E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
complicated urinary tract infection or acute pyelonephritis |
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E.1.1.1 | Medical condition in easily understood language |
complicated urinary tract infections |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10046571 |
E.1.2 | Term | Urinary tract infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• 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 |
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E.2.2 | Secondary objectives of the trial |
• 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 of the study
8. Subjects must agree to use a highly-effective method of birth control; male subjects must agree to use an effective barrier method of contraception from Screening through Late Follow-Up (LFU) and for 90 days following the last dose if sexually active with a female of childbearing potential (FOCP); female subjects must not be pregnant or nursing, and must commit to either sexual abstinence or use at least 2 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. |
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E.4 | Principal 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 <30 mL/min, as estimated by the Cockcroft-Gault formula:
eCCr[mL/min]=(140−Age [yrs]) × Body Weight [kg] × [0.85 if Female]/72 × Serum Creatinine [mgdL⁄]
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 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 (see Appendix 2 for allowed single dose, short-acting antibiotics)
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 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, 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 electrocardiograms (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
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E.5 End points |
E.5.1 | 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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Test-of-Cure Visit (TOC): Day 19 (± 2 days) |
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E.5.2 | 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 |
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E.5.2.1 | 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) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Georgia |
Moldova, Republic of |
Russian Federation |
Serbia |
South Africa |
Ukraine |
United States |
Bulgaria |
Czechia |
Estonia |
Hungary |
Latvia |
Poland |
Romania |
Slovakia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study is the time at which all required data has been collected to answer the research question(s) in the protocol. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |