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) (ADAPT-PO)

• ClinicalTrials.gov Identifier: NCT03788967
• Recruitment Status: Completed
• First Posted: December 28, 2018
• Results First Posted: July 25, 2022
• Last Update Posted: July 25, 2022
• Sponsor: Spero Therapeutics
• Information provided by (Responsible Party): Spero Therapeutics

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Complicated Urinary Tract Infection; Acute Pyelonephritis	Drug: TBPM-PI-HBr; Drug: Ertapenem; Drug: Dummy Infusion; Drug: Dummy tablets	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1372 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-blind, Double-dummy, Multicenter, Prospective Study to Assess the Efficacy, Safety and Pharmacokinetics of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) Compared to Intravenous Ertapenem in Patients With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)
• Actual Study Start Date: June 3, 2019
• Actual Primary Completion Date: May 20, 2020
• Actual Study Completion Date: May 27, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: TBPM-PI-HBr 600 mg; 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.	Drug: TBPM-PI-HBr; TBPM-PI-HBr tablets administered orally.; Other Name: SPR994; Drug: Dummy Infusion; Dummy intravenous infusion.
Active Comparator: Ertapenem 1 g; 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.	Drug: Ertapenem; Antibiotic Therapy for cUTI.; Drug: Dummy tablets; Dummy tablets orally.

Outcome Measures

Primary Outcome Measures :

1. Overall Response (Combined Clinical Cure and Microbiological Eradication) at Test-of-Cure (TOC) in Micro Intent-to-Treat Population [ Time Frame: 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.
2. Number of Participants With Treatment Emergent Adverse Events (TEAEs) in The Safety Population [ Time Frame: 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.

Secondary Outcome Measures :

1. Overall Response (Combined Clinical Cure Plus Microbiological Eradication) At Test-Of-Cure (TOC) In The Microbiologically Evaluable (ME) - TOC Population [ Time Frame: 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.
2. Clinical Cure at End-of-Treatment (EOT), TOC, and Sustained Clinical Cure at Late Follow-Up (LFU) Days in the Micro-ITT Populations [ Time Frame: 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.
3. Clinical Cure at EOT Days the Clinically Evaluable (CE-EOT) Populations [ Time Frame: 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.
4. Clinical Cure at TOC in the CE-TOC Populations [ Time Frame: 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.
5. Sustained Clinical Cure at LFU in the CE-LFU Populations [ Time Frame: 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.
6. Clinical Cure at EOT in the ME-EOT Populations [ Time Frame: 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.
7. Clinical Cure at TOC Days in the ME-TOC Populations [ Time Frame: 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.
8. Sustained Clinical Cure at LFU in the ME-LFU Population [ Time Frame: 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.
9. By-Patient Microbiological Eradication at EOT, TOC, and Sustained Microbiological Eradication at LFU Days in the Micro-ITT Population [ Time Frame: 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.
10. By-Pathogen Microbiological Eradication Rate at EOT in the Micro-ITT Population [ Time Frame: 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.
11. By-Pathogen Microbiological Eradication Rate at TOC in the Micro-ITT Population [ Time Frame: 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.
12. By-Pathogen Sustained Microbiological Eradication Rate at LFU in the Micro-ITT Population (m-ITT) [ Time Frame: 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.
13. By-Patient Microbiological Eradication at EOT in the ME-EOT Populations [ Time Frame: 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.
14. By-Patient Microbiological Eradication at TOC in the ME-TOC Population [ Time Frame: 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.
15. By-Patient Sustained Microbiological Eradication at LFU Days in the ME-LFU Populations [ Time Frame: 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.
16. By-pathogen Microbiological Eradication Rate in Participants at EOT in the ME-EOT Populations [ Time Frame: 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.
17. By-pathogen Microbiological Eradication Rate in Participants at TOC in the ME-TOC Populations [ Time Frame: 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.
18. By-pathogen Sustained Microbiological Eradication Rate in Participants at LFU in the ME-LFU Populations [ Time Frame: 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.
19. Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) In Subgroup Including: Stratified Infection Category [ Time Frame: 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.
20. Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Stratified Age Category [ Time Frame: 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.
21. Overall Response Rate (Combined Clinical Cure Plus Microbiological Eradication) at TOC In Subgroup Including Region [ Time Frame: 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.
22. Time (Days) to Resolution or Improvement of Signs and Symptoms of cUTI and AP Present a Baseline in the Micro-ITT Populations [ Time Frame: 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.
23. Time (Days) to Defervescence in Micro-ITT Population With a Documented Fever at Screening or Day 1 [ Time Frame: 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.
24. Rate of Clinical Relapse at the LFU Days in the Micro-ITT Population [ Time Frame: 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.
25. Rates Of Superinfection And New Infection In The Micro-ITT Population [ Time Frame: 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.
26. Apparent Volume of Distribution (Vss) at Steady State in TBPM-PI-HBr Recipients in the Pharmacokinetic (PK) Population [ Time Frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3 ]
27. Cmax in TBPM-PI-HBr Recipients in the PK Population [ Time Frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3 ]
28. Area Under Curve (AUC 0-24) in TBPM-PI-HBr Recipients in the PK Population [ Time Frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3 ]
29. Minimum Concentration (Cmin) in TBPM-PI-HBr Recipients in the PK Population [ Time Frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3 ]
30. Systemic Clearance (CL) in TBPM-PI-HBr Recipients in the PK Population [ Time Frame: Predose and post-dose at 0.25h, 0.5h, 1h, 2h, and 8h on Days 1 and 3 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

1. Male and female participants at least 18 years of age.
2. Able to provide informed consent.
3. Able to ingest oral tablets for the anticipated treatment duration. If present at baseline, nausea and/or vomiting should have been mild or well-controlled with antiemetic therapy, in order to tolerate oral study drug.

4. Have a diagnosis of cUTI or AP as defined below:

   a. cUTI definition:

   At least Two of the following signs and symptoms:

   i. Chills, rigors, or fever; fever must be observed and documented by a health care provider (oral, tympanic, rectal or core temperature >38.0°C [>100.4°F])

   ii. Dysuria, urgency to void, or increased urinary frequency

   iii. Nausea or vomiting, as reported by the participants

   iv. Lower abdominal, suprapubic, or pelvic pain

   And at least One of the following risk factors for cUTI:

   i. Implanted urinary tract instrumentation (e.g., nephrostomy tube, ureteric stents, or other urinary tract prosthetic material), ongoing intermittent bladder catheterization, or presence of an indwelling bladder catheter (Note: bladder catheters that have been in place for >24 hours prior to Screening must be removed or replaced prior to collection of the Screening urine for urinalysis and culture, unless removal or replacement is considered unsafe or contraindicated).

   ii. Current known functional or anatomical abnormality of the urogenital tract, including anatomic abnormalities of the urinary tract, neurogenic bladder, or post-void residual urine volume of ≥ 100 mL within the past 6 months.

   iii. Complete or partial obstructive uropathy (e.g., nephrolithiasis, tumor, fibrosis, urethral stricture) that is expected to be medically or surgically treated during study drug therapy (prior to end of the treatment [EOT]).

   iv. Known intrinsic renal disease with blood urea nitrogen (BUN) >20 mg/deciliter (dL), or blood urea >42.8 mg/dL, or serum creatinine (Cr) >1.4 mg/dL.

   v. Urinary retention, including urinary retention in men due to previously diagnosed benign prostatic hyperplasia (BPH).

   b. AP definition: Acute flank pain (onset within 7 days prior to randomization) or costovertebral angle tenderness on physical examination.

   And at least One of the following signs and symptoms:

   i. Chills, rigors, or fever; fever must be observed and documented by a health care provider (oral, tympanic, rectal or core temperature >38.0°C [>100.4°F]).

   ii. Peripheral white blood cell count (WBC) >10,000/mm3 or bandemia (≥15% immature polymorphonuclear neutrophils (PMNs), regardless of WBC count).

   iii. Nausea or vomiting, as reported by the participants.

   iv. Dysuria, urgency to void, or increased urinary frequency.

   Note: Participants who meet the definition for cUTI (Inclusion Criterion 4a) and also have flank pain or costovertebral tenderness should be randomized as cUTI rather than AP.

5. Have an adequate urine specimen for evaluation and culture obtained within 24 h prior to randomization with evidence of pyuria that includes at least one of the following:

   1. At least 10 WBCs per high power field (hpf) in urine sediment.
   2. At least 10 WBCs per cubic millimeter (mm3) in unspun (non-centrifuged) urine.
   3. Positive leukocyte esterase (LE) on urinalysis. Note: Participants could be randomized and administered investigational product (IP) prior to knowledge of urine culture results.
6. Expectation, in the judgment of the Investigator, that the participant would survive with effective antibiotic therapy and appropriate supportive care for the anticipated duration of the study.
7. Willing to comply with all the study activities and procedures throughout the duration of the study.
8. Participants were required to use a highly-effective method of birth control; male participants were required to use an effective barrier method of contraception from Screening through LFU and for 90 days following the last dose if sexually active with a female of childbearing potential (FOCP); female participants must not have been pregnant or nursing, and were required to commit to either sexual abstinence or use at least two medically accepted, effective methods of birth control (e.g., condom, spermicidal gel, oral contraceptive, indwelling intrauterine device, hormonal implant/patch, injections, approved cervical ring) from Screening through LFU and for 90 days following the last dose.

Exclusion Criteria

1. Presence of any known or suspected disease or condition that, in the opinion of the Investigator, may have confounded the assessment of efficacy, including but not limited to the following:

   1. Perinephric or renal corticomedullary abscess.
   2. Uncomplicated urinary tract infection (cUTI) - (acute cystitis that does not meet the cUTI disease definition, see Inclusion Criterion 4a).
   3. Polycystic kidney disease.
   4. Recent history of trauma to the pelvis or urinary tract.
   5. Confirmed or suspected acute or chronic bacterial prostatitis, orchitis, or epididymitis.
   6. Chronic vesicoureteral reflux.
   7. Previous or planned renal transplantation.
   8. Previous or planned cystectomy or ileal loop surgery.
   9. Known or suspected non-renal source of infection (e.g., infective endocarditis, osteomyelitis, meningitis, pneumonia).
   10. Confirmed or suspected infection that is caused by a pathogen that is resistant to either IP (e.g., carbapenem-resistant pathogen), including infection caused by fungi (e.g., candiduria) or mycobacteria (e.g., urogenital tuberculosis).
2. Gross hematuria requiring intervention other than administration of IP 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 (except surgery required relieving an obstruction or placing urinary tract instrumentation).

4. Creatinine clearance (CrCl) of ≤30 mL/min, as estimated by the Cockcroft-Gault formula:

   estimated Creatinine Clearance (eC_Cr) [mL/min]=((140-Age [yrs]) × Body Weight [kg] × [0.85 if Female])/(72 × Serum Creatinine [mg⁄dL]).

5. Anticipated concomitant use of non-study antibacterial drug therapy between randomization and the LFU Visit that would potentially effect outcome evaluations of cUTI/ AP, including but not limited to antibacterials with potential activity versus uropathogens, antibacterial drug prophylaxis, and antibacterial bladder irrigation.
6. Anticipated concomitant use of gastric acid-reducing medications between randomization and end-of-treatment (EOT), including proton pump inhibitors, histamine-2 receptor antagonists, and antacids.

7. Receipt of more than a single dose of a short-acting potentially effective antibiotic started within 72 h prior to randomization.

   Exception: Participants who received more than a single dose of short-acting potentially effective antibiotic within 72 h prior to randomization may be eligible for enrollment if they meet all of the following criteria:

   1. In the opinion of the Investigator they have failed the prior antibiotic therapy (e.g., have worsening signs and symptoms of cUTI/AP).
   2. Had a documented uropathogen (growth in urine culture >10^5 CFU/mL) that is resistant to the prior antibiotic therapy.
   3. Had a documented uropathogen that is carbapenem-susceptible.
   4. Received approval from the Medical Monitor to enroll the participants.
8. Severe hepatic impairment at Screening, as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5x upper limit of normal (ULN) or total bilirubin >3x ULN, or clinical signs of cirrhosis or end-stage hepatic disease (e.g., ascites, hepatic encephalopathy).
9. Any signs of severe sepsis, including shock or profound hypotension defined as systolic blood pressure <90 mmHg or a decrease of >40 mmHg from baseline that is not responsive to fluid challenge.
10. Pregnant or breastfeeding women.
11. History of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures).
12. Receipt of any investigational medication during the last 30 days or 5 half-lives, whichever is longer, prior to randomization.
13. Known history of human immunodeficiency virus (HIV) infection and or acquired immunodeficiency syndrome (AIDS)-defining illness, or known history of HIV infection and known CD4 count <200/mm^3 within the past year.
14. Presence of immunodeficiency or an immunocompromised condition including neutropenia (<1,000 neutrophils/mm^3 obtained from the local laboratory at Screening), hematologic malignancy, bone marrow transplant, or receiving immunosuppressive therapy such as cancer chemotherapy, medications for the rejection of transplantation, and long-term use of systemic corticosteroids (e.g., ≥20 mg/day of prednisone or systemic equivalent for at least 2 weeks).
15. A mean QT interval corrected using Fridericia's formula (QTcF) >480 msec based on triplicate ECGs at Screening.
16. History of significant hypersensitivity or allergic reaction to β-lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems), product excipients (mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and Opadry®) or any contraindication to the use of ertapenem.
17. History of known genetic metabolism anomaly associated with carnitine deficiency (e.g., carnitine transporter defect, methylmalonic aciduria, propionic acidemia)
18. Requirement for concomitant use of valproic acid, divalproex sodium, or probenecid between randomization and EOT.
19. Unable or unwilling to comply with the protocol.
20. An employee of the Investigator or study center with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as a family member of the employee or the Investigator.

Contacts and Locations

Locations

United States, California

Medical Facility

La Mesa, California, United States, 91942

United States, Florida

Medical Facility

Miami, Florida, United States, 33144

Bulgaria

Medical Facility

Blagoevgrad, Bulgaria, 2700

Medical Facility

Dobrich, Bulgaria, 9300

Medical Facility

Ruse, Bulgaria, 7000

Medical Facility

Shumen, Bulgaria, 9700

Medical Facility

Sofia, Bulgaria, 1431

Medical Facility

Sofia, Bulgaria, 1606

Medical Facility

Veliko Tarnovo, Bulgaria, 5000

Czechia

Medical Facility

Karlovy Vary, Czechia, 360 66

Medical Facility

Liberec, Czechia, 460 63

Medical Facility

Prague, Czechia, 140 59

Medical Facility

Zlin, Czechia, 762 75

Medical Facility

Ústí Nad Labem, Czechia, 401 13

Estonia

Medical Facility

Kohtla-Jarve, Estonia, 31025

Medical Facility

Tallinn, Estonia, 10617

Medical Facility

Voru, Estonia, 65526

Georgia

Medical Facility

Tbilisi, Georgia, 0144

Medical Facility

Tbilisi, Georgia, 0159

Medical Facility

Tbilisi, Georgia, 0160

Medical Facility

Tbilisi, Georgia, 0172

Medical Facility

Zestap'oni, Georgia, 2000

Hungary

Medical Facility

Budapest, Hungary, H-1082

Medical Facility

Budapest, Hungary, H-1204

Medical Facility

Nagykanizsa, Hungary, H-8800

Medical Facility

Nyíregyháza, Hungary, 4400

Medical Facility

Tatabánya, Hungary, 2800

Latvia

Medical Facility

Riga, Latvia, LV-1002

Medical Facility

Riga, Latvia, LV-1038

Medical Facility

Valmiera, Latvia, LV-4201

Moldova, Republic of

Medical Facility

Chisinau, Moldova, Republic of, MD-2004

Medical Facility

Chisinau, Moldova, Republic of, MD2025

Poland

Medical Facility

Katowice, Poland, 40-211

Medical Facility

Kraków, Poland, 31-559

Medical Facility

Oswiecim, Poland, 32-600

Medical Facility

Wrocław, Poland, 51-162

Medical Facility

Łódź, Poland, 90-153

Romania

Medical Facility

Bucharest, Romania, 020125

Medical Facility

Bucharest, Romania, 021494

Medical Facility

Bucharest, Romania, 050659

Medical Facility

Craiova, Romania, 200642

Medical Facility

Iaşi, Romania, 700503

Medical Facility

Oradea, Romania, 410469

Russian Federation

Medical Facility

Arkhangelsk, Russian Federation, 163001

Medical Facility

Lomonosov, Russian Federation, 198412

Medical Facility

Penza, Russian Federation, 440026

Medical Facility

Pyatigorsk, Russian Federation, 357500

Medical Facility

Saint Petersburg, Russian Federation, 191186

Medical Facility

Saint Petersburg, Russian Federation, 193312

Medical Facility

Saint Petersburg, Russian Federation, 194017

Medical Facility

Saint Petersburg, Russian Federation, 194044

Medical Facility

Saint Petersburg, Russian Federation, 194064

Medical Facility

Saint Petersburg, Russian Federation, 195009

Medical Facility

Saint Petersburg, Russian Federation, 195067

Medical Facility

Saint Petersburg, Russian Federation, 196247

Medical Facility

Saint Petersburg, Russian Federation, 197022

Medical Facility

Saint Petersburg, Russian Federation, 197374

Medical Facility

Saint Petersburg, Russian Federation, 198205

Medical facility

Saint Petersburg, Russian Federation, 199106

Medical Facility

Smolensk, Russian Federation, 214019

Medical Facility

Smolensk, Russian Federation, 214025

Medical Facility

Vsevolozhsk, Russian Federation, 188643

Medical Facility

Yaroslavl, Russian Federation, 150062

Serbia

Medical Facility

Belgrade, Serbia, 11 000

Medical Facility

Belgrade, Serbia, 11080

Medical Facility

Kragujevac, Serbia, 34 000

Medical Facility

Novi Sad, Serbia, 21 000

Medical Facility

Vršac, Serbia, 26300

Slovakia

Medical Facility

Bratislava, Slovakia, 826 06

Medical Facility

Galanta, Slovakia, 924 22

Medical Facility

Lučenec, Slovakia, 984 01

Medical Facility

Martin, Slovakia, 03659

Medical Facility

Poprad, Slovakia, 05845

Medical Facility

Svidník, Slovakia, 089 01

South Africa

Medical Facility

Benoni, South Africa, 1500

Medical Facility

Chatsworth, South Africa, 4092

Medical Facility

Durban, South Africa, 4001

Medical Facility

Johannesburg, South Africa, 2013

Medical Facility

Middelburg, South Africa, 1050

Medical Facility

Pretoria, South Africa, 0001

Ukraine

Medical Facility

Cherkasy, Ukraine, 18009

Medical Facility

Chernihiv, Ukraine, 14034

Medical Facility

Dnipro, Ukraine, 49027

Medical Facility

Ivano-Frankivs'k, Ukraine, 76008

Medical Facility

Ivano-Frankivs'k, Ukraine, 76018

Medical Facility

Kharkiv, Ukraine, 61037

Medical Facility

Kharkiv, Ukraine, 61103

Medical Facility

Lviv, Ukraine, 79010

Medical Facility

Lviv, Ukraine, 79059

Medical Facility

Mykolaiv, Ukraine, 54058

Medical Facility

Odesa, Ukraine, 65025

Medical Facility

Odesa, Ukraine, 65074

Medical Facility

Uzhhorod, Ukraine, 88000

Medical Facility

Vinnytsia, Ukraine, 21018

Medical Facility

Zaporizhia, Ukraine, 69600

Medical Facility

Zhytomyr, Ukraine, 10002

Sponsors and Collaborators

Spero Therapeutics

Investigators

• Study Director: David Melnick, MD; Spero Therapeutics Inc

  Study Documents (Full-Text)

Documents provided by Spero Therapeutics:

Study Protocol  [PDF] May 26, 2020

Statistical Analysis Plan  [PDF] September 3, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Eckburg PB, Muir L, Critchley IA, Walpole S, Kwak H, Phelan AM, Moore G, Jain A, Keutzer T, Dane A, Melnick D, Talley AK. Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection. N Engl J Med. 2022 Apr 7;386(14):1327-1338. doi: 10.1056/NEJMoa2105462.

• Responsible Party: Spero Therapeutics
• ClinicalTrials.gov Identifier: NCT03788967
• Other Study ID Numbers: SPR994-301; 2018-003671-35 ( EudraCT Number )
• First Posted: December 28, 2018
• Results First Posted: July 25, 2022
• Last Update Posted: July 25, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Spero Therapeutics:

Complicated Urinary Tract Infection; Acute Pyelonephritis

Additional relevant MeSH terms:

Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Disease Attributes; Pathologic Processes; Urologic Diseases; Nephritis, Interstitial; Nephritis; Kidney Diseases; Pyelitis; Ertapenem; Anti-Bacterial Agents; Anti-Infective Agents