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 (greater than or equal to (≥)18 years of age) with cUTI or AP.
The study included a pre-planned interim analysis with stopping criteria for efficacy and futility that was performed by an independent data monitoring committee (IDMC). For full details please refer to the protocol and statistical analysis plan.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
1,690
TBP-PI-HBr film-coated immediate-release tablets.
Sterile powder for reconstitution administered as IV.
0.9% sodium chloride administered as IV infusion.
TBP-PI-HBr matching dummy tablets.
Medical facility
Miami, Florida, United States
Medical Facility
Miami, Florida, United States
Medical Facility
Buenos Aires, Argentina
Medical Facility
Córdoba, Argentina
Medical Facility
La Plata, Argentina
Medical Facility
Mendoza, Argentina
Number of Participants With Overall Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-Treat (Micro-ITT) Population
Overall response includes combined clinical cure plus microbiological eradication. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP present at baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Microbiological eradication (favorable microbiological response) 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: At Day 17 (TOC)
Number of Participants With Overall Response (Combined Per-Participant Clinical Cure and Favorable Microbiological Response) at the TOC Visit in the Microbiologically Evaluable (ME) Population
Overall response includes combined clinical cure plus microbiological eradication. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP present at baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Microbiological eradication (favorable microbiological response) 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: At Day 17 (TOC)
Number of Participants With Overall Response at the End-of-Treatment (EOT) and Late Follow-Up (LFU) Visits in the Micro-ITT Population
Overall response includes combined clinical cure plus microbiological eradication. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP present at baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Microbiological eradication (favorable microbiological response) 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: At Day 10 (EOT) and Day 28 (LFU)
Number of Participants With Overall Response at EOT and LFU Visits in the ME Population
Overall response includes combined clinical cure plus microbiological eradication. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP present at baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Microbiological eradication (favorable microbiological response) 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: At Day 10 (EOT) and Day 28 (LFU)
Number of Participants With Clinical Response at EOT, TOC and LFU Visits in the Micro-ITT Population
Clinical response at EOT and TOC is based on the Investigator's assessment of changes in baseline cUTI/AP signs and symptoms. Clinical cure: complete resolution or marked improvement of baseline symptoms with no new symptoms and no need for additional antimicrobial therapy. Clinical failure: baseline symptoms not fully resolved, new symptoms occur requiring non-study antibiotics, or death. Clinical indeterminate: insufficient data to classify response (e.g., lost to follow-up or missing data). Clinical response at LFU is based on change from baseline. Cure, including sustained clinical cure: met cure criteria at TOC and remained free of new or recurrent cUTI/AP symptoms at LFU with no need for further antibiotics. Failure, including clinical relapse: met cure criteria at TOC but developed new cUTI/AP symptoms at LFU requiring antibiotics. Clinical indeterminate: insufficient data to classify as sustained cure or relapse.
Time frame: At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU)
Number of Participants With Clinical Response at EOT, TOC and LFU Visits in the CE Population
Clinical response at EOT and TOC is based on the Investigator's assessment of changes in baseline cUTI/AP signs and symptoms. Clinical cure: complete resolution or marked improvement of baseline symptoms with no new symptoms and no need for additional antimicrobial therapy. Clinical failure: baseline symptoms not fully resolved, new symptoms occur requiring non-study antibiotics, or death. Clinical indeterminate: insufficient data to classify response (e.g., lost to follow-up or missing data). Clinical response at LFU is based on change from baseline. Cure, including sustained clinical cure: met cure criteria at TOC and remained free of new or recurrent cUTI/AP symptoms at LFU with no need for further antibiotics. Failure, including clinical relapse: met cure criteria at TOC but developed new cUTI/AP symptoms at LFU requiring antibiotics. Clinical indeterminate: insufficient data to classify as sustained cure or relapse.
Time frame: At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU)
Number of Participants With Clinical Response at EOT, TOC and LFU Visits in the ME Population
Clinical response at EOT and TOC is based on the Investigator's assessment of changes in baseline cUTI/AP signs and symptoms. Clinical cure: complete resolution or marked improvement of baseline symptoms with no new symptoms and no need for additional antimicrobial therapy. Clinical failure: baseline symptoms not fully resolved, new symptoms occur requiring non-study antibiotics, or death. Clinical indeterminate: insufficient data to classify response (e.g., lost to follow-up or missing data). Clinical response at LFU is based on change from baseline. Cure, including sustained clinical cure: met cure criteria at TOC and remained free of new or recurrent cUTI/AP symptoms at LFU with no need for further antibiotics. Failure, including clinical relapse: met cure criteria at TOC but developed new cUTI/AP symptoms at LFU requiring antibiotics. Clinical indeterminate: insufficient data to classify as sustained cure or relapse.
Time frame: At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU)
Number of Participants With Microbiological Response at EOT, TOC and LFU Visits in the Micro-ITT Population
Participants were evaluated for microbiological response based on blood and urine cultures as: Eradication, defined as reduction of Baseline uropathogens to \<10\^3 CFU/mL on urine culture and negative repeated blood culture (if blood culture was positive at Baseline) ;Persistence, defined as Isolation from urine culture of ≥10\^3 CFU/mL or from blood of any of the Baseline uropathogen(s) identified at study entry; 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.
Time frame: At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU)
Number of Participants With Microbiological Response at EOT, TOC and LFU Visits in the ME Population
Participants were evaluated for microbiological response based on blood and urine cultures as: Eradication, defined as reduction of baseline uropathogens to \<10\^3 CFU/mL on urine culture and negative repeated blood culture (if blood culture was positive at Baseline); Persistence, defined as Isolation from urine culture of ≥10\^3 CFU/mL or from blood of any of the Baseline uropathogen(s) identified at study entry; 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.
Time frame: At Day 10 (EOT), Day 17 (TOC) and Day 28 (LFU)
Number of Participants With Overall Response at EOT, TOC, and LFU Visits in Participants With Drug-Resistant Enterobacterales in Micro-ITT Population
Overall response includes combined clinical cure plus microbiological eradication. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP present at baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Microbiological eradication (favorable microbiological response) 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 10 (EOT), Day 17 (TOC) and Day 28 (LFU)
Number of Participants With Overall Response at EOT, TOC, and LFU Visits in Participants With Drug-Resistant Enterobacterales in the ME Population
Overall response includes combined clinical cure plus microbiological eradication. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP present at baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Microbiological eradication (favorable microbiological response) 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 10 (EOT), Day 17 (TOC) and Day 28 (LFU)
Number of Participants With Clinical Response at the EOT and TOC Visits in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population
Participants were evaluated for clinical response outcome based on assessment of signs and symptoms as: Cure, including sustained clinical cure (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 (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); or 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: Day 10 (EOT) and Day 17 (TOC)
Number of Participants With Clinical Response at the LFU Visit in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population
Participants were evaluated for clinical response outcome based on assessment of signs and symptoms as: Cure, including sustained clinical cure (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 (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); or 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: At Day 28 (LFU)
Number of Participants With Clinical Response at the EOT, TOC and LFU Visits in Participants With Drug-resistant Enterobacterales in the ME Population
Participants were 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: Day 10 (EOT), Day 17 (TOC) and Day 28(LFU)
Number of Participants With Microbiological Response at the EOT and TOC Visits in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population
Participants were 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: Day 10 (EOT) and Day 17 (TOC)
Number of Participants With Microbiological Response at the LFU Visit in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population
Participants were 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: At Day 28 (LFU)
Number of Participants With Microbiological Response at the EOT and TOC Visits in Participants With Drug-resistant Enterobacterales in the ME Population
Participants were 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: Day 10 (EOT) and Day 17 (TOC)
Number of Participants With Microbiological Response at the LFU Visit in Participants With Drug-resistant Enterobacterales in the ME Population
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: At Day 28 (LFU)
Number of Participants With at Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events
An Adverse Event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal investigational/experimental) product, whether or not related to this product. Serious Adverse Event (SAE) is any AE occurring at any dose and regardless of causality that results in death, is life threatening, requires immediate or prolongation of hospitalization, results in significant disability, congenital anomaly and is a medically important reaction. TEAEs are defined as events that are newly occurring or worsening from the time of the first dose of IP through LFU.
Time frame: From first dose of study drug (Day 1) up to last follow-up visit (Day 28)
Plasma Concentrations of TBP-PI-HBr
Time frame: 0.25 hour (h), 0.5h, 1h, 1.5h, 2h, 4h and 6h postdose at Day 2
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