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    Clinical Trial Results:
    A Phase III, Randomized, Multicenter, Parallel-Group, Double-Blind, Double-Dummy Study in Adolescent and Adult Female Participants Comparing the Efficacy and Safety of Gepotidacin to Nitrofurantoin in the Treatment of Uncomplicated Urinary Tract Infection (Acute Cystitis)

    Summary
    EudraCT number
    		 2020-000553-27
    Trial protocol
    		 BG   PL  
    Global end of trial date
    01 Dec 2022

    Results information
    Results version number
    		 v1
    This version publication date
    14 Jun 2023
    First version publication date
    14 Jun 2023
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    212390
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04187144
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 GreatWest Road, Brentford,Middlesex, United Kingdom, TW8 9GS
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002443-PIP01-18
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The study was conducted to evaluate the therapeutic response (combined per participant microbiological and clinical response) of oral gepotidacin compared to oral nitrofurantoin for treatment of uncomplicated UTI (acute cystitis) in adolescent and adult female participants.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Apr 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Bulgaria: 356
    Country: Number of subjects enrolled
    India: 63
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    United States: 1095
    Country: Number of subjects enrolled
    Korea, Republic of: 30
    Worldwide total number of subjects
    1605
    EEA total number of subjects
    398
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    11
    Adults (18-64 years)
    1253
    From 65 to 84 years
    326
    85 years and over
    15

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1731 unique participants were screened, of these 1605 unique participants were enrolled. This includes one participant that was enrolled twice in error.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gepotidacin
    Arm description
    		 Participants with uncomplicated urinary tract infection (uUTI) (acute cystitis) randomized to receive gepotidacin 1500 milligram (mg) (2*750 mg, tablets), twice daily (BID), orally on Day 1 to Day 5. The total daily dose of gepotidacin received was 3000 mg. Participants also received 1 capsule of placebo matched with nitrofurantoin BID, orally on Day 1 to Day 5. All doses were administered after food consumption and with water.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gepotidacin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with uncomplicated urinary tract infection (acute cystitis) were administered with oral doses of 1500 milligrams (mg) (2*750 mg) gepotidacin tablet plus nitrofurantoin capsules matching placebo twice daily (BID) for 5 days.

    Arm title
    		 Nitrofurantoin
    Arm description
    		 Participants with uncomplicated urinary tract infection (acute cystitis) randomized to receive nitrofurantoin 100 mg capsule, BID, orally on Day 1 to Day 5. The total daily dose of nitrofurantoin received was 200 mg. Participants also received 2 tablets of placebo matched with gepotidacin BID, orally on Day 1 to Day 5. All doses were administered after food consumption and with water.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nitrofurantoin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with uncomplicated urinary tract infection (acute cystitis) were administered with oral doses of 100 mg (25 mg nitrofurantoin macrocrystals and 75 mg nitrofurantoin) nitrofurantoin capsules plus gepotidacin tablet matching placebo BID for 5 days.

    Number of subjects in period 1
    		Gepotidacin Nitrofurantoin
    Started
    805
    800
    Safety Population
    804
    798
    Microbiological ITT (microITT)Population
    331 [1]
    324 [2]
    Micro-ITT NTF-S Population
    292 [3]
    275 [4]
    Micro-ITT NTF-S (IA Set) Population
    277 [5]
    264 [6]
    Completed
    748
    759
    Not completed
    57
    41
         Consent withdrawn by subject
    20
    18
         Physician decision
    5
    3
         Adverse event, non-fatal
    19
    4
         Protocol Deviation
    1
    4
         ScreenFailure - CreatinineClearance/BodyMassIndex
    -
    1
         Lost to follow-up
    12
    11
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Intermediate milestone is a subset of started population. Hence number of subjects at this milestone are less than started.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Intermediate milestone is a subset of started population. Hence number of subjects at this milestone are less than started.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Intermediate milestone is a subset of started population. Hence number of subjects at this milestone are less than started.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Intermediate milestone is a subset of started population. Hence number of subjects at this milestone are less than started.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Intermediate milestone is a subset of started population. Hence number of subjects at this milestone are less than started.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Intermediate milestone is a subset of started population. Hence number of subjects at this milestone are less than started.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gepotidacin
    Reporting group description
    		 Participants with uncomplicated urinary tract infection (uUTI) (acute cystitis) randomized to receive gepotidacin 1500 milligram (mg) (2*750 mg, tablets), twice daily (BID), orally on Day 1 to Day 5. The total daily dose of gepotidacin received was 3000 mg. Participants also received 1 capsule of placebo matched with nitrofurantoin BID, orally on Day 1 to Day 5. All doses were administered after food consumption and with water.

    Reporting group title
    Nitrofurantoin
    Reporting group description
    		 Participants with uncomplicated urinary tract infection (acute cystitis) randomized to receive nitrofurantoin 100 mg capsule, BID, orally on Day 1 to Day 5. The total daily dose of nitrofurantoin received was 200 mg. Participants also received 2 tablets of placebo matched with gepotidacin BID, orally on Day 1 to Day 5. All doses were administered after food consumption and with water.

    Reporting group values
    		 Gepotidacin Nitrofurantoin Total
    Number of subjects
    		 805 800 1605
    Age Categorical
    Units: Participants
        Less than (<) 18 years
    		 8 3 11
        More than or equal to (>=) 18 years to 50 years
    		 427 430 857
        More than (>) 50 years
    		 370 367 737
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 48.2 ( 17.84 ) 48.4 ( 17.72 ) -
    Sex/Gender, Customized
    Units: Participants
        Female
    		 805 800 1605
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 246 232 478
        Not Hispanic or Latino
    		 559 568 1127
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 2 1 3
        Asian
    		 51 65 116
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 74 62 136
        White
    		 674 668 1342
        More than one race
    		 2 4 6
        Unknown or Not Reported
    		 1 0 1
    Baseline Acute Cystitis Recurrence
    Recurrent infection was defined as a confirmed infection with at least 1 episode within the past 3 months, at least 2 episodes within the past 6 months, or at least 3 episodes within the past 12 months before study entry.
    Units: Subjects
        Recurrent Infection
    		 334 338 672
        Non-Recurrent Infection
    		 471 462 933

    End points

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    End points reporting groups
    Reporting group title
    Gepotidacin
    Reporting group description
    		 Participants with uncomplicated urinary tract infection (uUTI) (acute cystitis) randomized to receive gepotidacin 1500 milligram (mg) (2*750 mg, tablets), twice daily (BID), orally on Day 1 to Day 5. The total daily dose of gepotidacin received was 3000 mg. Participants also received 1 capsule of placebo matched with nitrofurantoin BID, orally on Day 1 to Day 5. All doses were administered after food consumption and with water.

    Reporting group title
    Nitrofurantoin
    Reporting group description
    		 Participants with uncomplicated urinary tract infection (acute cystitis) randomized to receive nitrofurantoin 100 mg capsule, BID, orally on Day 1 to Day 5. The total daily dose of nitrofurantoin received was 200 mg. Participants also received 2 tablets of placebo matched with gepotidacin BID, orally on Day 1 to Day 5. All doses were administered after food consumption and with water.

    Primary: Number of participants with therapeutic response (TR) (combined per participant clinical and microbiological response) at the Test-of-Cure (TOC) visit - Micro-ITT NTF-S (IA Set)

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    End point title
    		 Number of participants with therapeutic response (TR) (combined per participant clinical and microbiological response) at the Test-of-Cure (TOC) visit - Micro-ITT NTF-S (IA Set)
    End point description
    TR at TOC (success/failure) is a measure of the overall efficacy response. A therapeutic success at TOC referred to participant who have been deemed both a microbiological success (reduction of all qualifying bacterial uropathogens recovered at Baseline [BL] to <10^3 colony forming units per milliliter [CFU/mL] without receiving other systemic antimicrobials [AB] before the TOC visit) and a clinical success (resolution of symptoms of acute cystitis present at BL and no symptoms without receiving other AB before the TOC visit [or AB for uUTI on day of TOC visit]). Lack of clinical or microbiological success (including missing outcome assessments) was considered as therapeutic failure. Micro-ITT NTF-S) (Interim Analysis [IA] Set) population included participants in the micro ITT NTF-S who per the interim analysis data had the opportunity to reach their Test of Cure (TOC) visit, or had not yet reached their TOC visit, but were already known to be failures.
    End point type
    Primary
    End point timeframe
    TOC visit (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    277
    264
    Units: Participants
        Therapeutic Success
    162
    115
        Therapeutic Failure
    115
    149
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Nitrofurantoin v Gepotidacin
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Adjusted Difference in Percent
    Point estimate
    14.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.4
         upper limit
    		 22.8
    Notes
    [1] - The difference in success rate between treatment groups (gepotidacin – nitrofurantoin) was calculated using Miettinen-Nurminen Summary Score Method adjusted for age group and acute cystitis recurrence strata combinations. Criteria for non-inferiority is if the Z-statistic for non-inferiority is greater than the 2.098 Z-statistic boundary.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The difference in success rate between treatment groups (gepotidacin – nitrofurantoin) was calculated using Miettinen-Nurminen Summary Score Method adjusted for age group and acute cystitis recurrence strata combinations. Criteria for superiority is if the one-sided p-value is less than the 0.018 p-value boundary
    Comparison groups
    Gepotidacin v Nitrofurantoin
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 1-sided p-value for Test of Superiority
    Parameter type
    		 p-value Boundary for Superiority
    Point estimate
    14.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.4
         upper limit
    		 22.8

    Primary: Number of participants with therapeutic response (TR) (combined per participant clinical and microbiological response) at the Test-of-Cure (TOC) visit – Micro-ITT NTF-S population

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    End point title
    		 Number of participants with therapeutic response (TR) (combined per participant clinical and microbiological response) at the Test-of-Cure (TOC) visit – Micro-ITT NTF-S population [2]
    End point description
    TR at TOC (success/failure) is a measure of the overall efficacy response. A therapeutic success at TOC referred to participant who have been deemed both a microbiological success (reduction of all qualifying bacterial uropathogens recovered at Baseline [BL] to <10^3 colony forming units per milliliter [CFU/mL] without receiving other systemic antimicrobials [AB] before the TOC visit) and a clinical success (resolution of symptoms of acute cystitis present at BL and no new symptoms without receiving other AB before the TOC visit [or AB for uUTI on day of TOC visit]). Lack of clinical or microbiological success (including missing outcome assessments) was considered as therapeutic failure.
    End point type
    Primary
    End point timeframe
    TOC visit (Days 9 to 16)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is only descriptive endpoint.
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Therapeutic Success
    172
    121
        Therapeutic Failure
    120
    154
    No statistical analyses for this end point

    Secondary: Number of participants with clinical outcome at the TOC visit - Micro-ITT NTF-S population

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    End point title
    		 Number of participants with clinical outcome at the TOC visit - Micro-ITT NTF-S population
    End point description
    Clinical outcomes at TOC were categorized as clinical resolution, clinical improvement, clinical worsening and unable to determine. Clinical resolution at TOC was defined as resolution of signs and symptoms of acute cystitis present at baseline (BL) (and no symptoms) without receiving any other AB before the TOC visit. Clinical improvement at TOC was defined as improvement (but not complete resolution) in total symptom score (CSS) from BL, without receiving any other AB before the TOC visit. Clinical worsening at TOC was defined as worsening or no change in CSS from BL or received other AB for the current infection (uUTI) before or on the date of the TOC visit. Unable to determine outcome criteria were: BL score is missing (and thus improvement/worsening cannot be determined), TOC assessment is missing, or receipt of other AB not for the current infection before the TOC visit (unless clinical worsening outcome criteria were met).
    End point type
    Secondary
    End point timeframe
    TOC visit (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Clinical Resolution
    199
    175
        Clinical Improvement (CI)
    51
    68
        Clinical Worsening (CW)
    20
    17
        Unable to Determine
    22
    15
    No statistical analyses for this end point

    Secondary: Number of participants with microbiological response at the TOC visit – Micro-ITT NTF-S population

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    End point title
    		 Number of participants with microbiological response at the TOC visit – Micro-ITT NTF-S population
    End point description
    Participant-level microbiological response at TOC was categorized as microbiological success and microbiological failure. Microbiological success at TOC was defined as all baseline qualifying uropathogens (QUP)s had a microbiological outcome of eradication at TOC visit. Microbiological failure was defined as lack of microbiological success, including those participants with UTD outcomes.
    End point type
    Secondary
    End point timeframe
    TOC visit (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Microbiological Success
    213
    158
        Microbiological Failure
    79
    117
    No statistical analyses for this end point

    Secondary: Number of participants with microbiological outcome (MO) at the TOC visit – Micro-ITT NTF-S population

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    End point title
    		 Number of participants with microbiological outcome (MO) at the TOC visit – Micro-ITT NTF-S population
    End point description
    Participant-level MOs at TOC were categorized as microbiological eradication (ME), microbiological persistence (MP), microbiological recurrence (MR) and unable to determine (UTD). ME at TOC was defined as all baseline qualifying uropathogens (QUP) have an outcome of eradication at TOC (i.e., <10^3 CFU/mL without the participant receiving other systemic antimicrobials before the TOC Visit). MP at TOC was defined as at least 1 QUP has an outcome of persistence (≥10^3 CFU/mL) at TOC. MR at TOC was defined as at least 1 QUP had an outcome of recurrence and none have an outcome of persistence at TOC. UTD at TOC was defined as all QUP outcomes are UTD at TOC.
    End point type
    Secondary
    End point timeframe
    TOC Visit (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Microbiological Eradication (ME)
    213
    158
        Microbiological Persistence (MP)
    13
    31
        Microbiological Recurrence (MR)
    19
    52
        Unable to Determine (UTD)
    47
    34
    No statistical analyses for this end point

    Secondary: Number of participants with clinical response at the TOC visit - Micro-ITT NTF-S population

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    End point title
    		 Number of participants with clinical response at the TOC visit - Micro-ITT NTF-S population
    End point description
    Clinical response at TOC was categorized as clinical success and clinical failure. Clinical success at TOC was defined as resolution of symptoms of acute cystitis present at BL (and no new symptoms), without receiving any other AB before the TOC visit. Lack of resolution, including receipt of an AB for uUTI at the TOC visit, or a missing outcome assessment was defined as Clinical Failure at TOC.
    End point type
    Secondary
    End point timeframe
    TOC visit (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Clinical Success
    199
    175
        Clinical Failure
    93
    100
    No statistical analyses for this end point

    Secondary: Number of participants with clinical outcome at the follow up (FU) visit - Micro-ITT NTF-S population

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    End point title
    		 Number of participants with clinical outcome at the follow up (FU) visit - Micro-ITT NTF-S population
    End point description
    Clinical outcomes at FU were categorized as SCR, DCR, CI, CW, CR and (UTD. SCR at FU was resolution of symptoms of acute cystitis demonstrated at the TOC persist at the FU (and no symptoms), without receiving other AB before the FU. DCR at FU was resolution of symptoms of acute cystitis present at BL after clinical failure at TOC without receiving AB before FU. CI at FU was improvement in CSS from BL, but not complete resolution without receiving AB before FU. CW at FU was worsening or no change in CSS at FU compared to BL after clinical failure at TOC or receiving other AB for the current infection (uUTI) before or on the date of the FU. CR at FU was symptoms of acute cystitis reoccur at FU after clinical success at TOC. Unable to determine outcome criteria at FU were BL score missing, FU assessment missing or received other AB not for the current infection (uUTI) prior to the assessment (unless CS or CR outcome criteria were met).
    End point type
    Secondary
    End point timeframe
    FU visit (Days 21 to 31)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Sustained Clinical Resolution (SCR)
    168
    154
        Delayed Clinical Resolution (DCR)
    34
    35
        Clinical Improvement (CI)
    15
    19
        Clinical Worsening (CW)
    26
    32
        Clinical Recurrence (CR)
    8
    7
        Unable to Determine (UTD)
    41
    28
    No statistical analyses for this end point

    Secondary: Number of participants with therapeutic response (TR) (combined per participant clinical and microbiological response) at the follow up (FU) visit - Micro-ITT NTF-S population

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    End point title
    		 Number of participants with therapeutic response (TR) (combined per participant clinical and microbiological response) at the follow up (FU) visit - Micro-ITT NTF-S population
    End point description
    TR at FU was categorized as therapeutic success and therapeutic failure. A therapeutic success at FU referred to participants who have been deemed both a microbiological success (reduction of all QUPs recovered at BL to <10^3 CFU/mL, following microbiological eradication at the TOC visit, without receiving other AB before the FU visit) and a clinical success (resolution of signs and symptoms of acute cystitis demonstrated at the TOC visit persist at the FU visit and no new signs and symptoms, without receiving other AB before the FU visit [or AB for uUTI on day of FU visit]). Lack of clinical or microbiological success (including missing outcome assessments) was considered as therapeutic failure.
    End point type
    Secondary
    End point timeframe
    FU visit (Days 21 to 31)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Therapeutic Success
    126
    95
        Therapeutic Failure
    166
    180
    No statistical analyses for this end point

    Secondary: Number of participants with clinical response at the follow up (FU) visit - Micro-ITT NTF-S population

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    End point title
    		 Number of participants with clinical response at the follow up (FU) visit - Micro-ITT NTF-S population
    End point description
    Clinical response at FU was categorized as clinical success and clinical failure. Clinical success at FU was defined as resolution of symptoms of acute cystitis demonstrated at TOC persist at the FU visit (and no new symptoms), without receiving other AB before the FU visit. Lack of sustained clinical resolution or a missing outcome assessment was defined as clinical failure.
    End point type
    Secondary
    End point timeframe
    FU visit (Days 21 to 31)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Clinical Success
    168
    154
        Clinical Failure
    124
    121
    No statistical analyses for this end point

    Secondary: Number of participants with microbiological response at the follow up (FU) visit – Micro-ITT NTF-S population

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    End point title
    		 Number of participants with microbiological response at the follow up (FU) visit – Micro-ITT NTF-S population
    End point description
    Participant- level microbiological response at FU was categorized as microbiological success and microbiological failure. Microbiological success at FU was defined as all baseline QUPs had a microbiological outcome of sustained eradication at FU visit. Microbiological failure at FU was defined as not meeting criteria of microbiological success including those participants with UTD outcome.
    End point type
    Secondary
    End point timeframe
    FU visit (Days 21 to 31)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Microbiological Success
    154
    119
        Microbiological Failure
    138
    156
    No statistical analyses for this end point

    Secondary: Number of participants with microbiological outcome (MO) at the follow up (FU) visit – Micro-ITT NTF-S population

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    End point title
    		 Number of participants with microbiological outcome (MO) at the follow up (FU) visit – Micro-ITT NTF-S population
    End point description
    Participant-level MOs at FU were categorized as sustained microbiological eradication (SME), microbiological recurrence (MR), microbiological persistence (MP), delayed microbiological eradication (DME) and unable to determine (UTD). SME at FU was defined as all baseline QUPs had an outcome of sustained eradication at FU (i.e., <10^3 CFU/mL without the participant receiving other systemic antimicrobials before the FU Visit). MR at FU was defined as at least one QUP had an outcome of recurrence (≥10^3 CFU/mL) and none had an outcome of persistence at FU. MP at FU was defined as at least one QUP had an outcome of persistence at FU. DME at FU was defined as at least one QUP had an outcome of delayed eradication and none had an outcome of persistence or recurrence at FU. UTD at FU was defined as all QUP outcomes were unable to determine at FU.
    End point type
    Secondary
    End point timeframe
    FU visit (Days 21 to 31)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    292
    275
    Units: Participants
        Sustained Microbiological Eradication (SME)
    154
    119
        Microbiological Persistence (MP)
    19
    44
        Microbiological Recurrence (MR)
    29
    23
        Delayed Microbiological Eradication (DME)
    20
    28
        Unable to Determine (UTD)
    70
    61
    No statistical analyses for this end point

    Secondary: Number of participants with clinical response at the TOC visit - Intent-to-Treat (ITT) population

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    End point title
    		 Number of participants with clinical response at the TOC visit - Intent-to-Treat (ITT) population
    End point description
    Clinical response at TOC was categorized as clinical success and clinical failure. Clinical success at TOC was defined as resolution of signs and symptoms of acute cystitis present at BL (and no new symptoms), without receiving any other AB before the TOC visit. Lack of resolution, including receipt of an AB for uUTI at the TOC visit, or a missing outcome assessment was defined as Clinical Failure.
    End point type
    Secondary
    End point timeframe
    TOC visit (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    805
    800
    Units: Participants
        Clinical Success
    549
    517
        Clinical Failure
    256
    283
    No statistical analyses for this end point

    Secondary: Number of participants with clinical outcome at the TOC visit - Intent-to-Treat (ITT) population

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    End point title
    		 Number of participants with clinical outcome at the TOC visit - Intent-to-Treat (ITT) population
    End point description
    Clinical outcomes at TOC were categorized as clinical resolution, clinical improvement, clinical worsening and unable to determine. Clinical resolution at TOC was defined as resolution symptoms of acute cystitis present at baseline (BL) (and no symptoms) without receiving any other AB before the TOC visit. Clinical improvement at TOC was defined as improvement (but not complete resolution) in CSS from BL, without receiving any other AB before the TOC visit. Clinical worsening at TOC was defined as worsening or no change in CSS from BL or received other AB for the current infection (uUTI) before or on the date of the TOC visit. Unable to determine outcome criteria were: BL score is missing (and thus improvement/worsening cannot be determined), TOC assessment is missing, or receipt of other AB not for the current infection before the TOC visit (unless clinical worsening outcome criteria were met).
    End point type
    Secondary
    End point timeframe
    TOC visit (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    805
    800
    Units: Participants
        Clinical Resolution
    549
    517
        Clinical Improvement
    153
    199
        Clinical Worsening
    36
    39
        Unable to Determine
    67
    45
    No statistical analyses for this end point

    Secondary: Number of participants with clinical response at the follow up (FU) visit - Intent-to-Treat (ITT) population

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    End point title
    		 Number of participants with clinical response at the follow up (FU) visit - Intent-to-Treat (ITT) population
    End point description
    Clinical response at FU was categorized as clinical success and clinical failure. Clinical success at FU was defined as resolution of symptoms of acute cystitis demonstrated at TOC persist at the FU visit (and no new symptoms), without receiving other AB before the FU visit. Lack of sustained clinical resolution or a missing outcome assessment was defined as clinical failure.
    End point type
    Secondary
    End point timeframe
    FU visit (Days 21 to 31)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    805
    800
    Units: Participants
        Clinical Success
    478
    443
        Clinical Failure
    327
    357
    No statistical analyses for this end point

    Secondary: Number of participants with clinical outcome at the follow up (FU) visit - Intent-to-Treat (ITT) population

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    End point title
    		 Number of participants with clinical outcome at the follow up (FU) visit - Intent-to-Treat (ITT) population
    End point description
    Clinical outcomes at FU were categorized as Sustained Clinical Response (SCR), Delayed Clinical Response (DCR), CI, CW, Clinical Recurrence (CR) and UTD. SCR at FU was resolution of symptoms of acute cystitis demonstrated at TOC persist at the FU (and no symptoms), without receiving other AB before the FU. DCR at FU was resolution of symptoms of acute cystitis present at BL after clinical failure at TOC without receiving AB before FU. CI at FU was improvement in CSS from BL, but not complete resolution without receiving AB before FU. CW at FU was worsening or no change in CSS at FU compared to BL after clinical failure at TOC or receiving other AB for the current infection (uUTI) before or on the date of the FU. CR at FU was symptoms of acute cystitis reoccur at FU after clinical success at TOC. UTD outcome criteria at FU were BL score missing, FU assessment missing or received other AB not for current infection (uUTI) prior to assessment (unless CS or CR outcome criteria were met).
    End point type
    Secondary
    End point timeframe
    FU visit (Days 21 to 31)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    805
    800
    Units: Participants
        Sustained Clinical Resolution (SCR)
    478
    443
        Delayed Clinical Resolution (DCR)
    108
    116
        Clinical Improvement (CI)
    40
    52
        Clinical Worsening (CW)
    51
    65
        Clinical Recurrence (CR)
    25
    28
        Unable to Determine (UTD)
    103
    96
    No statistical analyses for this end point

    Secondary: Number of participants with treatment-emergent adverse events (TEAEs)

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    End point title
    		 Number of participants with treatment-emergent adverse events (TEAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of first dose (Day 1) through the final follow-up visit (Day 21-31)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    804
    798
    Units: Participants
    285
    200
    No statistical analyses for this end point

    Secondary: Change from baseline in hematology parameters: neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count at On Therapy and Test of Cure Visit

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    End point title
    		 Change from baseline in hematology parameters: neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count at On Therapy and Test of Cure Visit
    End point description
    Blood samples were collected for the analysis of hematology parameters: neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    736
    737
    Units: Giga cells per Liter (10^9 cells/L)
    arithmetic mean (standard deviation)
        Eosinophils, Baseline
    0.161 ( 0.1350 )
    0.163 ( 0.1331 )
        Eosinophils, On-Therapy
    0.006 ( 0.0841 )
    0.013 ( 0.0814 )
        Eosinophils, Test of Cure
    0.015 ( 0.0906 )
    0.018 ( 0.1081 )
        Basophils, Baseline
    0.054 ( 0.0227 )
    0.053 ( 0.0228 )
        Basophils, On-Therapy
    -0.001 ( 0.0195 )
    0.001 ( 0.0194 )
        Basophils, Test of Cure
    0.000 ( 0.0209 )
    0.001 ( 0.0183 )
        Lymphocytes, Baseline
    2.091 ( 0.6954 )
    2.121 ( 0.7122 )
        Lymphocytes, On-Therapy
    -0.018 ( 0.4523 )
    -0.076 ( 0.5051 )
        Lymphocytes, Test of Cure
    -0.010 ( 0.5292 )
    0.059 ( 0.5839 )
        Monocytes, Baseline
    0.529 ( 0.1803 )
    0.525 ( 0.1790 )
        Monocytes, On-Therapy
    -0.020 ( 0.1487 )
    0.003 ( 0.1711 )
        Monocytes, Test of Cure
    -0.029 ( 0.1731 )
    -0.012 ( 0.1778 )
        Neutrophils, Baseline
    4.582 ( 1.8893 )
    4.755 ( 1.8821 )
        Neutrophils, On-Therapy
    -0.490 ( 1.6201 )
    -0.453 ( 1.7453 )
        Neutrophils, Test of Cure
    -0.534 ( 2.0207 )
    -0.494 ( 1.9072 )
        Platelets, Baseline
    280.3 ( 68.46 )
    287.2 ( 73.51 )
        Platelets, On-Therapy
    -1.1 ( 33.03 )
    -2.5 ( 36.67 )
        Platelets, Test of Cure
    6.8 ( 42.12 )
    5.5 ( 58.04 )
    No statistical analyses for this end point

    Secondary: Number of participants with serious adverse events (SAEs)

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    End point title
    		 Number of participants with serious adverse events (SAEs)
    End point description
    An SAE is defined as any untoward medical occurrence that, at any dose may result in death or is life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity or is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment or is associated with liver injury and impaired liver function. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of first dose (Day 1) through the final follow-up visit (Day 21-31)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    804
    798
    Units: Participants
    5
    5
    No statistical analyses for this end point

    Secondary: Change from baseline in hematology parameter: hemoglobin level

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    End point title
    		 Change from baseline in hematology parameter: hemoglobin level
    End point description
    Blood samples were collected for the analysis of hemoglobin level. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    739
    737
    Units: Gram per Liter (g/L)
    arithmetic mean (standard deviation)
        Baseline
    132.5 ( 13.25 )
    131.7 ( 14.28 )
        On-Therapy
    -1.5 ( 6.74 )
    -1.9 ( 6.82 )
        Test of Cure
    -1.3 ( 7.44 )
    -1.4 ( 8.33 )
    No statistical analyses for this end point

    Secondary: Change from baseline in hematology parameter: hematocrit level

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    End point title
    		 Change from baseline in hematology parameter: hematocrit level
    End point description
    Blood samples were collected for the analysis of hematocrit level. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    739
    737
    Units: Percentage of hematocrit
    arithmetic mean (standard deviation)
        Baseline
    0.4314 ( 0.04146 )
    0.4292 ( 0.04348 )
        On-Therapy
    -0.0033 ( 0.02832 )
    -0.0041 ( 0.02715 )
        Test of Cure
    -0.0045 ( 0.02806 )
    -0.0029 ( 0.03194 )
    No statistical analyses for this end point

    Secondary: Change from baseline in hematology parameter: erythrocytes (RBC) count

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    End point title
    		 Change from baseline in hematology parameter: erythrocytes (RBC) count
    End point description
    Blood samples were collected for the analysis of erythrocytes count. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    739
    737
    Units: Tera cells per Liter (10^12 cells/L)
    arithmetic mean (standard deviation)
        Baseline
    4.539 ( 0.4211 )
    4.539 ( 0.4379 )
        On-Therapy
    -0.046 ( 0.2309 )
    -0.060 ( 0.2513 )
        Test of Cure
    -0.038 ( 0.2634 )
    -0.049 ( 0.3052 )
    No statistical analyses for this end point

    Secondary: Change from baseline in hematology parameter: mean corpuscular hemoglobin (MCH)

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    End point title
    		 Change from baseline in hematology parameter: mean corpuscular hemoglobin (MCH)
    End point description
    Blood samples were collected for the analysis of MCH. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    739
    737
    Units: Picogram (pg)
    arithmetic mean (standard deviation)
        Baseline
    29.28 ( 2.537 )
    29.09 ( 2.644 )
        On-Therapy
    -0.02 ( 0.795 )
    -0.02 ( 0.820 )
        Test of Cure
    -0.04 ( 0.780 )
    0.02 ( 0.917 )
    No statistical analyses for this end point

    Secondary: Change from baseline in hematology parameter: mean corpuscular volume (MCV)

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    End point title
    		 Change from baseline in hematology parameter: mean corpuscular volume (MCV)
    End point description
    Blood samples were collected for the analysis of MCV. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    739
    737
    Units: Femtolitre (fL)
    arithmetic mean (standard deviation)
        Baseline
    95.30 ( 7.191 )
    94.82 ( 7.511 )
        On-Therapy
    0.26 ( 4.287 )
    0.35 ( 4.303 )
        Test of Cure
    -0.15 ( 4.049 )
    0.39 ( 4.730 )
    No statistical analyses for this end point

    Secondary: Change from baseline in clinical chemistry parameters: serum blood urea nitrogen (BUN), glucose non-fasting, calcium, chloride, sodium, magnesium, phosphate, and potassium levels

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    End point title
    		 Change from baseline in clinical chemistry parameters: serum blood urea nitrogen (BUN), glucose non-fasting, calcium, chloride, sodium, magnesium, phosphate, and potassium levels
    End point description
    Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    781
    777
    Units: millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Serum Urea Nitrogen, Baseline
    4.742 ( 2.1107 )
    4.724 ( 1.8645 )
        Serum Urea Nitrogen, On- Therapy
    -0.056 ( 1.4269 )
    -0.018 ( 1.1663 )
        Serum Urea Nitrogen, Test of Cure
    0.022 ( 1.4000 )
    0.131 ( 1.4826 )
        Serum Calcium, Baseline
    2.363 ( 0.1196 )
    2.362 ( 0.1083 )
        Serum Calcium, On-Therapy
    -0.010 ( 0.0950 )
    -0.018 ( 0.0944 )
        Serum Calcium, Test of Cure
    -0.014 ( 0.1070 )
    -0.016 ( 0.0981 )
        Serum Chloride, Baseline
    101.0 ( 3.27 )
    100.9 ( 3.27 )
        Serum Chloride, On-Therapy
    0.3 ( 2.80 )
    0.1 ( 2.85 )
        Serum Chloride, Test of Cure
    0.4 ( 2.93 )
    0.4 ( 3.02 )
        Serum Glucose, Baseline
    5.590 ( 1.9980 )
    5.719 ( 2.1915 )
        Serum Glucose, On-Therapy
    0.230 ( 1.5120 )
    0.328 ( 1.9380 )
        Serum Glucose, Test of Cure
    0.215 ( 1.4412 )
    0.266 ( 1.6667 )
        Serum Magnesium, Baseline
    0.839 ( 0.0749 )
    0.835 ( 0.0802 )
        Serum Magnesium, On-Therapy
    -0.001 ( 0.0635 )
    -0.015 ( 0.0616 )
        Serum Magnesium, Test of Cure
    -0.011 ( 0.0674 )
    -0.015 ( 0.0689 )
        Serum Potassium, Baseline
    4.32 ( 0.414 )
    4.27 ( 0.415 )
        Serum Potassium, On-Therapy
    -0.04 ( 0.417 )
    -0.03 ( 0.428 )
        Serum Potassium, Test of Cure
    -0.03 ( 0.438 )
    0.00 ( 0.461 )
        Serum Phosphate, Baseline
    1.141 ( 0.1828 )
    1.139 ( 0.1725 )
        Serum Phosphate, On-Therapy
    -0.005 ( 0.1782 )
    -0.027 ( 0.1836 )
        Serum Phosphate, Test of Cure
    0.002 ( 0.1851 )
    -0.004 ( 0.1939 )
        Serum Sodium, Baseline
    138.8 ( 2.64 )
    138.8 ( 2.76 )
        Serum Sodium, On-Therapy
    0.0 ( 2.64 )
    -0.2 ( 2.64 )
        Serum Sodium, Test of Cure
    0.2 ( 2.91 )
    0.1 ( 2.91 )
    No statistical analyses for this end point

    Secondary: Change from baseline in clinical chemistry parameters: total bilirubin, direct bilirubin and creatinine levels

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    End point title
    		 Change from baseline in clinical chemistry parameters: total bilirubin, direct bilirubin and creatinine levels
    End point description
    Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    779
    776
    Units: micromoles per Liter (umol/L)
    arithmetic mean (standard deviation)
        Serum Direct Bilirubin, Baseline
    4.61 ( 1.669 )
    4.47 ( 1.128 )
        Serum Direct Bilirubin, On- Therapy
    -0.18 ( 1.192 )
    -0.18 ( 1.114 )
        Serum Direct Bilirubin, Test of Cure
    -0.19 ( 1.059 )
    0.15 ( 1.288 )
        Serum Total Bilirubin, Baseline
    6.57 ( 3.940 )
    6.56 ( 3.518 )
        Serum Total Bilirubin, On-Therapy
    -0.28 ( 2.510 )
    -0.42 ( 2.672 )
        Serum Total Bilirubin, Test of Cure
    -0.01 ( 2.976 )
    -0.29 ( 3.230 )
        Serum Creatinine, Baseline
    58.8 ( 30.59 )
    58.1 ( 17.22 )
        Serum Creatinine, On-Therapy
    0.8 ( 30.31 )
    0.3 ( 10.31 )
        Serum Creatinine, Test of Cure
    1.7 ( 14.00 )
    1.5 ( 13.40 )
    No statistical analyses for this end point

    Secondary: Change from baseline in clinical chemistry parameters: albumin and total protein levels

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    End point title
    		 Change from baseline in clinical chemistry parameters: albumin and total protein levels
    End point description
    Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    781
    777
    Units: gram per Liter (g/L)
    arithmetic mean (standard deviation)
        Serum Albumin, Baseline
    45.2 ( 3.33 )
    45.2 ( 3.11 )
        Serum Albumin, On-Therapy
    -0.4 ( 2.38 )
    -0.8 ( 2.56 )
        Serum Albumin, Test of Cure
    -0.5 ( 2.65 )
    -0.6 ( 2.84 )
        Serum Protein, Baseline
    71.5 ( 5.12 )
    71.6 ( 4.72 )
        Serum Protein, On-Therapy
    -0.7 ( 3.71 )
    -1.2 ( 3.89 )
        Serum Protein, Test of Cure
    -1.0 ( 4.19 )
    -1.1 ( 4.32 )
    No statistical analyses for this end point

    Secondary: Change from baseline in clinical chemistry parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels

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    End point title
    		 Change from baseline in clinical chemistry parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels
    End point description
    Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    777
    774
    Units: Units per Liter (U/L)
    arithmetic mean (standard deviation)
        Serum ALT, Baseline
    20.3 ( 20.34 )
    19.5 ( 14.66 )
        Serum ALT, On-Therapy
    0.2 ( 10.8 )
    -0.1 ( 7.9 )
        Serum ALT, Test of Cure
    0.4 ( 15.81 )
    -0.2 ( 9.93 )
        Serum AST, Baseline
    21.0 ( 13.72 )
    20.2 ( 10.48 )
        Serum AST, On-Therapy
    0.1 ( 9.83 )
    0.0 ( 7.90 )
        Serum AST, Test of Cure
    0.9 ( 9.89 )
    -0.5 ( 8.29 )
        Serum ALP, Baseline
    81.4 ( 29.96 )
    81.7 ( 28.99 )
        Serum ALP, On- Therapy
    -0.5 ( 9.61 )
    -0.1 ( 12.91 )
        Serum ALP, Test of Cure
    -1.0 ( 12.00 )
    -0.4 ( 15.38 )
    No statistical analyses for this end point

    Secondary: Number of participants with urinalysis dipstick results

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    End point title
    		 Number of participants with urinalysis dipstick results
    End point description
    Urine samples were collected for urinalysis: Urine Glucose (GLU), Urine Protein (PRO), Urine Occult Blood (BLO), Urine Ketones (KET), Urine Nitrite (NIT) and Urine Leukocyte Esterase (LEU). Baseline is defined as the latest pre-dose assessment with a non-missing value. The dipstick test gives results in a semi-quantitative manner, and results can be read as Negative, Trace, Small, Moderate, Large, Positive, 50 milligram per deciliter (mg/dL), 150 mg/dL, >=500 mg/dL, 30 mg/dL, 100 mg/dL, 200 mg/dL, 5 mg/dL, 20 mg/dL, >=80 mg/dL indicating concentrations in the urine sample. In the category (GLU, Baseline, Negative), GLU indicates parameter, Baseline is the visit and Negative indicates the concentration in the urine sample.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    789
    783
    Units: Participants
        GLU, Baseline, Negative
    751
    738
        GLU, Baseline, 50 mg/dL
    4
    5
        GLU, Baseline, 150 mg/dL
    3
    4
        GLU, Baseline, >= 500 mg/dL
    21
    26
        GLU, On-Therapy, Negative
    700
    697
        GLU, On-Therapy, 50 mg/dL
    7
    7
        GLU, On-Therapy, 150 mg/dL
    1
    5
        GLU, On-Therapy, >= 500 mg/dL
    23
    28
        GLU, Test of Cure, Negative
    686
    693
        GLU, Test of Cure, 50 mg/dL
    9
    10
        GLU, Test of Cure, 150 mg/dL
    12
    4
        GLU, Test of Cure, >= 500 mg/dL
    12
    20
        PRO, Baseline, Negative
    524
    529
        PRO, Baseline, 30 mg/dL
    171
    149
        PRO, Baseline, 100 mg/dL
    78
    85
        PRO, Baseline, >=500 mg/dL
    5
    6
        PRO, On-Therapy, Negative
    575
    631
        PRO, On-Therapy, 30 mg/dL
    110
    83
        PRO, On-Therapy, 100 mg/dL
    43
    19
        PRO, On-Therapy, >=500 mg/dL
    3
    4
        PRO, Test of Cure, Negative
    605
    605
        PRO, Test of Cure, 30 mg/dL
    88
    88
        PRO, Test of Cure, 100 mg/dL
    25
    34
        PRO, Test of Cure, >=500 mg/dL
    1
    0
        BLO, Baseline, Positive
    0
    2
        BLO, Baseline, Negative
    345
    348
        BLO, Baseline, Trace
    2
    0
        BLO, Baseline, Small
    229
    217
        BLO, Baseline, Moderate
    128
    129
        BLO, Baseline, Large
    80
    81
        BLO, On-Therapy, Negative
    560
    520
        BLO, On-Therapy, Small
    116
    161
        BLO, On-Therapy, Moderate
    23
    30
        BLO, On-Therapy, Large
    32
    26
        BLO, Test of Cure, Negative
    517
    511
        BLO, Test of Cure, Small
    128
    139
        BLO, Test of Cure, Moderate
    49
    45
        BLO, Test of Cure, Large
    25
    32
        KET, Baseline, Negative
    754
    748
        KET, Baseline, 5 mg/dL
    14
    18
        KET, Baseline, 20 mg/dL
    11
    7
        KET, On-Therapy, Negative
    712
    699
        KET, On-Therapy, 5 mg/dL
    14
    22
        KET, On-Therapy, 20 mg/dL
    5
    15
        KET, On-Therapy, >=80 mg/dL
    0
    1
        KET, Test of Cure, Negative
    706
    700
        KET, Test of Cure, 5 mg/dL
    7
    20
        KET, Test of Cure, 20 mg/dL
    6
    7
        NIT, Baseline, Negative
    552
    531
        NIT, Baseline, Positive
    237
    252
        NIT, On-Therapy, Negative
    694
    697
        NIT, On-Therapy, Positive
    37
    40
        NIT, Test of Cure, Negative
    697
    669
        NIT, Test of Cure, Positive
    22
    58
        LEU, Baseline, Negative
    245
    232
        LEU, Baseline, Trace
    96
    91
        LEU, Baseline, Small
    75
    80
        LEU, Baseline, Moderate
    120
    116
        LEU, Baseline, Large
    251
    262
        LEU, Baseline, Missing
    2
    1
        LEU, On-Therapy, Negative
    510
    475
        LEU, On-Therapy, Trace
    79
    82
        LEU, On-Therapy, Small
    50
    49
        LEU, On-Therapy, Moderate
    34
    57
        LEU, On-Therapy, Large
    58
    74
        LEU, Test of Cure, Negative
    526
    494
        LEU, Test of Cure, Trace
    61
    49
        LEU, Test of Cure, Small
    43
    48
        LEU, Test of Cure, Moderate
    35
    59
        LEU, Test of Cure, Large
    54
    77
    No statistical analyses for this end point

    Secondary: Absolute mean values of urine specific gravity

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    End point title
    		 Absolute mean values of urine specific gravity
    End point description
    Urine samples were collected from participants to assess urine specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    779
    773
    Units: Ratio
    arithmetic mean (standard deviation)
        Baseline
    1.0172 ( 0.00693 )
    1.0174 ( 0.00686 )
        On-Therapy
    1.0176 ( 0.00716 )
    1.0167 ( 0.00696 )
        Test of Cure
    1.0179 ( 0.00712 )
    1.0179 ( 0.00719 )
    No statistical analyses for this end point

    Secondary: Absolute mean values of urine potential of hydrogen (pH)

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    End point title
    		 Absolute mean values of urine potential of hydrogen (pH)
    End point description
    Urine samples were collected from participants to assess urine pH levels. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    763
    764
    Units: pH
    arithmetic mean (standard deviation)
        pH, Baseline
    5.7 ( 0.8 )
    5.7 ( 0.79 )
        pH, On-Therapy
    5.6 ( 0.66 )
    5.6 ( 0.69 )
        pH, Test of Cure
    5.6 ( 0.69 )
    5.7 ( 0.71 )
    No statistical analyses for this end point

    Secondary: Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at On-Therapy and Test of Cure Visit

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    End point title
    		 Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at On-Therapy and Test of Cure Visit
    End point description
    SBP and DBP were measured in a semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    804
    798
    Units: Millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        SBP, Baseline
    122 ( 13.33 )
    122.7 ( 13.98 )
        SBP, On-Therapy
    -1.1 ( 10.14 )
    -1.1 ( 10.72 )
        SBP, Test of Cure
    -0.4 ( 11.67 )
    -1.8 ( 12.19 )
        DBP, Baseline
    76.9 ( 8.17 )
    77 ( 9 )
        DBP, On-Therapy
    -0.5 ( 7.30 )
    -0.6 ( 7.73 )
        DBP, Test of Cure
    -0.1 ( 7.98 )
    -1.3 ( 8.37 )
    No statistical analyses for this end point

    Secondary: Change from baseline in body temperature

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    End point title
    		 Change from baseline in body temperature
    End point description
    Temperature was measured in a semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    804
    798
    Units: Celsius
    arithmetic mean (standard deviation)
        Temperature, Baseline
    36.61 ( 0.346 )
    36.63 ( 0.317 )
        Temperature, On-Therapy
    -0.01 ( 0.334 )
    -0.01 ( 0.372 )
        Temperature, Test of Cure
    -0.01 ( 0.349 )
    -0.04 ( 0.351 )
    No statistical analyses for this end point

    Secondary: Change from baseline in pulse rate at On Therapy and Test of Cure Visit

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    End point title
    		 Change from baseline in pulse rate at On Therapy and Test of Cure Visit
    End point description
    Pulse rate was measured in a semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment with a non-missing value. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    804
    798
    Units: beats per minute (bpm)
    arithmetic mean (standard deviation)
        Pulse rate, Baseline
    73.2 ( 9.64 )
    73.7 ( 10.32 )
        Pulse rate, On-Therapy
    0.9 ( 8.24 )
    1.3 ( 8.66 )
        Pulse rate, Test of Cure
    1.8 ( 9.74 )
    1.7 ( 9.95 )
    No statistical analyses for this end point

    Secondary: Number of participants with maximum change from baseline in electrocardiograms (ECG) parameter: QT interval corrected for heart rate according to Bazett's formula (QTcB) at Worst-case Post-baseline

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    End point title
    		 Number of participants with maximum change from baseline in electrocardiograms (ECG) parameter: QT interval corrected for heart rate according to Bazett's formula (QTcB) at Worst-case Post-baseline
    End point description
    Triplicate 12-lead ECGs (over an approximate 5- to 10-minute period) were performed using an ECG machine. Baseline is defined as the latest pre-dose assessment with a non-missing value. The row titles <=450, >450 to <=480, >480 to <=500 millisecond (msec) are the values at baseline. The category titles <= 30, 31-60, >60 msec are the maximum change from baseline values. The maximum change from baseline value category was determined by comparing the baseline value category to the worst-case post-baseline value category for each participant, which considered unscheduled and out of visit window assessments. Data of number of participants with any change at worst-case post-baseline (maximum grade increase post-baseline) is presented. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to Day 31
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    791
    784
    Units: Participants
        <= 450 msec|<=30 msec
    675
    700
        >450 to <=480 msec|<=30 msec
    40
    37
        >480 to <=500 msec|<=30 msec
    0
    1
        <= 450 msec|31-60 msec
    23
    12
        >450 to <=480 msec|31-60 msec
    2
    0
        >480 to <=500 msec|31-60 msec
    0
    0
        <= 450 msec|>60 msec
    1
    0
        >450 to <=480 msec|>60 msec
    0
    0
        >480 to <=500 msec|>60 msec
    0
    0
        <= 450 msec|Missing
    47
    31
        >450 to <=480 msec|Missing
    3
    3
        >480 to <=500 msec|Missing
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Maximum Change from Baseline in Electrocardiograms (ECG) parameter- QT interval corrected for heart rate according to Fridericia's formula (QTcF) at Worst-case Post-baseline

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    End point title
    		 Number of Participants with Maximum Change from Baseline in Electrocardiograms (ECG) parameter- QT interval corrected for heart rate according to Fridericia's formula (QTcF) at Worst-case Post-baseline
    End point description
    Triplicate 12-lead ECGs (over an approximate 5- to 10-minute period) were performed using an ECG machine. Baseline is defined as the latest pre-dose assessment with a non-missing value. The row titles <=450 msec, >450 msec to <=480 msec are the values at baseline. The category titles <= 30, 31-60, >60 msec are the maximum change from baseline values. The maximum change from baseline value category was determined by comparing the baseline value category to the worst-case post-baseline value category for each participant, which considered unscheduled and out of visit window assessments. Data of number of participants with any change at worst-case post-baseline (maximum grade increase post-baseline) is presented. Safety population included all randomized participants who receive at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to Day 31
    End point values
    		 Gepotidacin Nitrofurantoin
    Number of subjects analysed
    791
    784
    Units: Participants
        <= 450|<=30 msec
    721
    742
        >450 to <=480|<=30 msec
    8
    4
        <= 450|31-60 msec
    12
    4
        >450 to <=480|31-60 msec
    0
    0
        <= 450|>60 msec
    0
    0
        >450 to <=480|>60 msec
    0
    0
        <= 450|Missing
    50
    33
        >450 to <=480|Missing
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All cause mortality, non-serious adverse events (Non-SAEs) and serious adverse events (SAEs) were collected from the time of first dose (Day 1) through the final follow-up visit (Day 21-31).
    Adverse event reporting additional description
    Safety population included all randomized participants who receive at least 1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 25.1
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Nitrofurantoin
    Reporting group description
    		 Participants with uncomplicated urinary tract infection (acute cystitis) randomized to receive nitrofurantoin 100 mg capsule, BID, orally on Day 1 to Day 5. The total daily dose of nitrofurantoin received was 200 mg. Participants also received 2 tablets of placebo matched with gepotidacin BID, orally on Day 1 to Day 5. All doses were administered after food consumption and with water.

    Reporting group title
    Gepotidacin
    Reporting group description
    		 Participants with uncomplicated urinary tract infection (acute cystitis) randomized to receive gepotidacin 1500 milligram (mg) (2*750 mg, tablets), twice daily (BID), orally on Day 1 to Day 5. The total daily dose of gepotidacin received was 3000 mg. Participants also received 1 capsule of placebo matched with nitrofurantoin BID, orally on Day 1 to Day 5. All doses were administered after food consumption and with water.

    Serious adverse events
    		 Nitrofurantoin Gepotidacin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 798 (0.63%)
    5 / 804 (0.62%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Atrial fribrillation
         subjects affected / exposed
    0 / 798 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 798 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 798 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 798 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 798 (0.25%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Nitrofurantoin Gepotidacin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    119 / 798 (14.91%)
    235 / 804 (29.23%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 798 (2.76%)
    21 / 804 (2.61%)
         occurrences all number
    27
    23
    Dizziness
         subjects affected / exposed
    11 / 798 (1.38%)
    18 / 804 (2.24%)
         occurrences all number
    12
    18
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 798 (1.00%)
    3 / 804 (0.37%)
         occurrences all number
    8
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    24 / 798 (3.01%)
    147 / 804 (18.28%)
         occurrences all number
    25
    166
    Nausea
         subjects affected / exposed
    35 / 798 (4.39%)
    65 / 804 (8.08%)
         occurrences all number
    36
    66
    Flatulence
         subjects affected / exposed
    4 / 798 (0.50%)
    28 / 804 (3.48%)
         occurrences all number
    4
    29
    Faeces soft
         subjects affected / exposed
    4 / 798 (0.50%)
    23 / 804 (2.86%)
         occurrences all number
    4
    30
    Vomiting
         subjects affected / exposed
    7 / 798 (0.88%)
    18 / 804 (2.24%)
         occurrences all number
    7
    18
    Abdominal pain
         subjects affected / exposed
    7 / 798 (0.88%)
    12 / 804 (1.49%)
         occurrences all number
    8
    12
    Abdominal discomfort
         subjects affected / exposed
    4 / 798 (0.50%)
    9 / 804 (1.12%)
         occurrences all number
    5
    9
    Infections and infestations
    Fungal infection
         subjects affected / exposed
    10 / 798 (1.25%)
    9 / 804 (1.12%)
         occurrences all number
    10
    9
    Urinary tract infection
         subjects affected / exposed
    15 / 798 (1.88%)
    11 / 804 (1.37%)
         occurrences all number
    15
    11
    COVID-19
         subjects affected / exposed
    5 / 798 (0.63%)
    9 / 804 (1.12%)
         occurrences all number
    6
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Nov 2019
    This global amendment added details for an interim analysis to be conducted and managed by an Independent Data Monitoring Committee and sample size impact on the primary analysis population.
    14 Apr 2021
    This global amendment added a secondary objective to assess clinical response in the primary analysis population also also increased the planned total enrollment population.
    03 Nov 2021
    This global amendment provided clarification on Inclusion Criteria 3 and 4, including no requirement for contraception use or abstinence within 14 days of study entry in women of childbearing potential (WOCBP) with a negative high sensitivity urine pregnancy test result at Baseline (Day 1), expanded the On therapy Visit window, allowed flexible options for pregnancy testing and dose administration for the On-therapy Visit, and further defined the optimum window for pregnancy testing while participants were receiving study treatment. The amendment also included additional minor administrative edits.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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