in the study, study sites must follow their institutional ethics committee and local country/national regulatory guidelines and enrollment will be contingent upon such approvals regarding the allowed lower age limit for clinical study participants.
-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
-The participant has nitrite or pyuria (>15WBC/HPFor the presence of 3+/large leukocyte esterase)from a pretreatment clean-catch midstream urine sample based on local laboratory procedures.
-The participant is female. A female participant is eligible to participate if she is woman of childbearing potential (WOCBP) who is not pregnant as confirmed by high sensitivity urine pregnancy test at Baseline (Day1) regardless of current or prior contraception or abstinence, is not breastfeeding, or is not a WOCBP.
Note: pregnancy test requirements, contraceptive guidance, and WOCBP definitions are provided in Appendix 2.
- The participant is capable of giving signed informed consent/assent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF)/assent form and in this protocol.
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| E.4 | Principal exclusion criteria |
-The participant resides in a nursing home or dependent care type-facility AND has a body mass index≥40.0 kg/m2 or a body mass index≥35.0kg/m2 and is experiencing obesity-related health conditions such as uncontrolled high blood pressure or uncontrolled diabetes
- Participant has a history of sensitivity to the study treatments,or components thereof,or a history of a drug or other allergy that contraindicates her participation
- Participant is immunocompromised or has altered immune defenses that may predispose the participant to a higher risk of treatment failure and/or complications,and participants receiving immunosuppressive therapy, including corticosteroid therapy
-Participants with a known CD4 count of<200 cells/mm3 should not be enrolled
-Participant has any of the following:Medical condition that requires medication that may be impacted by inhibition of acetylcholinesterase,such as: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 OR any surgical or medical condition (active or chronic) that may interfere with drug absorption,distribution,metabolism,or excretion of the study treatment)
-Participant has a known glucose-6-phosphate dehydrogenase deficiency and in the judgment of the investigator,would not be able or willing to comply with the protocol or complete study follow-up
-Participant has a serious underlying disease that could be imminently life-threatening,or the participant is unlikely to survive for the duration of the study period
-Participant has acute cystitis that is known or suspected to be due to fungal,parasitic,or viral pathogens
-Participant has symptoms known or suspected to be caused by another disease process,ex overactive bladder,chronic incontinence,or chronic interstitial cystitis,that interfere with the clinical efficacy assessments or preclude complete resolution of acute cystitis symptoms
-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,or neurogenic bladder,or the participant has a history of anatomical or functional abnormalities of the urinary tract
-Participant has an indwelling catheter,nephrostomy,ureter stent,or other foreign material in the urinary tract.
-Participant who, in the opinion of the investigator, has an otherwise complicated UTI,an active upper UTI,signs and symptom onset≥96hours before study entry,or a temperature ≥101°F(≥38°C), flank pain, chills, or any other manifestations suggestive of upper UTI
-Participant has known anuria,oliguria,or significant impairment of renal function or presents with vaginal discharge at Baseline.
-Participant has congenital long QT syndrome or known prolongation of the corrected QT(QTc)interval
-Participant has uncompensated heart failure
-Participant has severe left ventricular hypertrophy
-Participant has a family history of QT prolongation or sudden death OR has a recent history of vasovagal syncope or episodes of symptomatic bradycardia or brady arrhythmia within the last 12months
-Participant is taking QT-prolonging drugs or drugs known to increase the risk of torsades de pointes (TdP)
-For any participant≥12to<18years of age,the participant has an abnormal electrocardiogram (ECG)reading
-Participant has a QTc>450msec or a QTc>480msec for participants with bundle-branch block
-Participant has a known alanine aminotransferase(ALT) value>2× upper limit of normal(ULN)
-Participant has a known bilirubin value>1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin<35%)
-Participanthas 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).Participants with asymptomatic viral hepatitis are eligible for study participation
-Participant has a previous history of cholestatic jaundice/hepatic dysfunction associated with nitrofurantoin
-Participant has received treatment with other systemic antimicrobials or systemic antifungals within 1 week before study entry AND must agree not to use the medications or nondrug therapies from the Baseline Visit through the TOC Visit
-Participant has been previously enrolled in this study or has previously been treated with gepotidacin AND has participated in a clinical trial and has received an investigational product within 30days or 5half-lives, whichever is longer |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Therapeutic response (combined per-participant microbiological and clinical response) at the TOC Visit
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary efficacy endpoint will be the therapeutic response (combined per-participant microbiological and clinical response) at the TOC Visit (i.e., 10 to 13 days after randomization, which is also 5 to 8 days after completion of study treatment) in participants who have a qualifying bacterial uropathogen at Baseline |
|
| E.5.2 | Secondary end point(s) |
-Clinical outcome and response at the TOC and Follow-up Visits.
-Microbiological outcome and response at the TOC and Follow-up Visits.
-Therapeutic response (combined per-participant microbiological and clinical response) at the Follow-up Visit.
-Gepotidacin plasma and urine concentrations.
-Treatment-emergent adverse events and serious adverse events and change from baseline results for clinical laboratory tests and vital sign measurements.
-Gram stain, quantitative bacteriology culture, and in vitro antimicrobial susceptibility test results at the Baseline, On-therapy, TOC, and Followup Visits
-Therapeutic response (combined microbiological and clinical response), clinical outcome and response, and microbiological outcome and response by uropathogen at each visit
-Probability of PK/PD target attainment with therapeutic clinical and microbiological response at the TOC Visit, utilizing population PK analysis andbaseline uropathogen minimum inhibbitory concentration (MIC) if data permit.
-Microbiological outcome at the On-therapy Visit
-Clinical outcome at the On-therapy Visit
- Investigator assessment of clinical response at the TOC and Follow-up Visits, as data permits
-Urinary tract infection Activity Impairment Assessment (AIA) scores at the Baseline, On-therapy, TOC, and Follow-up Visits |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Participants will return to the study site on Day 28 (±3) for a Follow-up Visit. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| India |
| Mexico |
| United States |
| Bulgaria |
| Romania |
| Spain |
| Czechia |
| Germany |
| Greece |
| Hungary |
| Slovakia |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The End of Trial is defined as the date of last visit of the last participant in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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