| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated Urinary Tract Infection including Acute Pyelonephritis |
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| E.1.1.1 | Medical condition in easily understood language |
| Complicated Urinary Tract Infection including Acute Pyelonephritis |
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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 | 100000005053 |
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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 evaluate the safety profile of ETX2514SUL versus placebo in patients with cUTI, including AP |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of ETX2514SUL in patients with cUTI, including AP, in the microbiologically modified Intent-to-Treat (m-MITT) Population;
• To compare the clinical cure rate in the 2 treatment groups in the modified Intent-to-Treat (MITT), m-MITT, Clinical Evaluable (CE), and Microbiological Evaluable (ME) Populations at the Test-of-Cure (TOC) Visit; and
• To compare the microbiological eradication rate in the m-MITT and ME Populations at the TOC Visit.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A signed informed consent form (ICF). If a study patient is unable to provide informed consent due to their medical condition, the patient’s legally authorized representative may consent on behalf of the study patient as permitted by local law and institutional Standard Operating Procedures;
2. Male or female, 18 to 90 years of age, inclusive;
3. Expectation, in the judgment of the Investigator, that the patient’s cUTI would require initial hospitalization and treatment with intravenous (IV) antibiotics;
4.Documented or suspected cUTI or AP, as defined below:
o cUTI
Signs or symptoms evidenced by at least 2 of the following:
- Documented fever accompanied by chills, rigors, or warmth;
- Nausea or vomiting within 24 hours of Screening, as reported by the patient;
- Dysuria, increased urinary frequency, or urinary urgency; or
- Lower abdominal pain, pelvic pain, or suprapubic tenderness on physical examination;
And urine specimen with evidence of pyuria:
- Positive leukocyte esterase on urinalysis; or
- White blood cell count ≥10 cells/mm3 in unspun urine; or
- White blood cell count ≥10 cells/high-power field (hpf) in urine sediment;
And at least 1 of the following associated risks:
- Use of intermittent bladder catheterization or presence of an indwelling bladder catheter;
- Current known functional or anatomical abnormality of the urogenital tract, including anatomic malformations or neurogenic bladder, or with a post-void residual urine volume of ≥100 mL;
- Complete or partial obstructive uropathy (eg, nephrolithiasis, tumor, fibrosis, urethral stricture) that is expected to be medically or surgically treated during study drug therapy (prior to End of Treatment [EOT]);
- 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; or
- Chronic urinary retention in men (eg, previously diagnosed benign prostatic hypertrophy);
o AP
Signs or symptoms evidenced by at least 2 of the following:
- Documented fever accompanied by chills, rigors, or warmth;
- Nausea or vomiting within 24 hours of Screening, as reported by the patient;
- Dysuria, increased urinary frequency, or urinary urgency; or
- Acute flank pain (onset within 7 days prior to randomization) or costo-vertebral angle tenderness on physical examination;
And urine specimen with evidence of pyuria:
- Positive leukocyte esterase on urinalysis; or
- White blood cell count ≥10 cells/mm3 in unspun urine; or
- White blood cell count ≥10 cells/hpf in urine sediment;
5. Have a baseline urine culture specimen obtained within 48 hours prior to randomization;
6. Expectation, in the judgment of the Investigator, that any implanted urinary instrumentation (eg, nephrostomy tubes, ureteric stents) will be surgically removed or replaced before or within 24 hours after randomization, unless removal or replacement is considered unsafe or contraindicated;
7. Expectation, in the judgment of the Investigator, that the patient will survive with effective antibiotic therapy and appropriate supportive care for the anticipated duration of the study;
8. Women of childbearing potential (ie, not post-menopausal or surgically sterilized) must have a negative pregnancy test (serum or urine) before randomization. Participating women of childbearing potential must be willing to consistently use 2 highly effective methods of contraception (ie, condom plus spermicide, combined oral contraceptive, implant, injectable, indwelling intrauterine device, or a vasectomized partner) from Screening until at least 30 days after administration of the last dose of study drug; and
9. Male participants will be required to use condoms with a spermicide during sexual intercourse between Screening and at least 90 days after administration of the last dose of study drug.
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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:
o Perinephric abscess;
o Renal corticomedullary abscess;
o Uncomplicated urinary tract infection (UTI);
o Any recent history of trauma to the pelvis or urinary tract;
o Polycystic kidney disease;
o Chronic vesicoureteral reflux;
o Previous or planned renal transplantation;
o Patients receiving dialysis, including hemodialysis, peritoneal dialysis, or continuous veno-venous hemofiltration;
o Previous or planned cystectomy or ileal loop surgery; and
o Known or suspected infection that is caused by a pathogen(s) that is known to be resistant to imipenem or β-lactam/β-lactamase inhibitor combinations, including infection caused by fungi (eg, candiduria) or mycobacteria (eg, urogenital tuberculosis);
2. Presence of suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination;
3. Gross hematuria requiring intervention other than administration of study drug or removal or exchange of a urinary catheter;
4. 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);
5. Renal function at Screening as estimated by creatinine clearance <70 mL/min using the Cockcroft-Gault formula and serum creatinine value obtained from a local laboratory;
6. Known non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to randomization that would interfere with evaluation of response to the study antibiotics;
7. Any signs of severe sepsis, including but not limited to the following:
o Shock or profound hypotension defined as systolic blood pressure <90 mmHg or a decrease of >40 mmHg from baseline (if known) that is not responsive to fluid challenge; or
o Disseminated intravascular coagulation as evidenced by prothrombin time or partial thromboplastin time ≥2 x the upper limit of normal (ULN) or <50,000 platelets/mm3 at Screening in patients in whom severe sepsis is suspected;
8. Pregnant or breastfeeding women;
9. Known seizure disorder requiring current treatment with anti-seizure medication which, in the opinion of the Investigator, would prohibit the patient from complying with the protocol. Patients with a history of epilepsy or who are on stable treatment (ie, no change in therapy within 30 days) with well controlled seizure disorder (ie, no recurrent episodes in the past 30 days) may be considered for enrollment in the study;
10. Treatment within 30 days prior to randomization with any cancer chemotherapy, immunosuppressive medications for transplantation, or medications for rejection of transplantation;
11. Patient requires continuing treatment with probenecid, methotrexate, ganciclovir, valproic acid, or divalproex sodium during the study;
12. Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy;
13. Aspartate aminotransferase or alanine aminotransferase >3 x ULN or total bilirubin >2 x ULN at Screening;
14. Receipt of a single dose of a long-acting, potentially-effective systemic antibiotic with activity against Gram-negative uropathogens for more than 24 hours within the 72-hour window prior to randomization. However, patients may enroll who:
o Have received >48 hours of prior antimicrobial therapy, and (1) in the opinion of the Investigator, have failed that preceding antimicrobial therapy (ie, have worsening signs and symptoms), and (2) are documented to have a cUTI or AP that is caused by a pathogen resistant to the prior therapy, and (3) the causative pathogen is known not to be resistant (eg, the causative pathogen is either susceptible, intermediate, or unknown susceptibility) to imipenem;
o Develop signs and symptoms of cUTI or AP while taking a systemic antibiotic for another indication (other than ETX2514SUL or imipenem/cilastatin), including antimicrobial prophylaxis for recurrent UTI; or
o Received a single dose of a short-acting (ie, having a dosage frequency of more than once daily [eg, every 12 hours or more frequently]) systemic antibiotic up to 24 hours prior to randomization. No more than 25% of patients will be enrolled who meet this criterion;
15. Requirement at time of randomization for any reason for additional systemic antimicrobial therapy (including antibacterial, antimycobacterial, or antifungal therapy) other than study drug, with the exception of a single oral dose of any antifungal treatment for vaginal candidiasis;
16. Likely to require the use of an antibiotic for cUTI or AP prophylaxis during the patient’s participation in the study (from randomization through the Late Follow-up Visit);
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of patients with an overall success (clinical cure and microbiologic eradication) in the m-MITT Population at the TOC Visit |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Test of Cure Visits (7 days after the End of the Trial) |
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| E.5.2 | Secondary end point(s) |
• Proportion of patients with a response of clinical cure in the Modified Intent-to-Treat (MITT), m-MITT, Clinical Evaluable (CE), and Microbiologic Evaluable (ME) Populations at the TOC Visit; and
• Proportion of patients with a response of microbiologic eradication in the m-MITT and ME Populations at the TOC Visit.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Test of Cure Visits (7 days after the End of the Trial) |
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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 | Yes |
| 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) | 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Belarus |
| Bulgaria |
| Russian Federation |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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