| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated urinary tract infections including acute pyelonephritis |
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| E.1.1.1 | Medical condition in easily understood language |
| Complicated urinary tract infections including infections reaching patients kidneys |
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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 | 10037597 |
| E.1.2 | Term | Pyelonephritis acute |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 |
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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 |
| The primary objective is to determine the optimal cefepime/AAI101 combination dose to be used in future Phase 3 studies via PK/PD modelling to assess the Probability of Target Attainment (PTA) and the effect of treatment on liver enzymes. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the safety and tolerability of cefepime/AAI101 combination.
The exploratory objective is to obtain a preliminary evaluation of the efficacy of cefepime/AAI101 combination therapy. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females 18 to 90 years of age, inclusive, at the time of signing of informed consent;
2.Expectation that the patient’s cUTI or acute pyelonephritis would require hospitalization and initial treatment with at least 7 days of i.v. antibiotics;
3.Female patients can participate if at least 1 of the following criteria are met:
- Surgical sterilization;
- Age > =50 years and post-menopausal as defined by amenorrhea for > = 12 months following cessation of all exogenous hormonal treatments;
- Age < 50 years and post-menopausal as defined by documented luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range PLUS amenorrhea for > = 12 months following cessation of all exogenous hormonal treatments; or
- Patient has a negative urine and/or serum pregnancy test (serum β-human chorionic gonadotropin) within 1 day prior to study entry, and agrees to use highly effective contraception methods during treatment and for at least 7 days after the last dose of i.v. study therapy;
4. Male patients are required to practice reliable birth control methods (condom or other barrier device) during the conduct of the study and for at least 35 days after the last dose of study drug;
5. Pyuria, defined as:
- White blood cell count >10 cells/mm3 in unspun urine or > = 10 cells/high power field in spun urine sediment; or
- Urinalysis/dipstick analysis positive for leukocyte esterase;
6. Clinical signs and/or symptoms of cUTI or acute pyelonephritis as defined in the section 4.1 of the study protocol :
Acute Pyelonephritis:
At least 2 of the following new or worsening symptoms:
• Fever (oral/tympanic > =38°C [> = 100.4°F] or rectal/core temperature > =38.3°C [ > =100.9°F]) observed and documented by a health care provider within 24 h of the screening visit, accompanied by patient symptoms of rigors, chills, or “warmth”;
• Flank pain (onset within 7 days prior to randomization);
• Dysuria, increased urinary frequency, or urinary urgency;
• Costovertebral angle tenderness or suprapubic tenderness on physical examination; or
• Nausea or vomiting within 24 h of the screening visit, as reported by the patient.
CUTI
At least 2 of the following new or worsening symptoms:
• Dysuria, increased urinary frequency, or urinary urgency;
• Fever (oral/tympanic > = 38°C [> =100.4°F] or rectal/core temperature > = 38.3°C [ > = 100.9°F]) must be observed and documented by a health care provider within 24 h of the screening visit, accompanied by patient symptoms of rigors, chills, or “warmth”;
• Lower abdominal pain or pelvic pain;
• Costovertebral angle tenderness or suprapubic tenderness on physical examination; or
• Nausea or vomiting within 24 h of the screening visit as reported by the patient; AND
At least 1 of the following complicating factors:
• Male patients with documented history of urinary retention, for example, benign prostatic hypertrophy;
• Use of intermittent bladder catheterization or presence of an indwelling bladder catheter;
NOTE: Indwelling bladder catheters that have been in place for > 24 h prior to the screening visit must be removed or replaced prior to collection of the screening visit urine for urinalysis and culture, unless removal or replacement is considered unsafe or contraindicated.
• Current obstructive uropathy that is scheduled to be medically or surgically relieved during i.v. study therapy and before EOT;
• Any functional or anatomical abnormality of the urogenital tract (including anatomic malformations or neurogenic bladder) with voiding disturbance resulting in at least 100 mL residual urine; or
• Azotemia, defined as blood urea nitrogen > 20 mg/dL, blood urea >42.8 mg/dL, or serum creatinine >1.4 mg/dL, due to known prior intrinsic renal disease.
7. Have a baseline urine culture specimen obtained within 48 h 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.
8. Expectation, in the judgement 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 h after randomization, unless removal or replacement is considered unsafe or contraindicated.
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| E.4 | Principal exclusion criteria |
1. History of serious allergy, hypersensitivity (e.g. anaphylaxis), or any serious reaction to cefepime, any cephalosporin, penicillins, β-lactamase inhibitors (e.g. tazobactam, sulbactam, or clavulanic acid), or other β-lactam agents;
2. Concurrent infection that would interfere with evaluation of response to the study antibiotics;
3. Need for concomitant systemic antimicrobial agents in addition to those designated in the various study treatment groups;
4. Receipt of any amount of potentially therapeutic antibacterial therapy after collection of the pretreatment baseline urine culture and before administration of the first dose of study drug;
5. Receipt of effective antibacterial drug therapy for cUTI for a continuous duration of >24 h during the previous 72 h before the study-qualifying baseline urine is obtained;
EXCEPTION: Patients who have failed treatment, both clinically and microbiologically, are eligible for the study if they have an identified uropathogen which is non-susceptible to the empiric treatment and likely to be susceptible to the study drug; OR patients who received antibacterial drugs for surgical prophylaxis and then developed cUTI.
6. Complicated urinary tract infection known at study entry to be caused by pathogens resistant to the study antibiotics;
7. Intractable urinary infection at baseline that the Investigator anticipates would require >10 days of study drug therapy;
8. Complete, permanent obstruction of the urinary tract that is not anticipated to be medically or surgically relieved during i.v. study therapy and before End of Treatment;
9. Confirmed fungal urinary tract infection at the screening visit
10. Presence of any known or suspected disease condition that, in the opinion of the Investigator, may confound the assessment of efficacy, including but not limited to, the following:
Perinephric abscess;
Renal corticomedullary abscess;
Uncomplicated urinary tract infection;
Any recent history of trauma to the pelvis or urinary tract;
Polycystic kidney disease;
Chronic vesicoureteral reflux;
Previous or planned renal transplantation;
Previous or planned cystectomy or ileal loop surgery;
Patients receiving dialysis, including hemodialysis, peritoneal dialysis, or continuous veno-venous hemofiltration; or
Known or suspected infection that is caused by pathogen(s) resistant to either study drug, including infection caused by fungi (e.g. candiduria) or mycobacteria (e.g. urogenital tuberculosis);
11. Suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination;
12. Estimated creatinine clearance <60 mL/min calculated by Cockcroft-Gault method
13. Any rapidly progressing disease or immediately life-threatening illness, including acute hepatic failure and respiratory failure;
14. Any signs of severe sepsis, including but not limited to, the following:
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; or
Disseminated intravascular coagulation as evidenced by prothrombin time or partial thromboplastin time >=2 × the upper limit of normal (ULN), or <50,000 platelets/mm3 at the screening visit in patients in whom severe sepsis is suspected;
15. A QT interval corrected using Fridericia’s formula >450 msec;
16. Immunocompromising condition including established acquired immune deficiency syndrome, hematological malignancy, or bone marrow transplantation; or immunosuppressive therapy including cancer chemotherapy, medications for prevention of organ transplantation rejection, or the administration of corticosteroids >=40 mg of prednisone per day administered continuously for >14 days prior to randomization;
17. One or more of the following laboratory abnormalities in baseline specimens obtained at the screening visit: aspartate aminotransferase, alanine transaminase (ALT), alkaline phosphatase, or total bilirubin level >3 × ULN;
18. One or more of the following laboratory abnormalities in baseline specimens obtained at the screening visit: platelet count <50,000/μL, absolute neutrophil count <1,000/mm3, or hemoglobin <8 g/dL;
19. Pregnant or expecting to conceive, breastfeeding, or plans to breast feed within 1 month of completion of the study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical and microbiologic response: Clinical cure in clinical outcomes (resolution of the signs and symptoms of cUTI/AP or return to preinfection
baseline if known) and Eradication in microbiological outcomes (microbiological success) at the Test of Cure (TOC). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Microbiologic response per pathogen and patient at Early Assessment (EA), End Of Treatment (EOT), TOC, and Late Follow-Up (LFUP)
Clinical response per patient and pathogen at EA, EOT, TOC, and FUP
Pharmacokinetic and safety profile |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK D1 (T0, T1h, T2h, T6h and T8h); D2 (T0), D4 (T0), D7 (T0, T1h, T2h, T6h and T8h).
Urine volume collected EOT over the following periods: 0 to 2h, 2 to 6h, 6 to 12 h and 12 to 24h.
Urine culture: prior to randomization, during treatment (D1, D3 and EOT), at the TOC, at the LFU and at Early Termination.
Blood cultures obtained if clinically indicated or if previous culture was positive. |
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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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 |
| Czech Republic |
| Hungary |
| Israel |
| Poland |
| Slovakia |
| Ukraine |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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