complicated urinary tract infection or acute pyelonephritis MedDRA version: 20.0 Level: PT Classification code 10046571 Term: Urinary tract infection System Organ Class: 10021881 - Infections and infestations
Conditions
Interventions
Product Name: tebipenem pivoxil hydrobromide
Product Code: TBPM-PI-HBr
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TEBIPENEM PIVOXIL HYDROBROMIDE
CAS Number: 161715-24-8
Current Spons
Sponsors
Spero Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male and female subjects 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 be 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) ii. Dysuria, urgency to void, or increased urinary frequency iii. Nausea or vomiting, as reported by the subject 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 milliliter (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-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 >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) 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 subject iv. Dysuria, urgency to void, or increased urinary frequency Note: Subjects 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 hours prior to randomization with evidence of pyuria that includes at least one of the following: a. At least 10 WBCs per high power field (hpf) in urine sediment b. At least 10 WBCs per cubic millimeter (mm3) in unspun urine c. Positive leukocyte esterase (LE) on urinalysis Note: Subjects may be randomized and administered IP prior to knowledge of urine culture results. 6. Expectation, in the judgment of the Investigator, that the subject will 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
Exclusion criteria
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, including but not limited to the following: a. Perinephric or renal corticomedullary abscess b. Uncomplicated urinary tract infection (uUTI [acute cystitis that does not meet the cUTI disease definition, see Inclusion Criterion 4a]) c. Polycystic kidney disease d. Recent history of trauma to the pelvis or urinary tract e. Confirmed or suspected acute or chronic bacterial prostatitis, orchitis, or epididymitis f. Chronic vesicoureteral reflux g. Previous or planned renal transplantation h. Previous or planned cystectomy or ileal loop surgery i. Known or suspected non-renal source of infection (e.g., infective endocarditis, osteomyelitis, meningitis, pneumonia) j. 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 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 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 or acquired immunodeficiency syndrome (AIDS)-defining illness, or known CD4 count <200/mm3 within the past year 14. Presence of immunodeficiency or an immunocompromised condition including neutropenia (<1,000 neutrophils/mm3 obtained from the local laboratory at Screening), hematologic malignancy, bone marrow transplant, or receiving immunosuppressive therapy such as cancer chemotherapy, medic
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To assess the overall response (combined clinical cure plus microbiological eradication) of oral TBPM-PI-HBr compared to intravenous (IV) ertapenem in subjects =18 years of age with cUTI/AP • To assess the safety of oral TBPM-PI-HBr compared to IV ertapenem in subjects =18 years of age with cUTI/AP;Timepoint(s) of evaluation of this end point: Test-of-Cure Visit (TOC): Day 19 (± 2 days);Secondary Objective: • To compare clinical cure rates between treatment groups • To compare microbiological eradication rates between treatment groups • To assess the population pharmacokinetics (PK) of TBPM-PI-HBr in subjects with cUTI/AP; the dosage of TBPM-PI-HBr will be confirmed based off a blinded analysis of PK data from the first approximately 35 enrolled TBPM-PI-HBr subjects;Primary end point(s): 1. Overall response (combined clinical cure plus microbiological eradication) at TOC in the microITT population • Clinical cure: 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: 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. Assessment of treatment emergent adverse events (TEAEs), clinical laboratory (hematology, clinical chemistry, and urinalysis) changes, ECGs, and vital sign changes in the Safety Analysis population | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall response (combined clinical cure plus microbiological eradication as defined above) at the TOC Visit in the ME population 2. Clinical cure at EOT, TOC, and LFU Visits in the micro-ITT, CE, and ME populations 3. By-subject and by-pathogen microbiological eradication at EOT, TOC, and LFU in the micro-ITT and ME populations 4. Overall response in subgroups, including: • Stratified infection category • Stratified age category • Country/Region 5. Time (days) to resolution or improvement of signs and symptoms of cUTI and AP present at baseline in the micro-ITT populations 6. Time (days) to defervescence in micro-ITT subjects with a documented fever at Screening or Day 1 7. Rate of clinical relapse at the LFU Visit in the micro-ITT population 8. Rates of superinfection and new infection in the micro-ITT population 9. Determine PK parameters (e.g., Vd, Cmax, AUC, T>MIC) in TBPM-PI-HBr recipients in the PK population;Timepoint(s) of evaluation of this end point: End-of-Treatment (EOT) Visit: Day 7-10, or up to Day 14 for bacteremic subjects Test-of-Cure Visit (TOC): Day 19 (± 2 days) Late Follow-Up (LFU) Visit: Day 25 (± 2 days) | — |
Countries
Bulgaria, Czech Republic, Estonia, Georgia, Hungary, Latvia, Moldova, Republic of, Poland, Romania, Russian Federation, Serbia, Slovakia, South Africa, Ukraine, United States
Contacts
Public ContactProject Management
PSI CRO AG
Outcome results
None listed