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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy and Safety of Eravacycline Compared with Levofloxacin in Complicated Urinary Tract Infections

    Summary
    EudraCT number
    		 2013-004556-38
    Trial protocol
    		 HU   DE   IT   EE   CZ   LV   GR   BG   PL  
    Global end of trial date
    01 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Nov 2018
    First version publication date
    22 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TP-434-010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01978938
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Tetraphase Pharmaceuticals, Inc.
    Sponsor organisation address
    480 Arsenal Street, Suite 110, Watertown, United States, 02472
    Public contact
    Chief Medical Officer, Tetraphase Pharmaceuticals, Inc., 1 617-715-3600, medinfo@tphase.com
    Scientific contact
    Chief Medical Officer, Tetraphase Pharmaceuticals, Inc., 1 617-715-3600, medinfo@tphase.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    01 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that eravacycline is non-inferior to levofloxacin in responder outcome (clinical and microbiological response versus failure) at the post-treatment (PT) visit (defined as 6 to 8 days after the completion of therapy).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which the study was conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 2014
    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
    Poland: 46
    Country: Number of subjects enrolled
    Bulgaria: 76
    Country: Number of subjects enrolled
    Czech Republic: 21
    Country: Number of subjects enrolled
    Estonia: 39
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Hungary: 60
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Latvia: 77
    Country: Number of subjects enrolled
    Georgia: 46
    Country: Number of subjects enrolled
    Moldova, Republic of: 23
    Country: Number of subjects enrolled
    Romania: 125
    Country: Number of subjects enrolled
    Ukraine: 189
    Country: Number of subjects enrolled
    Russian Federation: 112
    Country: Number of subjects enrolled
    Colombia: 14
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    South Africa: 34
    Worldwide total number of subjects
    908
    EEA total number of subjects
    457
    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)
    0
    Adults (18-64 years)
    592
    From 65 to 84 years
    311
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with a diagnosis of complicated urinary tract infection (cUTI), including participants with acute pyelonephritis, were recruited into this study.

    Pre-assignment
    Screening details
    		 Screening and baseline assessments were performed after informed consent was obtained and within 36 hours prior to enrollment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    The Sponsor designee designated a randomisation administrator who maintained the randomisation codes to ensure that the blind was properly maintained and that only designated personnel who required knowledge of treatment assignments were unblinded. The study blind codes were broken after the statistical analysis plan was finalized and the database was locked.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eravacycline
    Arm description
    		 Eravacycline was administered intravenously (IV) at a dose of 1.5 milligrams per kilogram (mg/kg) of body weight every 24 hours (q24h). At minimum, the first 3 doses were administered IV. After an IV-to-oral (PO) transition, provided adequate clinical improvement, participants were administered 200 mg PO twice a day (BID) for a total therapy of 7 dosing cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eravacycline IV
    Investigational medicinal product code
    Other name
    TP-434
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each participant received 7 dose cycles of the study drug. At a minimum, the first 3 doses were administered IV. During each 24-hour dosing cycle on IV administration days, participants received 1 infusion over 60 minutes.

    Investigational medicinal product name
    Eravacycline PO
    Investigational medicinal product code
    Other name
    TP-434
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After an IV-to-PO transition, provided adequate clinical improvement, participants received PO doses (200 mg) administered BID (approximately 12 hours apart).

    Arm title
    		 Levofloxacin
    Arm description
    		 Levofloxacin (750 mg) was administered IV q24h. At minimum, the first 3 doses were administered IV. After an IV-to-PO transition, provided adequate clinical improvement, participants were administered 750 mg PO once a day (QD) for a total therapy of 7 dosing cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Levofloxacin IV
    Investigational medicinal product code
    Other name
    Levaquin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each participant received 7 dose cycles of study drug. At a minimum, the first 3 doses were administered IV. Levofloxacin (750 mg) was administered over a 60-minute infusion q24h.

    Investigational medicinal product name
    Levofloxacin PO
    Investigational medicinal product code
    Other name
    Levaquin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After an IV-to-PO transition, provided adequate clinical improvement, participants received a PO dose (750 mg) administered QD for 1 dose and a PO placebo dose for the second dose of the day (approximately 12 hours apart) to maintain treatment group blind.

    Number of subjects in period 1
    		Eravacycline Levofloxacin
    Started
    455
    453
    Received at least 1 dose of study drug
    454
    451
    Completed
    432
    439
    Not completed
    23
    14
         Consent withdrawn by subject
    8
    4
         Did not meet inclusion criteria
    -
    1
         Adverse event, non-fatal
    2
    1
         Previously scheduled procedure
    -
    1
         Lost to follow-up
    12
    6
         Noncompliance
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eravacycline
    Reporting group description
    		 Eravacycline was administered intravenously (IV) at a dose of 1.5 milligrams per kilogram (mg/kg) of body weight every 24 hours (q24h). At minimum, the first 3 doses were administered IV. After an IV-to-oral (PO) transition, provided adequate clinical improvement, participants were administered 200 mg PO twice a day (BID) for a total therapy of 7 dosing cycles.

    Reporting group title
    Levofloxacin
    Reporting group description
    		 Levofloxacin (750 mg) was administered IV q24h. At minimum, the first 3 doses were administered IV. After an IV-to-PO transition, provided adequate clinical improvement, participants were administered 750 mg PO once a day (QD) for a total therapy of 7 dosing cycles.

    Reporting group values
    		 Eravacycline Levofloxacin Total
    Number of subjects
    		 455 453 908
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 291 301 592
        From 65-84 years
    		 161 150 311
        85 years and over
    		 3 2 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.7 ( 18.82 ) 51.7 ( 19.81 ) -
    Gender categorical
    Units: Subjects
        Female
    		 291 302 593
        Male
    		 164 151 315
    Race
    Units: Subjects
        White
    		 434 433 867
        Black or African American
    		 14 14 28
        Asian
    		 3 1 4
        American Indian or Alaskan Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Other
    		 4 5 9
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 15 18 33
        Not Hispanic or Latino
    		 440 435 875

    End points

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    End points reporting groups
    Reporting group title
    Eravacycline
    Reporting group description
    		 Eravacycline was administered intravenously (IV) at a dose of 1.5 milligrams per kilogram (mg/kg) of body weight every 24 hours (q24h). At minimum, the first 3 doses were administered IV. After an IV-to-oral (PO) transition, provided adequate clinical improvement, participants were administered 200 mg PO twice a day (BID) for a total therapy of 7 dosing cycles.

    Reporting group title
    Levofloxacin
    Reporting group description
    		 Levofloxacin (750 mg) was administered IV q24h. At minimum, the first 3 doses were administered IV. After an IV-to-PO transition, provided adequate clinical improvement, participants were administered 750 mg PO once a day (QD) for a total therapy of 7 dosing cycles.

    Subject analysis set title
    Intent-To-Treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consisted of all randomised participants regardless of whether or not the participant received study drug. A participant was considered randomised when the Investigator or Investigator’s designee received the interactive web-based response system-generated randomisation number.

    Subject analysis set title
    Microbiological ITT (micro-ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The micro-ITT population consisted of all participants in the ITT population who had at least 1 baseline bacterial pathogen from a urine or blood culture that caused a urinary tract infection against which eravacycline had expected antibacterial activity.

    Subject analysis set title
    Microbiological Modified ITT (micro-MITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The micro-MITT population consisted of all participants in the micro-ITT population who received at least 1 dose of study drug.

    Subject analysis set title
    Microbiologically Evaluable (ME)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The ME population consisted of all participants in the micro-ITT and clinically evaluable populations who had a suitable urine specimen and an interpretable urine culture.

    Primary: Participants In The Micro-MITT Population With A Microbiologic Response

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    End point title
    		 Participants In The Micro-MITT Population With A Microbiologic Response
    End point description
    This outcome measure (Food and Drug Administration [FDA] and European Medicines Agency [EMA]) compared the microbiological responses of eravacycline to levofloxacin for both treatment groups in the micro-MITT population. Responses were success, failure, or indeterminate/missing. Success was considered a reduction of the baseline pathogen(s) to <10^4 colony-forming units/milliliter (CFU/mL). Failure required blood cultures at or beyond end of therapy (EOT) to be positive for baseline pathogen(s), or urine culture to grow ≥10^4 CFU/mL of the baseline pathogen(s). Indeterminate/missing indicated no interpretable culture data available.
    End point type
    Primary
    End point timeframe
    PT Visit
    End point values
    		 Eravacycline Levofloxacin
    Number of subjects analysed
    297
    302
    Units: Participants
        Success
    194
    213
        Failure
    85
    78
        Indeterminate/missing
    18
    11
    Statistical analysis title
    		 micro-MITT Population and Microbiological Response
    Statistical analysis description
    For the EMA, a 10% non-inferiority (NI) margin was used to determine success and the primary efficacy analysis was based on the micro-MITT population (co-primary efficacy outcome). The primary efficacy outcome was microbiological success at the PT visit in the micro-MITT population. Since the lower limit of the 99% confidence interval (CI) did not exceed the established NI margin, NI of eravacycline to levofloxacin in the micro-MITT population was not declared.
    Comparison groups
    Eravacycline v Levofloxacin
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.2
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -14.6
         upper limit
    		 4.8
    Notes
    [1] - To test the null hypothesis, an adjusted 2-sided 99% CI (using the Miettinen-Nurminen method) for the observed difference in microbiological success rates (eravacycline treatment group minus levofloxacin treatment group) was calculated for the micro-MITT population. If the lower limit of the 99% CI for the difference in microbiological success rates in the micro-MITT population exceeded –10%, then the null hypothesis was rejected and the NI of eravacycline to levofloxacin was declared.

    Primary: Participants In The ME Population With A Microbiologic Response

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    End point title
    		 Participants In The ME Population With A Microbiologic Response
    End point description
    This outcome measure (FDA and EMA) compared the microbiological responses of eravacycline to levofloxacin for both treatment groups in the ME population. Responses were either success or failure. Indeterminate/missing responses were not included. Success was considered a reduction of the baseline pathogen(s) to <10^4 CFU/mL. Failure required blood cultures at or beyond EOT to be positive for baseline pathogen(s), or urine culture to grow ≥10^4 CFU/mL of the baseline pathogen(s). Indeterminate/missing indicated no interpretable culture data available.
    End point type
    Primary
    End point timeframe
    PT Visit
    End point values
    		 Eravacycline Levofloxacin
    Number of subjects analysed
    255
    276
    Units: Participant
        Success
    180
    203
        Failure
    75
    73
    Statistical analysis title
    		 ME Population and Microbiologic Response
    Statistical analysis description
    For the EMA, a 10% NI margin was used to determine success and the primary efficacy analysis was based on the ME population (co-primary efficacy outcome). The primary efficacy outcome was microbiological success at the PT visit in the ME population. Since the lower limit of the 99% CI did not exceed the established NI margin, NI of eravacycline to levofloxacin in the ME population was not declared.
    Comparison groups
    Eravacycline v Levofloxacin
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -3
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 7.7
    Notes
    [2] - To test the null hypothesis, an adjusted 2-sided 99% CI (using the Miettinen-Nurminen method) for the observed difference in microbiological success rates (eravacycline treatment group minus levofloxacin treatment group) was calculated for the ME population. If the lower limit of the 99% CI for the difference in microbiological success rates in the ME population exceeded –10%, then the null hypothesis was rejected and the NI of eravacycline to levofloxacin was declared.

    Secondary: Participants In The Micro-ITT Population With A Responder Outcome At The PT Visit

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    End point title
    		 Participants In The Micro-ITT Population With A Responder Outcome At The PT Visit
    End point description
    This was the primary outcome measure for the FDA. Clinical responses were either cure, failure, or indeterminate/missing; microbiological responses were characterized programmatically as either success, failure, or indeterminate/missing. Clinical cure was defined as complete resolution or significant improvement of signs or symptoms of the infection; microbiological success was a reduction of the baseline pathogen(s) to <10^4 CFU/mL. An outcome of Responder required a clinical response of cure and a microbiological response of success. Any other combination of the clinical and microbiological responses was considered either Non-responder or Indeterminate.
    End point type
    Secondary
    End point timeframe
    PT Visit
    End point values
    		 Eravacycline Levofloxacin
    Number of subjects analysed
    298
    302
    Units: Participants
        Responder
    180
    202
        Non-responder
    100
    91
        Indeterminate
    18
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The timeframe for adverse event reporting was from the first dose of study drug through 30 days after the last dose of study drug or the late PT visit (whichever was later).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Eravacycline
    Reporting group description
    		 Eravacycline was administered IV at a dose of 1.5 mg/kg q24h. At minimum, the first 3 doses were administered IV. After an IV-to-PO transition, provided adequate clinical improvement, participants were administered 200 mg PO BID for a total therapy of 7 dosing cycles.

    Reporting group title
    Levofloxacin
    Reporting group description
    		 Levofloxacin (750 mg) was administered IV q24h. At minimum, the first 3 doses were administered IV. After an IV-to-PO transition, provided adequate clinical improvement, participants were administered 750 mg PO QD for a total therapy of 7 dosing cycles.

    Serious adverse events
    		 Eravacycline Levofloxacin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 455 (1.54%)
    6 / 450 (1.33%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 450 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 450 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 450 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 450 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 450 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 450 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 450 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 450 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 450 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 450 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Orchitis
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 450 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 450 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 450 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Eravacycline Levofloxacin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    129 / 455 (28.35%)
    26 / 450 (5.78%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 455 (3.08%)
    6 / 450 (1.33%)
         occurrences all number
    14
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    82 / 455 (18.02%)
    14 / 450 (3.11%)
         occurrences all number
    111
    15
    Vomiting
         subjects affected / exposed
    33 / 455 (7.25%)
    6 / 450 (1.33%)
         occurrences all number
    35
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2014
    Amendment 1.0 (Version 2.0 dated 08 May 2014): • Clarification of eligibility criteria • Clarification of sample size calculations • Clarification of statistical methods and efficacy assessments • Clarification of primary population to be used in analysis for the EMA to comply with guidance document • Addition of collection of clinical response data for participants who discontinue early from study drug administration • Clarification of microbiologic response criteria to align with United States (US) FDA guidance • Clarification of timing and criteria for IV-to-PO step-down • Clarification of timing of verification of PO study drug compliance, and • Other global administrative changes and clarifications
    12 Mar 2015
    Amendment 2.0 (Version 3.0 dated 12 March 2015): • Clarification of timing for study procedures and for procedures used to establish eligibility • Extension of blood culture collection through late PT visit (rather than the EOT visit) • Clarification of criteria for positive and negative leukocyte esterase • Clarification of microbiological failure as related to inclusion • Enrollment cap for participants with pyelonephritis with normal urinary tract anatomy changed based on US and European Union (EU) regulatory guidances • Introduction of alternative method for establishing eligibility related to creatinine clearance, for Investigator flexibility • Clarification of circumstances in which antibiotics may be used prior to study enrollment • Clarification of definition of “clinical failure” to include participants who required concomitant systemic antibiotics for a condition other than cUTI • Microbiological threshold changed to align with US and EU regulatory guidances • Clarification of analysis populations in alignment with the statistical analysis plan (SAP) and with US and EU regulatory guidances • Clarification of efficacy evaluations in alignment with the SAP, and • Other global administrative changes and clarifications

    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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