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A Study of Oral Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) Compared to Intravenous Imipenem-cilastatin in Participants With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) (PIVOT-PO)

Primary Purpose

Urinary Tract Infection, Acute Pyelonephritis

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
TBP-PI-HBr
Imipenem-cilastatin
Dummy Infusion
Dummy Tablets
Sponsored by
Spero Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Urinary Tract Infection

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Have a diagnosis of cUTI or AP. Have an adequate urine specimen for evaluation and culture obtained within 24 hours prior to randomization with evidence of pyuria that includes at least one of the following: at least 10 white blood cells (WBCs) per high power field (HPF) in urine sediment at least 10 WBCs per millimeters cubed (mm^3) in unspun urine positive leukocyte esterase (LE) on urinalysis Note: Participants may be randomized and administered study drug prior to knowledge of urine culture results, but pyuria must be documented. Expectation, in the judgment of the Investigator, that the participant will survive with effective antimicrobial therapy and appropriate supportive care for the anticipated duration of the study. Exclusion Criteria: Presence of any known or suspected disease or condition that, in the opinion of the Investigator, may confound the assessment of efficacy. Gross hematuria requiring intervention other than administration of study drug or removal/placement of urinary tract instrumentation. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period. Creatinine clearance (CrCl) of ≤30 milliliters per minute (mL/min), as estimated by the Cockcroft-Gault formula. Anticipated concomitant use of non-study antimicrobial drug therapy between randomization and the LFU visit that would potentially effect outcome evaluations of cUTI/AP. Receipt of more than a single dose of a potentially effective antimicrobial within 72 hours prior to study randomization. Severe hepatic impairment at Screening, as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5×upper limit of normal (ULN) or total bilirubin >3×ULN, or clinical signs of cirrhosis or end-stage hepatic disease (e.g., ascites, hepatic encephalopathy). Pregnant or lactating women. History of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures). History of proven or suspected Clostridioides difficile associated diarrhea. History of human immunodeficiency virus (HIV) infection. QT interval corrected using Fridericia's formula (QTcF) >480 milliseconds (msec) based on screening ECG. History of known genetic metabolism anomaly associated with carnitine deficiency. Requirement for concomitant use of valproic acid, divalproex sodium, or probenecid between randomization and EOT. Note: Other inclusion and exclusion criteria as per protocol may apply.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    TBP-PI-HBr 600 mg + Dummy Infusion

    Imipenem-cilastatin 500 mg + Dummy Tablets

    Arm Description

    Participants will receive TBP-PI-HBr 600 mg, orally and dummy infusion IV, every 6 hours from Days 1 through 10.

    Participants will receive imipenem-cilastatin 500 mg, IV and matched dummy tablets, orally, every 6 hours from Days 1 through 10.

    Outcomes

    Primary Outcome Measures

    Number of Participants With Overall Response at the Test-of-Cure (TOC) Visit
    Overall response includes combination of clinical cure and favorable microbiological response. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at Baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Favorable microbiological response (microbiological eradication) is defined as a reduction of Baseline uropathogens to <10^3 colony forming unit per milliliter (CFU/mL) and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline and participant is alive.

    Secondary Outcome Measures

    Number of Participants in the Microbiologically Evaluable Population With Overall Response at the TOC Visit
    Overall response includes combination of clinical cure and favorable microbiological response. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at Baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Favorable microbiological response (microbiological eradication) is defined as a reduction of Baseline uropathogens to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at Baseline and participant is alive.
    Number of Participants With Overall Response at the End-of-Treatment (EOT) and Late Follow-Up (LFU) Visits
    Overall response includes combination of clinical cure and favorable microbiological response. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at Baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Favorable microbiological response (microbiological eradication) is defined as a reduction of Baseline uropathogens to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at Baseline and participant is alive.
    Number of Participants With Clinical Response at the EOT, TOC and LFU Visits
    Participants will be evaluated for clinical response outcome based on assessment of signs and symptoms as: Cure, including sustained clinical cure: Sustained clinical cure is defined as met criteria for clinical cure at TOC, and remained free of new or recurrent signs and symptoms of cUTI or AP at LFU visit such that no further antibacterial therapy is warranted; Failure, including clinical relapse: Clinical relapse is defined as met criteria for clinical cure at TOC, but new signs and symptoms of cUTI or AP are present at LFU visit and participant requires antibacterial therapy for cUTI; Clinical indeterminate: insufficient data are available to determine if participant is a sustained clinical cure or clinical relapse. If a participant is assessed as a clinical failure at EOT, participant is automatically considered a failure at TOC and LFU visits. If a participant is assessed as a clinical failure at TOC, participant is automatically considered a failure at LFU visit.
    Number of Participants With Microbiological Response at the EOT, TOC and LFU Visits
    Participants will be evaluated for microbiological response based on blood and urine cultures as:Eradication, including sustained microbiologic eradication, i.e.,microbiologic eradication at TOC and no subsequent urine culture after TOC demonstrating recurrence of original Baseline uropathogen at ≥10^3 CFU/mL;Persistence, including microbiologic recurrence, i.e.,isolation from urine culture at ≥10^3 CFU/mL or blood culture of any of Baseline uropathogen(s) at any time after documented eradication at TOC visit up to and including LFU visit;Microbiologic indeterminate:no follow-up urine culture is available, or urine culture results are missing, or follow-up urine culture cannot be interpreted for any reason. If a participant is assessed as a microbiological persistence at EOT,participant is automatically considered persistent at TOC and LFU. If assessed as persistent at TOC, participant is automatically considered a persistent at LFU.
    Number of Participants With Overall Response at the EOT, TOC, and LFU Visits in Participants With Drug-resistant Enterobacterales
    Overall response includes combination of clinical cure and favorable microbiological response. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at Baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Favorable microbiological response (microbiological eradication) is defined as a reduction of Baseline uropathogens to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at Baseline and participant is alive.
    Number of Participants With Clinical Response at the EOT, TOC, and LFU Visits in Participants With Drug-resistant Enterobacterales
    Participants will be evaluated for clinical response outcome based on assessment of signs and symptoms as: Cure, including sustained clinical cure: Sustained clinical cure is defined as met criteria for clinical cure at TOC, and remained free of new or recurrent signs and symptoms of cUTI or AP at LFU visit such that no further antibacterial therapy is warranted; Failure, including clinical relapse: Clinical relapse is defined as met criteria for clinical cure at TOC, but new signs and symptoms of cUTI or AP are present at LFU visit and participant requires antibacterial therapy for cUTI; Clinical indeterminate: insufficient data are available to determine if participant is a sustained clinical cure or clinical relapse. If a participant is assessed as a clinical failure at EOT, participant is automatically considered a failure at TOC and LFU visits. If a participant is assessed as a clinical failure at TOC, participant is automatically considered a failure at LFU visit.
    Number of Participants With Microbiological Response at the EOT, TOC, and LFU Visits in Participants With Drug-resistant Enterobacterales
    Participants will be evaluated for microbiological response based on blood and urine cultures as:Eradication, including sustained microbiologic eradication, i.e.,microbiologic eradication at TOC and no subsequent urine culture after TOC demonstrating recurrence of original Baseline uropathogen at ≥10^3 CFU/mL;Persistence, including microbiologic recurrence, i.e.,isolation from urine culture at ≥10^3 CFU/mL or blood culture of any of Baseline uropathogen(s) at any time after documented eradication at TOC visit up to and including LFU visit;Microbiologic indeterminate:no follow-up urine culture is available, or urine culture results are missing, or follow-up urine culture cannot be interpreted for any reason. If a participant is assessed as a microbiological persistence at EOT,participant is automatically considered persistent at TOC and LFU. If assessed as persistent at TOC, participant is automatically considered a persistent at LFU.
    Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    Plasma Concentration of Tebipenem

    Full Information

    First Posted
    September 22, 2023
    Last Updated
    September 22, 2023
    Sponsor
    Spero Therapeutics
    Collaborators
    GlaxoSmithKline
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06059846
    Brief Title
    A Study of Oral Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) Compared to Intravenous Imipenem-cilastatin in Participants With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)
    Acronym
    PIVOT-PO
    Official Title
    A Phase 3, Randomized, Double-blind, Double-dummy, Multicenter, Multinational Study to Assess the Efficacy and Safety of Orally Administered Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) Compared to Intravenously Administered Imipenem-cilastatin in Patients With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    November 2023 (Anticipated)
    Primary Completion Date
    August 2025 (Anticipated)
    Study Completion Date
    March 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Spero Therapeutics
    Collaborators
    GlaxoSmithKline

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The primary purpose of this study is to assess the efficacy of oral TBP-PI-HBr as compared with intravenous (IV) imipenem-cilastatin with respect to the overall response (combined clinical cure plus microbiological eradication) at the Test-of-Cure (TOC) visit in hospitalized adult participants (≥18 years of age) with cUTI or AP.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Urinary Tract Infection, Acute Pyelonephritis

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    2648 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    TBP-PI-HBr 600 mg + Dummy Infusion
    Arm Type
    Experimental
    Arm Description
    Participants will receive TBP-PI-HBr 600 mg, orally and dummy infusion IV, every 6 hours from Days 1 through 10.
    Arm Title
    Imipenem-cilastatin 500 mg + Dummy Tablets
    Arm Type
    Active Comparator
    Arm Description
    Participants will receive imipenem-cilastatin 500 mg, IV and matched dummy tablets, orally, every 6 hours from Days 1 through 10.
    Intervention Type
    Drug
    Intervention Name(s)
    TBP-PI-HBr
    Other Intervention Name(s)
    SPR994
    Intervention Description
    TBP-PI-HBr film-coated immediate-release tablets.
    Intervention Type
    Drug
    Intervention Name(s)
    Imipenem-cilastatin
    Intervention Description
    Sterile powder for reconstitution administered as IV.
    Intervention Type
    Drug
    Intervention Name(s)
    Dummy Infusion
    Intervention Description
    0.9% sodium chloride administered as IV infusion.
    Intervention Type
    Drug
    Intervention Name(s)
    Dummy Tablets
    Intervention Description
    TBP-PI-HBr matching dummy tablets.
    Primary Outcome Measure Information:
    Title
    Number of Participants With Overall Response at the Test-of-Cure (TOC) Visit
    Description
    Overall response includes combination of clinical cure and favorable microbiological response. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at Baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Favorable microbiological response (microbiological eradication) is defined as a reduction of Baseline uropathogens to <10^3 colony forming unit per milliliter (CFU/mL) and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline and participant is alive.
    Time Frame
    Day 17
    Secondary Outcome Measure Information:
    Title
    Number of Participants in the Microbiologically Evaluable Population With Overall Response at the TOC Visit
    Description
    Overall response includes combination of clinical cure and favorable microbiological response. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at Baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Favorable microbiological response (microbiological eradication) is defined as a reduction of Baseline uropathogens to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at Baseline and participant is alive.
    Time Frame
    Day 17
    Title
    Number of Participants With Overall Response at the End-of-Treatment (EOT) and Late Follow-Up (LFU) Visits
    Description
    Overall response includes combination of clinical cure and favorable microbiological response. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at Baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Favorable microbiological response (microbiological eradication) is defined as a reduction of Baseline uropathogens to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at Baseline and participant is alive.
    Time Frame
    Days 10 and 28
    Title
    Number of Participants With Clinical Response at the EOT, TOC and LFU Visits
    Description
    Participants will be evaluated for clinical response outcome based on assessment of signs and symptoms as: Cure, including sustained clinical cure: Sustained clinical cure is defined as met criteria for clinical cure at TOC, and remained free of new or recurrent signs and symptoms of cUTI or AP at LFU visit such that no further antibacterial therapy is warranted; Failure, including clinical relapse: Clinical relapse is defined as met criteria for clinical cure at TOC, but new signs and symptoms of cUTI or AP are present at LFU visit and participant requires antibacterial therapy for cUTI; Clinical indeterminate: insufficient data are available to determine if participant is a sustained clinical cure or clinical relapse. If a participant is assessed as a clinical failure at EOT, participant is automatically considered a failure at TOC and LFU visits. If a participant is assessed as a clinical failure at TOC, participant is automatically considered a failure at LFU visit.
    Time Frame
    Days 10, 17, and 28
    Title
    Number of Participants With Microbiological Response at the EOT, TOC and LFU Visits
    Description
    Participants will be evaluated for microbiological response based on blood and urine cultures as:Eradication, including sustained microbiologic eradication, i.e.,microbiologic eradication at TOC and no subsequent urine culture after TOC demonstrating recurrence of original Baseline uropathogen at ≥10^3 CFU/mL;Persistence, including microbiologic recurrence, i.e.,isolation from urine culture at ≥10^3 CFU/mL or blood culture of any of Baseline uropathogen(s) at any time after documented eradication at TOC visit up to and including LFU visit;Microbiologic indeterminate:no follow-up urine culture is available, or urine culture results are missing, or follow-up urine culture cannot be interpreted for any reason. If a participant is assessed as a microbiological persistence at EOT,participant is automatically considered persistent at TOC and LFU. If assessed as persistent at TOC, participant is automatically considered a persistent at LFU.
    Time Frame
    Days 10, 17, and 28
    Title
    Number of Participants With Overall Response at the EOT, TOC, and LFU Visits in Participants With Drug-resistant Enterobacterales
    Description
    Overall response includes combination of clinical cure and favorable microbiological response. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP that were present at Baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Favorable microbiological response (microbiological eradication) is defined as a reduction of Baseline uropathogens to <10^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at Baseline and participant is alive.
    Time Frame
    Days 10, 17, and 28
    Title
    Number of Participants With Clinical Response at the EOT, TOC, and LFU Visits in Participants With Drug-resistant Enterobacterales
    Description
    Participants will be evaluated for clinical response outcome based on assessment of signs and symptoms as: Cure, including sustained clinical cure: Sustained clinical cure is defined as met criteria for clinical cure at TOC, and remained free of new or recurrent signs and symptoms of cUTI or AP at LFU visit such that no further antibacterial therapy is warranted; Failure, including clinical relapse: Clinical relapse is defined as met criteria for clinical cure at TOC, but new signs and symptoms of cUTI or AP are present at LFU visit and participant requires antibacterial therapy for cUTI; Clinical indeterminate: insufficient data are available to determine if participant is a sustained clinical cure or clinical relapse. If a participant is assessed as a clinical failure at EOT, participant is automatically considered a failure at TOC and LFU visits. If a participant is assessed as a clinical failure at TOC, participant is automatically considered a failure at LFU visit.
    Time Frame
    Days 10, 17, and 28
    Title
    Number of Participants With Microbiological Response at the EOT, TOC, and LFU Visits in Participants With Drug-resistant Enterobacterales
    Description
    Participants will be evaluated for microbiological response based on blood and urine cultures as:Eradication, including sustained microbiologic eradication, i.e.,microbiologic eradication at TOC and no subsequent urine culture after TOC demonstrating recurrence of original Baseline uropathogen at ≥10^3 CFU/mL;Persistence, including microbiologic recurrence, i.e.,isolation from urine culture at ≥10^3 CFU/mL or blood culture of any of Baseline uropathogen(s) at any time after documented eradication at TOC visit up to and including LFU visit;Microbiologic indeterminate:no follow-up urine culture is available, or urine culture results are missing, or follow-up urine culture cannot be interpreted for any reason. If a participant is assessed as a microbiological persistence at EOT,participant is automatically considered persistent at TOC and LFU. If assessed as persistent at TOC, participant is automatically considered a persistent at LFU.
    Time Frame
    Days 10, 17, and 28
    Title
    Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    Time Frame
    From first dose of study drug (Day 1) up to Day 28
    Title
    Plasma Concentration of Tebipenem
    Time Frame
    At multiple time points post dose on Day 2

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Have a diagnosis of cUTI or AP. Have an adequate urine specimen for evaluation and culture obtained within 24 hours prior to randomization with evidence of pyuria that includes at least one of the following: at least 10 white blood cells (WBCs) per high power field (HPF) in urine sediment at least 10 WBCs per millimeters cubed (mm^3) in unspun urine positive leukocyte esterase (LE) on urinalysis Note: Participants may be randomized and administered study drug prior to knowledge of urine culture results, but pyuria must be documented. Expectation, in the judgment of the Investigator, that the participant will survive with effective antimicrobial therapy and appropriate supportive care for the anticipated duration of the study. Exclusion Criteria: Presence of any known or suspected disease or condition that, in the opinion of the Investigator, may confound the assessment of efficacy. Gross hematuria requiring intervention other than administration of study drug or removal/placement of urinary tract instrumentation. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period. Creatinine clearance (CrCl) of ≤30 milliliters per minute (mL/min), as estimated by the Cockcroft-Gault formula. Anticipated concomitant use of non-study antimicrobial drug therapy between randomization and the LFU visit that would potentially effect outcome evaluations of cUTI/AP. Receipt of more than a single dose of a potentially effective antimicrobial within 72 hours prior to study randomization. Severe hepatic impairment at Screening, as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5×upper limit of normal (ULN) or total bilirubin >3×ULN, or clinical signs of cirrhosis or end-stage hepatic disease (e.g., ascites, hepatic encephalopathy). Pregnant or lactating women. History of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures). History of proven or suspected Clostridioides difficile associated diarrhea. History of human immunodeficiency virus (HIV) infection. QT interval corrected using Fridericia's formula (QTcF) >480 milliseconds (msec) based on screening ECG. History of known genetic metabolism anomaly associated with carnitine deficiency. Requirement for concomitant use of valproic acid, divalproex sodium, or probenecid between randomization and EOT. Note: Other inclusion and exclusion criteria as per protocol may apply.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Caroline Wass
    Phone
    +1 857-242-1555
    Email
    cwass@sperotherapeutics.com
    First Name & Middle Initial & Last Name or Official Title & Degree
    Masha Gaber
    Phone
    +1 857-242-1555
    Email
    mgaber@sperotherapeutics.com
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Kamal Hamed, MD
    Organizational Affiliation
    Spero Therapeutics
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    No

    Learn more about this trial

    A Study of Oral Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) Compared to Intravenous Imipenem-cilastatin in Participants With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)

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