| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated Urinary Tract Infection and/or Acute Polyonephritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Urinary Tract Infection requiring hospitalisation |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| 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 |
| Evaluate the microbiological and clinical outcome of treatment with finafloxacin for 5 days versus finafloxacin for 10 days versus ciprofloxacin for 10 days |
|
| E.2.2 | Secondary objectives of the trial |
| •The clinical and microbiological response at the On Therapy (OT) visit (Day 3) •The clinical and microbiological response at the End of Therapy (EoT) visit (Day 10) •The clinical and microbiological response at the End of Study (EoS) visit (Day 24) •Separate analyses will be performed for all time points with the outcome variable clinical responder and also microbiological responder •The safety and tolerability of multiple doses of finafloxacin of both 5 days and 10 days of treatment with finafloxacin (i.v. and oral) in subjects with cUTI, compared to 10 days of ciprofloxacin (i.v. and oral) as a reference comparator •The predictive capacity of PK/PD data of both 5 days and 10 days of treatment with finafloxacin (i.v. and oral) in subjects with cUTI, using 10 days of ciprofloxacin (i.v. and oral) as a reference comparator on clinical outcomes (EMA guidance) •Other exploratory parameters as defined by the data (post hoc analyses). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All subjects MUST:
1.be male or female subjects ≥ 18 years of age.
2.if a female
a.and subject is of childbearing potential, must have documented use of using an effective contraceptive method (such as IUD, hormonal birth control, condom and spermicidal jelly, etc.) during the study, a documented negative serum pregnancy test and must be non-lactating.
b.subject is of non-childbearing potential, must be post-menopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy
3.If a male, should agree to use reliable birth control methods (contraception or other barrier device) during study participation.
4.have at least two of the following (acute?) signs and symptoms
a.Chills or rigors or warmth associated with fever (e.g., oral temperature greater than 38 degrees Celsius)
b.Flank pain (pyelonephritis) or pelvic pain (cUTI)
c.Nausea or vomiting
d.Dysuria, urinary frequency, or urinary urgency
e.Costo-vertebral angle tenderness on physical examination
of complicated lower urinary tract infection including acute complicated and uncomplicated pyelonephritis (cPN or uPN) (see 5.3).
5.provide one pre-treatment adequate urine culture (the urine culture must return a positive culture in order for the subject to remain eligible for the study) (for males: midstream clean catch, for females: in-out catheterisation or midstream clean catch) which must be provided within 24 hours before the start of administration of the first dose of study drug, defined as ≥ 105 CFU/mL (in case of pyelonephritis ≥ 104 CFU/mL). Patients may be admitted to the study pending baseline urine culture results.
NOTE: Because biofilms on indwelling catheters (e.g., Foley catheters) are more likely to be present after the catheter has been in place for a period of time, samples should be collected following the placement of a new catheter. If the placement of a new catheter is contraindicated or is not feasible, specimens should be collected using aseptic techniques with the urine obtained through a properly disinfected collection port. Urine samples should never be obtained from the collection bag.
If the subject’s pre-treatment culture shows the presence of a ciprofloxacin resistant pathogen or negative urine culture (defined as < 104 cfu/mL of causative pathogens), the Investigator’s medical judgement will determine whether or not the subject should continue in the study:
•in case of resistant pathogen, the Investigator has to decide according to clinical signs and symptoms whether the subject can stay in the study.
•in the case of a NEGATIVE culture (see above) the subject must be switched to standard care, because the inclusion criterion was not fulfilled.
6.have pyuria (i.e. a dipstick analysis positive for leukocyte esterase or at least 10 white blood cells per cubic millimetre [1 µl])
7.be considered ill enough to be hospitalized and require initial parenteral therapy to manage cUTI and/or acute pyelonephritis by the standard of care.
8.provide written informed consent to participate in the study.
9.be willing and able to comply with all study procedures and activities.
|
|
| E.4 | Principal exclusion criteria |
1. Uncomplicated cystitis in females.
2. Failed previous antibiotic treatment within the last 4 weeks due to culture confirmed fluoroquinolone resistant pathogens.
3. Having Ileal loops, urinary diversion with bowel segments or suspected or confirmed vesico-ureteral reflux, suspected or confirmed perinephric or intrarenal abscess (if an abscess is suspected an ultrasound should be performed to confirm and exclude).
4. History of renal transplant any permanent complicating factors of the urinary tract (including complete obstruction, suspected or confirmed
prostatitis or epididymitis) which cannot be effectively treated during the therapy of the infection.
5. Indwelling urinary catheters expected to remain in place after therapy has been completed.
6. The urinary tract infection or any other concomitant bacterial infection that requires systemic antibiotic therapy (in addition to the study treatment) at the time of randomisation. Antibiotics with only grampositive
activity are permitted.
7. Any infection that, in the opinion of the Investigator, would be considered intractable and likely to require more than 10 days of study drug therapy.
8. Any recent use (e.g., within 48 hours before the first dose of study medication) of an antimicrobial therapy with a drug that has activity in the treatment of urinary tract infection.
9. Having been exposed to any fluoroquinolone in the 30 days before Day 1 (study enrolment), previous participation in a finafloxacin clinical trial or participation within the last 30 days in any other clinical study in
general.
10. Known uncontrolled condition of hypertension or symptomatic hypotension, known ischaemic heart disease or history of myocardial infarction (within 12 months before study enrolment), coronary
arterybypass surgery or percutaneous transluminal coronary angioplasty.
11. Significantly immunocompromised (defined as a WBC < 1000) and/or having a known infection with human immunodeficiency virus (HIV/AIDS), any haematological malignancy, bone marrow transplantation, or current immunosuppressive therapy (including but not limited to cancer chemotherapy, or medications for prevention of organ transplantation rejection).
12. Any concomitant psychiatric, neurological or behavioural disorder, including epilepsy or other lesions of the central nervous system sufficient in the opinion of the Investigator to prevent or compromise the subject´s particiaption in the sudy.
13. Any known concomitant bacterial or fungal sexually transmitted disease.
14. Having, in the opinion of the Investigator, any clinically significant serious or unstable physical illness likely to impact on the subject's wellbeing or the conduct and analysis of the study, including, but not
limited to, acute hepatic failure, respiratory failure, severe, persistent diarrhoea and septic shock.
15. Any surgical or medical condition which might interfere with the distribution, metabolism or excretion of the drug, including, but not limited to moderate (including estimated creatinine clearance of 20 - 39
mL/min) or severe impairment of renal function (including an estimated creatinine clearance of < 20 mL/min), requirement for peritoneal dialysis, haemodialysis or haemofiltration, or oliguria.
16. Any malignant disease or a history of malignant neoplasm requiring a treatment with immune suppressive properties within the last 6 months before baseline.
17. Known history of drug abuse.
18. Clinically abnormal haematology, biochemistry and urinalysis results at baseline including, but not limited to:
• AST, ALT, or alkaline phosphatase level greater than 3 times the upper limit of normal (ULN).
• Total bilirubin greater than 2 times ULN.
• WBC count less than 1000/μL, platelet count less than 50,000/μL.
• Haematocrit less than 25%.
• Serum creatinine >265 micromole/l or creatinine clearance < 40mL/minute.
19. Any clinically significant ECG abnormality on the baseline ECG subjects at risk for torsade de pointes arrhythmia or a history of significant or inadequately treated cardiac disease.
20. Documented history of hypersensitivity or allergy to or known contraindication to the use of fluoroquinolones.
21. Any history of tendon lesions or ruptures either during quinolone treatment or for any other reason.
22. Concomitant tizanidine use.
23. Any administration of corticosteroids equivalent to or greater than 20 mg of prednisone per day for more than 14 days before randomisation.
24. the subject, planned to be enrolled is an employee or relative of any involved study Investigator or any involved institution including MerLion or Galenus.
25. Life expectancy of less than 3 months.
26. Women who are pregnant or nursing.
27. Any other condition that, in the opinion of the Investigator, would prevent the subject from effectively participating in the study, place the subject at risk or affect the assessment of efficacy and safety of the
study medication. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this study is the clinical and microbiological response of patients with cUTI or pyelonephritis to treatment with finafloxacin for 5 days versus finafloxacin for 10 days versus ciprofloxacin for 10 days as a reference comparator at the ToC visit (Day 17) in the microbiological intent–to-treat population (micro-ITT
population). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ToC visit (Day 17) in the micro-ITT population |
|
| E.5.2 | Secondary end point(s) |
•The clinical and microbiological response at the On Therapy (OT) visit (Day 3)
•The clinical and microbiological response at the End of Therapy (EoT) visit (Day 10)
•The clinical and microbiological response at the End of Study (EoS) visit (Day 24)
•Separate analyses will be performed for all time points with the outcome variable clinical responder and also microbiological responder
•To assess the safety and tolerability of multiple doses of finafloxacin of both 5 days and 10 days of treatment with finafloxacin (i.v. and oral) in subjects with cUTI, compared to 10 days of ciprofloxacin (i.v. and oral) as a reference comparator
•To assess the predictive capacity of PK/PD data of both 5 days and 10 days of treatment with finafloxacin (i.v. and oral) in subjects with cUTI, using 10 days of ciprofloxacin (i.v. and oral) as a reference comparator on clinical outcomes (EMA guidance)
•Other exploratory parameters as defined by the data (post hoc analyses).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
On Therapy visit - Day 3;
End of Therapy visit - Day 10
End of Study visit - Day 24 |
|
| 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) | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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