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    Clinical Trial Results:
    A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Safety and Efficacy of Intravenous Sulbactam-ETX2514 in the Treatment of Hospitalized Adults With Complicated Urinary Tract Infections, Including Acute Pyelonephritis.

    Summary
    EudraCT number
    		 2017-002608-29
    Trial protocol
    		 BG  
    Global end of trial date
    17 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 May 2019
    First version publication date
    25 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CS2514-2017-0003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Entasis Therapeutics
    Sponsor organisation address
    Gatehouse Park BioHub, 35 Gatehouse Drive, Waltham, United States, MA 02451
    Public contact
    Robin Isaacs, Entasis Therapeutics, 001 781-810-8940, Enquiries@entasistx.com
    Scientific contact
    Robin Isaacs, Entasis Therapeutics, 001 781-810-8940 , Enquiries@entasistx.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
    21 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety profile of sulbactam-ETX2514 (ETX2514SUL) versus placebo in patients with complicated urinary tract infection (cUTI), including acute pyelonephritis (AP). The efficacy (secondary) objectives of this study were the following: · To evaluate the efficacy of ETX2514SUL in patients with cUTI, including AP, for the Microbiologically Modified Intent-to-Treat (m-MITT) Population · To compare the clinical cure rate in the 2 treatment groups for the Modified Intent-to-Treat (MITT), m-MITT, Clinically Evaluable (CE), and Microbiologically Evaluable (ME) Populations at the Test-of-Cure (TOC) Visit · To compare the microbiological eradication rate for the m-MITT and ME Populations at the TOC Visit.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and with all applicable laws and regulations of the locale and country where the study was conducted, and in compliance with Good Clinical Practice (GCP) Guidelines. The rationale of the study, procedural details, and investigational goals were explained to each patient, along with potential risks and benefits. Each patient was assured of his/her right to withdraw from the study at any time. Prior to the initiation of any study procedures, each patient signed and dated an approved Informed Consent Form (ICF). The original was kept on file by the Investigator with the patient’s records, and a copy was given to each patient.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belarus: 15
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Ukraine: 24
    Country: Number of subjects enrolled
    Bulgaria: 19
    Worldwide total number of subjects
    80
    EEA total number of subjects
    19
    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)
    55
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening procedures were performed as standard of care within 48 hours prior to randomization on Day 1, with the exception of local laboratory serum creatinine determination, which was obtained at the local laboratory within 24 hours prior to the first dose of Study Drug.

    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
    Blinding implementation details
    The Investigator, site personnel, Sponsor, and the Sponsor’s designees involved in monitoring, data management, and other aspects of the study were blinded to treatment assignment. An unblinded site monitor was assigned to review unblinded pharmacy data and followed documented procedures to ensure that the blind was maintained throughout the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ETX2514SUL+ IMI
    Arm description
    		 ETX2514/sulbactam (ETX2514SUL) + imipenem/cilastatin (IMI)
    Arm type
    		 Experimental

    Investigational medicinal product name
    ETX2514
    Investigational medicinal product code
    Other name
    ETX2514
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received 1 g ETX2514/1 g sulbactam intravenous (IV) administered every 6 hours (q6h) over 3 hours. In addition, all patients were administered background therapy with 500 mg/500 mg IMI IV q6h infused over 30 minutes. Infusions occurred q6h for 7 calendar days (28 doses), with a prolongation of therapy up to 14 days if clinically indicated in patients with concurrent bacteremia.

    Investigational medicinal product name
    Sulbactam sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received 1 g ETX2514/1 g sulbactam intravenous (IV) administered every 6 hours (q6h) over 3 hours. In addition, all patients were administered background therapy with 500 mg/500 mg IMI IV q6h infused over 30 minutes. Infusions of Study Drug occurred for 7 calendar days (28 doses), with a prolongation of therapy up to 14 days if clinically indicated in patients with concurrent bacteremia.

    Investigational medicinal product name
    IMI
    Investigational medicinal product code
    Other name
    Imipenem/cilastatin
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All patients were administered background therapy with 500 mg/500 mg IMI administered intravenous infused over 30 minutes every 6 hours for 7 calendar days (28 doses), with a prolongation of therapy up to 14 days if clinically indicated in patients with concurrent bacteremia.

    Arm title
    		 Placebo + IMI
    Arm description
    		 Matching placebo + imipenem/cilastatin (IMI)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received matching placebo (0.9% sodium chloride) IV administered q6h over 3 hours. In addition, all patients were administered background therapy with 500 mg/500 mg IMI IV q6h infused over 30 minutes. Infusions occurred q6h for 7 calendar days (28 doses), with a prolongation of therapy up to 14 days if clinically indicated in patients with concurrent bacteremia.

    Investigational medicinal product name
    IMI
    Investigational medicinal product code
    Other name
    Imipenem/cilastatin
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All patients were administered background therapy with 500 mg/500 mg IMI administered intravenous infused over 30 minutes every 6 hours for 7 calendar days (28 doses), with a prolongation of therapy up to 14 days if clinically indicated in patients with concurrent bacteremia.

    Number of subjects in period 1
    		ETX2514SUL+ IMI Placebo + IMI
    Started
    53
    27
    Completed
    52
    27
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ETX2514SUL+ IMI
    Reporting group description
    		 ETX2514/sulbactam (ETX2514SUL) + imipenem/cilastatin (IMI)

    Reporting group title
    Placebo + IMI
    Reporting group description
    		 Matching placebo + imipenem/cilastatin (IMI)

    Reporting group values
    		 ETX2514SUL+ IMI Placebo + IMI Total
    Number of subjects
    		 53 27 80
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 36 19 55
        From 65-84 years
    		 17 8 25
    Gender categorical
    Units: Subjects
        Female
    		 27 11 38
        Male
    		 26 16 42

    End points

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    End points reporting groups
    Reporting group title
    ETX2514SUL+ IMI
    Reporting group description
    		 ETX2514/sulbactam (ETX2514SUL) + imipenem/cilastatin (IMI)

    Reporting group title
    Placebo + IMI
    Reporting group description
    		 Matching placebo + imipenem/cilastatin (IMI)

    Primary: Overall Response at TOC Visit Based on FDA Criteria (m-MITT Population)

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    End point title
    		 Overall Response at TOC Visit Based on FDA Criteria (m-MITT Population)
    End point description
    This endpoint was defined as the proportion of patients with an overall success (clinical cure and microbiologic eradication) for the m-MITT Population (patients who met MITT criteria and had at least 1 baseline uropathogen from an appropriately collected pretreatment baseline urine or blood sample) at the Test-of-Cure (TOC) Visit. This endpoint was programmatically determined based on the clinical and microbiologic outcomes from the FDA criteria (demonstration that the baseline bacterial pathogen(s) was reduced to <10E4 CFU/mL on urine culture and negative on repeat blood culture [if positive at baseline]) as 1 of the following overall responses: - Overall success: A patient who was deemed a clinical cure AND who achieved microbiologic eradication. - Overall failure: A patient who was deemed a clinical failure OR was deemed to have microbiological persistence. - Overall indeterminate: Insufficient data were available to determine if the patient was an overall success or failure.
    End point type
    Primary
    End point timeframe
    From the start of treatment until the TOC Visit. The TOC Visit was to be completed 7 days (±1 day) after the end of treatment for all patients.
    End point values
    		 ETX2514SUL+ IMI Placebo + IMI
    Number of subjects analysed
    47
    21
    Units: Patients
        Success
    36
    17
        Failure
    9
    4
        Indeterminate
    2
    0
    Statistical analysis title
    		 Difference in the overall success rate per FDA
    Comparison groups
    ETX2514SUL+ IMI v Placebo + IMI
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.5
         upper limit
    		 19.8

    Primary: Overall Response at TOC Visit Based on EMA Criteria (m-MITT Population)

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    End point title
    		 Overall Response at TOC Visit Based on EMA Criteria (m-MITT Population)
    End point description
    This endpoint was defined as the proportion of patients with an overall success (clinical cure and microbiologic eradication) for the m-MITT Population (patients who met MITT criteria and had at least 1 baseline uropathogen from an appropriately collected pretreatment baseline urine or blood sample) at TOC Visit. This endpoint was programmatically determined based on the clinical and microbiologic outcomes from the EMA criteria (demonstration that the baseline bacterial pathogen(s) was reduced to <10E3 CFU/mL on urine culture and negative on repeat blood culture [if positive at baseline]) as 1 of the following overall responses: - Overall success: A patient who was deemed a clinical cure AND who achieved microbiologic eradication. - Overall failure: A patient who was deemed a clinical failure OR was deemed to have microbiological persistence. - Overall indeterminate: Insufficient data were available to determine if the patient was an overall success or failure.
    End point type
    Primary
    End point timeframe
    From the start of treatment until the TOC Visit. The TOC Visit was to be completed 7 days (±1 day) after the end of treatment for all patients.
    End point values
    		 ETX2514SUL+ IMI Placebo + IMI
    Number of subjects analysed
    47
    21
    Units: Patients
        Success
    35
    17
        Failure
    10
    4
        Indeterminate
    2
    0
    Statistical analysis title
    		 Difference in the overall success rate per EMA
    Comparison groups
    ETX2514SUL+ IMI v Placebo + IMI
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.8
         upper limit
    		 17.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the first dose of Study Drug until the Late Follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    ETX2514SUL+ IMI
    Reporting group description
    		 ETX2514/sulbactam (ETX2514SUL) + imipenem/cilastatin (IMI)

    Reporting group title
    Placebo + IMI
    Reporting group description
    		 Matching placebo + imipenem/cilastatin (IMI)

    Serious adverse events
    		 ETX2514SUL+ IMI Placebo + IMI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 ETX2514SUL+ IMI Placebo + IMI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 53 (37.74%)
    8 / 27 (29.63%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    Vascular pain
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 53 (9.43%)
    2 / 27 (7.41%)
         occurrences all number
    7
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Diarrhoea
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Dysbacteriosis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 27 (3.70%)
         occurrences all number
    2
    1
    Vomiting
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Infections and infestations
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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