| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated Urinary Tract Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated urinary tract infections including lower urinary tract infections with complicating factors in addition to acute pyelonephritis. |
|
| 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 | PT |
| E.1.2 | Classification code | 10054088 |
| E.1.2 | Term | Urinary tract infection bacterial |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 objectives of this study are to:
• Determine the microbiological response in the Microbiologically Evaluable (ME) Population at Test-of-Cure
(TOC).
• Evaluate the safety of coadministered IV ceftaroline fosamil and NXL104 in subjects with cUTI. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study include:
• Determine the clinical response in the Clinically Evaluable (CE) Population at TOC.
• Determine the microbiological and clinical responses in the microbiological Intent-to-Treat (mITT) Population
at TOC.
• Evaluate microbiological and clinical responses at End of Therapy (EOT) and at Late Follow-up (LFU).
• Evaluate microbiological and clinical responses at TOC in subjects with complicated lower urinary tract
infection (cLUTI) or acute pyelonephritis (AP).
• Evaluate the pharmacokinetics of ceftaroline fosamil (prodrug), ceftaroline, ceftaroline M-1 (inactive
metabolite), and NXL104 in subjects with cUTI. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, at least 18 years of age.
2. Have pyuria, defined as ≥ 10 white blood cells (WBCs) per mm3 in unspun urine or ≥ 10 WBCs per high
power field in spun urine.
3. A local urine Gram stain must demonstrate the presence of gram-negative bacilli.
4. Clinical signs and/or symptoms of cUTI defined as:
a. Acute pyelonephritis, as indicated by BOTH of the following:
i. Fever ≥ 38.0ºC oral
ii. Flank pain or costovertebral angle tenderness
OR
b. Complicated lower urinary tract infection, as indicated by at least one of the following symptoms AND at least
one of the following complicating factors:
i. Symptoms (at least one):
• Dysuria
• Frequency
• Suprapubic pain
• Urgency
• Acute hematuria
ii. Complicating factors (at least one):
• Male gender
• Current bladder instrumentation or indwelling urinary catheter (any tube, stent, or foreign body conduit that
extends from the inside to the outside of the body) that is expected to be removed during the course of IV study
drug administration
• Obstructive uropathy (eg, nephrolithiasis, tumor, fibrosis) that is expected to be medically or surgically treated
during the course of IV study drug administration
• Urogenital surgery (eg, prostatectomy, transurethral resections) within 7 days prior to administration of the first
dose of study drug
• Functional or anatomical abnormality of the urogenital tract including anatomic
malformations or neurogenic bladder, or with a postvoid residual urine volume of at least 100 mL
5. Have a pretreatment baseline urine culture specimen obtained within 48 hours before 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, but a local urine Gram stain must be performed and demonstrate the
presence of gram-negative bacilli prior to start of study drug.
6. The subject’s infection would require initial treatment with IV antibiotics.
7. The subject must require initial hospitalization to manage the cUTI by the standard of care.
8. Female subjects of child-bearing potential, including those who are fewer than 2 years post-menopausal,
must agree to, and comply with, using 2 highly effective methods of birth control (ie, condom plus spermicide,
combined oral contraceptive, implant, injectable, indwelling intrauterine device, sexual abstinence, or a
vasectomized partner) while participating in this study. In addition, all women of childbearing potential must
agree to continue to use 2 forms of birth control throughout the study and for at least 30 days after administration
of the last dose of study drug.
9. Signed informed consent, willingness, and ability to comply with all study procedures and restrictions. |
|
| E.4 | Principal exclusion criteria |
1. History of any hypersensitivity or allergic reaction to any β-lactam (eg, cephalosporins, penicillins,
carbapenems).
2. Requirement for concomitant systemic antibiotic or antifungal therapy for any reason.
EXCEPTION: Topical antifungal or a single oral dose of any antifungal for treatment of vaginal candidiasis.
3. Known urinary tract infection or colonization with Pseudomonas aeruginosa, methicillin-resistant
Staphylococcus aureus, or any Enterococcus species.
4. The cUTI is known to be caused by a pathogen resistant to doripenem.
5. Confirmed fungal urinary tract infection with a colony count ≥ 103 CFU/mL.
6. Receipt of any amount of potentially therapeutic antibiotic therapy after the collection of the pretreatment
baseline urine culture and before administration of the first dose of study drug.
7. Receipt of more than 1 dose of a potentially therapeutic antibiotic agent for the treatment of the current cUTI
within 96 hours before obtaining the study-qualifying pretreatment baseline urine culture.
EXCEPTIONS: 1) Subjects who failed prior antibiotic treatment with a culture growing a pathogen resistant to
the prior treatment; 2) Subjects receiving UTI prophylaxis are eligible to enroll if all other eligibility criteria are
met, including obtaining a study-qualifying pretreatment baseline urine culture. These subjects must discontinue
oral antibiotic prophylaxis from the time the pretreatment baseline urine culture is obtained until after TOC.
8. Intractable UTI anticipated to require more than 10 days of study drug therapy.
9. Complete, permanent obstruction of the urinary tract.
10. Permanent indwelling bladder catheter or instrumentation (including nephrostomy) or current urinary catheter
that will not be removed during IV study drug administration.
11. Suspected or confirmed perinephric or intrarenal abscess.
12. Suspected or confirmed prostatitis.
13. Ileal loops or vesico-ureteral reflux.
14. Impairment of renal function including a calculated CrCl of < 30 mL/min, requirement for peritoneal dialysis,
hemodialysis or hemofiltration, or oliguria (< 20 cc urine output per hour over 24 hours).
15. Renal transplantation.
16. Evidence of immediately life-threatening disease, including, but not limited to, current or impending
respiratory failure, acute heart failure, shock, acute coronary syndrome, unstable arrhythmias, hypertensive ketoacidosis), or acute cerebrovascular events.
17. Life expectancy less than 3 months
18. Evidence of significant hepatic, hematological, or immunologic disease or dysfunction determined by any of
the following:
• Known acute viral hepatitis
• Aspartate amino transferase or alanine amino transferase level greater than 5-fold the upper limit of normal or
total bilirubin greater than 3-fold the upper limit of normal
• Manifestations of end-stage liver disease, such as ascites or hepatic encephalopathy
• Current or anticipated neutropenia defined as less than 500 neutrophils/mm3
• Thrombocytopenia with platelet count less than 60,000 cells/mm3
• Known infection with human immunodeficiency virus and either a CD4 count less than or equal to 200 cells/
mm3 at the last measurement or current diagnosis of another Acquired Immune Deficiency Syndrome-defining
illness
• Bone marrow-ablative chemotherapy or radiation therapy within the prior 3 months
• Receiving > 20 mg of prednisone (or equivalent systemic corticosteroid) per day
19. Probenecid administration within 3 days prior to initiation of study drug therapy or requirement for
concomitant therapy with probenecid.
20. Past or current history of epilepsy or seizure disorder.
EXCEPTION: Well-documented febrile seizure of childhood.
21. Women who are pregnant or nursing.
22. Participation in any study involving administration of an investigational agent or device within 30 days prior
to randomization into this study or previous participation in the current study.
23. Previous participation in a study of ceftaroline fosamil, NXL104, ceftazidime/NXL104, or coadministered
ceftaroline fosamil and NXL104
24. Any condition that, in the opinion of the Investigator, would compromise the safety of the subject or the
quality of the data |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
Proportion of subjects with a favorable microbiological response in the ME Population at TOC. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The timing of the primary endpoint is TOC which occurs 5-11 days after the end of therapy. The study requires 7-10 days study drug administration. Therefore the timing of the primary endpoint is about 12-21 days after enrollment in the study. Note TOC could occur earlier if study drug is discontinued early.
|
|
| E.5.2 | Secondary end point(s) |
• Proportion of subjects with a clinical response of cure in the CE Population at TOC
• Proportion of subjects with a favorable microbiological response in the mITT Population at TOC
• Proportion of subjects with a clinical response of cure in the mITT Population at TOC
• Proportion of subjects with a sustained favorable microbiological response in the ME Population at
LFU
• Proportion of subjects with a clinical response of sustained clinical cure in the CE Population at LFU
• Proportion of subjects with a favorable microbiological response in the ME Population at TOC and the
proportion of subjects with a clinical response of cure in the CE Population at TOC in subjects with
cLUTI or AP
• Per-pathogen outcome in the mITT and ME Populations at TOC
• Proportion of subjects with a favorable microbiological response in the ME Population at EOT
• Proportion of subjects with a clinical response of cure in the CE Population at EOT
• Incidence of emergent infections |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints may occur at:
End of Therapy (EOT) which occurs at the end of study drug administration and is 7-10 days after enrollment. Note, EOT could occur earlier if study drug is discontinued early.
Test-of-cure (TOC) which is defined at E.5.1.1.
Late Follow-up (LFU) which is 28-42 days after EOT therefore making this window 35-52 days after enrollment. Note LFU could occur earlier if study drug is discontinued early and EOT occurs earlier than 7-10 days after enrollment.
|
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.4 | Double blind | No |
| 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 | No |
| 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 | 10 |
| 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 |
| Germany |
| Lebanon |
| Poland |
| Russian Federation |
| Turkey |
| 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
| |
| 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 | 2 |
| 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 | 5 |
Print
