| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated urinary tract infections including acute pyelonephritis |
|
| E.1.1.1 | Medical condition in easily understood language |
Complicated urinary tract infections including infections reaching
patients kidneys |
|
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037597 |
| E.1.2 | Term | Pyelonephritis acute |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10046577 |
| E.1.2 | Term | Urinary tract infections |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 |
| The primary objective of this study is to assess the efficacy of cefepime-AAI101 compared to Piperacillin/Tazobactam in the treatment of cUTI, including acute pyelonephritis (AP). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are the following:
• To assess the safety and tolerability of cefepime-AAI101 in hospitalized patients with cUTI or AP; and
• To characterize the PK of cefepime-AAI101 in patients with cUTI or AP. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients ≥18 years of age at the time of signing of informed consent;
2. Expectation that the patient’s cUTI or AP will require hospitalization and initial treatment withat least 7 days of i.v. antibiotics;
3. Female patients who are no longer of childbearing potential must meet 1 of the following
criteria: (a) Women ≥50 years of age who are considered post-menopausal as they have beenamenorrhoeic for ≥12 months following cessation of all pharmaceutical or exogenoushormonal treatment; (b) Women <50 years of age who are considered post-menopausal as they have beenamenorrhoeic for ≥12 months following cessation of all pharmaceutical or exogenous treatment and if follicle-stimulating hormone (FSH) levels are in the post-menopausal range. If the FSH levels are not available at the time of randomization, the patient must have a negative pregnancy test and agree to use highly effective contraception methods until the FSH result is available; or
(c) Permanent sterilization, defined as hysterectomy, bilateral oophorectomy, or bilateral salpingectomy;
4. Female patients of childbearing potential must have a negative urine and/or serum pregnancy test (serum β-human chorionic gonadotropin) within 1 day prior to study entry;
5. Male patients, female patients receiving hormone replacement therapy (HRT), and female patients of childbearing potential must agree to use highly effective contraception methods as defined below: NOTE: Female patients who are no longer of childbearing potential (i.e., confirmed to be permanently sterile as defined above or post-menopausal) and patients who are exclusively in same-sex relationships will not be required to use contraception. (a) Male patients and their partners of childbearing potential or partners sterilized by tubal ligation, female patients receiving HRT, female patients who have been sterilized by tubal ligation, and female patients of childbearing potential are required to use a condom (male or female) in conjunction with spermicidal gel, foam, cream, film, or suppository from the time of dosing until 90 days after the last dose; and (b) Male patients and their partners of childbearing potential and female patients of childbearing potential are required to use an additional highly effective form of contraception from the time of first dose until 90 days after the last dose. Additional highly effective methods of contraception include the following: Diaphragm or cervical vault cap in conjunction with spermicidal gel, foam, cream, film, or suppository;/ Male sterilization (for female patients, the vasectomized male partner should be the sole partner for that patient);/ Intrauterine device; or/ Established use of oral, injected, or implanted hormonal methods of contraception;
6. Pyuria, defined as: (a) White blood cell count >10 cells/mm3 in unspun urine or ≥10 cells/high power field in spun urine sediment; or (b) Urinalysis/dipstick analysis positive for leukocyte esterase;
7. Clinical signs and/or symptoms of cUTI (Complicated Urinary Tract Infection) or AP (Acute Pyelonephritis), as defined in Protocol, Table 1;
NOTE: If the criteria for both cUTI and AP are met, the infection type will be considered cUTI for randomization and analysis purposes.
8. Have a baseline urine culture specimen obtained within 48 hours prior to randomization and the first dose of study drug; and NOTE: Patients may be enrolled in this study and start i.v. study drug therapy before the Investigator knows the results of the baseline urine culture.
9. Expectation, in the judgment of the Investigator, that any implanted urinary instrumentation (e.g., nephrostomy tubes, ureteric stents, etc.) will be surgically removed or replaced before or within 24 hours after randomization, unless removal or replacement is considered unsafe or contraindicated. |
|
| E.4 | Principal exclusion criteria |
1. Known urine culture with Gram positive primary pathogen at > or = 10[5] colony-forming units (CFU)/mL (not contaminant) or suspected Gram-positive pathogen by Gram staining (Note: Gram staining is optional)
2. History of significant hypersensitivity or allergic reaction to cefepime, piperacillin/tazobactam, any of the excipients used in the respective formulations, any beta lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems, or monobactams), or any BLIs (e.g., tazobactam, sulbactam, or clavulanic acid);
3. In the opinion of the Investigator, the patient is considered unlikely to survive the approximately 6-week study period;
4. Weight >180 kg;
5. Concurrent infection that would interfere with evaluation of response to the study antibiotics;
6. Need for or receipt of concomitant systemic antimicrobial agents after signing of informed consent, in addition to those designated in the study-treatment groups, with the exception of a single oral dose of any antifungal treatment for vaginal candidiasis;
7. Receipt of potentially effective systemic antibacterial therapy for a continuous duration of >24 hours during the previous 72 hours before the study-qualifying baseline urine is obtained (Exception defined in Protocol, Exc. Criteria 7)
8. Complicated urinary tract infection (UTI) known at study entry to be caused by pathogens resistant to the study antibiotics;
9. Likely to require the use of an antibiotic for cUTI or AP prophylaxis during the patient’s participation in the study;
10. Intractable UTI at baseline that the Investigator anticipates would require >14 days of study drug therapy;
11. Complete, permanent obstruction of the urinary tract that is not anticipated to be medically or surgically relieved during i.v. study therapy and before EOT;
12. Gross hematuria requiring intervention other than administration of study drug or removal or exchange of a urinary catheter;
13. Presence of any known or suspected disease or condition that, in the opinion of the Investigator, may confound the assessment of efficacy. (Explained in Protocol, Exc. Criteria 13)
14. Suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination;
15. Impairment of renal function with estimated glomerular filtration rate <30 mL/min/1.73 m2 calculated by the 4-variable Modification of Diet in Renal Disease (MDRD) study equation (see Appendix D);
16. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period (except surgery required to relieve an obstruction or place a stent or nephrostomy prior to EOT);
17. Any condition or circumstance that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of study data;
18. Any rapidly progressing disease or immediately life-threatening illness, including acute hepatic failure and respiratory failure;
19. Presence of sepsis, producing life-threatening organ dysfunction, defined as ≥2 of the following criteria: a. Systolic blood pressure ≤100 mmHg that is not responsive to fluid challenge; b. Respiratory rate ≥22 breaths/min; and/or c. Altered mental status;
20. A QT interval corrected using Fridericia’s formula >450 msec;
21. Immunocompromising condition, including known history of acquired immune deficiency syndrome or known recent CD4 count <200/mm3, hematological malignancy, or bone marrow transplantation; or immunosuppressive therapy including cancer chemotherapy, medications for prevention of organ transplantation rejection, or the administration of corticosteroids ≥20 mg of prednisone or equivalent per day administered continuously for >14 days prior to randomization;
22. One or more of the following laboratory abnormalities in baseline specimens obtained at Screening: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or total bilirubin level >3 × upper limit of normal, or current clinically significant liver disease, including any form of known liver cirrhosis;
23. One or more of the following laboratory abnormalities at Screening: platelet count <50,000/μL, absolute neutrophil count <1,000/mm3, or hemoglobin <8 g/dL;
24. Pregnant or expecting to conceive, breastfeeding, or plans to breastfeed within 1 month of completion of the study;
25. Currently participating in, or has participated in, any other clinical study involving the administration of investigational or experimental medication (not licensed by regulatory agencies) at the time of presentation or during the previous 30 days or 5 half-lives, whichever is longer, prior to Screening, or is anticipated to participate in such a clinical study during the course of the study; or
26. Unable or unwilling, in the judgment of the Investigator, to comply with the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy parameter is the proportion of patients in the Microbiological Modified Intent-to-Treat (m-MITT) Population who achieve overall treatment success at TOC. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| “Test of Cure” is the time point. All patients will be treated for a minimum of 7 days; however, treatment may continue for up to 14 days for patients with a positive blood culture at baseline at the discretion of the Investigator. A Test of Cure (TOC) visit will occur 7 days after End of Treatment (EOT) (EOT + 7 days [±2 days]). |
|
| E.5.2 | Secondary end point(s) |
There are multiple secondary endpoints:
• The proportion of patients in the m-MITT Population with overall treatment success at EOT and LFU;
• The proportion of patients in the m-MITT and ME Populations with a microbiological outcome of Eradication at Day 3, EOT, TOC, and LFU;
• The proportion of patients with a clinical outcome of Cure or Improvement (Day 3 only) in the m-MITT, Clinically Evaluable (CE), and ME Populations at Day 3, EOT, TOC, LFU;
• Per-pathogen clinical outcome of Cure and microbiological outcome of Eradication in the m-MITT and ME Populations at Day 3, EOT, TOC, and LFU;
• Subset of patients infected with extended-spectrum β-lactamase producing pathogens with a clinical outcome of Cure and microbiological outcome of Eradication in the m-MITT and ME Populations at Day 3, EOT, TOC, and LFU. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 3, EOT, TOC, LFU are the timepoints for the secondary endpoints. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Argentina |
| Belarus |
| Bulgaria |
| Croatia |
| Estonia |
| Georgia |
| Hungary |
| Latvia |
| Lithuania |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Ukraine |
| United States |
|
| 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
|
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 14 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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