| 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 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 | 19.1 |
| 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 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| 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 demonstrate that ZTI-01 is non-inferior to piperacillin/tazobactam in overall success (clinical cure and microbiologic eradication) in the microbiologic Modified Intent-to-Treat (mMITT) Population at the TOC Visit. |
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| E.2.2 | Secondary objectives of the trial |
- To compare the clinical cure rates in the two treatment groups in the Modified Intent-to-Treat (MITT), m-MITT, Clinical Evaluable- (CE) TOC, and Microbiologic Evaluable- (ME) TOC Populations at the TOC Visit,
- To compare the microbiological eradication rate in the m-MITT and METOC 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) or, in case of a lack of decision-making capacity and as permitted by local law and institutional Standard Operating Procedures, consent on behalf of study subject by a legally authorized representative;
2. Male or female, at least 18 years of age;
3.Expectation, in the judgment of the Investigator, that the patient’s cUTI or AP would require hospitalization and treatment with intravenous (IV) antibiotics;
4. Documented or suspected cUTI or AP as defined below:
ocUTI:
• Signs or symptoms evidenced by at least 2 of the following:
Chills, rigors, or warmth associated with fever:
Note: Fever must be observed and documented by a health care provider within 24 hours of screening (oral, tympanic, rectal or core temperature 38°C [100.4°F]);
Nausea or vomiting within 24 hours of screening, as reported by the patient;
Dysuria, increased urinary frequency, or urinary urgency;
Lower abdominal pain or pelvic pain;
•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 one of the following associated risks:
- Use of intermittent bladder catheterization or presence of an indwelling bladder catheter (Note: indwelling 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);
- 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 EOT);
- Azotemia, defined as blood urea nitrogen (BUN) >20 mg/dL, blood urea >42.8 mg/dL, or serum creatinine > 1.4 mg/dL, due to known prior intrinsic renal disease;
- Chronic urinary retention in men, for example, previously diagnosed benign prostatic hypertrophy;
o Acute pyelonephritis:
• Signs or symptoms evidenced by at least 2 of the following:
Chills, rigors, or warmth associated with fever:
Note: Fever must be observed and documented by a health care provider within 24 hours of screening (oral, tympanic, rectal or core temperature 38°C [100.4°F]);
Nausea or vomiting within 24 hours of screening, as reported by the patient;
Dysuria, increased urinary frequency, or urinary urgency;
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;
Note: Patients may be randomized into this study and start IV study drug therapy before the Investigator knows the results of the baseline urine culture.
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 h after randomization, unless removal or replacement is considered unsafe or contraindicated;
7. Expectation, in the judgement of the Investigator, that the patient will survive with effective antibiotic therapy and appropriate supportive care for the anticipated duration of the study;
8. The patient requires initial hospitalization to manage the cUTI or AP in accordance with the standard of care;
9. Women of childbearing potential (ie, not post-menopausal or surgically sterilized) must have a negative pregnancy test before randomization. Participating women of childbearing potential, or partners of participant who are of childbearing potential, must be willing to consistently use a highly effective method of contraception between screening and the end of the study (LFU Visit);
Note: Highly effective methods of contraception include the following: hormonal implants/patch, injectable hormones, oral hormonal contraceptives, intra-uterine device, approved cervical ring, prior bilateral oophorectomy, prior hysterectomy, prior bilateral tubal ligation, true abstinence (if approved by the Investigator), or a vasectomized partner.
10.Male study participants will be required to use condoms with a spermicide during sexual intercourse from screening to the end of the study, even if their sexual partner is or may be pregnant.
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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 abscess;
b.Renal corticomedullary abscess;
c.Uncomplicated urinary tract infection;
d.Any recent history of trauma to the pelvis or urinary tract;
e.Polycystic kidney disease;
f.Chronic vesicoureteral reflux;
g.Previous or planned renal transplantation;
h.Patients receiving dialysis, including hemodialysis, peritoneal dialysis or continuous veno-venous hemofiltration (CVVH);
i.Previous or planned cystectomy or ileal loop surgery;
j.Known or suspected infection that is caused by pathogen(s) that is resistant to either study drug (fosfomycin or a β-lactam/β-lactam inhibitor [BL/BLI] combination), 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 End of Treatment [EOT]);
5.Renal function at screening as estimated by creatinine clearance < 20 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;
7.Any signs of severe sepsis, including but not limited to the following:
a.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;
b.Disseminated intravascular coagulation as evidenced by prothrombin time (PT) or partial thromboplastin time (PTT) 2 × 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 Investigator’s opinion, 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 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.Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy;
12.Aspartate aminotransferase or alanine aminotransferase > 5 × ULN (upper limit of normal) or total bilirubin > 3 × ULN at Screening;
13.Receipt of any 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:
a.Have received > 48 hours of prior antimicrobial therapy and, (1) in the Investigator’s opinion, 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 fosfomycin or a BL/BLI combination;
b.Develop signs and symptoms of cUTI or AP while taking a systemic antibiotic for another indication (other than fosfomycin or BL/BLI combination), including antimicrobial prophylaxis for recurrent UTI;
c.Received a single dose of a short-acting (ie, having a dosage frequency of more than once daily [eg, q12 h or more frequently]) systemic antibiotic up to 24 hours prior to randomization (see Appendix C for definition and a list of allowable short-acting antibiotics). No more than 25% of patients will be enrolled who meet this criterion;
14.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;
15.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 [LFU] Visit);
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of patients with an overall success (clinical cure and microbiologic eradication) in the microbiologic Modified Intent-to-Treat (m-MITT) Population at the TOC Visit. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Test-of-Cure Visit (Day 19) |
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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) TOC, and Microbiologic Evaluable- (ME) TOC Populations at the TOC Visit;
- Proportion of patients with a response of microbiologic eradication in the m-MITT and METOC Populations at the TOC Visit;
- Proportion of patients with a response of sustained clinical cure in the MITT, m-MITT, CELFU, and ME-LFU Populations at the LFU Visit.
The following additional efficacy analyses will be conducted to support the efficacy findings for the primary and secondary outcomes:
- Proportion of patients with a response of sustained microbiologic eradication in the m-MITT and MELFU Populations at the LFU Visit;
- Proportion of patients with a response of sustained clinical cure in the MITT, m-MITT, CELFU, and ME-LFU Populations at the LFU Visit.
- Proportion of patients with a response of clincial cure in the MITT and m-MITT at Day 5
- Per-pathogen microciologic eradication rate i nthe m_MITT and ME-TOC Populations at hte TOC Visit;
- All-cause mortality through the LFU Visit in the MITT Population;
- Summary (number and percentage of patients) of the assessment of clinical signs and symptoms of cUTI and AP at each time point throughout the study by treatment group in the MITT Population;
- Incidence of superinfection, new infection, and colonization by treatment group for the mMITT Population;
- Descriptive statistics of the length of hospital stay by treatment group for the MITT Population.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Test-of-Cure (Day 19)
Late Follow-Up Visit (Day 26) |
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Croatia |
| Czech Republic |
| Estonia |
| Georgia |
| Greece |
| Hungary |
| Latvia |
| Lithuania |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| Ukraine |
| United States |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 2 |
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