| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated Urinary Tract Infection, Including Pyelonephritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients who have a complex infection in their urine or 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 | 14.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10046577 |
| E.1.2 | Term | Urinary tract infections |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 demonstrate the non-inferiority of CXA-201 versus comparator (levofloxacin) in adult subjects with cUTI (including pyelonephritis) based on the difference in composite microbiological eradication and clinical cure rate in the mMITT population at the test-of-cure (TOC) visit (7 days [± 2 days] after last treatment) (CXA-201 minus comparator [levofloxacin]), using a non inferiority margin of 10%. |
|
| E.2.2 | Secondary objectives of the trial |
• To demonstrate the non-inferiority of CXA-201 versus comparator (levofloxacin) in adult subjects with cUTI (including pyelonephritis) based on the difference in composite microbiological eradication and clinical cure rate in the ME population at the TOC visit (7 days [± 2 days] after last treatment) (CXA-201 minus comparator [levofloxacin]), using a non-inferiority margin of 10%
• To compare the clinical and microbiological response of CXA-201 versus comparator
(levofloxacin) at the end of therapy (EOT), TOC, and late follow up (LFU; 28-35 days post last dose of study drug) visits
• Evaluate the safety of CXA-201 in subjects with cUTI (including pyelonephritis). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide written informed consent prior to any study-related procedure not part of normal medical care (a legally acceptable representative may provide consent if the subject is unable to do so, provided this is approved by local country and institution specific guidelines).
2. Be males or females ≥ 18 years of age.
3. If female, subject is non-lactating, and is either:
a. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or
b. Of childbearing potential and is practicing a barrier method of birth control (e.g., a diaphragm or contraceptive sponge) along with 1 of the following methods: oral or parenteral contraceptives (for 3 months prior to study drug administration), or a vasectomized partner. Or, subject is practicing abstinence from sexual intercourse.
Subjects must be willing to practice these methods for the duration of the trial and for at least 35 days after last dose of study medication.
4. Males 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 last dose of study medication.
5. Pyuria (white blood cell [WBC] count > 10/μL in unspun urine or ≥ 10 per high power field in spun urine).
6. Clinical signs and/or symptoms of cUTI, either of:
a. Pyelonephritis, as indicated by at least 2 of the following:
i. Documented fever (oral temperature > 38°C) accompanied by patient symptoms
of rigors, chills, or “warmth”;
ii. Flank pain;
iii. Costovertebral angle tenderness or suprapubic tenderness on physical exam;
iv. nausea or vomiting;
OR
b. Complicated lower UTI, as indicated by at least 2 of the following:
i. At least 2 of the following new or worsening symptoms of cUTI:
1. Dysuria; urinary frequency or urinary urgency;
2. Documented fever (oral temperature > 38°C) accompanied by patient symptoms of rigors, chills, or “warmth”;
3. Suprapubic pain or flank pain;
4. Costovertebral angle tenderness or suprapubic tenderness on physical
exam; or
5. Nausea or vomiting; plus,
ii. At least 1 of the following complicating factors:
1. Males with documented history of urinary retention;
2. Indwelling urinary catheter that is scheduled to be removed during IV study therapy and before the EOT;
3. Current obstructive uropathy that is scheduled to be medically or surgically relieved during IV study therapy and before the EOT; or
4. 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.
7. Have a pretreatment baseline urine culture specimen obtained within 24 hours before the start of administration of the first dose of study drug.
NOTE: Subjects may be enrolled in this study and start IV study drug therapy before the Investigator knows the results of the baseline urine culture.
8. Require IV antibacterial therapy for the treatment of the presumed cUTI. |
|
| E.4 | Principal exclusion criteria |
1. Have a documented history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam or quinilone antibacterial (Note: for β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment).
2. Have a concomitant infection at the time of randomization, which requires non-study systemic antibacterial therapy in addition to IV study drug therapy. (Drugs with only gram-positive activity [e.g., vancomycin, linezolid] are allowed.)
3. 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.
4. Receipt of any dose of a potentially therapeutic antibacterial agent for the treatment of the current UTI within 48 hours before the study-qualifying pretreatment baseline urine is obtained (exceptions: subjects with an active cUTI who have received prior antibiotics may be enrolled provided a minimum of 48 hours have elapsed between the last dose of the prior antibiotic and the time of
obtaining the baseline urine specimen. Subjects receiving current antibiotic prophylaxis for cUTI who present with signs and symptoms consistent with an active new cUTI may be enrolled provided all other eligibility criteria are met including obtaining a pre-treatment qualifying baseline urine culture).
5. Intractable urinary infection at baseline that the Investigator anticipates would require more than 7 days of study drug therapy.
6. Complete, permanent obstruction of the urinary tract.
7. Confirmed fungal urinary tract infection at time of randomization (with ≥ 10'3 fungal CFU/mL).
8. Permanent indwelling bladder catheter or urinary stent including nephrostomy.
9. Suspected or confirmed perinephric or intrarenal abscess.
10. Suspected or confirmed prostatitis.
11. Known ileal loop or vesico-ureteral reflux.
12. Severe impairment of renal function including an estimated creatinine clearance (CrCl 13. ) < 30 mL/min, requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (< 20 mL/h urine output over 24 hours).
13. Current urinary catheter that is not scheduled to be removed before the EOT (intermittent straight catheterization during the IV study drug administration period is acceptable).
14. Any condition or circumstance that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of study data.
15. Any rapidly progressing disease or immediately life-threatening illness including acute hepatic failure, respiratory failure, and septic shock.
16. Immunocompromising condition, including established Acquired Immune Deficiency Syndrome (AIDS), hematological malignancy, or bone marrow transplantation, or immunosuppressive therapy including cancer chemotherapy, medications for prevention of organ transplantation rejection, or the administration of corticosteroids equivalent to or greater than 40 mg of prednisone per day
administered continuously for more than 14 days preceding randomization.
17. One or more of the following laboratory abnormalities in baseline specimens: aspartate aminotransferase (AST [SGOT]), alanine aminotransferase (ALT [SGPT]), alkaline phosphatase, or total bilirubin level greater than 3 times the upper limit of normal (ULN), absolute neutrophil count less than 500/μL, platelet count less than 40,000/μL, or hematocrit less than 20%.
18. Participation in any clinical study of an investigational product within 30 days prior to the proposed first day of study drug.
19. Previous participation in any study of CXA-101 or CXA-201.
20. Women who are pregnant or nursing. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Composite microbiological eradication and clinical cure rate in the mMITT population at the TOC visit
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The main assessment will occur 7 days (+/-2 days) after completing treatment with study drug. Another assessment will take place 28-35 days after completing treatment to see if the infection recurred or if the subject remains cured. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints
•Composite microbiological eradication and clinical cure rate in the ME population at the TOC visit
• Clinical response CXA-201 versus comparator (levofloxacin) at the end of therapy (EOT), test-ofcure (TOC), and late follow up (LFU; 28-35 days post last dose of study drug) visits
• Microbiological response of CXA-201 versus comparator (levofloxacin) at the end of therapy
(EOT), test-of-cure (TOC), and late follow up (LFU; 28-35 days post last dose of study drug) visits
• Per-pathogen microbiological eradication rates
Safety Endpoints
Safety will be evaluated in the safety population through review of summaries of :
• AEs
• Laboratory evaluations
• Vital signs
• Physical examinations
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The main assessment will occur 7 days (+/-2 days) after completing treatment with study drug. Another assessment will take place 28-35 days after completing treatment to see if the infection recurred or if the subject remains cured |
|
| 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 | Yes |
| 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 |
|
| 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 | 31 |
| 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 |
| Bulgaria |
| Chile |
| Croatia |
| Czech Republic |
| India |
| Italy |
| Korea, Republic of |
| Lithuania |
| Peru |
| Poland |
| Slovenia |
| Spain |
| Ukraine |
| United States |
|
| 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
|
| The study will be stopped when the last subject included in the double-blind treatment period completes the study or when the last ongoing subject has discontinued treatment, whichever occurs first. |
|
| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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