Finafloxacin for the Treatment of cUTI and/or Acute Pyelonephritis
Condition: Urinary Tract Infections; Acute Pyelonephritis
MeSH terms: Urinary Tract Infections; Pyelonephritis
Intervention: Finafloxacin 800 mg i.v. once daily; Finafloxacin placebo i.v. once daily; Finafloxacin 800 mg tablets once daily; Finafloxacin placebo tablets once daily; Ciprofloxacin 400 mg i.v. twice daily; Ciprofloxacin placebo i.v. twice daily; Ciprofloxacin 500 mg oral twice daily; Ciprofloxacin placebo oral twice daily
Intervention description: Infused over 60 mins [i.v. pump]) for at least 3 days.; Infused over 60 mins [i.v. pump]) for at least 3 days.; Administered as four 200 mg tablets; Administered as four tablets; Infused over approximately 60 mins [i.v. pump]) for at least 3 days; Infused over approximately 60 mins [i.v. pump]) for at least 3 days; Administered as two 250 mg capsules.; Administered as two capsules.
Intervention MeSH terms: Ciprofloxacin; Finafloxacin; Fluoroquinolones
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 225.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Urinary Tract Infection; Pyelonephritis

Summary:

      The primary objective of this study is to evaluate the microbiological and clinical outcome
      of treatment with finafloxacin for 5 days versus finafloxacin for 10 days versus
      ciprofloxacin for 10 days as a reference comparator.

      Finafloxacin shows increased activity in an acidic environment which is associated with
      indications such as uUTI and cUTI. Given the acidic pH of urine and concentration of
      finafloxacin excreted via the urinary tract in humans it should be proven if the finafloxacin
      treatments offer significant advantages over the currently available treatments for UTI.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Be male or female subjects ≥ 18 years of age.

          2. If a female and

               1. 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, Contraception must have been used for
                  at least 2 months before starting the study. A documented negative urine
                  pregnancy test must be provided and the subject must be non-lactating.

               2. subject is of non-childbearing potential, must be post-menopausal (i.e. has had
                  amenorrhea for a minimum of 12 consecutive months) or surgically sterile due to
                  bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.

               3. subject is truly abstinent. This is accepted as a method of contraception, but
                  only when this is in line with the preferred and usual lifestyle of the subject.
                  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation
                  methods) and withdrawal are not acceptable methods of contraception.

          3. If a male, should agree to use reliable birth control methods (contraception or other
             barrier device) during study participation.

          4. Must have complicated lower urinary tract infection or acute complicated or
             uncomplicated pyelonephritis (cPN or uPN; see section 5.3) and must have at least two
             of the following acute signs and symptoms

               1. Chills or rigors or warmth associated with fever (e.g. oral temperature greater
                  than 38.0 degrees Celsius ).

               2. Flank pain (pyelonephritis) or pelvic pain (cUTI).

               3. Nausea or vomiting.

               4. Dysuria, urinary frequency, or urinary urgency.

               5. Costo-vertebral angle tenderness (pyelonephritis) on physical examination.

          5. Provide one pre-treatment adequate urine sample (the urine sample 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.
             The urine sample must be provided within 24 hours before the start of administration
             of the first dose of study drug.

             A positive urine culture is defined as:

               -  ≥ 105 CFU/mL of one causative pathogen in the case of cUTI

               -  ≥ 104 CFU/mL of one causative pathogen in case of Pyelonephritis

             A negative urine culture is defined as:

               -  < 105 CFU/mL of causative pathogen/s and/or non-target pathogens at any number of
                  CFUs in the case of cUTI

               -  < 104 CFU/mL of causative pathogen/s and/or non-target pathogens at any number of
                  CFUs in the case of Pyelonephritis Patients may be admitted to the study pending
                  baseline urine culture results. Treatment should NOT be delayed pending 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 the Investigator has to decide according to clinical signs and symptoms
             whether the subject can stay in the study.

             In the event of a negative urine culture, the subject must be withdrawn from the study
             and switched to standard care, because the inclusion criterion is not fulfilled.

             A urine culture is defined as contaminated if:

               -  at least one causative pathogen with ≥ 105 CFU/mL is present AND at least one
                  non-pathogen or additional causative pathogen/s at any number of CFU/mL are
                  present in the case of cUTI

               -  at least one causative pathogen with ≥ 104 CFU/mL is present AND at least one
                  non-pathogen or additional causative pathogen/s with any number of CFU/mL in the
                  case of pyelonephritis Subjects with contaminated urine cultures will be
                  permitted to continue in the study, although this will impact on the subject's
                  eligibility for analysis (see section 9.3).

          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 for at least 3 days 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.

        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 gram-positive 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. In the 12 months before study enrolment: known uncontrolled condition of hypertension
             or symptomatic hypotension, known uncontrolled cardiac arrhythmia, known ischaemic
             heart disease or history of myocardial infarction, coronary artery bypass 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 participation in the study.

         13. Any known concomitant bacterial or fungal sexually transmitted disease with the
             exception of candidiasis.

         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 30 - 59 mL/min) or severe impairment of renal
             function (including an estimated creatinine clearance of < 30 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 in the 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%.

               -  Creatinine clearance < 60mL/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.