Key Points
Question
Among females with clinically diagnosed uncomplicated urinary tract infections treated with gepotidacin, what proportion experience symptom improvement at 24 hours?
Findings
This single-arm nonrandomized clinical trial enrolled 97 participants. In the clinically evaluable population, 54.4% of participants had symptom improvement at 24 hours after treatment initiation and 90.0% of participants had complete symptom resolution by day 10, with an acceptable safety profile.
Meaning
This study’s results suggest that gepotidacin provides rapid symptom relief as early as 24 hours after treatment initiation for participants with uncomplicated urinary tract infections.
This nonrandomized clinical trial investigates clinical symptom response during treatment with gepotidacin among females with clinically diagnosed uncomplicated urinary tract infections to assess how quickly patients experienced improvement.
Abstract
Importance
Uncomplicated urinary tract infections (uUTIs) are common infections in women, and symptoms negatively impact patients’ quality of life. Rapid symptom improvement is a high priority for patients and health care practitioners; however, few studies describe the early clinical effects of treatment.
Objective
To evaluate clinical symptom improvement daily from 24 hours until end of gepotidacin treatment (96 hours) and on day 10 in females with uUTIs.
Design, Setting, and Participants
This phase 3b, open-label, single-arm, multicenter nonrandomized clinical trial (October 2, 2024, to March 10, 2025) screened females (aged ≥12 years) with 2 or more uUTI symptoms and urinary nitrites or pyuria at 21 US sites.
Intervention
Oral gepotidacin (1500 mg) twice daily for 5 days.
Main Outcomes and Measures
The primary outcome was clinical symptom improvement (decrease in total clinical symptom score [CSS] of ≥1 from baseline without other systemic antimicrobials, with or without resolution) at 24 (±4) hours after treatment initiation. Secondary outcomes were clinical symptom improvement at 48, 72, and 96 (all ±4) hours after treatment initiation, clinical symptom resolution (reduction in total CSS to 0 without other systemic antimicrobials) at 24, 48, 72, and 96 (all ±4) hours after treatment initiation, and safety. Exploratory outcome was clinical symptom improvement and resolution at day 10 (+3 days).
Results
Overall, 103 females were evaluated, with 97 enrolling, 96 completing the study, 93 completing the study treatment, and 90 (mean [SD] age, 46.1 [16.4] years) included in the clinically evaluable population for the primary outcome. At 24 hours, 49 participants (54.4%; 95% CI, 43.6%-65.0%) in the clinically evaluable population had clinical symptom improvement. The number of participants with clinical symptom improvement at 48, 72, and 96 hours was 71 of 89 (79.8%; 95% CI, 69.9%-87.6%), 81 of 90 (90.0%; 95% CI, 81.9%-95.3%), and 77 of 89 (86.5%; 95% CI, 77.6%-92.8%), respectively. Clinical symptom resolution increased from 3 of 90 patients (3.3%) at 24 hours to 81 of 90 (90.0%) at day 10. Fifty-eight adverse events, mostly mild or moderate, were reported in 27 participants from the safety population. There were no serious adverse events.
Conclusions and Relevance
In this phase 3b nonrandomized clinical trial, female participants with uUTIs experienced a rapid clinical response to gepotidacin as early as 24 hours after treatment initiation. These data may aid informed decision-making in the use of gepotidacin for treating uUTIs.
Trial Registration
ClinicalTrials.gov Identifier: NCT06597344
Introduction
Uncomplicated urinary tract infections (uUTIs; acute cystitis) are UTIs confined to the bladder in afebrile individuals and are common in women, with an incidence of approximately 50% to 60%.1,2 Symptoms commonly include dysuria, frequency, urgency, and suprapubic pain, and most patients rate their symptoms as moderate or severe in intensity.3 In addition to the physical burden, symptoms can disrupt patients’ daily lives.3,4,5 US data show activity impairment in more than 50% of patients with uUTIs, including impairment in sexual relations (67%), sleep (61%), and exercise (52%).5 Health-related quality of life was also significantly worse for patients with uUTIs compared with a matched US population for physical, mental, and health utility indexes.5 The emotional impact of a uUTI is pronounced, with negative emotions such as frustration, worry, anger from treatment failure, and feelings of dread and helplessness at the prospect of recurrence.3 Recurrent uUTIs are associated with greater activity impairment and worse health-related quality of life compared with nonrecurrent uUTIs.5
Antibiotic treatment for uUTIs is typically empiric, and the choice depends on availability, patient allergies and tolerance, and local resistance prevalence.6 Treatment with an inappropriate or ineffective antibiotic can lead to suboptimal outcomes, such as lack of symptom relief, increased antimicrobial resistance rates, treatment failure, and recurrence.7,8,9 In the US, up to 17% of patients with uUTIs experience treatment failure and persistent symptoms, creating a burden of additional prescriptions and health care visits.7,10,11 US data (2015-2017) indicated that 22% of outpatients with a uUTI received an antibiotic to which the causative uropathogen was resistant, and these patients were almost twice as likely to require a second prescription or hospitalization compared with patients who received an appropriate antibiotic.9 In other US studies, patients with first treatment failure had significantly higher health care resource use and costs vs patients with initial treatment success.10,11 Effective empiric treatment and rapid symptom improvement are high priorities for patients and health care practitioners and are associated with the resumption of normal activities.12,13 Although studies have reported clinical symptom response, few evaluated this outcome within the first 24 hours after treatment initiation.13,14,15
The need for effective empiric therapy is increased by the increasing global concern of antimicrobial resistance,16 fueling the urgent need for novel oral agents. Gepotidacin is a novel, first-in-class triazaacenaphthylene oral antibacterial that inhibits bacterial DNA replication by a unique mechanism of action and distinct binding site17,18 and provides well-balanced inhibition of 2 different type II topoisomerases for most uropathogens.19 This results in activity against pathogens such as Escherichia coli and Staphylococcus saprophyticus, including isolates resistant to current antibacterials.20,21 Noninferiority of gepotidacin to nitrofurantoin was demonstrated in the pivotal, phase 3 global uUTI trials EAGLE-226 and EAGLE-327 and superiority in EAGLE-3,27 with an acceptable safety profile in both trials.22 EAGLE-2 and EAGLE-326,27 evaluated therapeutic response (a composite of clinical and microbiological response) at test of cure (days 10-13),22 with the earliest evaluation of symptom improvement at the on-therapy visit (days 2-4).23 Based on the findings of these trials, gepotidacin was approved in March 2025 by the US Food and Drug Administration (FDA) for the treatment of female adult and pediatric patients 12 years or older weighing 40 kg or more with uUTIs caused by the following susceptible microorganisms: E coli, Klebsiella pneumoniae, Citrobacter freundii complex, S saprophyticus, and Enterococcus faecalis.24 Subsequently, gepotidacin was approved in August 2025 by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of female adults and adolescents 12 years or older weighing 40 kg or more with uUTIs.25
Given the importance of rapid symptom relief in uUTIs, this study investigated clinical symptom response during treatment with gepotidacin to assess how quickly patients experienced improvement. A particular focus was placed on the first 24 hours after treatment initiation, and daily symptom assessment was performed through the end of treatment and followed up on day 10.
Methods
Study Design
This phase 3b, open-label, single-arm, multicenter nonrandomized clinical trial conducted across 21 US sites (12 dedicated research facilities, 7 clinic or outpatient facilities, and 2 hospitals) assessed clinical symptom response and safety during and after oral gepotidacin treatment in adolescent and adult females with uUTIs (eFigure in Supplement 1). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki28 and the International Council for Harmonisation guidelines for good clinical practice. Written informed consent was obtained from all participants. The protocol was approved by all necessary ethics committees and institutional review boards. The full trial protocol is available in Supplement 2. A patient council was consulted during the design of the study and recommendations were implemented. The study was designed and reported following the Transparent Reporting of Evaluations With Nonrandomized Designs (TREND) reporting guideline to enhance transparency and completeness in reporting nonrandomized intervention research.
Participants
Eligible participants were nonpregnant female patients 12 years or older with a body weight of 40 kg or more who presented with 2 or more clinical symptoms of uUTI (dysuria, frequency, urgency, or lower abdominal or suprapubic pain) less than 96 hours before study entry and had evidence of urinary nitrites or pyuria (presence of ≥3 [large leukocyte esterase]) from a pretreatment clean-catch midstream urine sample (per local laboratory procedures). Participants were excluded if they had symptoms due to preexisting urologic or other conditions that might have interfered with clinical efficacy assessments or presented with clinical features (eg, flank pain and fever) suggestive of a complicated UTI. Full eligibility criteria are described in the eMethods in Supplement 1.
A total of 103 participants were screened: 97 were enrolled in the study and included in the intention-to-treat (ITT) population (Figure 1). The study was conducted at 21 sites in the US between October 2, 2024, and March 10, 2025.
Figure 1. Participant Disposition Flowchart.
AE indicates adverse event; ITT, intention to treat.
aA total of 90 participants were clinically evaluable at 24 hours; 89 at 48 hours; 90 at 72 hours; 89 at 96 hours; and 90 at 120 hours.
Study Intervention
Participants received oral gepotidacin (1500 mg) twice daily (approximately every 12 hours, with at least a 6-hour window between doses) for 5 days (10 doses). The first dose was administered at the study site during the baseline visit, and participants self-administered subsequent doses as outpatients. Each treatment day was assessed during a 24 (±4)–hour period, starting with the first dose of gepotidacin (eFigure in Supplement 1).
Procedures
Each participant attended 7 scheduled study visits: an in-person baseline visit, 4 on-therapy telephone calls at 24, 48, 72, and 96 (all ±4) hours after baseline, and 2 follow-up telephone calls at day 10 (+3 days) and day 28 (±3 days) after baseline. Additional unscheduled onsite or telephone visits could be arranged for safety concerns, lack of response to study intervention, or early withdrawal. The clinical symptom score (CSS) was assessed at all time points (except day 28) by telephone interview conducted by a single third-party vendor. Each clinical symptom of uUTI was scored based on severity (scale of 0-3, with 0 indicating none and 3 indicating severe) and the scores summed to a total CSS (range, 0-12) (eTable 1 in Supplement 1). The requirement of 2 or more symptoms at study entry meant that all participants had a total CSS of 2 or higher (ie, ≥2 symptoms each of at least mild [score of 1] severity) at baseline. If any individual CSS was missing, the total CSS was set to missing and an outcome of unable to determine assigned for the participant at the respective time point. Safety assessments were conducted at all time points.
Outcomes
The primary outcome was clinical symptom improvement (with or without resolution), defined as a decrease in total CSS of 1 or more from baseline without the need for other systemic antimicrobials at 24 (±4) hours after the start of gepotidacin treatment. Baseline characteristics, such as age, sex, race, and ethnicity (eTable 2 in Supplement 1), were collected by the physician who was involved during the first onsite visit. Race and ethnicity data were collected in accordance with regulatory guidelines to ensure our trial population represented demographics and confirm that gepotidacin’s clinical benefits and safety are generalizable across diverse patient subgroups. Race categories included American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, multiracial, unknown, or not reported.
Secondary outcomes included clinical symptom improvement at 48, 72, and 96 (all ±4) hours after treatment initiation; clinical symptom resolution, defined as a reduction in total CSS to 0 without the need for other systemic antimicrobials, at 24, 48, 72, and 96 (all ±4) hours after treatment initiation; and the safety and tolerability of gepotidacin (including adverse events [AEs], such as treatment-emergent adverse events [TEAEs], serious adverse events [SAEs], and adverse events of special interest [AESIs]). The safety analyses were based on the safety population. In all AE summaries, only TEAEs are presented (any AE with an onset date on or after the treatment start date and time). All AEs were coded using the Medical Dictionary for Regular Activities (MedDRA), version 27.1 and summarized by standard of care and preferred terms. Four AESIs were predefined for this study: cardiovascular events, gastrointestinal events, Clostridioides difficile–associated diarrhea events, and potential acetylcholinesterase inhibition (AChE-I) events, which were identified by a prespecified list of preferred terms or determined by algorithm.
Outcomes of clinical symptom improvement, as previously defined, also included clinical symptom resolution (unless specified as without resolution). Exploratory outcomes included clinical symptom improvement and clinical symptom resolution at day 10 (+3 days) after treatment initiation. Full outcome definitions are described in eTable 3 in Supplement 1.
Statistical Analysis
Approximately 90 participants were planned for enrollment to ensure at least 82 evaluable participants were included in the primary analysis, such that the half width of the 95% CI would be approximately 10% or less under an assumption that 74% of participants would meet the primary end point criteria as observed in the pooled data of 2 previous phase 3 clinical studies.22 All results were analyzed descriptively: continuous data were summarized as number, mean, and SD, whereas categorical data were summarized as the number and percentage of participants in each category. For all outcomes, the baseline value was the latest predose assessment with a nonmissing value.
The ITT population comprised all enrolled participants (ie, excluding screening failures). The clinically evaluable (CE) population at 24 hours (CE24) comprised all participants in the ITT population who adhered to the 2 doses of gepotidacin as prescribed before the 24 (±4)–hour CSS assessment (if available) or before 24 (+4) hours from the first dose (if the CSS assessment was missing). The CE populations at 48, 72, and 96 hours (CE48, CE72, and CE96) comprised all participants in the ITT population who adhered to 80% or more of the planned doses of gepotidacin as prescribed before the 48, 72, and 96 (all ±4)–hour CSS assessment (if available) or before 48, 72, and 96 (all +4) hours from the first dose (if the CSS assessment was missing). The CE population at 120 hours (CE120) comprised all participants in the ITT population who adhered to 80% or more of the planned doses of gepotidacin as prescribed up to 120 (+4) hours (ie, end of treatment). There was no statistical hypothesis testing planned in this study. The safety population included all enrolled participants who received 1 or more doses of the study drug.
Results
Baseline Demographics
Most participants in the ITT population completed the study (96 of 97 [99%]) and completed the study treatment (93 of 97 [96%]). One of the 97 participants (1%) withdrew from the study and discontinued study treatment due to lost to follow-up and 3 (3%) discontinued study treatment due to AEs. Ninety of the 97 female participants (93%; mean [SD] age, 46.1 [16.4] years) were included in the CE24 primary analysis population. All participants in the ITT population were included in the safety population. In the ITT population, mean (SD) age was 45.7 (16.4) years, 54 (56%) were 50 years or younger, and 40 (41%) were postmenopausal (Table 1). Mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 29.0 (4.9). Of 97 participants, 69 (71%) were White and 28 (29%) had deidentified race; 55 (57%) were Hispanic/LatinX and 42 (43%) were not. Of 96 participants, 58 (60%) had a history of recurrent infection, and the mean (SD) total CSS was 7.7 (2.2).
Table 1. Baseline Demographics and Clinical Characteristics in the ITT and CE24 Populations.
| Characteristic | No. (%) of patients | |
|---|---|---|
| ITT (n = 97) | CE24 (n = 90) | |
| Sex | ||
| Female | 97 (100) | 90 (100) |
| Menopause status | ||
| Postmenopausal | 40 (41) | 37 (41) |
| Age, mean (SD), y | 45.7 (16.4) | 46.1 (16.4) |
| Age group, y | ||
| ≤50 | 54 (56) | 50 (56) |
| >50 | 43 (44) | 40 (44) |
| 51-64 | 31 (32) | 29 (32) |
| ≥65 | 12 (12) | 11 (12) |
| Ethnicity | ||
| Hispanic or Latinx | 55 (57) | 52 (58) |
| Not Hispanic or Latinx | 42 (43) | 38 (42) |
| Racea | ||
| White | 69 (71) | 67 (74) |
| Deidentified | 28 (29) | 23 (26) |
| BMI, mean (SD) | 29.0 (4.9) | 29.0 (4.7) |
| Baseline total CSS, mean (SD) | 7.7 (2.2) | 7.6 (2.1) |
| Baseline total CSS group | ||
| 2-5 (Mild) | 15 (15.6)b | 14 (15.7)c |
| 6-8 (Moderate) | 49 (51.0)b | 47 (52.8)c |
| 9-12 (Severe) | 32 (33.3)b | 28 (31.5)c |
| History of uUTI recurrence at baseline | ||
| Recurrent | 58 (60)b | 56 (62) |
| Nonrecurrent | 38 (40)b | 34 (38) |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CE24, clinically evaluable at 24 hours; CSS, clinical symptom score; ITT, intention to treat; uUTI, uncomplicated urinary tract infection.
Race was reported as 2 categories to safeguard participant privacy and to reduce the risk of reidentification from combinations of indirectly identifying variables (eg, age, sex, race, ethnicity, and region). Deidentification procedures were implemented such that table cells with small counts (n < 11) were combined or otherwise masked.
Baseline total CSS and history of uUTI recurrence at baseline data were missing for 1 participant (n = 96).
One participant took the first dose of gepotidacin before the baseline CSS assessment; this was reported as an important protocol deviation and was treated as missing in the analysis (n = 89).
Clinical Outcomes
In the CE24 population, 49 of 90 participants (54.4%; 95% CI, 43.6%-65.0%) had clinical symptom improvement (with or without resolution) at 24 hours (Table 2). Forty-six of 90 participants (51.1%) in the CE24 population had clinical symptom improvement without resolution at 24 hours. Subsequently, 71 of 89 (79.8%; 95% CI, 69.9%-87.6%), 81 of 90 (90.0%; 95% CI, 81.9%-95.3%), and 77 of 89 (86.5%; 95% CI, 77.6%-92.8%) participants had clinical symptom improvement at 48, 72, and 96 hours, respectively, increasing to 86 of 90 (95.6%; 95% CI, 89.0%-98.8%) at day 10. Clinical symptom resolution steadily increased with gepotidacin treatment, from 3 of 90 participants (3.3%) at 24 hours to 48 of 89 participants (53.9%) at 96 hours and 81 of 90 (90.0%) at day 10. No participants required an additional nonstudy antimicrobial up to day 10; 2 participants required an additional nonstudy antimicrobial later during the study follow-up period (1 for uUTIs from days 15 to 25 and 1 for respiratory syncytial virus on day 25).
Table 2. Clinical Outcome by Time Point and Analysis Populationsa .
| Clinical outcome | No. (%) of participants (N = 90) | ||||
|---|---|---|---|---|---|
| 24 h (CE24)b | 48 h (CE48)c | 72 h (CE72)c | 96 h (CE96)c | Day 10 (CE120)d | |
| Clinical symptom improvement (including clinical symptom resolution), No. (%) [95% CI] | 49 (54.4) [43.6-65.0] | 71 (79.8) [69.9-87.6] | 81 (90.0) [81.9-95.3] | 77 (86.5) [77.6-92.8] | 86 (95.6) [89.0-98.8] |
| Clinical symptom resolution | 3 (3) | 11 (12) | 29 (32) | 48 (54) | 81 (90) |
| Clinical symptom improvement (excluding clinical symptom resolution) | 46 (51) | 60 (67) | 52 (58) | 29 (33) | 5 (6) |
| No change | 25 (28) | 5 (6) | 3 (3) | 4 (4) | 0 |
| Clinical worsening | 10 (11) | 6 (7) | 3 (3) | 3 (3) | 2 (2) |
| Unable to determine | 6 (7) | 7 (8) | 3 (3) | 5 (6) | 2 (2) |
Abbreviations: CE24, clinically evaluable at 24 hours; CE48, clinically evaluable at 48 hours; CE72, clinically evaluable at 72 hours; CE96, clinically evaluable at 96 hours; CE120, clinically evaluable at 120 hours; CSS, clinical symptom score.
All changes are relative to baseline.
Comprised all participants in the intention-to-treat population who adhered to the 2 doses of gepotidacin as prescribed before the 24 (±4)–hour CSS assessment (if available) or before 24 (±4) hours from the first dose (if the CSS assessment was missing).
Comprised all participants in the intention-to-treat population who adhered to 80% or more of the planned doses of gepotidacin as prescribed before the 48, 72, and 96 (all ±4)–hour CSS assessment (if available) or before 48, 72, and 96 (+4)–hour from the first dose (if the CSS assessment was missing).
Comprised all participants in the intention-to-treat population who adhered to 80% or more of the planned doses of gepotidacin as prescribed up to 120 (+4) hours (ie, end of treatment).
Mean CSS and Symptom Severity
The mean CSS for each symptom (dysuria, frequency, urgency, and lower abdominal or suprapubic pain) and the total CSS decreased by 24 hours after gepotidacin initiation and continued to decrease over time (Figure 2). For each symptom, the proportion of participants with a symptom severity of none (ie, did not have the symptom) increased from baseline to 24 hours and continued to increase over time (eTable 4 in Supplement 1). A similar shift occurred in the improvement of symptom severity, with participants moving from generally moderate/severe to mild severity over the study period.
Figure 2. Line Graphs of Change in Mean Clinical Symptom Scores (CSSs) From Baseline Over Time for the Clinically Evaluable at 24 Hours Populationa.
Data points have been staggered to allow clear visualization in the figure. All changes are relative to baseline. Error bars indicate SDs.
aComprised all participants in the ITT population who adhered to the 2 doses of gepotidacin as prescribed before the 24h (±4h) CSS assessment (if available), or before 24h (+4h) from the first dose (if the CSS assessment was missing).
bBaseline: n = 89; 24 h: n = 86; 48 h: n = 86; 72 h: n = 88; 96 h: n = 87; Day 10: n = 90.
cBaseline: n = 89; 24 h: n = 86; 48 h: n = 84; 72 h: n = 88; 96 h: n = 86; Day 10: n = 87.
dBaseline: n = 89; 24 h: n = 85; 48 h: n = 84; 72 h: n = 88; 96 h: n = 86; Day 10: n = 87.
Safety
Overall, 58 AEs were experienced by 27 of the 97 participants (28%) in the safety population (Table 3); most AEs were mild (20 of 27 [74%]) or moderate (5 of 27 [19%]) in severity. Twenty-four of 97 participants (25%) experienced study drug–related AEs. No participants experienced SAEs. No AEs led to study withdrawal. Three participants (3%) experienced drug-related AEs leading to study drug discontinuation; these participants did not receive nonstudy antimicrobial therapy. There were no clinically meaningful findings in vital signs or electrocardiographic measurements during the study, in the safety population as a whole, or among the participants reporting AEs. No AEs were associated with significant changes in vital signs or electrocardiographic measures.
Table 3. Overall Summary of AEs by End of Follow-Up in the Safety Populationa.
| AE | No. (%) of participants (n = 97) |
|---|---|
| Total No. of AEsb | 58 |
| Patients who experienced at least 1 AE | 27 (28) |
| AE by maximum severity | |
| Grade 1 (mild) | 20 (21) |
| Grade 2 (moderate) | 5 (5) |
| Grade 3 (severe) | 2 (2) |
| Grade 4 (life-threatening) | 0 |
| Grade 5 (fatal) | 0 |
| Drug-related AE | 24 (25) |
| Drug-related AE leading to study drug discontinuationc | 3 (3) |
| Serious AE | 0 |
| AE leading to study drug discontinuation | 3 (3) |
| AE leading to study withdrawal | 0 |
| AESIs | |
| Gastrointestinald | 23 (24) |
| Potential acetylcholinesterase inhibition | |
| Gastrointestinal potential acetylcholinesterase inhibition | 21 (22) |
| Nongastrointestinal potential acetylcholinesterase inhibitione | 2 (2) |
| Clostridioides difficile–associated diarrhea | 0 |
| Cardiovascular | 0 |
Abbreviations: AE, adverse event; AESI, adverse event of special interest.
All enrolled participants who received at least 1 dose of gepotidacin.
All AEs displayed are treatment-emergent AEs, defined as any AE with an onset date/time on or after treatment initiation date/time.
Three participants experienced mild/moderate drug-related AEs leading to study drug discontinuation (1 participant due to dizziness, drooling, headache, hypoesthesia oral, nausea, paresthesia oral, and diarrhea; 1 participant due to diarrhea, nausea, and vomiting; and 1 participant due to diplopia).
Diarrhea was the most common gastrointestinal AESI (16 participants).
Nongastrointestinal potential acetylcholinesterase inhibition AESI included drooling (1 participant) and dyspnea (1 participant).
Diarrhea (16 [16%]), flatulence (6 [6%]), dizziness (5 [5%]), abdominal pain (4 [4%]), headache (3 [3%]), abdominal discomfort (2 [2%]), and nausea (2 [2%]) were the most common AEs, reported by 2% or more of 97 participants in the safety population. Diarrhea AEs were generally mild to moderate in severity except for in 2 participants (2%) with severe diarrhea.
In the safety population of 97 participants, gastrointestinal AEs were reported by 23 participants (24%). All gastrointestinal AEs reported were AESIs, and for 21 participants (22%), the gastrointestinal AESIs occurred within 12 hours of the study dose and thus were also reported as potential AChE-I AESIs per protocol. Among the participants with a potential AChE-I AESI, the median (range) time of onset for the first event was 11 (0-78) hours and the median (IQR) duration was 5 (1-21) days. Nongastrointestinal potential AChE-I events were reported in 2 participants (drooling [1 participant] and dyspnea [1 participant]). Among gastrointestinal AESIs, no C difficile–associated diarrhea events were reported. No QT prolongation, torsades de pointes, or other cardiovascular AESIs were reported.
One participant had a positive pregnancy test result on day 27 (22 days after the last gepotidacin dose). Based on dosing dates and the participant’s last menstrual period, the estimated timing of gepotidacin exposure ended before conception. The pregnancy resulted in a full-term, healthy, single infant.
Discussion
Effective empiric treatment providing rapid symptom improvement is important to patients with uUTIs to address the impact on daily living and quality of life.3,5 In this phase 3b nonrandomized clinical trial, we evaluated daily uUTI clinical symptom improvement during and after treatment with gepotidacin, with a primary outcome focused on response at 24 hours. Secondary outcomes included clinical symptom improvement and clinical symptom resolution (at 48, 72, and 96 [±4] hours) and safety tolerability. Exploratory outcomes included clinical symptom improvement and clinical symptom resolution at day 10 (+3 days). Gepotidacin, an FDA- and MHRA-approved, first-in-class, triazaacenaphthylene antibacterial, provided a rapid and sustained clinical response for the improvement of uUTI symptoms in a cohort of female participants similar to those seen in clinical practice.24,25 A total of 54.4% of participants experienced symptom improvement (with or without resolution) 24 hours after treatment initiation and nearly 80% at 48 hours. By day 10, 90% of participants had clinical symptom resolution. No participants received nonstudy systemic antimicrobials before day 10 (and only 2 participants thereafter, one for uUTI and the other for a respiratory infection, during the study follow-up), meaning that the primary and secondary efficacy outcomes were unaffected by confounding antimicrobial use.
Few previous antibiotic studies have reported symptom improvement in uUTIs at similar early time points. A 2005 study investigating the time to uUTI symptom improvement after treatment with ciprofloxacin reported that half the patients (50%) (N = 276) had symptom improvement 6 hours after the first dose, increasing to 87% and 91% by 24 and 48 hours, respectively.13 These authors also reported that 96% of patients achieved clinical cure (resolution of signs and symptoms) by test of cure (days 5-11)13; this is similar to the findings of the current study at day 10. In a 2010 study of ciprofloxacin examining quality-of-life and symptom improvement, median time to symptom improvement was 2.4 days in 249 patients responsive to treatment.15 In a 2012 study comparing care pathways for uUTI management, 22 of 41 patients (54%) who received trimethoprim had a symptom duration of 2 days or less, 15 of 41 (36%) had a duration of 3 to 6 days, and 4 of 41 (10%) had a duration of 7 days or longer.14
The EAGLE-2 and EAGLE-3 phase 3 uUTI studies did not include an early assessment of symptoms, with the earliest data from an established time point of 2 to 4 days after treatment initiation. In pooled data from these studies, most participants receiving gepotidacin or nitrofurantoin had clinical symptom improvement (with or without resolution) at the on-therapy visit (days 2-4; 81.4% and 82.1%, respectively) and by test of cure (days 10-13; 88.6% and 89.9%, respectively).23 These findings are similar to the results of the current study, which is more reflective of clinical practice, and found that 79.8% of participants treated with gepotidacin achieved clinical symptom improvement (with or without resolution) by 48 hours and 95.6% by day 10. Symptom assessment in EAGLE-2 and EAGLE-3 as well as the current study used the same CSS tool22; however, although symptoms in EAGLE-2 and EAGLE-3 were assessed by a physician or medical staff at each trial site, the current trial used a single external vendor for all assessments.
Safety data reported herein are consistent with the known safety profile of gepotidacin,22 and no new safety or tolerability concerns were identified. No SAEs were observed, and the frequency of discontinuation due to AEs was low (3% [3 of 97]). Among the 3 participants who discontinued study drug due to AEs, these were generally mild or moderate in severity, and no participants withdrew from the study.
Strengths and Limitations
A strength of this study is that symptoms were assessed daily in the same participants, which enabled continuous evaluation of small symptom changes and treatment response. Using a single external vendor for the CSS assessments is a further strength, ensuring consistency and limiting potential bias in assigning clinical response outcomes. The practical nature of the study, with inclusion criteria being reflective of symptom-based diagnostic criteria, means that the findings are likely to be reflective of patients and clinical practice.
Our study also has inherent limitations associated with an open-label, single-arm design, and the relatively small sample size limits the generalizability of the findings. As there was a high percentage of individuals who identified as Hispanic or Latinx and a small percentage of women who were 65 years or older, the demographics of the enrolled population were not necessarily reflective of the general population, which may also limit generalizability. Moreover, all data were analyzed descriptively, which limits interpretation.
Conclusions
In this phase 3b nonrandomized clinical trial of female participants with uUTIs, gepotidacin demonstrated a rapid and sustained clinical response, addressing an important and understudied consideration for patients. More than half of participants (54%) had symptom improvement at 24 hours following treatment initiation, increasing to nearly 80% at 48 hours, and 90% of participants achieved complete symptom resolution at day 10. Gepotidacin was well tolerated, with no SAEs, no new safety concerns, and no AEs leading to study withdrawal. Together these findings support gepotidacin as an option to address the unmet need for new oral antibacterials in uUTI treatment and provide a basis for more informed discussions between patients and clinicians regarding treatment expectations.
eMethods. Supplementary Methods
eTable 1. CSS Assessment for uUTI
eTable 2. Summary of Baseline Race (ITT Population)
eTable 3. Outcome Definitions
eTable 4. Proportion of Participants With Individual Clinical Symptoms by Severity at Each Timepoint (CE24 Populationa; N=90)
eFigure. Study Design Flowchart
Trial Protocol
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods. Supplementary Methods
eTable 1. CSS Assessment for uUTI
eTable 2. Summary of Baseline Race (ITT Population)
eTable 3. Outcome Definitions
eTable 4. Proportion of Participants With Individual Clinical Symptoms by Severity at Each Timepoint (CE24 Populationa; N=90)
eFigure. Study Design Flowchart
Trial Protocol
Data Sharing Statement
