Study to Assess the Efficacy, Safety and Pharmacokinetics of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) Compared to Intravenous Ertapenem in Participants With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)

Phase 3

Completed

Conditions: Complicated Urinary Tract Infection
Acute Pyelonephritis

Interventions: Drug: TBPM-PI-HBr
Drug: Ertapenem
Drug: Dummy tablets
Drug: Dummy Infusion

Registration Number: NCT03788967

Lead Sponsor: Spero Therapeutics

Brief Summary: The key purpose of this study is to evaluate the efficacy, safety and pharmacokinetics (PK) of tebipenem pivoxil hydrobromide (TBPM-PI-HBr) compared to intravenous (IV) ertapenem, in participants with complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1372

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ertapenem 1 g	Dummy tablets	Ertapenem for IV injection, administered as a 1-gram IV infusion over 30 min once daily (q24h ± 0.5 h) plus dummy placebo tablets administered orally q8h (±0.5 h) up to Day 14; no dose adjustment of ertapenem was required for participants with renal insufficiency.
TBPM-PI-HBr 600 mg	Dummy Infusion	TBPM-PI-HBr 600 mg (300 mg×2 ) film-coated tablets, administered orally three times per day (every 8 hours \[q8h\] ± 0.5 h) plus a single dummy IV infusion over 30 minutes (min) once daily (every 24 hours \[q24h\] ± 0.5 h) up to Day 15; participants with moderate renal insufficiency (creatinine clearance \[CrCl\] \>30 to ≤50 mL/min) required TBPM-PI-HBr dosage adjustment to 300 mg (one tablet) q8h ± 0.5 h.
TBPM-PI-HBr 600 mg	TBPM-PI-HBr	TBPM-PI-HBr 600 mg (300 mg×2 ) film-coated tablets, administered orally three times per day (every 8 hours \[q8h\] ± 0.5 h) plus a single dummy IV infusion over 30 minutes (min) once daily (every 24 hours \[q24h\] ± 0.5 h) up to Day 15; participants with moderate renal insufficiency (creatinine clearance \[CrCl\] \>30 to ≤50 mL/min) required TBPM-PI-HBr dosage adjustment to 300 mg (one tablet) q8h ± 0.5 h.
Ertapenem 1 g	Ertapenem	Ertapenem for IV injection, administered as a 1-gram IV infusion over 30 min once daily (q24h ± 0.5 h) plus dummy placebo tablets administered orally q8h (±0.5 h) up to Day 14; no dose adjustment of ertapenem was required for participants with renal insufficiency.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment Emergent Adverse Events (TEAEs) in The Safety Population	From the first dose of administration up to Day 25 post-treatment ± 2 days (up to approximately 27 days)	An Adverse Event (AE) was defined as any untoward medical occurrence in a subject 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.
Overall Response (Combined Clinical Cure and Microbiological Eradication) at Test-of-Cure (TOC) in Micro Intent-to-Treat Population	Day 19 (TOC)	Overall response is participants with combined clinical cure and microbiological eradication. Clinical cure is defined as 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 antimicrobial therapy is warranted. Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 colony forming unit/milliliter (CFU/mL) and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.

Secondary Outcome Measures

Name	Time	Method
Sustained Clinical Cure at LFU in the CE-LFU Populations	Day 25 (LFU)	Clinical cure is defined as number of participants with 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 antimicrobial therapy is warranted. Sustained clinical cure is defined as number of participants who met criteria for clinical cure at TOC and remained free of signs and symptoms of cUTI or AP at LFU.
Clinical Cure at EOT in the ME-EOT Populations	Day 15 (EOT)	Clinical cure is defined as number of participants with 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 antimicrobial therapy is warranted.
Clinical Cure at TOC Days in the ME-TOC Populations	Day 19 (TOC)	Clinical cure is defined as number of participants with 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 antimicrobial therapy is warranted.
By-Pathogen Sustained Microbiological Eradication Rate at LFU in the Micro-ITT Population (m-ITT)	Day 25 (LFU)	Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Sustained Microbiological Eradication is defined as microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10\^5 CFU/mL. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogen analyzed.
By-pathogen Microbiological Eradication Rate in Participants at TOC in the ME-TOC Populations	Day 19 (TOC)	Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of participants analyzed.
By-pathogen Sustained Microbiological Eradication Rate in Participants at LFU in the ME-LFU Populations	Day 25 (LFU)	Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Sustained Microbiological Eradication is defined participants with microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10\^5 CFU/mL.Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogen analyzed.
By-Pathogen Microbiological Eradication Rate at EOT in the Micro-ITT Population	Days 15 (EOT)	Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.
By-Patient Microbiological Eradication at EOT in the ME-EOT Populations	Day 15 (EOT)	Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.
By-Patient Microbiological Eradication at TOC in the ME-TOC Population	Day 15 (TOC)	Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.
Cmax in TBPM-PI-HBr Recipients in the PK Population	Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Minimum Concentration (Cmin) in TBPM-PI-HBr Recipients in the PK Population	Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Overall Response (Combined Clinical Cure Plus Microbiological Eradication) At Test-Of-Cure (TOC) In The Microbiologically Evaluable (ME) - TOC Population	Day 19 (TOC)	Overall response is participants with combined clinical cure and microbiological eradication. Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of cUTI or acute pyelonephritis (AP) that were present at baseline and no new symptoms, such that no further antimicrobial therapy is warranted. Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.
Clinical Cure at End-of-Treatment (EOT), TOC, and Sustained Clinical Cure at Late Follow-Up (LFU) Days in the Micro-ITT Populations	Days 15 (EOT), Day 19 (TOC) and Day 25 (LFU)	Clinical cure is defined as number of participants with 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 antimicrobial therapy is warranted. Sustained clinical cure is defined as participants who met criteria for clinical cure at TOC and remained free of signs and symptoms of cUTI or AP at LFU.
Clinical Cure at EOT Days the Clinically Evaluable (CE-EOT) Populations	Day 15 (EOT)	Clinical cure is defined as number of participants with 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 antimicrobial therapy is warranted.
Clinical Cure at TOC in the CE-TOC Populations	Day 19 (TOC)	Clinical cure is defined as number of participants with 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 antimicrobial therapy is warranted.
Sustained Clinical Cure at LFU in the ME-LFU Population	Day 25 (LFU)	Clinical cure is defined as number of participants with 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 antimicrobial therapy is warranted. Sustained clinical cure is defined as participants who met criteria for clinical cure at TOC and remained free of signs and symptoms of cUTI or AP at LFU.
By-Patient Microbiological Eradication at EOT, TOC, and Sustained Microbiological Eradication at LFU Days in the Micro-ITT Population	Days 15 (EOT), 19 (TOC) and 25 (LFU)	Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication is defined as number of participants with reduction of Baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at Baseline. Sustained Microbiological Eradication is defined as number of participants with microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10\^5 CFU/mL.
By-pathogen Microbiological Eradication Rate in Participants at EOT in the ME-EOT Populations	Day 15 (EOT)	Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.
By-Pathogen Microbiological Eradication Rate at TOC in the Micro-ITT Population	Day 19 (TOC)	Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Microbiological eradication rate is the percentage of pathogens being eradicated from the overall number of pathogens analyzed.
By-Patient Sustained Microbiological Eradication at LFU Days in the ME-LFU Populations	Day 25 (LFU)	Microbiological eradication is defined as number of participants with reduction of baseline urine pathogen(s) to \<10\^3 colony forming unit/milliliter (CFU/mL) and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. Sustained Microbiological Eradication is defined participants with microbiologic eradication at the TOC and no subsequent urine culture after TOC demonstrating recurrence of the original baseline uropathogen at ≥10\^5 CFU/mL.
Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Including Region	Day 25 (LFU)	Overall response rate is percentage of participants with combined clinical cure plus microbiological eradication. Clinical cure is defined as 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 antimicrobial therapy is warranted. Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 colony forming unit/milliliter (CFU/mL) and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline. The point estimate and confidence interval (CI) is presented for Central and eastern Europe subgroup.
Time (Days) to Defervescence in Micro-ITT Population With a Documented Fever at Screening or Day 1	Day 25 (LFU)	Time to Defervescence (days) = date of first post-baseline temperature measure with maximum daily Temperature ≤38°C at the date of randomization.
Systemic Clearance (CL) in TBPM-PI-HBr Recipients in the PK Population	Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Stratified Age Category	Day 19 (TOC)	Overall response rate is percentage of participants with combined clinical cure plus microbiological eradication. Clinical cure is defined as 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 antimicrobial therapy is warranted. Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.
Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) In Subgroup Including: Stratified Infection Category	Day 19 (TOC)	Overall response rate is percentage of participants with combined clinical cure plus microbiological eradication. Clinical cure is defined as 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 antimicrobial therapy is warranted. Microbiological eradication is defined as reduction of baseline urine pathogen(s) to \<10\^3 colony forming unit/milliliter (CFU/mL) and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline.
Time (Days) to Resolution or Improvement of Signs and Symptoms of cUTI and AP Present a Baseline in the Micro-ITT Populations	Day 25 (LFU)	Time (days) to resolution or improvement of signs and symptoms of cUTI and AP present at baseline was defined as follows: date of the first visit at which all baseline signs/symptoms have improved by at least 1 grade with worsening of none and development of no new signs/symptoms of the index infection minus the date of randomization.
Rate of Clinical Relapse at the LFU Days in the Micro-ITT Population	Day 25 (LFU)	Clinical relapse is participants who met criteria for clinical cure at TOC, but new signs and symptoms of cUTI or AP are present at the LFU Visit and the subject requires antibiotic therapy for the cUT. Clinical cure is defined as 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 antimicrobial therapy is warranted.
Rates Of Superinfection And New Infection In The Micro-ITT Population	Day 25 (LFU)	Superinfection was isolation of a new uropathogen at ≥105 CFU/mL (other than the original Baseline pathogen\[s\] from blood and/or urine) from a urine culture that was accompanied by clinical signs and symptoms of infection requiring alternative antimicrobial therapy (e.g., the participant was assessed by the investigator as a clinical failure) during the period up to and including EOT. New infection was isolation of a new uropathogen at ≥105 CFU/mL (other than the original baseline pathogen\[s\] from blood and/or urine) from a urine culture that was accompanied by clinical signs and symptoms of infection requiring alternative antimicrobial therapy (e.g., the participant was assessed by the Investigator as a clinical failure) in the period after EOT.
Apparent Volume of Distribution (Vss) at Steady State in TBPM-PI-HBr Recipients in the Pharmacokinetic (PK) Population	Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3
Area Under Curve (AUC 0-24) in TBPM-PI-HBr Recipients in the PK Population	Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3

Trial Locations

Locations (2): Medical facility
🇷🇺
Saint Petersburg, Russian Federation
Medical Facility
🇺🇦
Zhytomyr, Ukraine

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