Urinary Tract Infection, Acute Pyelonephritis
Conditions
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 (greater than or equal to (≥)18 years of age) with cUTI or AP.
Detailed description
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.
Interventions
Sterile powder for reconstitution administered as IV.
DRUGTBP-PI-HBr
TBP-PI-HBr film-coated immediate-release tablets.
DRUGDummy Infusion
0.9% sodium chloride administered as IV infusion.
DRUGDummy Tablets
TBP-PI-HBr matching dummy tablets.
Sponsors
Spero Therapeutics
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have a diagnosis of cUTI or AP. 2. 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: 1. at least 10 white blood cells (WBCs) per high power field (HPF) in urine sediment 2. at least 10 WBCs per millimeters cubed (mm\^3) in unspun urine 3. 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. 3. 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
1. Presence of any known or suspected disease or condition that may confound the assessment of efficacy. 2. Gross hematuria requiring intervention other than administration of study drug or removal/placement of urinary tract instrumentation. 3. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period. 4. Creatinine clearance (CrCl) of ≤30 milliliters per minute (mL/min), as estimated by the Cockcroft-Gault formula. 5. Anticipated concomitant use of non-study antimicrobial drug therapy between randomization and the LFU visit that would potentially effect outcome evaluations of cUTI/AP. 6. Receipt of a potentially effective antimicrobial within 72 hours prior to study randomization. 7. 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). 8. Pregnant or lactating women. 9. History of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures). 10. History of proven or suspected Clostridioides difficile associated diarrhoea. 11. History of human immunodeficiency virus (HIV) infection. 12. QT interval corrected using Fridericia's formula (QTcF) \>480 milliseconds (msec) based on screening ECG. 13. History of known genetic metabolism anomaly associated with carnitine deficiency. 14. Requirement for concomitant use of valproic acid, divalproex sodium, or probenecid between randomization and EOT. Note: Other inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-Treat (Micro-ITT) Population | At Day 17 (TOC) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | At Day 17 (TOC) | 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. |
| Number of Participants With Overall Response at the End-of-Treatment (EOT) and Late Follow-Up (LFU) Visits in the Micro-ITT Population | At Day 10 (EOT) and Day 28 (LFU) | 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. |
| Number of Participants With Overall Response at EOT and LFU Visits in the ME Population | At Day 10 (EOT) and Day 28 (LFU) | 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. |
| Number of Participants With Clinical Response at EOT, TOC and LFU Visits in the Micro-ITT Population | At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU) | 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. |
| Number of Participants With Clinical Response at EOT, TOC and LFU Visits in the CE Population | At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU) | 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. |
| Number of Participants With Clinical Response at EOT, TOC and LFU Visits in the ME Population | At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU) | 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. |
| Number of Participants With Microbiological Response at EOT, TOC and LFU Visits in the Micro-ITT Population | At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU) | 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. |
| Number of Participants With Microbiological Response at EOT, TOC and LFU Visits in the ME Population | At Day 10 (EOT), Day 17 (TOC) and Day 28 (LFU) | 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. |
| Number of Participants With Overall Response at EOT, TOC, and LFU Visits in Participants With Drug-Resistant Enterobacterales in Micro-ITT Population | Day 10 (EOT), Day 17 (TOC) and Day 28 (LFU) | 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. |
| Number of Participants With Overall Response at EOT, TOC, and LFU Visits in Participants With Drug-Resistant Enterobacterales in the ME Population | Day 10 (EOT), Day 17 (TOC) and Day 28 (LFU) | 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. |
| Number of Participants With Clinical Response at the EOT and TOC Visits in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population | Day 10 (EOT) and Day 17 (TOC) | 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. |
| Number of Participants With Clinical Response at the LFU Visit in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population | At Day 28 (LFU) | 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. |
| Number of Participants With Clinical Response at the EOT, TOC and LFU Visits in Participants With Drug-resistant Enterobacterales in the ME Population | Day 10 (EOT), Day 17 (TOC) and Day 28(LFU) | 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. |
| Number of Participants With Microbiological Response at the EOT and TOC Visits in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population | Day 10 (EOT) and Day 17 (TOC) | 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. |
| Number of Participants With Microbiological Response at the LFU Visit in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population | At Day 28 (LFU) | 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. |
| Number of Participants With Microbiological Response at the EOT and TOC Visits in Participants With Drug-resistant Enterobacterales in the ME Population | Day 10 (EOT) and Day 17 (TOC) | 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. |
| Number of Participants With Microbiological Response at the LFU Visit in Participants With Drug-resistant Enterobacterales in the ME Population | At Day 28 (LFU) | 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 at Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events | From first dose of study drug (Day 1) up to last follow-up visit (Day 28) | 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. |
| Plasma Concentrations of TBP-PI-HBr | 0.25 hour (h), 0.5h, 1h, 1.5h, 2h, 4h and 6h postdose at Day 2 | — |
Countries
Argentina, Bosnia and Herzegovina, Brazil, Bulgaria, Croatia, Estonia, Georgia, Greece, Hungary, India, Latvia, Moldova, Poland, Romania, Serbia, Slovakia, South Africa, Turkey (Türkiye), United States
Contacts
STUDY_DIRECTORDavid Hong, MD
Spero Therapeutics
Participant flow
Recruitment details
The planned enrollment for the full study was 2648 participants. As specified in the protocol, a pre-planned interim analysis occurred when approximately 60% of participants reached the test-of-cure visit. The study met the primary endpoint for efficacy at the interim analysis and the study was stopped. Enrollment was paused during the interim analysis. Therefore, a total of 1690 participants were enrolled in the study at various investigative sites from 21 Dec 2023 to 06 Feb 2025.
Pre-assignment details
Participants with a clinical diagnosis of complicated urinary tract infection/acute pyelonephritis (cUTI/AP) were randomized in a 1:1 ratio to receive either tebipenem pivoxil hydrobromide (TBP-PI-HBr) or imipenem-cilastatin.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 63.8 years STANDARD_DEVIATION 15.13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 47 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 797 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 54 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1595 Participants |
| Sex: Female, Male Female | 915 Participants |
| Sex: Female, Male Male | 406 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 843 | 2 / 844 |
| other Total, other adverse events | 68 / 843 | 23 / 844 |
| serious Total, serious adverse events | 29 / 843 | 22 / 844 |
Outcome results
None listed