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)

Urinary Tract Infection Clinical Trial

— 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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06059846
• Other study ID #: SPR994-305
• Secondary ID: 2023-503785-22-0
• Status: Recruiting
• Phase: Phase 3
• Start date: December 21, 2023
• Est. completion date: December 2025

Study information

• Verified date: May 2024
• Source: Spero Therapeutics
• Contact: Caroline Wass
• Phone: +1 857-242-1555
• Email: cwass[@]sperotherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2648
• Est. completion date: December 2025
• Est. primary completion date: November 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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, in the opinion of the Investigator, 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 more than a single dose 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 diarrhea.

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 exclusion criteria as per protocol may apply.

Related Conditions & MeSH terms

• Acute Pyelonephritis
• Communicable Diseases
• Infections
• Pyelonephritis
• Urinary Tract Infection
• Urinary Tract Infections

Intervention

Drug:
• TBP-PI-HBr
TBP-PI-HBr film-coated immediate-release tablets.
• Imipenem-cilastatin
Sterile powder for reconstitution administered as IV.
• Dummy Infusion
0.9% sodium chloride administered as IV infusion.
• Dummy Tablets
TBP-PI-HBr matching dummy tablets.

Locations

Country	Name	City	State
Bosnia and Herzegovina	Medical Facility	Banja Luka
Bulgaria	Medical Facility	Blagoevgrad
Bulgaria	Medical Facility	Dobrich
Bulgaria	Medical Facility	Gabrovo
Bulgaria	Medical facility	Lom
Bulgaria	Medical Facility	Pleven
Bulgaria	Medical Facility	Plovdiv
Bulgaria	Medical facility	Ruse
Bulgaria	Medical facility	Shumen
Bulgaria	Medical Facility	Sliven
Bulgaria	Medical facility	Sofia
Bulgaria	Medical Facility	Varna
Croatia	Medical Facility	Cakovec
Croatia	Medical Facility	Slavonski Brod
Croatia	Medical Facility	Zagreb
Georgia	Medical facility	Tbilisi
Hungary	Medical Facility	Eger
Hungary	Medical Facility	Nyiregyhaza
Moldova, Republic of	Medical Facility	Chisinau
Poland	Medical Facility	Krakow
Poland	Medical Facility	Leczna
Poland	Medical Facility	Lodz
Poland	Medical Facility	Warsaw
Romania	Medical Facility	Brasov
Romania	Medical facility	Bucharest
Romania	Medical facility	Craiova
Romania	Medical Facility	Iasi
Romania	Medical Facility	Oradea
Romania	Medical Facility	Timisoara
Serbia	Medical facility	Belgrade
Serbia	Medical facility	Kragujevac
Serbia	Medical facility	Nis
Serbia	Medical facility	Novi Sad
Slovakia	Medical Facility	Bratislava
Slovakia	Medical Facility	Malacky
South Africa	Medical facility	Benoni
South Africa	Medical facility	Durban
South Africa	Medical Facility	Pretoria
United States	Medical facility	Miami	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Spero Therapeutics	GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Bosnia and Herzegovina,  Bulgaria,  Croatia,  Georgia,  Hungary,  Moldova, Republic of,  Poland,  Romania,  Serbia,  Slovakia,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Day 17
Secondary	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.	Day 17
Secondary	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.	Days 10 and 28
Secondary	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.	Days 10, 17, and 28
Secondary	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.	Days 10, 17, and 28
Secondary	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.	Days 10, 17, and 28
Secondary	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.	Days 10, 17, and 28
Secondary	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.	Days 10, 17, and 28
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		From first dose of study drug (Day 1) up to Day 28
Secondary	Plasma Concentration of Tebipenem		At multiple time points post dose on Day 2